Proton Rearrangement Research Articles

Thiazaphospholidines – A theoretical insight on formation and chemical structure

Phosphorylated heterocycles constitute an interesting class of molecules featuring complex, often unproven reaction mechanisms. Their synthesis is approached through experimental trial-and-error methods. Here we present a theoretical study of the reaction mechanism leading to the formation of thiazaphospholidine, as an example of such compounds. Our results reveal that proton rearrangement, rather than nucleophilic attack, plays a significant role in the rate-determining step of the reaction. This insight allows the prediction of which isomer will form from unsymmetrical reagents, potentially leading to more efficient experimental procedures for producing tailor-made structures that exhibit desired properties. We demonstrate that seemingly simple reactions, such as the nucleophilic substitution of an amino group on trivalent phosphorus, may require a more intricate explanation involving less favored tautomeric structures and a multi-step approach and are therefore not completely intuitive.

Networks of Hydrogen Bond Networks in Water Clusters.

Water clusters play a prominent role in atmospheric and solution chemistry. Numerous arrangements of protons, H-bond configurations or networks, shape the cluster properties. Studies of small water clusters by cryogenic scanning tunneling microscopy and high-resolution rovibrational spectroscopy have established proton rearrangement mechanisms forming pathways between H-bond networks. The mechanisms, concerted tunneling in particular, describe the local processes connecting pairs of configurations. Here, proton rearrangement networks mapping these transformations are defined and explored to provide a global view of the H-bond configurations in clusters. The networks are constructed for clusters of different sizes and structures. Their analysis reveals an odd-even effect with respect to the number of water molecules, exponential growth of the small-world character, bimodality of the degree distributions, and gapped assortativity of the networks. The last two properties signify the unexpected division of H-bond configurations into two classes according to their network connectivity. The results demonstrate qualitative differences between proton rearrangement mechanisms, suggest a strong influence of the cluster structure. The generated networks are of interest as real-world models for network rewiring; they establish an alternative platform for studies of proton rearrangements in H-bonded systems.

Reduction of CO2 with Hydrated Electrons: Ab Initio Computational Studies for Finite-Size Cluster Models.

In the present work, the mechanisms of the reduction of the CO2 molecule with hydrated electrons to the hydroxyl-formyl (HOCO) radical were studied with ab initio computational methods. Hydrated hydronium radicals, H3O(H2O)n (n = 0,3,6), are considered as finite-size models of the hydrated electron in liquid water. The investigation of cluster models allows the application of high-accuracy electronic-structure methods, which are not computationally feasible in condensed-phase simulations. Reaction paths and potential-energy (PE) profiles of the proton-coupled electron-transfer reaction from hydrated H3O radicals to the CO2 molecule were explored on the ground-state PE surface. The computationally efficient unrestricted second-order Møller-Plesset method is employed, and its accuracy has been carefully benchmarked in comparison with complete-active-space self-consistent-field and multi-reference second-order perturbation calculations. The results provide insights into the interplay of electron transfer from the diffuse Rydberg-type unpaired electron of H3O to the CO2 molecule, the contraction of the electron cloud by the re-hybridization of the carbon atom of CO2, and proton transfer from the nearest water molecule to the CO2- anion, followed by Grotthus-type proton rearrangements to form stable clusters. Starting from local energy minima of hydrogen-bonded CO2-H3O(H2O)n complexes, the reaction to form HOCO-(H2O)n+1 complexes is exothermic by about 1.3 eV (125 kJ/mol). The reaction is barrier controlled with a barrier of the order of a few tenths of an electron volt, depending on size and conformation of the water cluster. This barrier is at least an order of magnitude lower than the barrier of the reaction of CO2 with any closed-shell partner molecule. The HOCO radicals can recombine by H-atom transfer (disproportionation), resulting in formic acid or a dihydroxycarbene product, as well as by the formation of a C-C bond, resulting in oxalic acid. The strong exothermicity of these radical-radical recombination reactions likely results in the fragmentation of the closed-shell products formic acid and oxalic acid, which explains the strong specificity for CO formation observed in recent experiments of Hamers and co-workers.

