Selective Protonation Research Articles

Development of Donor-acceptor-type Molecules and Their Application as Analytical Reagents

π-Extended donor-acceptor (D-A)-type molecules, which bear both electron-donor and electron-acceptor substituents on the backbone, exhibit unique optical properties, such as bathochromic shifts in absorption and emission, large Stokes shifts, solvatochromic behavior, and fluorescence quenching in polar solvents. These unique properties are attributed to intramolecular charge transfer (ICT) or twisted intramolecular charge transfer (TICT) in the ground and excited states. This review article introduces three types of D-A-type molecules that are used as detection reagents for (1) methanol, (2) amino acids during solid-phase peptide synthesis (SPPS), and (3) amines present in the biological environment. For methanol detection, D-A-type fluorophores with basic guanidine moieties were developed to differentiate between methanol (MeOH) and ethanol (EtOH) based on the small difference in their pKa values (ΔpKa=0.4). Selective protonation of the guanidine moiety in methanol disrupts the D-A structure, allowing emission in the resultant polar environment. Similarly, an acid-base reaction between the hydrogen chloride (HCl) salts of the D-A-type molecules and amines is applied to detect amines during SPPS. In this method, a colorless solution of an HCl salt of the D-A-type molecule is deprotonated by amines, forming a yellow solution. This is the first reported quantitative and non-destructive colorimetric method for detecting amines. Finally, a turn-on-type amine-labeling reagent was developed for the nucleophilic aromatic substitution (SNAr) reaction. This new reagent enables protein staining of living cells with a large Stokes shift and without solvent-polarity-dependent fluorescence quenching.

Divergent Aromatization of α-Halobenzyl γ-Butenolides Initiated by Selective Enol Protonation to Benzo[c]fluorenones and Naphthalenes.

An unprecedented divergent aromatization reaction of α-halobenzyl γ-butenolides has been described for the selective and concise synthesis of highly substituted benzo and higher π-extended fluorenones, and 1,3-disubstituted naphthalenes depending on the migration ability of the quaternary α-substituent. This aromatization switch from Ag+-mediated planarization to ylidenebutenolides likely originates from selective protonation on the enolic double bond rather than the benzyl halides by TfOH.

Selective Photoreduction of CO2 to CH4 Triggered by Metal-Vacancy Pair Sites.

Selectively achieving the photoreduction of carbon dioxide (CO2) to methane (CH4) remains a significant challenge, which primarily arises from the complexity of the protonation process. In this work, we designed metal-vacancy pair sites in defective metal oxide semiconductors, which anchor the reactive intermediates with a bridged linkage for the selective protonation to produce CH4. As an example, oxygen-deficient Nb2O5 nanosheets are synthesized, in which the niobium-oxygen vacancy pair sites are demonstrated by X-ray photoelectron spectroscopy and electron paramagnetic resonance spectra. In situ Fourier transform infrared spectroscopy monitors the *CH3O intermediate, a key intermediate for CH4 production, during the CO2 photoreduction in oxygen-deficient Nb2O5 nanosheets. Importantly, the built metal-vacancy pair sites regulate the *CH3O formation step as a spontaneous process, making the reduction of CO2 to CH4 the preferred method. Therefore, the oxygen-deficient Nb2O5 nanosheets exhibit a CH4 formation rate of 19.14 μmol g-1 h-1, with an electron selectivity of ∼94.1%.

Visible-Light-Photoexcited Palladium-Catalyzed Silylmethylation of Benzyl Alcohol Derivatives

AbstractAn intramolecular C–H silylmethylation of benzylic alcohol derivatives catalyzed by a visible-light-photoexcited palladium complex was developed. Irradiation of the palladium complex with blue LEDs resulted in efficient activation of a C–I bond, and subsequent intramolecular radical arylation afforded siloxacycle products. Selective protonation or oxidation of the C–Si bond of the cyclized materials afforded ortho-methylated and ortho-hydroxymethylated derivatives of the benzylic alcohol derivatives.

