Nonclassical Ion Research Articles

An inspiration to the studies on mechanisms of acupuncture and moxibustion action derived from 2021 Nobel Prize in Physiology or Medicine

Abstract The editorial board of Acupuncture and Herbal Medicine recently convened an academic seminar with a focus on studies regarding the mechanisms mediating acupuncture efficacy and moxibustion action inspired by the 2021 Nobel Prize in Physiology or Medicine. Specifically, Professor Bailong Xiao introduced the Nobel Prize for research on the mechanically activated Piezo ion channel, evaluating the structure of the Piezo channel and its physiological and pathological functions, and proposed a possible role for the Piezo channel in acupuncture mechanical stimulation. Professor Michael Xi Zhu introduced the discovery of the transient receptor potential (TRP) family, reporting that the therapeutic effects of Chinese medicine and acupuncture may be achieved via the TRP family, and that information regarding associations between the meridian and lymphatic systems may have important research and medical value. In addition, Professor Tianle Xu reviewed the history of ion channel research, particularly the physiological and pharmacological effects of non-classical ion channels (eg, the acid sensing ion channel family) and pointed out that the characterization and neural circuits of acupuncture deqi manipulation are important for elucidating the mechanisms of acupuncture actions. Professor Yongming Li similarly proposed that the 2021 Nobel Prize may open the door to disclosing the histological basis of acupuncture and moxibustion and analyzing the main scientific concerns regarding the clinical translation of acupuncture and moxibustion from basic to translational research. Finally, Professor Yi Guo summarized the study progress of the acupoint microenvironment induced by acupuncture over the course of nearly 30 years and put forward the hypothesis that acupuncture may initiate the physical-chemical coupling network by activating ion channel receptors in acupoints via physical and mechanical stimulation. Therefore, we conclude that a primary achievement of the 2021 Nobel Prize in Physiology or Medicine is in helping interpret how acupuncture and moxibustion adjust homeostasis (ie, by activating mechanical and thermal sensation), which is conducive to validating and promoting the clinical efficacy of acupuncture modalities.

Total Synthesis of Stemarene and Betaerene Diterpenoids: Divergent Ring-Formation Strategy and Late-Stage C–H Functionalization

A unified protecting group-free approach to two stemarene and two betaerene diterpenoids through a bioinspired two-phase strategy has been developed, and three of them were obtained for the first t...

Kinetic Verification of the Stochastic Ion Heating Mechanism in Collisionless Magnetic Reconnection

Abstract The origin of anomalous, non-classical ion heating during magnetic reconnection has been a longstanding problem. It is verified via fully kinetic analyses and particle-in-cell simulations that stochastic heating is the main ion heating mechanism in collisionless magnetic reconnection up to moderate guide fields. Strong in-plane Hall electric fields that form during reconnection render ion motions chaotic and de facto broaden the ion distribution function. The mechanism is consistent with numerous observed features of ion heating in reconnection, such as the preferential heating of ions with higher mass-to-charge ratios and the non-conservation of the ion magnetic moment.

The controversy about nonclassical ions: Finished too early?

AbstractThe debate on nonclassical ions centered almost exclusively on the behavior of 2‐norbornyl esters. The hallmark of a nonclassical charge distribution in solvolysis reactions was always seen in the seemingly exceptional fast reaction of the 2‐exo‐derivatives, with slow rates of the endo‐esters. While the nonclassical bridged structure of the free norbornyl ion has been unequivocally established, possible steric contributions to the rate differences in solution remained a matter of debate. Many formerly used solvents were less suited to exhibit uniform reaction mechanisms; the most appropriate solvent hexafluorisopropanol was introduced rather late. Solvolysis rates of many cyclic esters including medium rings can be predicted by force field calculated strain energy differences ΔSIsp3/sp2 between sp3 and sp2 states. Large deviations from the correlation are observed for 2‐tosyloxy norbornane‐ and for 17‐tosyloxy steroids; they indicate that both nonclassical charge delocalization and steric hindrance play a major role for the reactivity differences. These reach an unprecedented rate constant ratio of >30.000 between, eg, the 17‐steroid epimers, much larger than the ratio of 1.550 in 2‐norbornyl reactions. The presence of alkyl groups or hydrogen antiperiplanar to the leaving group can lead to extreme reactivities by 1,2‐shifts or Wagner‐Meerwein rearrangement if asymmetric bridged transition states can occur which approach the stability of tertiary cations. The long controversy about nonclassical ions illustrates how progress in science can deviate significantly from the ideal pathways lined out by Karl Popper.

