Initial Protonation Research Articles

Impact of Protonation Sites on Collision-Induced Dissociation-MS/MS Using CIDMD Quantum Chemistry Modeling.

Protonation is the most frequent adduct found in positive electrospray ionization collision-induced mass spectra (CID-MS/MS). In a parallel report Lee, J. J. Chem. Inf. Model. 2024, 10.1021/acs.jcim.4c00760, we developed a quantum chemistry framework to predict mass spectra by collision-induced dissociation molecular dynamics (CIDMD). As different protonation sites affect fragmentation pathways of a given molecule, the accuracy of predicting tandem mass spectra by CIDMD ultimately depends on the choice of its protomers. To investigate the impact of molecular protonation sites on MS/MS spectra, we compared CIDMD-predicted spectra to all available experimental MS/MS spectra by similarity matching. We probed 10 molecules with a total of 43 protomers, the largest study to date, including organic acids (sorbic acid, citramalic acid, itaconic acid, mesaconic acid, citraconic acid, and taurine) as well as aromatic amines including uracil, aniline, bufotenine, and psilocin. We demonstrated how different protomers can converge different fragmentation pathways to the same fragment ions but also may explain the presence of different fragment ions in experimental MS/MS spectra. For the first time, we used in silico MS/MS predictions to test the impact of solvents on proton affinities, comparing the gas phase and a mixture of acetonitrile/water (1:1). We also extended applications of in silico MS/MS predictions to investigate the impact of protonation sites on the energy barriers of isomerization between protomers via proton transfer. Despite our initial hypothesis that the thermodynamically most stable protomer should give the best match to the experiment, we found only weak inverse relationships between the calculated proton affinities and corresponding entropy similarities of experimental and CIDMD-predicted MS/MS spectra. CIDMD-predicted mechanistic details of fragmentation reaction pathways revealed a clear preference for specific protomer forms for several molecules. Overall, however, proton affinity was not a good predictor corresponding to the predicted CIDMD spectra. For example, for uracil, only one protomer predicted all experimental MS/MS fragment ions, but this protomer had neither the highest proton affinity nor the best MS/MS match score. Instead of proton affinity, the transfer of protons during the electrospray process from the initial protonation site (i.e., mobile proton model) better explains the differences between the thermodynamic rationale and experimental data. Protomers that undergo fragmentation with lower energy barriers have greater contributions to experimental MS/MS spectra than their thermodynamic Boltzmann populations would suggest. Hence, in silico predictions still need to calculate MS/MS spectra for multiple protomers, as the extent of distributions cannot be readily predicted.

A high-throughput screening of catalyst for efficient nitrogen fixation: Transition metal single-atom anchored on an emerging synthesized biphenyl network

Synthesizing efficient and selective green ideal catalysts has been an increasingly critical, yet unsolved, issue for the ammonia synthesis industry, hindering the growing global demand for environmental protection and energy efficiency. Electrocatalytic nitrogen reduction reaction (eNRR) is a promising technology for low-energy ammonia synthesis. However, designing efficient electrocatalysts for NRR remains challenging. The emergence of graphene-like substrates offers exciting prospects for addressing this challenge and facilitating single-atom catalysts in eNRR. Here, we report the innovative selection of a recently synthesized two-dimensional biphenyl network (2D BPN) compound as a substrate. Its excellent conductivity and porosity enable stable transition metal atoms (TMs) support for constructing eNRR electrocatalysts. we evaluated the feasibility of 23 TMs anchored on BPN for eNRR by high-throughput first-principles calculations. Through a systematic five-step strategy, we identified several single-atom catalysts (SACs) with potential for eNRR, including Mo@BPN, V@BPN, W@BPN, and Re@BPN. Among them, Mo@BPN exhibited the best balance in the adsorption of key reaction intermediates (e.g., N2H and NH3) and demonstrated a low limiting potential (-0.37 V). In addition, the underlying mechanism of NRR activity was elucidated by analyzing the extrinsic patterns revealed through the screened catalysts. A triangular volcano diagram, incorporating the initial protonation step, adsorption free energy, and final protonation step, revealed the NRR activity trend. Overall, this study provides a solid theoretical foundation and valuable guidance for future experimental exploration of efficient electrocatalysts for ammonia synthesis on BPN. Crucial insights into the theoretical design of efficient electrocatalysts are also offered.

