Regioselective Protonation Research Articles

Characterization and Engineering of Two Highly Paralogous Sesquiterpene Synthases Reveal a Regioselective Reprotonation Switch.

Sesquiterpene synthases (STPSs) catalyze carbocation-driven cyclization reactions that can generate structurally diverse hydrocarbons. The deprotonation-reprotonation process is widely used in STPSs to promote structural diversity, largely attributable to the distinct regio/stereoselective reprotonations. However, the molecular basis for reprotonation regioselectivity remains largely understudied. Herein, we analyzed two highly paralogous STPSs, Artabotrys hexapetalus (-)-cyperene synthase (AhCS) and ishwarane synthase (AhIS), which catalyze reactions that are distinct from the regioselective protonation of germacrene A (GA), resulting in distinct skeletons of 5/5/6 tricyclic (-)-cyperene and 6/6/5/3 tetracyclic ishwarane, respectively. Isotopic labeling experiments demonstrated that these protonations occur at C3 and C6 of GA in AhCS and AhIS, respectively. The cryo-electron microscopy-derived AhCS complex structure provided the structural basis for identifying different key active site residues that may govern their functional disparity. The structure-guided mutagenesis of these residues resulted in successful functional interconversion between AhCS and AhIS, thus targeting the three active site residues [L311-S419-C458]/[M311-V419-A458] that may act as a C3/C6 reprotonation switch for GA. These findings facilitate the rational design or directed evolution of STPSs with structurally diverse skeletons.

Characterization and Engineering of Two Highly Paralogous Sesquiterpene Synthases Reveal a Regioselective Reprotonation Switch

AbstractSesquiterpene synthases (STPSs) catalyze carbocation‐driven cyclization reactions that can generate structurally diverse hydrocarbons. The deprotonation‐reprotonation process is widely used in STPSs to promote structural diversity, largely attributable to the distinct regio/stereoselective reprotonations. However, the molecular basis for reprotonation regioselectivity remains largely understudied. Herein, we analyzed two highly paralogous STPSs, Artabotrys hexapetalus (−)‐cyperene synthase (AhCS) and ishwarane synthase (AhIS), which catalyze reactions that are distinct from the regioselective protonation of germacrene A (GA), resulting in distinct skeletons of 5/5/6 tricyclic (−)‐cyperene and 6/6/5/3 tetracyclic ishwarane, respectively. Isotopic labeling experiments demonstrated that these protonations occur at C3 and C6 of GA in AhCS and AhIS, respectively. The cryo‐electron microscopy‐derived AhCS complex structure provided the structural basis for identifying different key active site residues that may govern their functional disparity. The structure‐guided mutagenesis of these residues resulted in successful functional interconversion between AhCS and AhIS, thus targeting the three active site residues [L311‐S419‐C458]/[M311‐V419‐A458] that may act as a C3/C6 reprotonation switch for GA. These findings facilitate the rational design or directed evolution of STPSs with structurally diverse skeletons.

Linker Independent Regioselective Protonation Triggered Detoxification of Sulfur Mustards with Smart Porous Organic Photopolymer.

The development of efficient metal-free photocatalysts for the generation of reactive oxygen species (ROS) for sulfur mustard (HD) decontamination can play a vital role against the stockpiling of chemical warfare agents (CWAs). Herein, one novel concept is conceived by smartly choosing a specific ionic monomer and a donor tritopic aldehyde, which can trigger linker-independent regioselective protonation/deprotonation in the polymeric backbone. In this context, the newly developed vinylene-linked ionic polymers (TPA/TPD-Ionic) are further explored for visible-light-assisted detoxification of HD simulants. Time-resolved-photoluminescence (TRPL) study reveals the protonation effect in the polymeric backbone by significantly enhancing the life span of photoexcited electrons. In terms of catalytic performance, TPA-Ionic outperformed TPD-Ionic because of its enhanced excitons formation and charge carrier abilities caused by the donor-acceptor (D-A) backbone and protonation effects. Moreover, the formation of singlet oxygen (1 O2 ) species is confirmed via in-situ Electron Spin Resonance (ESR) spectroscopy and density functional theory (DFT) analysis, which explained the crucial role of solvents in the reaction medium to regulate the (1 O2 ) formation. This study creates a new avenue for developing novel porous photocatalysts and highlights the crucial roles of sacrificial electron donors and solvents in the reaction medium to establish the structure-activity relationship.