The multiconfiguration Spin-Coupled approach for the description of the three-center two-electron chemical bond of some carbenium and nonclassical ions

The intrinsically elusive concepts of electronic “delocalization” and “chemical resonance” are briefly reviewed emphasizing their connection with Spin-Coupled (SC) descriptions of electronic structure. Multiconfiguration Spin-Coupled (MC-SC) calculations are performed to describe the three-center two-electron (3c-2e) bonding in some representative carbenium and nonclassical carbonium ions. Within the MC-SC approach, it is found that these cations present significant electronic energy stabilization when described by more than one valence SC spatial orbital configuration. It is shown that it is necessary to have a superposition of two chemical structures to completely span the orbital valence space of these cations. Two characteristic bonding themes are clearly distinguished. One specific to allyl-type carbenium ions and another specific to the nonclassical carbonium ions. In both situations, the 3c-2e bond is described by two chemical structures. The 3c-2e bond present in these carbocations is described clearly within this conceptual framework. The results point out for the robustness of the Spin-Coupled description in yielding a general picture of bonding, even when considering valence-bond type multiconfiguration effects.

Identification and Characterization of a Bacterial Homolog of Chloride Intracellular Channel (CLIC) Protein

Chloride intracellular channels (CLIC) are non-classical ion channels lacking a signal sequence for membrane targeting. In eukaryotes, they are implicated in cell volume regulation, acidification, and cell cycle. CLICs resemble the omega class of Glutathione S-transferases (GST), yet differ from them in their ability to form ion channels. They are ubiquitously found in eukaryotes but no prokaryotic homolog has been characterized. We found that indanyloxyacetic acid-94 (IAA-94), a blocker of CLICs, delays the growth of Escherichia coli. In silico analysis showed that the E. coli stringent starvation protein A (SspA) shares sequence and structural homology with CLICs. Similar to CLICs, SspA lacks a signal sequence but contains an omega GST fold. Electrophysiological analysis revealed that SspA auto-inserts into lipid bilayers and forms IAA-94-sensitive ion channels. Substituting the ubiquitously conserved residue leucine 29 to alanine in the pore-forming region increased its single-channel conductance. SspA is essential for cell survival during acid-induced stress, and we found that acidic pH increases the open probability of SspA. Further, IAA-94 delayed the growth of wild-type but not sspA null mutant E. coli. Our results for the first time show that CLIC-like proteins exist in bacteria in the form of SspA, forming functional ion channels.

Cyclopentyl, cyclohexyl, and cycloheptyl cations: computational studies of the structures, stability, 13C NMR chemical shifts, and possible rearrangement pathways

Various structures of the cyclopentyl cation were computed at the MP2/cc-pVTZ and CCSD (T)/cc-pVTZ levels. Energetically, the classical cyclopentyl cation 1 and the 1,2-hydrogen-bridged structure 3 were found to be almost identical. The structures and energies of the cyclohexyl and cycloheptyl cations were also calculated at the MP2/cc-pVTZ level. The σ-delocalized nonclassical ion 16 was found to be the lowest energy structure for the cycloheptyl cation. The 13C NMR chemical shifts of the ions were also computed and compared with the experimental results.

Computational simulations of hydrogen circular migration in protonated acetylene induced by circularly polarized light.