Catalytic mechanisms of methylcyclohexane cracking and light olefins production over zeolites

In this work, the catalytic mechanisms of methylcyclohexane (MCH) cracking and light olefins production were systematically investigated over three zeolites catalysts of Si-ZSM-5, hydrated ZSM-5 and HZSM-5. HZSM-5 exhibited the highest activity in terms of MCH conversion and selectivity towards light olefins. The mechanisms of MCH activation over HZSM-5 show that protolytic ring-opening is more energetically favorable when compared to protolytic dehydrogenation and thermal cracking. Four distinct pathways can result in the production of light olefins. But the pathway for the productions of propylene and butane is energetically favorable. Both protolytic C–C bond cleavage and the regeneration of the Brønsted acid site significantly influence production of light olefins. The rate-limiting steps for protolytic ring-opening and the production of light olefins are the initial protonation of C–C bonds. We hope this work can provide potential significance in understanding the hydrocarbon fuels cracking and aiding in identifying target products.

Proton Activation in the Presence of a Weak Acid Facilitated by Second Coordination Sphere Effects in Iron Porphyrins**

AbstractThe catalytic activity of two iron‐based porphyrin complexes containing pyridine‐functionalized second coordination spheres, referred to as Py2XPFe and CuPy2XPFe, have been investigated for the hydrogen evolution reaction (HER) and compared with the unsubstituted analog TMPFe in acetonitrile. The CuPy2XPFe incorporates a second metal center within the pyridine residues and represents a heterodinuclear system, while the structurally analogous Py2XPFe lacks an additional metal in the second coordination sphere. Both the Py2XFe and CuPy2XPFe complexes are observed to activate the weak acid, acetic acid (AcOH) at the FeII/I couple rather than at the more energy intensive FeI/0 couple observed for the unfunctionalized TMPFe complex at low acid concentrations. The ability of the monometallic Py2XPFe to activate the weak proton source at the FeII/I couple manifests as an ECEC(E)′ type electrochemical mechanism, rather than an EECC(E)′ type mechanism as observed for TMPFe. The CuPy2XPFe displays improved reactivity compared with the Py2XPFe and TMPFe under the same substrate conditions, however the mechanistic nuances into bimetallic CuPy2XPFe system are currently unclear. The concentration of AcOH was incrementally increased and the rate constants of the initial protonation step i. e. formation of a hydridic species (k1,app), as well as of the protonation of the hydridic species to produce dihydrogen (kglobal) were calculated using the Foot‐of‐the‐wave and plateau current rate equation methodologies, respectively. The kinetic analysis indicates that the activation of protons through the ECEC(E)′ type mechanism for the Py2XPFe results in a system in which k1,app< kglobal. As both the monometallic Py2XPFe and bimetallic CuPy2XPFe activate the AcOH at less cathodic potentials than TMPFe under identical conditions, the overpotentials (ηTOF/2) for these complexes are thus dramatically lower. The reactivity difference of the Py2XPFe when compared to non‐substituted iron porphyrin analogs is due to the hanging group's influence, which is believed to either act as hydrogen bond promoters for the active site or aids to stabilize a catalytic intermediate species during catalysis.

Preorganized Internal Electric Field Promotes a Double-Displacement Mechanism for the Adenine Excision Reaction by Adenine DNA Glycosylase.