Oxidative Addition of a Phosphinite P–O Bond at Nickel

Oxidative addition is an essential elementary reaction in organometallic chemistry and catalysis. While a diverse array of oxidative addition reactions has been reported to date, examples of P-O bond activation are surprisingly rare. Herein, we report the ligand-templated oxidative addition of a phosphinite P-O bond in the diphosphinito aniline compound HN(2-OPiPr2-3,5-tBu-C6H2)2 [H(P2ONO)] at Ni0 to form (PONO)Ni(HPiPr2) after proton rearrangement. Notably, the P-O cleavage occurs selectively over an amine N-H bond activation. Additionally, the ligand cannibalization is reversible, as addition of XPR2 (X = Cl, Br; R = iPr, Cy) to (PONO)Ni(HPiPr2) readily produces either symmetric or unsymmetric (P2ONO)NiX species and free HPiPr2. Finally, the mechanisms of both the initial P-O bond cleavage and its subsequent reconstruction are investigated to provide further insight into how to target P-O bond activation.

Nucleophilic Reactivity at a ═CH Arm of a Lutidine-Based CNC/Rh System: Unusual Alkyne and CO2 Activation.

Reaction of an amido pincer complex [(CNC)*Rh(CO)] (1) (CNC* is the deprotonated form of CNC) with carbon dioxide gave a neutral complex [(CNC-CO2)Mes*Rh(CO)] (2), which is the result of a C-C bond-forming reaction between the deprotonated arm of the CNC* ligand and CO2. The molecular structure of 2 showed a zwitterionic complex, where the CO2 moiety is covalently connected to the former ═CH arm of the CNC* pincer ligand. The unusual structure of 1 allowed us to explore the reactivity of the CO2 moiety with selected primary amines RNH2 (benzylamine and ammonia), which afforded cationic complexes [(CNC)MesRh(CO)][HRNC(O)O] (R = Bz (3), H (4)). Compounds 3 and 4 are the result of a C-N coupling between the incoming amine and the CO2 fragment covalently connected to the pincer ligand in 2, a process that involves protonation of the "CH-CO2" fragment in 2 from the respective amines. Once revealed the nucleophilic character of the ═CH fragment in 1, we explored its reactivity with alkynes, a study that enlightened a novel reactivity trend in alkyne activation. Reaction of 1 with terminal alkynes RC≡CH (R = Ph, 2-py, 4-C6H4-CF3) yielded neutral complexes [(CNC-CH═CHR)Mes*Rh(CO)] (R = Ph (5), 2-py (6), 4-C6H4-CF3 (7)) in good yields. Deuterium labeling experiments with PhC≡CD confirmed that complex 5 is the product of a formal insertion of the alkyne into the C(sp2)-H bond of the deprotonated arm in 1. This structural proposal was further confirmed by the X-ray molecular structure of phenyl complex 5, which showed the alkyne covalently linked to the pincer ligand. Besides, this novel transformation was analyzed by DFT methods and showed a metal-ligand cooperative mechanism, based on the initial electrophilic attack of the alkyne to the ═CH arm of the CNCMes* ligand (making a new C-C bond) followed by the action of a protic base (HN(SiMe3)2), which is able to perform a proton rearrangement that leads to the final product 5.

Metal Halide Exchange in Benzylborane NHC‐Adducts: The Effect of Backbone Alkylation in the N‐Heterocyclic Carbene

AbstractAmong other main group elements, the chemistry of boron has been stimulated by N‐heterocyclic carbenes (NHCs) as important ligands, the nature of which can significantly control the outcome of reactions. In four‐coordinate benzyl boranes of type (NHC)BH2CH2(o‐BrC6H4), we demonstrate this effect at the example of a lithiation silylation procedure. For NHC=IiPr lithiation of the arene ring by lithium‐bromide exchange with tBuLi ultimately leads to backbone substitution with proton rearrangement, as demonstrated by trapping with trimethylsilyl chloride. In contrast, such process is suppressed for NHC=IiPrMe, which undergoes lithiation and subsequent trimethyl‐silylation at the arene moiety.