Construction of Substituted [4]Acene Frameworks Based on Double Cationic Cyclizations of Fluoroalkenes

AbstractIn this study, 5-substituted and 5,6-disubstituted [4]acenes were synthesized by the double cationic cyclization of fluoroalkenes. (a) After being treated with Me2AlCl (1.2 equiv), 2-trifluoromethyl-1-alkenes bearing two aryl groups underwent domino Friedel–Crafts-type cyclization (two-ring construction) followed by dehydrogenation to generate 5-fluorinated [4]acenes. The same (trifluoromethyl)alkenes were treated with both Me2AlCl (1.2 equiv) and Me3Al (1.0 equiv), resulting in selective one-ring construction and the creation of bicyclic 1,1-difluoro-1-alkenes. (b) When treated with triflic acid, the bicyclic difluoroalkenes underwent regioselective protonation to generate CF2 cations; Friedel–Crafts-type cyclization of these cations provided tetracyclic ketones. The obtained ketones act as an appropriate platform for the introduction of substituents at the 5-position of [4]acenes. (c) When treated with DDQ/H+, the bicyclic difluoroalkenes underwent oxidative generation of allylic CF2 cations; Friedel–Crafts-type cyclization of these cations produced tetracyclic enones. The enones were subjected to double addition of carbanions to facilitate the introduction of two substituents at the 5- and 6-positions of dihydro[4]acenes.

Brønsted Acid-Catalyzed Enantioselective Cycloisomerization of Arylalkynes.

The first example of an enantioselective carbocyclization of an alkyne-containing substrate catalyzed by chiral Brønsted acids was achieved. The use of the 2-hydroxynaphthyl substituent on the alkyne as a directing group constituted the key parameter enabling both efficient regioselective protonation of the carbon-carbon triple bond and chiral induction. The key cationic intermediate could be depicted either as a cationic vinylidene ortho-quinone methide or a stabilized vinyl cation. Atropoisomeric phenanthrenes derivatives were produced in high yields and good enantioselectivities under mild, metal-free reaction conditions in the presence of chiral N-triflylphosphoramide catalysts. The carbenic nature of the cationic intermediate was also exploited to describe an example of alkyne/alkane cycloisomerization.

1,4-Hydroboration Reactions of Electron-Poor Aromatic Rings by N-Heterocyclic Carbene Boranes.

Reactions of N-heterocyclic carbene boranes (NHC-boranes) with electron-poor aromatic rings under photoredox conditions provide dearomatized 3-NHC-boryl-1,5-cycohexadienes, which are formally products of 1,4-hydroboration reactions. When regioisomers are possible, the more crowded (doubly ortho-substituted) product is formed preferably or exclusively. The mechanism may involve oxidation of the NHC-borane to an NHC-boryl radical, reduction of the electron-poor aromatic ring to a radical anion, coupling of the radical and the radical anion to give a cyclohexadienyl anion, and finally regioselective protonation.

Catalytic Regio- and Enantioselective Proton Migration from Skipped Enynes to Allenes

Summary Chiral allenes are highly valuable as versatile synthetic intermediates and core skeletons of various functional organic molecules. Despite marked recent advances, the straightforward catalytic enantioselective synthesis of hydrocarbon allenes from readily available starting materials without relying on polar functional groups is still very challenging. Here, we report a copper(I)-catalyzed enantioselective proton migration from skipped enynes to allenes as an efficient approach in chiral allene synthesis. With catalyst loading as low as 0.5 mol %, the reaction proceeds smoothly under mild conditions without the need for additional stoichiometric reagents or generation of waste. Novel chiral ligand L6 plays a critical role in furnishing high catalyst activity, promoting regioselective protonation to produce allenes instead of conjugated enynes, and inducing axial chirality of allenes. The multiple roles of the chiral ligand are rationalized by density functional theory calculations.

Interrogating the steric outcome during H2 heterolysis: in-plane steric effects in the regioselective protonation of the PN3P-pincer ligand.

H2 heterolysis to generate well-defined nickel hydride-proton complexes was achieved by the 2nd generation PN3P-pincer nickel platform. The regioselective protonation in the ligand framework was demonstrated for the first time to highlight the importance of in-plane hindrance during the H2 splitting process.