Adenine DNA glycosylase (MutY) is a monofunctional glycosylase, removing adenines (A) misinserted opposite 8-oxo-7,8-dihydroguanine (OG), a common product of oxidative damage to DNA. Through multiscale calculations, we decipher a detailed adenine excision mechanism of MutY that is consistent with all available experimental data, involving an initial protonation step and two nucleophilic displacement steps. During the first displacement step, N-glycosidic bond cleavage is accompanied by the attack of the carboxylate group of residue Asp144 at the anomeric carbon (C1'), forming a covalent glycosyl-enzyme intermediate to stabilize the fleeting oxocarbenium ion. After departure of the excised base, water nucleophiles can be recruited to displace Asp144, completing the catalytic cycle with retention of stereochemistry at the C1' position. The two displacement reactions are found to mostly involve the movement of the oxocarbenium ion, occurring with large charge reorganization and thus sensitive to the internal electric field (IEF) exerted by the polar protein environment. Intriguingly, we find that the negatively charged carboxylate group is a good nucleophile for the oxocarbenium ion, yet an unactivated water molecule is not, and that the electric field catalysis strategy is used by the enzyme to enable its unique double-displacement reaction mechanism. A strong IEF, pointing toward 5' direction of the substrate sugar ring, greatly facilitates the second displacement reaction at the expense of elevating the barrier of the first one, thereby allowing both reactions to occur. These findings not only increase our understanding of the strategies used by DNA glycosylases to repair DNA lesions, but also have important implications for how internal/external electric field can be applied to modulate chemical reactions.

Design Principles for Transition Metal Nitride Stability and Ammonia Generation in Acid

Transition metal nitrides have shown great promise for reducing or eliminating the use of expensive precious-metal-based catalysts (e.g., Pt) in proton exchange membrane fuel cells and electrolyzers, but the use of these nitrides in such technologies is severely hindered by their dissolution at acidic pHs [1-2]. More importantly, the decomposition of transition metal nitrides in acid generates ammonia from the protonation of lattice nitrogen, giving rise to many false positives in previous reports of nitride catalysts for electrochemical nitrogen reduction to ammonia. For example, while nitrides such as VN [3], NbN [4], and Mo2N [5] have been computationally predicted to catalyze the reduction of nitrogen to ammonia, the experimentally observed ammonia has been attributed to the decomposition of nitrides in acid [6-8]. To tackle this challenge, motivated by our previous work [9-12] on the design principles of transition-metal-oxide-based catalysts, we established the stability descriptors of transition metal nitrides in acid. Such stability descriptors not only offer a fundamental understanding of nitride dissolution but also provide new guiding principles to optimize the intrinsic stability of nitrides for diverse acidic applications.In this work [13], combining ab initio calculations with synchrotron X-ray spectroscopies, we identified electronic-structure-based design principles governing the extent and kinetics of nitride dissolution and ammonia production in acid. We found that lowering the nitrogen 2p band center of transition metal nitrides with respect to the Fermi level leads to weakened metal-nitrogen bonds, increased labile metallic character, and a reduced barrier for the protonation of lattice nitrogen to produce ammonia, correlating with faster dissolution kinetics of nitrides in acid. Moreover, increasing the solubility of dissolved metal ions in acid was found to be critical in preventing surface oxide passivation to ensure the complete conversion from transition metal nitrides to ammonia. Based on these observations, a new mechanistic picture was formulated, where the initial protonation step of lattice nitrogen is critical to trigger nitride dissolution, and this proposed reaction scheme was supported by the pH-dependent dissolution kinetics of nitrides in acid.These design principles and mechanistic insights for producing ammonia and dissolving metal cations from the decomposition of nitrides in acid are essential for a variety of clean energy applications. For instance, such design principles can be leveraged to boost the stability of nitride catalysts for proton-exchange membrane fuel cells and electrochemical ammonia synthesis, where the dissolution of nitrides in acid has hindered their functions. Moreover, these descriptors for nitride dissolution and ammonia formation in acid provide emerging opportunities for designing novel nitride chemistries for distributed, on-demand ammonia generation. As nitrides represent an exciting, yet markedly unexplored chemical space, this work provides a blueprint to design multinary nitrides in such a vast materials space for various acidic applications, including electrocatalysis and beyond.