Recent advances in the synthetic method and mechanism for the important N‐heterocyclic compound of 3‐methylindole

Abstract3‐Methylindole, as an important N‐heterocycle compound, is widely applied in the fields of medicine, agriculture and industry for synthesizing momentous drugs and plant growth regulators as well as the production of spices. Therefore, the efficient synthesis of 3‐methylindole is very important and has attracted much attention from chemists. In this paper, the synthetic methods of 3‐methylindole were classified into Fischer proton rearrangement, radical reaction, coupling cyclization, electrophilic reaction, nucleophilic reaction, reduction reaction and oxidation reaction. Also, the recent advances in the synthetic method and mechanism were reviewed, in which the most promising method for the green and cheap synthesis of 3‐methylindole from biomass‐derived glycerol and aniline was proposed.

Density Functional Theory-Based Calculation Shed New Light on the Bizarre Addition of Cysteine Thiol to Dopaquinone.

Two types of melanin pigments, brown to black eumelanin and yellow to reddish brown pheomelanin, are biosynthesized through a branched reaction, which is associated with the key intermediate dopaquinone (DQ). In the presence of l-cysteine, DQ immediately binds to the –SH group, resulting in the formation of cysteinyldopa necessary for the pheomelanin production. l-Cysteine prefers to bond with aromatic carbons adjacent to the carbonyl groups, namely C5 and C2. Surprisingly, this Michael addition takes place at 1,6-position of the C5 (and to some extent at C2) rather than usually expected 1,4-position. Such an anomaly on the reactivity necessitates an atomic-scale understanding of the binding mechanism. Using density functional theory-based calculations, we investigated the binding of l-cysteine thiolate (Cys–S−) to DQ. Interestingly, the C2–S bonded intermediate was less energetically stable than the C6–S bonded case. Furthermore, the most preferred Cys–S−-attacked intermediate is at the carbon-carbon bridge between the two carbonyls (C3–C4 bridge site) but not on the C5 site. This structure allows the Cys–S− to migrate onto the adjacent C5 or C2 with small activation energies. Further simulation demonstrated a possible conversion pathway of the C5–S (and C2–S) intermediate into 5-S-cysteinyldopa (and 2-S-cysteinyldopa), which is the experimentally identified major (and minor) product. Based on the results, we propose that the binding of Cys–S− to DQ proceeds via the following path: (i) coordination of Cys–S− to C3–C4 bridge, (ii) migration of Cys–S− to C5 (C2), (iii) proton rearrangement from cysteinyl –NH3+ to O4 (O3), and (iv) proton rearrangement from C5 (C2) to O3 (O4).

Influence of hydrated protons on temperature and humidity responsiveness of silk fibroin hydrogel ionotronics

Summary Silk fibroin hydrogel ionotronics (SFHIs) have received increasing attention due to their good mechanical and electrical adjustability, as well as their environmental responsiveness and friendliness. However, fundamental issues related to the conductivity mechanisms and their influences on the temperature and humidity responses are still unclear. In this study, the conductive mechanisms of SFHIs were investigated by combining the experimental characterization with the theoretical analysis. The results suggested the vital role of hydrated protons in the conduction mechanism of SFHIs. The hydrated protons significantly affected the temperature and humidity responses of SFHIs with behaviors obeying distinct theoretical models. Precisely, the temperature response followed the rate of proton rearrangement reaction, while humidity response obeyed the percolation theory. Hence, a combined model was developed to decouple the experimental temperature and humidity responses of SFHIs during synchronic variation. In sum, a rational approach for decoupling the temperature and humidity responses of SFHIs was successfully developed, suitable for future design of smart SFHIs.

Copper bis(thiosemicarbazone) Complexes with Pendent Polyamines: Effects of Proton Relays and Charged Moieties on Electrocatalytic HER