The hydrogens in protonated acetylene are very mobile and can easily migrate around the C2 core by moving between classical and non-classical structures of the cation. The lowest energy structure is the T-shaped, non-classical cation with a hydrogen bridging the two carbons. Conversion to the classical H2CCH(+) ion requires only 4 kcal/mol. The effect of circularly polarized light on the migration of hydrogens in oriented C2H3 (+) has been simulated by Born-Oppenheimer molecular dynamics. Classical trajectory calculations were carried out with the M062X/6-311+G(3df,2pd) level of theory using linearly and circularly polarized 32 cycle 7 μm cosine squared pulses with peak intensity of 5.6 × 10(13) W/cm(2) and 3.15 × 10(13) W/cm(2), respectively. These linearly and circularly polarized pulses transfer similar amounts of energy and total angular momentum to C2H3 (+). The average angular momentum vectors of the three hydrogens show opposite directions of rotation for right and left circularly polarized light, but no directional preference for linearly polarized light. This difference results in an appreciable amount of angular displacement of the three hydrogens relative to the C2 core for circularly polarized light, but only an insignificant amount for linearly polarized light. Over the course of the simulation with circularly polarized light, this corresponds to a propeller-like motion of the three hydrogens around the C2 core of protonated acetylene.

Ion Mobility Mass Spectrometry as a Potential Tool To Assign Disulfide Bonds Arrangements in Peptides with Multiple Disulfide Bridges

Disulfide bridges play a major role in defining the structural properties of peptides and proteins. However, the determination of the cysteine pairing is still challenging. Peptide sequences are usually achieved using tandem mass spectrometry (MS/MS) spectra of the totally reduced unfolded species, but the cysteine pairing information is lost. On the other hand, MS/MS experiments performed on native folded species show complex spectra composed of nonclassical ions. MS/MS alone does not allow either the cysteine pairing or the full sequence of an unknown peptide to be determined. The major goal of this work is to set up a strategy for the full structural characterization of peptides including disulfide bridges annotation in the sequence. This strategy was developed by combining ion mobility spectrometry (IMS) and collision-induced dissociation (CID). It is assumed that the opening of one S-S bridge in a peptide leads to a structural evolution which results in a modification of IMS drift time. In the presence of multiple S-S bridges, the shift in arrival time will depend on which disulfide(s) has (have) been reduced and on the shape adopted by the generated species. Due to specific fragmentations observed for each species, CID experiments performed after the mobility separation could provide not only information on peptide sequence but also on the localization of the disulfide bridges. To achieve this goal, synthetic peptides containing two disulfides were studied. The openings of the bridges were carried out following different experimental conditions such as reduction, reduction/alkylation, or oxidation. Due to disulfide scrambling highlighted with the reduction approaches, oxidation of S-S bonds into cysteic acids appeared to be the best strategy. Cysteine connectivity was then unambiguously determined for the two peptides, without any disulfide scrambling interference.

Theoretical Studies on Structures and Electronic State of Alkyl‐Substituted Ethyl Cations

This paper describes the gas phase structural details for a series of alkyl‐substituted ethyl cations 1–11 by mainly natural bond orbital (NBO) analysis. For the simplest ethyl cation, two kinds of optimized structures (nonclassical 1 and classical 2) were found to have minima on the potential surface, and the nonclassical 1 was more stable than the corresponding classical 2 by 1.19 kcal/moL at Møller‐Plesset (MP) level calculations in the gas phase. The calculated values of Wiberg’s bond index revealed that the central ethylic C1–C2 bonds of the nonclassical cations 1, 6, 7, and 10 have 1.10–1.46 bond multiplicities. The compliance constant (Cii) values indicated that the cation center C1 of nonclassical 2‐butyl cation 6 (0.209 Å/mdyn) acquires stronger hyperconjugative stabilization from C2–R3 (C–H) bond than that of the nonclassical ethyl cation 1 (0.388 Å/mdyn). Moreover, the gas phase stabilities for the alkyl‐substituted ethyl cations 1–11 were also estimated by the hydride affinities based on isodesmic equations.

Sustaining a Controversy: The Non-classical Ion Debate

ABSTRACT: This paper examines a scientific controversy that raged for twenty years in physical organic chemistry during the second half of the twentieth century. After explaining what was at stake in the Non-Classical Ion Debate, I attempt—by examining the methodological reflections of some of the participants—a partial explanation of why this debate was so difficult to resolve. Instead of suggesting a breakdown of scientific method or the futility of appeals to evidence, the endurance of this controversy instead reveals the heuristic character of many of the explanations and predictions generated by theoretical organic chemistry. The results in this case are used to suggest a new role for the study of scientific controversies in revealing the economics of inquiry in scientific fields.