Mechanistic roles of metal- and ligand-protonated species in hydrogen evolution with [Cp*Rh] complexes

Protonation reactions involving organometallic complexes are ubiquitous in redox chemistry and often result in the generation of reactive metal hydrides. However, some organometallic species supported by η5-pentamethylcyclopentadienyl (Cp*) ligands have recently been shown to undergo ligand-centered protonation by direct proton transfer from acids or tautomerization of metal hydrides, resulting in the generation of complexes bearing the uncommon η4-pentamethylcyclopentadiene (Cp*H) ligand. Here, time-resolved pulse radiolysis (PR) and stopped-flow spectroscopic studies have been applied to examine the kinetics and atomistic details involved in the elementary electron- and proton-transfer steps leading to complexes ligated by Cp*H, using Cp*Rh(bpy) as a molecular model (where bpy is 2,2'-bipyridyl). Stopped-flow measurements coupled with infrared and UV-visible detection reveal that the sole product of initial protonation of Cp*Rh(bpy) is [Cp*Rh(H)(bpy)]+, an elusive hydride complex that has been spectroscopically and kinetically characterized here. Tautomerization of the hydride leads to the clean formation of [(Cp*H)Rh(bpy)]+. Variable-temperature and isotopic labeling experiments further confirm this assignment, providing experimental activation parameters and mechanistic insight into metal-mediated hydride-to-proton tautomerism. Spectroscopic monitoring of the second proton transfer event reveals that both the hydride and related Cp*H complex can be involved in further reactivity, showing that [(Cp*H)Rh] is not necessarily an off-cycle intermediate, but, instead, depending on the strength of the acid used to drive catalysis, an active participant in hydrogen evolution. Identification of the mechanistic roles of the protonated intermediates in the catalysis studied here could inform design of optimized catalytic systems supported by noninnocent cyclopentadienyl-type ligands.

Expedient synthesis of spiro[3.3]heptan-1-ones via strain-relocating semipinacol rearrangements

A novel approach for the formation of the highly strained spiro[3.3]heptan-1-one motif was developed through the reaction of 1-sulfonylcyclopropanols and lithiated 1-sulfonylbicyclo[1.1.0]butanes. Following initial nucleophilic addition to the cyclopropanone formed in situ, the resulting 1-bicyclobutylcyclopropanol intermediate is prone to a ‘strain-relocating’ semipinacol rearrangement in the presence of acid, directly affording the substituted spiro[3.3]heptan-1-one. The process is shown to be fully regio- and stereospecific when starting from a substituted cyclopropanone equivalent, leading to optically active 3-substituted spiro[3.3]heptan-1-ones. The reaction likely proceeds via initial protonation of the bicyclobutyl moiety followed by [1,2]-rearrangement of the resulting cyclopropylcarbinyl cation.

Electro- and photochemical H2 generation by Co(ii) polypyridyl-based catalysts bearing ortho-substituted pyridines.

Cobalt(ii) complexes featuring hexadentate amino-pyridyl ligands have been recently discovered as highly active catalysts for the Hydrogen Evolution Reaction (HER), whose high performance arises from the possibility of assisting proton transfer processes via intramolecular routes involving detached pyridine units. With the aim of gaining insights into such catalytic routes, three new proton reduction catalysts based on amino-polypyridyl ligands are reported, focusing on substitution of the pyridine ortho-position. Specifically, a carboxylate (C2) and two hydroxyl substituted pyridyl moieties (C3, C4) are introduced with the aim of promoting intramolecular proton transfer which possibly enhances the efficiency of the catalysts. Foot-of-the-wave and catalytic Tafel plot analyses have been utilized to benchmark the catalytic performances under electrochemical conditions in acetonitrile using trifluoroacetic acid as the proton source. In this respect, the cobalt complex C3 turns out to be the fastest catalyst in the series, with a maximum turnover frequency (TOF) of 1.6 (±0.5) × 105 s-1, but at the expense of large overpotentials. Mechanistic investigations by means of Density Functional Theory (DFT) suggest a typical ECEC mechanism (i.e. a sequence of reduction - E - and protonation - C - events) for all the catalysts, as previously envisioned for the parent unsubstituted complex C1. Interestingly, in the case of complex C2, the catalytic route is triggered by initial protonation of the carboxylate group resulting in a less common (C)ECEC mechanism. The pivotal role of the hexadentate chelating ligand in providing internal proton relays to assist hydrogen elimination is further confirmed within this novel class of molecular catalysts, thus highlighting the relevance of a flexible polypyridine ligand in the design of efficient cobalt complexes for the HER. Photochemical studies in aqueous solution using [Ru(bpy)3]2+ (where bpy = 2,2'-bipyridine) as the sensitizer and ascorbate as the sacrificial electron donor support the superior performance of C3.