Electron-impact ionization of benzoic acid, nicotinic acid and their n-butyl esters: An approach to regioselective proton affinities derived from ionization and appearance energy data

Electron-impact ionization mass spectra, the decay of metastable ions, ionization and appearance energies and bond energies, as dissociation energies, are reported for the title compounds. An ionization energy of 9.47 eV was obtained for benzoic acid, 9.43 eV for benzoic acid n-butyl ester, 9.61 eV for nicotinic acid and 9.97 eV for nicotinic acid n-butyl ester. Molecular ions of both butyl esters show two common main fragmentation pathways: the first process is a McLafferty rearrangement, characterized by the transfer of one H-atom from the aliphatic ester chain, which leads to the ions of either the organic acid or 1-butene. From their appearance energies and known thermodynamic data, gas-phase formation enthalpies ( Δ H f 0 ) of the parent n-butyl esters are calculated. Values of Δ H f 0 = ( − 4.29 ± 0.3 ) eV for benzoic acid n-butyl ester and Δ H f 0 = ( − 3.66 ± 0.3 ) eV for nicotinic acid n-butyl ester were obtained. The second process is characterized by the transfer of two H-atoms from the ester chain leading to a protonated form of the corresponding organic acids and C 4H 7 radicals. Good evidence is provided for the formation of methylallyl radicals. Appearance energies are used to calculate a proton affinity (PA) for benzoic acid. The obtained value of PA = (8.73 ± 0.3) eV, corresponding to a protonation of the carbonyl group, is in close corroboration with published data (PA = 8.51 eV). Activation energies for the intermediate H-transfers were found to be insignificant. This methodic gateway is applied to the system of nicotinic acid and its butyl ester. Adopting the formation of a methylallyl radical, the obtained proton affinity of nicotinic acid, PA = 8.58 eV, is very near to the published data of benzoic acid. An alternative fragmentation mechanism leading to a value of PA ≈ 9.5 eV (typical for a protonation of the pyridine-nitrogen) is very unlikely. It is concluded that this transfer of two H-atoms from the ester chain is controlled by a charge switching between the carboxylic oxygen atoms which leads to a regiospecific protonation site, in this case to the protonated carbonyl group. This is conform with a B3LYP DFT calculation with a corresponding proton affinity of PA = 8.29 eV.

Desymmetrization of Cyclohexa‐2,5‐dienes Through a Diastereoselective Protonation—Hydroamination Cascade.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Desymmetrization of Cyclohexa-2,5-dienes through a Diastereoselective Protonation−Hydroamination Cascade

[reaction: see text] Intramolecular hydroamination of cyclohexa-2,5-dienes led with high selectivity to the corresponding bicyclic allylic amines. This study demonstrates that the reaction does not proceed through a direct hydroamination of one of the diastereotopic olefins but more likely involves a diastereoselective protonation of a pentadienyl anion, followed by addition of a lithium amide across the double bond of the resulting 1,3-diene, and is concluded by a highly regioselective protonation of the final allylic anion.

Synthesis of Phosphorus Ylides Bearing a PH Bond from a Kinetically Stabilized 1,3,6‐Triphosphafulvene

In mixing 2,4,6-tris(2,4,6-tri-tert-butylphenyl)-1,3,6-triphosphafulvene with alkyllithium compounds and acetic acid, both of nucleophilic alkylation and electrophilic protonation occurred at the exo sp2-phosphorus atoms to afford [2,4-bis(2,4,6-tri-tert-butylphenyl)-1,3-diphosphacyclopentadienylidene](alkyl)(2,4,6-tri-tert-butylphenyl)phosphoranes which are phosphorus ylides that bear a P-H bond. A phosphorus ylide bearing both P-H and P-F bonds was obtained by reaction of 2,4,6-tris(2,4,6-tri-tert-butylphenyl)-1,3,6-triphosphafulvene with hydrogen tetrafluoroborate, and the structure was determined by X-ray crystallography. Both P=C double bond and P(+)-C(-) zwitterionic character was indicated by the metric parameters. The isolated phosphorus ylide bearing a P-H bond, [2,4-bis(2,4,6-tri-tert-butylphenyl)-1,3-diphosphacyclopentadienylidene](2,4,6-tri-tert-butylphenyl)phosphorane, showed no isomerization by H-migration to the corresponding phosphinodiphospholes, probably due to the pi-accepting ability of the unsaturated PC bonds and aromaticity of the C3P2 ring. The ylide structure and aromaticity of 2,4-diphosphacyclopenta-2,4-dienylidenephosphorane was characterized by theoretical calculations. In addition, the regioselective protonation of the lithiated phosphinodiphospholes generated from the 1,3,6-triphosphafulvene is discussed.