AbstractA series of new bis(thiosemicarbazonato) Cu(II) complexes with pendent polyamines, diacetyl‐(N, ‐dimethylethylenediaminothiosemicarbazonato)‐(N’‐methyl‐3‐thio‐semicarbazonato)butane‐2,3‐diimine)‐copper(II) (Cu‐1), diacetyl‐bis(N‐dimethylethylenediamino‐3‐thiosemicarbazonato)butane‐2,3‐diimine)‐copper(II) (Cu‐3), and their cationic derivatives Cu‐2 and Cu‐4, have been synthesized and fully characterized by spectroscopic, electrochemical, and X‐ray diffraction methods. Complexes Cu‐1–Cu‐4 are analogues of Cu(ATSM), which contains a similar N2S2 donor core with terminal non‐coordinating amines. Substitution of the methyl group(s) of the terminal amines of H2ATSM with N,N‐dimethylethylenediamine followed by alkylation generates a charged quaternary amine in the ligand framework. The charged site tunes the redox potentials of the complexes with minimal changes in their physical and electronic properties. The HER activity of all four copper complexes were evaluated in acetonitrile with glacial acetic acid. All of the complexes have lower HER overpotentials than Cu(ATSM), which is attributed to charge effects. The pendent amines of Cu‐1 and Cu‐3 have the lowest HER overpotential as the pendent tertiary amine also serves as a proton relay to enhance proton rearrangement under catalytic conditions. Complex Cu‐3 showed the highest activity with a TOF of 12 × 103 s−1, an overpotential of 0.65 V, and faradaic efficiency of 100 %.

Quantum Chemical Study of the Formation of Urea in Interstellar Medium

Background: Many observational studies have found the presence of organic molecules in interstellar medium (ISM) via spectroscopy. NH2CONH2 (urea) was first detected in ISM in 2014. Containing two NH2 groups, urea is an important biological molecule in metabolism as a carrier for waste nitrogen. The discovery of urea in ISM suggests the possibility of the formation of other biomolecules which contain peptide bonds, such as proteins. This supports the origin of life theory proposing that these biomolecules were initially formed in space and later arrived to Earth.
 Methods: This study investigates two possible reaction pathways for the formation of protonated urea (ureaH+) in dense molecular clouds via molecules previously observed in the ISM, formamide (HCONH2) and protonated hydroxylamine (NH2OH2+). The thermodynamics and optimized geometries were calculated for the final steps of the formation of ureaH+ using Gaussian16 at the APFD/6-31G(d,p) level of theory and a transition state was confirmed.
 Results: The overall mechanism, as well as the studied proton rearrangement of an intermediate to ureaH+, were found to be exothermic and exergonic processes.
 Conclusion: From the calculations, the conditions of ISM provide an adequate environment for the formation of ureaH+ and urea.

Mechanistic examination of Cα -Cβ tyrosyl bond cleavage: Spectroscopic investigation of the generation of α-glycyl radical cations from tyrosyl (glycyl/alanyl)tryptophan.

In this study, dissociative one-electron transfer dissociation of [CuII (dien)Y(G/A)W]•2+ [dien = diethylenetriamine; Y(G/A)W = tyrosyl (glycyl/alanyl)tryptophan] was used to generate the tripeptide radical cations [Y(G/A)W]•+ ; subsequent loss of the Tyr side chain formed [Gα • (G/A)W]+ . The π-centered species [YGWπ • ]+ generated the α-centered species [Gα • GW]+ through Cα -Cβ bond cleavage, as revealed using infrared multiple photon dissociation (IRMPD) measurements and density functional theory (DFT) calculations. Comparisons of experimental and theoretical IR spectra confirmed that both the charge and spin densities of [Y(G/A)Wπ • ]+ were delocalized initially at the tryptophan indolyl ring; subsequent formation of the final [Gα • (G/A)W]+ structure gave the highest spin density at the α-carbon atom of the N-terminal glycine residue, with a proton solvated by the first amide oxygen atom. The IRMPD mass spectra and action spectra of the [Gα • (G/A)W]+ species were all distinctly different from those of their isomeric [G(G/A)Wπ • ]+ species. The mechanism of formation of the captodative [Gα • (G/A)W]+ species-with the charge site separated from the radical site-from [Y(G/A)Wπ • ]+ has been elucidated. DFT calculations suggested that the Cα -Cβ bond cleavage of the tyrosine residue in the radical cationic [Y(G/A)Wπ • ]+ precursor involves (a) through-space electron transfer between the indolyl and phenolic groups; (b) formation of proton-bound dimers through Cα -Cβ cleavage of the tyrosine residue; and (c) a concerted proton rearrangement from the phenolic OH group to the carboxyl group and formation of the α-carbon-centered product [Gα • (G/A)W]+ through hydrogen bond cleavage. The barriers for the electron transfer (a), the Cα -Cβ cleavage (b), and the protonation rearrangement (c) were 12.8, 26.5, and 10.3 kcal mol-1 , respectively.