Boosting photo-assisted efficient electrochemical CO2 reduction reaction on transition metal single-atom catalysts supported on the C6N6 nanosheet.

CO2 reduction to value-added chemicals turns out to be a promising and efficient approach to resolve the increasing energy crisis and global warming. However, the catalytic efficiency of CO2 reduction reaction (CO2RR) to form C1 products (CO, HCOOH, CH3OH, CH4) needs to be quite efficient. Herein with the help of density functional theory, CO2RR towards C1 products was investigated on a transition metal (TM = Fe, Co, Ni) embedded C6N6 framework. The stable geometry of the catalysts, CO2 adsorption configurations, and CO2RR mechanisms were systematically studied for all the systems considered. The possible different adsorption configurations and adsorption energy calculations indicated that CO2 could be chemically adsorbed on the Co@C6N6 system. On the other hand, physical adsorption of CO2 is more preferable on Fe@C6N6 and Ni@C6N6 systems. As a competitive reaction, hydrogen evolution reaction (HER) was investigated and the systems were found to show more selectivity for CO2RR than for HER. OCHO formation turned out to be more favorable than COOH formation as initial protonation intermediates for CO2RR on the TM@C6N6 systems. The present work demonstrates that the Co@C6N6 catalyst can favor the electrocatalytic CO2RR among all systems. In addition, the photocatalytic activity of the systems was also investigated. The systems are found to be active for photoreduction of CO2 to CH3OH and CH4 in the presence of reducing agents such as H2 and H2O as they possess appropriate absorption spectrum in the visible region as well as suitable band edge positions. These findings open a way for designing single atom catalysts for important catalytic reactions.

Surface Water as an Initial Proton Source for the Electrochemical CO Reduction Reaction on Copper Surfaces

AbstractWe have employed in situ electrochemical shell‐isolated nanoparticle‐enhanced Raman spectroscopy (SHINERS) and density functional theory (DFT) calculations to study the CO reduction reaction (CORR) on Cu single‐crystal surfaces under various conditions. Coadsorbed and structure‐/potential‐dependent surface species, including *CO, Cu−Oad, and Cu−OHad, were identified using electrochemical spectroscopy and isotope labeling. The relative abundance of *OH follows a “volcano” trend with applied potentials in aqueous solutions, which is yet absent in absolute alcoholic solutions. Combined with DFT calculations, we propose that the surface H2O can serve as a strong proton donor for the first protonation step in both the C1 and C2 pathways of CORR at various applied potentials in alkaline electrolytes, leaving adsorbed *OH on the surface. This work provides fresh insights into the initial protonation steps and identity of key interfacial intermediates formed during CORR on Cu surfaces.

Surface Water as an Initial Proton Source for the Electrochemical CO Reduction Reaction on Copper Surfaces.