N‐(Morpholine‐4‐dithio)phthalimide: A Shelf‐Stable, Bilateral Platform Molecule Enabling Access to Diverse Unsymmetrical Disulfides**

AbstractSynthetic methods for unsymmetrical disulfides are greatly needed owing to their applications in drug discovery, linker chemistry, and materials sciences. In this study, a new shelf‐stable and easy‐to‐prepare bilateral disulfurating platform molecule, N‐(morpholine‐4‐dithio)phthalimide, has been developed for the divergent synthesis of unsymmetrical disulfides. The amino and imide leaving groups of this reagent can be orthogonally transformed. Under acidic conditions, the amino moiety undergoes selective protonation and thus can be displaced by various carbon nucleophiles, such as allyl trimethylsilanes, alkynyl silanes, and electron‐rich arenes, leaving the phthalimide moiety untouched. Meanwhile, the phthalimide leaving group is amenable to substitution under basic or neutral conditions. The combination of these transformations provides rapid access to diverse unsymmetrical disulfides through two C−S bond‐forming reactions.

N-(Morpholine-4-dithio)phthalimide: A Shelf-Stable, Bilateral Platform Molecule Enabling Access to Diverse Unsymmetrical Disulfides.

Synthetic methods for unsymmetrical disulfides are greatly needed owing to their applications in drug discovery, linker chemistry, and materials sciences. In this study, a new shelf-stable and easy-to-prepare bilateral disulfurating platform molecule, N-(morpholine-4-dithio)phthalimide, has been developed for the divergent synthesis of unsymmetrical disulfides. The amino and imide leaving groups of this reagent can be orthogonally transformed. Under acidic conditions, the amino moiety undergoes selective protonation and thus can be displaced by various carbon nucleophiles, such as allyl trimethylsilanes, alkynyl silanes, and electron-rich arenes, leaving the phthalimide moiety untouched. Meanwhile, the phthalimide leaving group is amenable to substitution under basic or neutral conditions. The combination of these transformations provides rapid access to diverse unsymmetrical disulfides through two C-S bond-forming reactions.

Basic Fluorescent Protonation-Type pH Probe Sensitive to Small ΔpKa of Methanol and Ethanol

An optical pH probe is a simple and effective tool for determining an accurate pH value in its localized area. However, basic pH probes with pKBH+ values above 8 have rarely been reported, although many components with high pKa such as arginine play important roles in vivo. Herein, we introduce novel colorimetric and fluorescent basic probes 1-5, which are designed using push-pull-type aminoquinoline and aminobenzoquinoline fluorophores, with pKBH+ values ranging from 8.4 to 9.9. After the basicity of the remarkably sensitive basic probe 4 was tuned, it was able to successfully distinguish between the pKa values of MeOH (15.5) and EtOH (15.9), thus displaying selective protonation and fluorescence enhancement in MeOH over EtOH. Our pH probes can be used to detect MeOH poisoning in commercial EtOH products such as hand sanitizers, providing an effective solution to this problem observed during the COVID-19 pandemic.

From BN-Naphthalenes to Benzoborole Dianions.

The synthesis of benzoborole dianions by alkali metal reduction of BN-naphthalene derivatives via a ring-contraction strategy has been developed. Reduction of 1-alkynyl 2,1-benzazaborine 1 a in Et2 O led to the elimination of alkynyllithium with the formation of 1-amino-1-benzoborole trilithium salt 2 a, whereas reduction of 1-phenyl 2,1-benzazaborine 1 c in THF yielded 1-phenyl-1-benzoborole dilithium salt 2 c with the elimination of ArNHLi. The trilithium and dilithium salts 2 a and 2 c have been fully characterized. Treatment of trilithium salt 2 a with Et3 NHCl led to the selective protonation of the amino lithium to afford the dilithium salt 2 aH, which could be cleanly oxidized to 1-amino-1-benzoborole 3 in an excellent yield. Reaction of 1-phenyl-1-benzoborole dilithium salt 2 c with MeI yielded the lithium borate 4 c, which is luminescent both in solution and in the solid state.