Evidence for the Prerequisite Formation of Phenoxyl Radicals in Radical-Mediated Peptide Tyrosine Nitration In Vacuo.

The elementary mechanism of radical-mediated peptide tyrosine nitration, which is a hallmark of post-translational modification of proteins under nitrative stress in vivo, has been elucidated in detail by using an integrated approach that combines the gas-phase synthesis of prototypical molecular tyrosine-containing peptide radical cations, ion-molecule reactions, and isotopic labeling experiments with DFT calculations. This reaction first involves the radical recombination of . NO2 towards the prerequisite phenoxyl radical tautomer of a tyrosine residue, followed by proton rearrangements, finally yielding the stable and regioselective 3-nitrotyrosyl residue product. In contrast, nitration with the π-phenolic radical cation tautomer is inefficient. This first direct experimental evidence for the elementary steps of the radical-mediated tyrosine nitration mechanism in the gas phase provides a fundamental insight into the regioselectivity of biological tyrosine ortho-nitration.

Utilizing Charge Effects and Minimizing Intramolecular Proton Rearrangement to Improve the Overpotential of a Thiosemicarbazonato Zinc HER Catalyst.

The zinc(II) complex of diacetyl-2-(4-methyl-3-thiosemicarbazone)-3-(2-hydrazonepyridine), ZnL1 (1), was prepared and evaluated as a precatalyst for the hydrogen evolution reaction (HER) under homogeneous conditions in acetonitrile. Complex 1 is protonated on the noncoordinating nitrogen of the hydrazonepyridine moiety to yield the active catalyst Zn(HL1)OAc (2) upon addition of acetic acid. Addition of methyl iodide to 1 yields the corresponding methylated derivative ZnL2I (3). In solution, partial dissociation of the coordinated iodide yields the cationic derivative 3'. Complexes 1-3 were characterized by 1H NMR, FT-IR, and UV-visible spectroscopies. The solid-state structures of 2 and 3 were determined by single crystal X-ray diffraction. HER studies conducted in acetonitrile with acetic acid as the proton source yield a turnover frequency (TOF) of 7700 s-1 for solutions of 1 at an overpotential of 1.27 V and a TOF of 6700 s-1 for solutions of 3 at an overpotential of 0.56 V. For both complexes, the required potential for catalysis, Ecat/2, is larger than the thermodynamic reduction potential, E1/2, indicative of a kinetic barrier attributed to intramolecular proton rearrangement. The effect is larger for solutions of 1 (+440 mV) than for solutions of 3 (+160 mV). Controlled potential coulometry studies were used to determine faradaic efficiencies of 71 and 89% for solutions of 1 and 3, respectively. For both catalysts, extensive cycling of potential under catalytic conditions results in the deposition of a film on the glassy carbon electrode surface that is active as an HER catalyst. Analysis of the film of 3 by X-ray photoelectron spectroscopy indicates the complex remains intact upon deposition. A proposed ligand-centered HER mechanism with 1 as a precatalyst to 2 is supported computationally using density functional theory (DFT). All catalytic intermediates in the mechanism were structurally and energetically characterized with the DFT/B3LYP/6-311g(d,p) in solution phase using a polarizable continuum model (PCM). The thermodynamic feasibility of the mechanism is supported by calculation of equilibrium constants or reduction potentials for each proposed step.

Proton Translocation via Tautomerization of Asn298 During the S2-S3 State Transition in the Oxygen-Evolving Complex of Photosystem II.