We have employed in situ electrochemical shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) and density functional theory (DFT) calculations to study the CO reduction reaction (CORR) on Cu single-crystal surfaces under various conditions. Coadsorbed and structure-/potential-dependent surface species, including *CO, Cu-Oad , and Cu-OHad , were identified using electrochemical spectroscopy and isotope labeling. The relative abundance of *OH follows a "volcano" trend with applied potentials in aqueous solutions, which is yet absent in absolute alcoholic solutions. Combined with DFT calculations, we propose that the surface H2 O can serve as a strong proton donor for the first protonation step in both the C1 and C2 pathways of CORR at various applied potentials in alkaline electrolytes, leaving adsorbed *OH on the surface. This work provides fresh insights into the initial protonation steps and identity of key interfacial intermediates formed during CORR on Cu surfaces.

Competing esterification and oligomerization reactions of typical long-chain alcohols to secondary organic aerosol formation

Organosulfate (OSA) nanoparticles, as secondary organic aerosol (SOA) compositions, are ubiquitous in urban and rural environments. Hence, we systemically investigated the mechanisms and kinetics of aqueous-phase reactions of 1-butanol/1-decanol (BOL/DOL) and their roles in the formation of OSA nanoparticles by using quantum chemical and kinetic calculations. The mechanism results show that the aqueous-phase reactions of BOL/DOL start from initial protonation at alcoholic OH-groups to form carbenium ions (CBs), which engage in the subsequent esterification or oligomerization reactions to form OSAs/organosulfites (OSIs) or dimers. The kinetic results reveal that dehydration to form CBs for BOL and DOL reaction systems is the rate-limiting step. Subsequently, about 18% of CBs occur via oligomerization to dimers, which are difficult to further oligomerize because all reactive sites are occupied. The rate constant of BOL reaction system is one order of magnitude larger than that of DOL reaction system, implying that relative short-chain alcohols are more prone to contribute OSAs/OSIs than long-chain alcohols. Our results reveal that typical long-chain alcohols contribute SOA formation via esterification rather than oligomerization because OSA/OSI produced by esterification engages in nanoparticle growth through enhancing hygroscopicity.

Identification of Active Sites for CO2 Reduction on Graphene-Supported Single-Atom Catalysts.

Transition metal- and nitrogen-codoped graphene (referred to as M-N-G, where M is a transition metal) has emerged as an important type of single-atom catalysts with high selectivities and activities for electrochemical CO2 reduction (CO2 R) to CO. However, despite extensive previous studies on the catalytic origin, the active site in M-N-G catalysts remains puzzling. In this study, density functional theory calculations and computational hydrogen electrode model is used to investigate CO2 R reaction energies on Zn-N-G, which exhibits outstanding catalytic performance, and to examine kinetic barriers of reduction reactions by using the climbing image nudged elastic band method. We find that single Zn atoms binding to N and C atoms in divacancy sites of graphene cannot serve as active sites to enable CO production, owing to *OCHO formation (* denotes an adsorbate) at an initial protonation process. This contradicts the widely accepted CO2 R mechanism whereby single metal atoms are considered catalytic sites. In contrast, the C atom that is the nearest neighbor of the single Zn atom (CNN ) is found to be highly active and the Zn atom plays a role as an enhancer of the catalytic activity of the CNN . Detailed analysis of the CO2 R pathway to CO on the CNN site reveals that *COOH is favorably formed at an initial electrochemical step, and every reaction step becomes downhill in energy at small applied potentials of about -0.3 V with respect to reversible hydrogen electrode. Electronic structure analysis is also used to elucidate the origin of the CO2 R activity of the CNN site.

Redox-Induced Structural Reorganization Dictates Kinetics of Cobalt(III) Hydride Formation via Proton-Coupled Electron Transfer.