Reduced Arene Complexes of Hafnium Supported by a Triamidoamine Ligand.

A series of hafnium complexes with a reduced arene of the general formula [K(L)][Hf(Xy‐N3N)(arene)] (Xy‐N3N={(3,5‐Me2C6H3)NCH2CH2}3N3−, L=THF, 18‐crown‐6; arene=C10H8 2−, C14H10 2−) mimic the chemistry of hafnium in its formal oxidation state +II. All compounds were obtained upon reduction of the chlorido complex [HfCl(Xy‐N3N)(thf)] with two equivalents of potassium naphthalenide or anthracenide. The reducing nature and the basicity of the reduced anthracene ligand were explored in the reaction of benzonitrile and azobenzene, and by deprotonation of tert‐butylacetylene, respectively. The reduction of benzonitrile provides an initial double nitrile insertion product under kinetic control that rearranges after extrusion of one of the inserted nitriles to a hafnium imido complex as the thermodynamic product. The reduction of azobenzene resulted in a diphenylhydrazido(2−) complex. Treatment of terminal alkynes with the anthracene or diphenylhydrazido(2−) complex led to the selective protonation of the corresponding dianionic ligand.

Probing the reactive center for site selective protonation in carbonyl sulphide in terms of conceptual density functional based site selectivity descriptors

Probing the reactive center for site selective protonation in carbonyl sulphide in terms of conceptual density functional based site selectivity descriptors

Pharmacophore-Directed Retrosynthesis Applied to Ophiobolin A: Simplified Bicyclic Derivatives Displaying Anticancer Activity.

Pharmacophore-directed retrosynthesis applied to ophiobolin A led to bicyclic derivatives that were synthesized and display anticancer activity. Key features of the ultimate defensive synthetic strategy include a Michael addition/facially selective protonation sequence to set the critical C6 stereocenter and a ring-closing metathesis to form the cyclooctene. Cytotoxicity assays toward a breast cancer cell line (MDA-MB-231) confirm the anticipated importance of structural complexity for selectivity (vs MCF10A cells) while C3 variations modulate stability.

Brønsted Acid Catalyzed Friedel–Crafts‐Type Coupling and Dedinitrogenation Reactions of Vinyldiazo Compounds

AbstractThe direct Friedel–Crafts‐type coupling and dedinitrogenation reactions of vinyldiazo compounds with aromatic compounds using a metal‐free strategy are described. This Brønsted acid catalyzed method is efficient for the formation of α‐diazo β‐carbocations (vinyldiazonium ions), vinyl carbocations, and allylic or homoallylic carbocation species via vinyldiazo compounds. By choosing suitable nucleophilic reagents to selectively capture these intermediates, both trisubstituted α,β‐unsaturated esters, β‐indole‐substituted diazo esters, and dienes are obtained with good to high yields and selectivity. Experimental insights implicate a reaction mechanism involving the selective protonation of vinyldiazo compounds and the subsequent release of dinitrogen to form vinyl cations that undergo intramolecular 1,3‐ and 1,4‐ hydride transfer processes as well as fragmentation.

Relayed Proton Brake in N-Pyridyl-2-iso-propylaniline Derivative: Two Brakes with One Proton.

The addition of methanesulfonic acid to N-(2,6-dimethylpyridin-4-yl)-N-methyl-2-iso-propylaniline led to the selective protonation of the pyridine nitrogen atom, resulting in a significant deceleration of the rotation rates around both N-pyridyl and N-(i-Pr)phenyl bonds through a relayed brake mechanism.

Characterization of volatile metabolites formed by molds on barley by mass and ion mobility spectrometry.