A Convenient Road to 1‐Chloropentacycloundecanes – A Joint Experimental and Computational Investigation

AbstractAn efficient synthetic strategy to obtain 1‐chloro‐Cs‐trishomocubane and 1‐chloro‐D3‐trishomocubane is described. 1‐Chloro‐Cs‐trishomocubane is synthesized by a regioselective Diels–Alder reaction, and B3PW91/6‐31G(d,p) calculations offer a plausible explanation of the reaction mechanism. Surprisingly, 1‐chloro‐Cs‐trishomocubane does not undergo an acid‐catalyzed rearrangement to form 1‐chloro‐D3‐trishomocubane and was obtained by chlorosulfation of Cookson's diketone. A possible mechanism of the reaction involving the formation of Cs‐ and D3‐trishomocubane nonclassical cations was proposed on the basis of a mechanistic [B3PW91/6‐31G(d,p) and MP2/cc‐pVDZ] study.

QTAIM-DI-VISAB computational study on the so-called nonclassical bicyclobutonium cation

QTAIM-DI-VISAB analyses at the CCSD and B3PW91 levels were used to characterize the bonding of the cyclopropylcarbinyl (1) and the so-called ‘nonclassical’ bicyclobutonium and 1methylbicyclobutonium cations, 2 and 3 as well as the transition state for rearrangement of 1 to 2. These analyses involved obtaining QTAIM molecular graphs and delocalization indexes (DIs) for pairs of atoms that were correlated with the proximities of atomic basins (VISAB). This study showed that the supposed nonclassical bicyclobutonium and 1-methylbicyclobutonium cations do not exhibit penta-coordinate carbons at their equilibrium geometries as has been claimed. Both species are best described as distorted cyclobutyl cations that exhibit a single ring critical point in the topology of the charge density.

Halogenated silanes, radicals, and cations: Theoretical predictions on ionization energies, structures and potential energy surfaces of cations, proton affinities, and enthalpies of formation

Quantum chemistry study has been carried out on the structure and energetics of halogenated silanes, radicals, and cations (SiH x X y 0,+1, X = F, Cl, Br; x + y = 1–4). The geometries are optimized at B3LYP/6-31+G(2df,p) level. The adiabatic ionization energiess (IE as), relative energetics of cations, proton affinities (PAs) of silanes, and the enthalpies of formation are predicted using G3(CC) model chemistry. Non-classical ion complex structures are found for hydrogenated cations and transition states connecting classical and non-classical structures are also located. The most stable cations for silylene and silyl radicals have their classical divalent and trivalent structures, and those for silanes have non-classical structures except for SiH 3Br + and SiH 2Br 2 +. The non-classical structures for halosilane cations imply difficulty in experimentally measurement of the adiabatic ionization energies using photoionization or photoelectron studies. For SiH 3X, SiH 2X 2, and SiHX 3, the G3(CC) adiabatic IE as to classical ionic structures closest to their neutrals agree better with the photoelectron spectroscopic measurements. The transition states between classical and non-classical structures also hamper the photoionization determination of the appearance energies for silylene cations from silanes. The G3(CC) results for SiH x 0,+1 agree excellently with the photoionization mass spectrometric study, and the results for fluorinated and chlorinated species also agree with the previous theoretical predictions at correlation levels from BAC-MP4 to CCSD(T)/CBS. The predicted enthalpy differences between SiH 2Cl +, SiHCl 2 +, and SiCl 3 + are also in accordance with previous kinetics study. The G3(CC) results show large discrepancies to the collision-induced charge transfer and/or dissociation reactions involving SiF x + and SiCl x + ions, for which the G3(CC) enthalpies of formation are also significantly differed from the previous theoretical predictions, especially on SiF x + ( x = 2–4). The G3(CC) IE a and PA of SiF 4 are significantly different from previous experimental and theoretical studies; however, they are supported by current benchmark calculations at level of CCSD(T)/CBS + core-valence correction.

Electronic Nature of Carbonium Ions and Their Silicon Analogues

Nonclassical ions or carbonium ions have multi-center bonding from delocalized sigma or pi electrons. The 2-norbornyl cation, its derivative 6,6-difluoro-2-norbornyl cation, tris-homocyclopropenyl cation, 7-norbornenyl cation, and 4-cyclopentenyl cation and their corresponding silicon analogues were studied in this work. All carbocations have topologically different 3c-2e systems. The magnitude of all delocalization indexes between each atomic pair of the 3c-2e bond can be used to predict homoaromaticity. The silicon analogues have a topologically different 3c-2e bond from their corresponding carbocation.

Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding.

Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding.

Infrared Photodissociation Spectroscopy of Protonated Acetylene and Its Clusters

The protonated acetylene cation, C2H3+, (also known as the vinyl cation) and the proton-bound acetylene dimer cation (C4H5+) are produced by a pulsed supersonic nozzle/pulsed electrical discharge cluster source. The parent ions are also generated with weakly attached argon "tag" atoms, e.g., C2H3+Ar and C4H5+Ar. These ions are mass selected in a specially designed reflectron time-of-flight mass spectrometer and studied with infrared laser photodissociation spectroscopy in the 800-3600 cm-1 region. Vibrational resonances are detected for both ions in the C-H stretching region. C2H3+ has a strong vibrational resonance near 2200 cm-1 assigned to the bridged proton stretch of the nonclassical ion, while C4H5+ has no such free-proton vibration. Instead, C4H5+ has resonances near 1300 cm-1, consistent with a symmetrically shared proton in a di-bridged structure. Although the shared proton structure is not the lowest energy isomer of C4H5+, this species is apparently stabilized under the supersonic beam conditions. Larger clusters containing additional acetylene units are also investigated via the elimination of acetylene. These species have new IR bands indicating that rearrangement reactions have taken place to produce core C4H5+ ions with the methyl cyclopropane cation structure and/or the protonated cyclobutadiene isomer. Ab initio (MP2) calculations provide structures and predicted spectra consistent with all of these experiments.

Intramolecular Cyclization of Ruthenium Vinylidene Complexes with a Tethering Vinyl Group: Facile Cleavage and Reconstruction of the C−C Double Bond

Protonation of ruthenium acetylide complexes [M]-*C*CCPh2CH2CH=CH2 (2a, [M] = (eta5-C5H5)(P(OPh)3)(PPh3)Ru; 2a', [M] = (eta5-C5H5)(dppp)Ru; *C = 13C-labeled carbon atom) with HBF4 in ether produces [[M]=*C=CHCH2CPh2*CH=CH2][BF4] (4, 4') exclusively via a metathesis process of the terminal vinyl group with the *C=*C of the resulting vinylidene group. For 4 in methanol, bond reconstruction of the two labeled *C atoms readily takes place via a retro-metathesis process followed by a cyclization of the resulting vinylidene ligand giving the cyclic carbene complex 5, which is fully characterized by single-crystal X-ray diffraction analysis. The protonation of 2a in MeOH is followed by a cyclization, also giving 5. Deuterium-labeling study indicates that the C-C bond formation of this cyclization proceeds simultaneously with the formation of 4 consistent with facile cleavage and reconstruction of C=C bonds. For comparison, complex 4 in alcohol yields, besides 5, the corresponding alkoxycyclohexene 6. Formation of 6 from 4 also involves a skeletal rearrangement with reconstruction of the C=C bond. Interestingly, [[Ru']=*C=C(Me)CH2CPh2*CH=CH2][BF4] (8') originally from a complex with two connected labeled carbon atoms also undergoes reestablishment of the *C=*C bond yielding the cyclic allenyl complex 9'. 13C-labeling studies clearly reveal the reestablishment of two C=C double bonds in the transformation of both 4 to 5 and 8' to 9'. The proposed mechanism implicates a cyclobutylidene intermediate formed either via a regiospecific [2+2] cycloaddition of two double bonds in the ruthenium vinylidene 4 or via a cyclization of 4 giving a nonclassical ion intermediate followed by a 1,2-alkyl shift.