Two-electron, one-proton reactions of a family of [CoCp(dxpe)(NCCH3)]2+ complexes (Cp = cyclopentadienyl, dxpe = 1,2-bis(di(aryl/alkyl)phosphino)ethane) form the corresponding hydride species [HCoCp(dxpe)]+ (dxpe = dppe (1,2-bis(diphenylphosphino)ethane), depe (1,2-bis(diethylphosphino)ethane), and dcpe (1,2-bis(dicyclohexylphosphino)ethane)) through a stepwise proton-coupled electron transfer process. For three [CoCp(dxpe)(NCCH3)]2+ complexes, peak shift analysis was employed to quantify apparent proton transfer rate constants from cyclic voltammograms recorded with acids ranging 22 pKa units. The apparent proton transfer rate constants correlate with the strength of the proton source for weak acids, but these apparent proton transfer rate constants curiously plateau (kpl) as the reaction becomes increasingly exergonic. The absolute apparent proton transfer rate constants across both these regions correlate with the steric bulk of the chelating diphosphine ligand, with bulkier ligands leading to slower kinetics (kplateau,depe = 3.5 × 107 M-1 s-1, kplateau,dppe = 1.7 × 107 M-1 s-1, kplateau,dcpe = 7.1 × 104 M-1 s-1). Mechanistic studies were conducted to identify the cause of the aberrant kPTapp-ΔpKa trends. When deuterated acids are employed, deuterium incorporation in the Cp ring is observed, indicating protonation of the CoCp(dxpe) species to form the corresponding hydride proceeds via initial ligand protonation. Digital simulations of cyclic voltammograms show ligand loss accompanying initial reduction gates subsequent PCET activity at higher driving forces. Together, these experiments reveal the details of the reaction mechanism: reduction of the Co(III) species is followed by dissociation of the bound acetonitrile ligand, subsequent reduction of the unligated Co(II) species to form a Co(I) species is followed by protonation, which occurs at the Cp ring, followed by tautomerization to generate the stable Co(III)-hydride product [HCoCp(dxpe)]+. Analysis as a function of chelating disphosphine ligand, solvent, and acid strength reveals that the ligand dissociation equilibrium is directly influenced by the steric bulk of the phosphine ligands and gates protonation, giving rise to the plateau of the apparent proton transfer rate constant with strong acids. The complexity of the reaction mechanism underpinning hydride formation, encompassing dynamic behavior of the entire ligand set, highlights the critical need to understand elementary reaction steps in proton-coupled electron transfer reactions.

Song: Oxidosqualene (OS) cyclase-Lanosterol synthase (to the tune of "Oh Christmas Tree").

This song deals with oxidosqualene cyclases, a class of enzymes that catalyze among the most fascinating and complex monoenzymatic reactions. While in photosynthetic eukaryotes there are dozens of different oxidosqualene cyclases that form a plethora of different cyclization products, in non-photosynthetic organisms, fungi and animals (vertebrates), the only product of cyclization is lanosterol, precursor of ergosterol and cholesterol, respectively. Therefore, in these organisms, the only oxidosqualene cyclase present is lanosterol synthase. Since all the steroid compounds occurring in vertebrates (bile salts, steroid hormones, neuroactive steroids, etc.) derive from cholesterol, they all owe their tetracyclic structure to the action of this enzyme. In the cyclization process of lanosterol synthase, what happens between the initial protonation and the final deprotonation is truly amazing: four rings are formed, several chiral centres are created, a positive charge travels through the triterpene skeleton of the substrate back and forth, and methyls and hydrides literally dance from one position to another. The structural comparison between the starting substrate and the final product is absolutely outstanding. It is, therefore, not surprising that such a fascinating enzyme was called "The Lord of the Rings". To this Lord, the present poem is dedicated, composed of seven stanzas, which can be sung on a well-known Christmas melody. To grasp well the different steps of the catalytic process described by the stanzas, one can resort to the numerous images available on the web.

Helium-Plasma-Ionization Mass Spectrometry of Metallocenes and Their Derivatives.