The contamination of barley by molds on the field or in storage leads to the spoilage of grain and the production of mycotoxins, which causes major economic losses in malting facilities and breweries. Therefore, on-site detection of hidden fungus contaminations in grain storages based on the detection of volatile marker compounds is of high interest. In this work, the volatile metabolites of 10 different fungus species are identified by gas chromatography (GC) combined with two complementary mass spectrometric methods, namely, electron impact (EI) and chemical ionization at atmospheric pressure (APCI)-mass spectrometry (MS). The APCI source utilizes soft X-radiation, which enables the selective protonation of the volatile metabolites largely without side reactions. Nearly 80 volatile or semivolatile compounds from different substance classes, namely, alcohols, aldehydes, ketones, carboxylic acids, esters, substituted aromatic compounds, alkenes, terpenes, oxidized terpenes, sesquiterpenes, and oxidized sesquiterpenes, could be identified. The profiles of volatile and semivolatile metabolites of the different fungus species are characteristic of them and allow their safe differentiation. The application of the same GC parameters and APCI source allows a simple method transfer from MS to ion mobility spectrometry (IMS), which permits on-site analyses of grain stores. Characterization of IMS yields limits of detection very similar to those of APCI-MS. Accordingly, more than 90% of the volatile metabolites found by APCI-MS were also detected in IMS. In addition to different fungus genera, different species of one fungus genus could also be differentiated by GC-IMS.

Stereochemical Features of the Crystallization of Eight-Membered 1,5-Diazaheterocycles with Chiral Aminoindanole Fragments at Nitrogen Atoms

The work juxtaposes crystal structures of two hydrochlorides of eight-membered 1,5-diazaheterocycles with chiral aminoindanole fragments located at the nitrogen atoms and having similar configurations. In spite of chemical and stereochemical identity of a half of diazaheterocycle molecules, in crystals these compound are realized in the general position rather than the special position on the twofold axis of rotation. The following reasons are considered to be responsible for the asymmetrization of the molecules in the crystal: conformation of the eight-membered heterocycle, selective protonation of only one of two nitrogen atoms, positions of the counter-ion and the solvent molecule within the unit cell, and a nonequivalent system of hydrogen bonds.

A Modular and Diastereoselective 5 + 1 Cyclization Approach to N-(Hetero)Aryl Piperidines.

A new general de novo synthesis of pharmaceutically important N-(hetero)aryl piperidines is reported. This protocol uses a robustly diastereoselective reductive amination/aza-Michael reaction sequence to achieve rapid construction of complex polysubstituted ring systems starting from widely available heterocyclic amine nucleophiles and carbonyl electrophiles. Notably, the diastereoselectivity of this process is enhanced by the presence of water, and DFT calculations support a stereochemical model involving a facially selective protonation of a water-coordinated enol intermediate.

Selective isotope labeling for NMR structure determination of proteins in complex with unlabeled ligands

The physiological role of proteins is frequently linked to interactions with non-protein ligands or posttranslational modifications. Structural characterization of these complexes or modified proteins by NMR may be difficult as the ligands are usually not available in an isotope-labeled form and NMR spectra may suffer from signal overlap. Here, we present an optimized approach that uses specific NMR isotope-labeling schemes for overcoming both hurdles. This approach enabled the high-resolution structure determination of the farnesylated C-terminal domain of the peroxisomal protein PEX19. The approach combines specific 13C, 15N and 2H isotope labeling with tailored NMR experiments to (i) unambiguously identify the NMR frequencies and the stereochemistry of the unlabeled 15-carbon isoprenoid, (ii) resolve the NMR signals of protein methyl groups that contact the farnesyl moiety and (iii) enable the unambiguous assignment of a large number of protein-farnesyl NOEs. Protein deuteration was combined with selective isotope-labeling and protonation of amino acids and methyl groups to resolve ambiguities for key residues that contact the farnesyl group. Sidechain-labeling of leucines, isoleucines, methionines, and phenylalanines, reduced spectral overlap, facilitated assignments and yielded high quality NOE correlations to the unlabeled farnesyl. This approach was crucial to enable the first NMR structure of a farnesylated protein. The approach is readily applicable for NMR structural analysis of a wide range of protein–ligand complexes, where isotope-labeling of ligands is not well feasible.