The polar wind: Recent observations

The polar wind is an ambipolar outflow of thermal plasma from the high-latitude ionosphere to the magnetosphere, and it primarily consists of H +, He + and O + ions and electrons. Statistical and episodic studies based primarily on ion composition observations on the ISIS-2, DE-1, Akebono and Polar satellites over the past four decades have confirmed the existence of the polar wind. These observations spanned the altitude range from 1000 to ∼50,500 km, and revealed several important features in the polar wind that are unexpected from “classical” polar wind theories. These include the day–night asymmetry in polar wind velocity, which is 1.5–2.0 times larger on the dayside; appreciable O + flow at high altitudes, where the velocity at 5000–10,000 km is of 1–4 km/s; and significant electron temperature anisotropy in the sunlit polar wind, in which the upward-to-downward electron temperature ratio is 1.5–2. These features are attributable to a number of “non-classical” polar wind ion acceleration mechanisms resulting from strong ionospheric convection, enhanced electron and ion temperatures, and escaping atmospheric photoelectrons. The observed polar wind has an averaged ion temperature of ∼0.2–0.3 eV, and a rate of ion velocity increase with altitude that correlates strongly with electron temperature and is greatest at low altitudes (<4000 km for H +). The rate of velocity increase below 4000 km is larger at solar minimum than at solar maximum. Above 4000 km, the reverse is the case. This suggests that the dominant polar wind ion acceleration process may be different at low and high altitudes, respectively. At a given altitude, the polar wind velocity is highly variable, and is on average largest for H + and smallest for O +. Near solar maximum, H +, He +, and O + ions typically reach a velocity of 1 km/s near 2000, 3000, and 6000 km, respectively, and velocities of 12, 7, and 4 km/s, respectively, at 10,000 km altitude. Near solar minimum, the velocity of all three species is smaller at high altitudes. Observationally it is not always possible to unambiguously separate an energized “non-polar-wind” ion such as a low-energy “cleft ion fountain” ion that has convected into a polar wind flux tube from an energized “polar-wind” ion that is accelerated locally by “non-classical” polar-wind ion acceleration mechanisms. Significant questions remain on the relative contribution between the cleft ion fountain, auroral bulk upflow, and the topside polar-cap ionosphere to the O + polar wind population at high altitudes, the effect of positive spacecraft charging on the lowest-energy component of the H + polar wind population, and the relative importance of the various classical and non-classical ion acceleration mechanisms. These questions pose several challenges in future polar wind observations: These include measurement of the lowest-energy component in the presence of positive spacecraft potential, definitive determination and if possible active control of the spacecraft potential, definitive discrimination between polar wind and other inter-mixed thermal ion populations, measurement of the three-dimensional ion drift velocity vector and the parallel and perpendicular ion temperatures or the detailed three-dimensional velocity distribution function, and resolution of He + and other minor ion species in the polar wind population.

Specific and non-specific influence of the environment on dihydrogen bonding and proton transfer to [RuH 2{P(CH 2CH 2PPh 2) 3}

The proton transfer from substituted phenols (ArOH = p-nitrophenol, p-nitophenyl-aza-phenol) to the ruthenium dihydride complex [(PP 3)RuH 2], where PP 3 = P(CH 2CH 2PPh 2) 3, was studied by variable temperature UV–visible spectroscopy in dichloromethane, THF, THF/CH 3OH and THF/CH 3CN mixtures, showing a significant influence of the polarity and/or the proton donating/proton accepting properties of the solvent on the position of the proton transfer equilibrium. The formation of ion pairs stabilized by hydrogen bonding between the non-classical cation [(PP 3)RuH(η 2-H 2)] + and the homoconjugated anion [ArOHOAr] − was determined in low-polar media. The increase of the media polarity has been proved to favor the proton transfer leading to the dissociation of hydrogen bonded ion pairs [{(PP 3) RuH(η 2-H 2)} +⋯{ArOHOAr} −]. Under comparable media polarity, the presence of a protic solvent in the mixture greatly favors the proton transfer due to the additional H-bonding with solutes. The structural, energetic and electronic features of the dihydrogen bonded adducts and of the proton transfer products were investigated by means of DFT/B3LYP calculations on the model dihydride [{P(CH 2CH 2PH 2) 3}RuH 2] using CH 3OH or CF 3OH as proton donors. The specific and non-specific influence of the media properties on the dihydrogen bonding and proton transfer was studied by introducing the second protic (proton donor or solvent) molecule in the model system or by CPCM calculations. The additional participation of external molecules, from either the solvent or the alcohol, strengthens remarkably the dihydrogen bonded adducts and eases the proton transfer process.