In biological water oxidation, a redox-active tyrosine residue (D1-Tyr161 or YZ) mediates electron transfer between the Mn4CaO5 cluster of the oxygen-evolving complex and the charge-separation site of photosystem II (PSII), driving the cluster through progressively higher oxidation states Si (i = 0–4). In contrast to lower S-states (S0, S1), in higher S-states (S2, S3) of the Mn4CaO5 cluster, YZ cannot be oxidized at cryogenic temperatures due to the accumulation of positive charge in the S1 → S2 transition. However, oxidation of YZ by illumination of S2 at 77–190 K followed by rapid freezing and charge recombination between YZ• and the plastoquinone radical QA•– allows trapping of an S2 variant, the so-called S2trapped state (S2t), that is capable of forming YZ• at cryogenic temperature. To identify the differences between the S2 and S2t states, we used the S2tYZ• intermediate as a probe for the S2t state and followed the S2tYZ•/QA•– recombination kinetics at 10 K using time-resolved electron paramagnetic resonance spectroscopy in H2O and D2O. The results show that while S2tYZ•/QA•– recombination can be described as pure electron transfer occurring in the Marcus inverted region, the S2t → S2 reversion depends on proton rearrangement and exhibits a strong kinetic isotope effect. This suggests that YZ oxidation in the S2t state is facilitated by favorable proton redistribution in the vicinity of YZ, most likely within the hydrogen-bonded YZ–His190–Asn298 triad. Computational models show that tautomerization of Asn298 to its imidic acid form enables proton translocation to an adjacent asparagine-rich cavity of water molecules that functions as a proton reservoir and can further participate in proton egress to the lumen.

Cyclic Bond Formation of Rhododendrol-quinone and Dopamine-quinone: Effects of Proton Rearrangement

The synthesis of melanin pigment involves intramolecular cyclic bond formation between benzene ring and side chain moieties of o-quinone as a necessary process for o-quinone conversion into a cycli...

A fragmentation study of isoflavones by IT-TOF-MS using biosynthesized isotopes.

To aid in the identification and quantification of biologically and agriculturally significant natural products, tandem mass spectrometry can provide accurate structural information with high selectivity and sensitivity. In this study, diagnostic fragmentation patterns of isoflavonoids were examined by liquid chromatography-ion trap-time of flight-mass spectrometry (LC-IT-TOF-MS). The fragmentation scheme for [M+H-2CO]+ ions derived from isoflavones and [M+H-B-ring-CO]+ ions derived from 5-hydroxyisoflavones, were investigated using different isotopically labeled isoflavones, specifically [1',2',3',4',5',6',2,3,4-13C9] and [2',3',5',6',2-D5] isoflavones. Specific isotopically labeled isoflavones were prepared through the biosynthetic incorporation of pharmacologically applied 13C- and D-labelled L-phenylalanine precursors in soybean plants following the application of insect elicitors. Using this approach, we empirically demonstrate that the [M+H-2CO]+ ion is generated by an intramolecular proton rearrangement during fragmentation. Furthermore, [M+H-B-ring-CO]+ ion is demonstrated to contain a C2H moiety derived from C-ring of 5-hydroxyisoflavones. A mechanistic understanding of characteristic isoflavone fragmentation patterns contributes to the efficacy and confidence in identifying related isoflavones by LC-MSn.