Differential Protonation at the Catalytic Six-Iron Cofactor of [FeFe]-Hydrogenases Revealed by 57Fe Nuclear Resonance X-ray Scattering and Quantum Mechanics/Molecular Mechanics Analyses.

[FeFe]-hydrogenases are efficient biological hydrogen conversion catalysts and blueprints for technological fuel production. The relations between substrate interactions and electron/proton transfer events at their unique six-iron cofactor (H-cluster) need to be elucidated. The H-cluster comprises a four-iron cluster, [4Fe4S], linked to a diiron complex, [FeFe]. We combined 57Fe-specific X-ray nuclear resonance scattering experiments (NFS, nuclear forward scattering; NRVS, nuclear resonance vibrational spectroscopy) with quantum-mechanics/molecular-mechanics computations to study the [FeFe]-hydrogenase HYDA1 from a green alga. Selective 57Fe labeling at only [4Fe4S] or [FeFe], or at both subcomplexes was achieved by protein expression with a 57Fe salt and in vitro maturation with a synthetic diiron site precursor containing 57Fe. H-cluster states were populated under infrared spectroscopy control. NRVS spectral analyses facilitated assignment of the vibrational modes of the cofactor species. This approach revealed the H-cluster structure of the oxidized state (Hox) with a bridging carbon monoxide at [FeFe] and ligand rearrangement in the CO-inhibited state (Hox-CO). Protonation at a cysteine ligand of [4Fe4S] in the oxidized state occurring at low pH (HoxH) was indicated, in contrast to bridging hydride binding at [FeFe] in a one-electron reduced state (Hred). These findings are direct evidence for differential protonation either at the four-iron or diiron subcomplex of the H-cluster. NFS time-traces provided Mössbauer parameters such as the quadrupole splitting energy, which differ among cofactor states, thereby supporting selective protonation at either subcomplex. In combination with data for reduced states showing similar [4Fe4S] protonation as HoxH without (Hred') or with (Hhyd) a terminal hydride at [FeFe], our results imply that coordination geometry dynamics at the diiron site and proton-coupled electron transfer to either the four-iron or the diiron subcomplex discriminate catalytic and regulatory functions of [FeFe]-hydrogenases. We support a reaction cycle avoiding diiron site geometry changes during rapid H2 turnover.

Selective Protonation of Unbounded Sodium Cholates for Reversible Blue-Shift Absorption Spectra of Single-Chirality Single-Walled Carbon Nanotube in Solution

In contradiction to the long-standing optical depletion of single-walled carbon nanotubes (SWCNT) by acid doping, this work reports the blue-shifted and optical density-increased S11 (the first Van Hove singularity transition) peak absorption spectra of single-chirality (6,5) SWCNT dispersed in specific surfactant compositions such as 1% SDS (sodium dodecyl sulfate) /1% SC (sodium cholate) and 2% SDS/0.5% SC, which were caused by addition of acid. These anomalous optical changes can be reversed by adding base, and they are discussed on the basis of surfactant arrangements on SWCNT sidewalls, which arose from the selective protonation of unbounded SC to shift the thermodynamic equilibrium of SC adsorbed SWCNT to the desorption of SC from SWCNT surface. The spectroscopic interpretation obeys the dipole moment transition related energy level variation and oscillator strength change.

Selective protonation and stereoelectronic effects govern catalysis in a pyridoxal-5′-phosphate-dependent enzyme

Selective protonation and stereoelectronic effects govern catalysis in a pyridoxal-5′-phosphate-dependent enzyme