Ferrocene and its derivatives and nickelocene undergo facile ionization when exposed directly to the ionizing plasma of a helium-plasma ionization (HePI) source. Mass spectra recorded from such samples under ambient positive-ion-generating conditions show intense peaks for the respective molecular ions [M+•] and protonated species [(M + H)+]. The protonation process occurs most efficiently when traces of water are present in the heated nitrogen used as the "heating gas." In fact, the relative population of the two categories of ions generated in this way can be manipulated by regulating the heating-gas flow. Moreover, rapid and highly efficient gas-phase hydrogen-deuterium exchange (HDX) reactions can be performed in the ion source by passing the heating gas through a vial with D2O before it reaches the HePI source. Moreover, the ionized species generated in this way can be subjected to in-source CID fragmentation in the QDa-HePI source very efficiently by varying the sampling-cone voltage. By this procedure, ions generated from ferrocene and nickelocene could be stripped so far as to ultimately generate the bare-metal cation. Other typical fragment-ions produced from protonated metallocenes included the M(cp)1+ ions (M = Fe or Ni), by elimination of a cyclopentadiene molecule, or the molecular cation, by loss of a H• radical. Moreover, H/D exchanges and subsequent tandem mass spectrometric analysis indicated that the central metal core participates in the initial protonation process of ferrocene under HePI conditions. However, in compounds such as ferrocene carboxaldehyde and ferrocene boronic acid, the protonation takes place at the peripheral functional group.

Organocatalytic asymmetric synthesis of α-amino esters from sulfoxonium ylides.

Described here is the first organocatalytic asymmetric N–H insertion reaction of α-carbonyl sulfoxonium ylides. Without a metal catalyst, this reaction represents an attractive complement to the well-established carbene insertion reactions. As a stable surrogate of diazocarbonyl compounds, sulfoxonium ylides reacted with a range of aryl amines to provide efficient access to α-aryl glycines with excellent enantiocontrol in the presence of a suitable chiral phosphoric acid catalyst. The high stability and weak basicity of sulfoxonium ylides not only enable this protocol to be user-friendly and practically useful, but also preclude catalyst decomposition, which is crucial to the excellent amenability to electron-poor amine nucleophiles. Detailed mechanistic studies indicated that the initial protonation is reversible and the C–N bond formation is rate-determining.

Spiropyran Meets Guanine Quadruplexes: Isomerization Mechanism and DNA Binding Modes of Quinolizidine-Substituted Spiropyran Probes.

The recent delivery of a fluorescent quinolizidine‐substituted spiropyran, which is able to switch in vivo and bind to guanine quadruplexes (G4) at physiological pH values, urged us to elucidate its molecular switching and binding mechanism. Combining multiscale dynamical studies and accurate quantum chemical calculations, we show that, both in water and in the G4 environment, the switching of the spiropyran ring is not promoted by an initial protonation event—as expected by the effect of low pH solutions—but that the deprotonated merocyanine form is an intermediate of the reaction leading to the protonated open species. Additionally, we investigate the binding of both deprotonated and protonated open forms of merocyanine to c‐MYC G4s. Both species bind to G4s albeit with different hydrogen‐bond patterns and provide distinct rotamers around the exocyclic double bond of the merocyanine forms. Altogether, our study sheds light on the pharmacophoric points for the binding of these probes to DNA, and thereby, contributes to future developments of new G4 binders of the remarkable family of quinolizidine‐substituted spiropyrans.

Chiral Phosphoric Acid Catalyzed Enantioselective Synthesis of α-Tertiary Amino Ketones from Sulfonium Ylides.

Herein we disclose a new catalytic asymmetric approach for the synthesis of chiral α-amino ketones, which is particularly useful for the less accessible acyclic α-tertiary cases. By a protonation-amination sequence, our approach represents a rare asymmetric H-heteroatom bond insertion by α-carbonyl sulfonium ylides, an attractive surrogate of diazocarbonyls. The mild intermolecular C-N bond formation was catalyzed by chiral phosphoric acids with excellent efficiency and enantioselectivity. The products are precursors to other important chiral amine derivatives, including drug molecules and chiral ligands. The enantioselectivity was controlled by dynamic kinetic resolution in the amination step, rather than the initial protonation. This process opens up a new platform for the development of other related insertion reactions.