Branching Reactions in Melanogenesis - Mechanism and Design Guidelines

The body color is essentially controlled by melanogenesis, which is the production of natural pigments, i.e. melanins. Melanogenesis can be generally defined as a cascade of multiple reactions, which is triggered by oxidation of p-substituted phenols or catechols like tyrosine or dopa. Oxidation of these phenols or catechols results in formation of reactive o-quinones. Some o-quinones can spontaneously undergo cyclization, which is ring-closure reaction by bonding between benzene ring carbon and p-substituent. In contrast, o-quinones can also react with thiols (R-SH) like cysteine. As the final product, the cyclization results in formation of black to brown eumelanin whereas the binding of cysteine results in formation of yellow to reddish brown pheomelanin. This can be said as the first branching of melanogenesis. The cyclization is followed by redox exchange between the cyclized molecule and a remaining o-quinone. A molecule resulting from the redox exchange is still unstable so that it undergoes further conversion. This conversion involves intramolecular proton rearrangements. In addition to proton rearrangements, this conversion can also undergo decarboxylation, which is desorption of -COOH, if the melanogenic substrate has a carboxyl group (-COOH) in p-substituent. Two types of monomers of eumelanin are directly generated by the decarboxylative and non-decarboxylative pathways, respectively. Thus, this decarboxylative/non-decarboxylative conversion process can be said as the second branching of melanogenesis. In physiological melanin synthetic conditions, the first branching is the reaction involving dopaquinone, which is an o-quinone obtained by tyrosine/dopa oxidation, and the second branching is the reaction involving dopachrome, which is a molecule obtained by cyclization dopaquinone and its redox exchange. In our recent work, we have conducted mechanistic investigation for melanogenesis with a focus on dopaquinone and dopachrome reactions from density functional theory based calculation [1-5]. Mechanistic understanding of the branching reactions is a key to predict or design the properties and functions of melanin. We make use a theoretical approach in which quantum mechanics is applied to molecular systems. Our results show that the rate-limiting step of dopachrome conversion is deprotonation from β-carbon (β-deprotonation) at the first step. Furthermore, the subsequent steps were found to be regulated by the protonation state of the quinonoid oxygens, which are zwitterionic oxygens bound with benzene ring. Our calculations reveal that the quinonoid protonation facilitates decarboxylation. Cu(II) coordinated by quinonoid oxygens was found to protect the oxygens against protonation, leading to suppression of decarboxylation. For dopaquinone, we investigate the first elementary step of the cyclization and the thiol binding. To evaluate the effects of substituent bound with the benzene ring, we calculate some dopaquinone-like systems, viz. dopaminequinone, dopaquinone, N-methyldopaminequinone, N-formyldopaminequinone, and the corresponding methylene (-CH2-)-inserted analogues. Our results show that quinones presenting their highest occupied molecular orbital (HOMO) at a higher energy level are reactive for cyclization, and that an anti-bonding shape of lowest unoccupied molecular orbital (LUMO) at a higher energy level in the benzene-substituent region is a signature for low reactivity toward thiol compounds. This view obtained here reasonably explains previously reported experimental results and would provide a physico-chemical basis of melanin synthesis. Our results will be clues for designing new materials using melanin.

Theoretical physics: Quarks fuse to release energy.

In nuclear fusion, energy is produced by the rearrangement of protons and neutrons. The discovery of an analogue of this process involving particles called quarks has implications for both nuclear and particle physics. See Letter p.89 The LHCb collaboration at CERN's Large Hadron Collider recently reported the discovery of a doubly charmed baryon with a large binding energy between the two charm quarks inside it. Marek Karliner and Jonathan Rosner report that this strong binding energy allows for a rearrangement of the quarks that releases energy in a quark-level analogue of deuterium–tritium nuclear fusion. They point out that the even larger binding energy between two bottom quarks can also enable such an exothermic rearrangement, with a considerably larger energy release.

Computational explanation for bioactivation mechanism of targeted anticancer agents mediated by cytochrome P450s: A case of Erlotinib.

EGFR inhibitors, even with therapeutics superiorities in anticancer, can cause idiosyncratic pulmonary and hepatic toxicities that are associated with the reactive electrophile bioactivated by Cytochrome P450s (P450s). Until now, neither has the electrophilic intermediate been caught experimentally, nor has the subtle mechanism been declared. Herein, the underlying mechanism of bioactivation mediated by P450s was explored by DFT calculations for a case of EGFR inhibitor, Erlotinib. Based on the calculation and analysis, we suggest that with other metabolites, reactive electrophiles of Erlotinib: epoxide and quinine-imine, can be generated by several steps along the oxidative reaction pathway. The generation of epoxide needs two steps: (1) the addition of Erlotinib to Compound I (Cpd I) and (2) the rearrangement of protons. Whereas, quinine-imine needs a further oxidation step (3) via which quinone is generated and ultimately turns into quinine-imine. Although both reactive electrophiles can be produced for either face-on or side-on pose of Erlotinib, the analysis of energy barriers indicates that the side-on path is preferred in solvent environment. In the rate-determining step, e.g. the addition of Erlotinib to the porphyrin, the reaction barrier for side-on conformation is decreased in aqueous and protein environment compared with gas phase, whereas, the barrier for face-on pose is increased in solvent environment. The simulated mechanism is in good agreement with the speculation in previous experiment. The understanding of the subtle mechanism of bioactivation of Erlotinib will provide theoretical support for toxicological mechanism of EGFR inhibitors.