First regioselective protonation or selenization of a bis(bidentate) phosphine: synthesis and characterization of cis, trans, cis-1,3-bis(diphenylphosphonium)-PH,P ′H ′-2,4-bis(diphenylphosphino)cyclobutane-diiodide and cis, trans, cis-1,3-bis(diphenylphosphinoselenoyl)-2,4-bis(diphenylphosphino)cyclobutane

Cis, trans, cis-1,2,3,4-tetrakis(diphenylphosphino)cyclobutane (dppcb) can be regioselectively protonated via oxidation with I 2 and subsequent hydrolysis producing cis, trans, cis-1,3-bis(diphenylphosphonium)-PH,P ′H ′-2,4-bis(diphenylphosphino)cyclobutane-diiodide (dppcbH 2I 2). Furthermore, dppcb can be regioselectively oxidized by Se to the diselenide cis, trans, cis-1,3-bis(diphenylphosphinoselenoyl)-2,4-bis(diphenylphosphino)cyclobutane (dppcbSe 2). dppcbH 2I 2 is the first regioselectively protonated derivative of a bis(bidentate) phosphine. In the case of dppcbSe 2 the regioselective selenization of a bis(bidentate) phosphine is successful for the first time. Both dppcbH 2I 2 and dppcbSe 2 have been fully characterized by X-ray structure analyses, NMR spectroscopy ( 77 Se{ 1 H} , 31 P{ 1 H} , 1 H ), FAB mass spectrometry, IR spectroscopy, elemental analyses and melting points. The use of dppcbH 2I 2 as a precursor for the production of a heterodifunctional ligand containing phosphine and phosphinoyl moieties is discussed in view of its X-ray structure. Versatile heterodifunctional ligands like dppcbSe 2 are interesting due to their possible catalytic applications.

ChemInform Abstract: Regioselective Proton Abstraction and 1,3‐Migration of a Phosphorus Group in 1,3‐Dienes by Iron Coordination: A New Method for the Synthesis of α‐Phosphono‐α,β‐unsaturated Ketones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Regioselective Proton Abstraction and 1,3-Migration of a Phosphorus Group in 1,3-Dienes by Iron Coordination: A New Method for the Synthesis of α-Phosphono-α,β-unsaturated Ketones

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTRegioselective Proton Abstraction and 1,3-Migration of a Phosphorus Group in 1,3-Dienes by Iron Coordination: A New Method for the Synthesis of α-Phosphono-α,β-unsaturated KetonesTatsuo Okauchi, Takao Teshima, Keishi Hayashi, Nobuo Suetsugu, and Toru MinamiView Author Information Department of Applied Chemistry Kyushu Institute of Technology Sensui-cho, Tobata, Kitakyushu 804-8550, Japan Cite this: J. Am. Chem. Soc. 2001, 123, 48, 12117–12118Publication Date (Web):November 8, 2001Publication History Received29 August 2001Revised23 October 2001Published online8 November 2001Published inissue 1 December 2001https://doi.org/10.1021/ja016958rCopyright © 2001 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views467Altmetric-Citations23LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (44 KB) Get e-AlertsSupporting Info (2)»Supporting Information Supporting Information SUBJECTS:Genetics,Iron,Ketones,Phosphates,Phosphorus Get e-Alerts

Recent Studies on the Regioselective C-Protonation of Enol Derivatives using Carbonyl-Containing Proton Donors

Enolate protonation can occur by two different pathways. With strong acids regioselective protonation generally occurs on the oxygen of the enolate to give an enol and then acid catalysed tautomerisation leads directly to the thermody-namically preferred carbonyl motif. However, with much weaker acids kinetic protonation on carbon can occur to give directly the carbonyl derivative. This review discuss recent developments into the use of chelating acids to promote this stereochemically important C-protonation and we comment on factors that appear to promote this selectivity.

Direct evidence of a magnetization transfer between laser-polarized xenon and protons of a cage-molecule in water

In a dedicated experimental setup, we directly prepare liquid-state NMR samples containing laser-polarized xenon with nuclear polarization larger than 5% at pressures up to 4 bars. Coating of the NMR tube surface allows us to increase the self-relaxation time of xenon in the gaseous phase to approximately 4.5 hours. Using a modified SPINOE pulse sequence, we present the first direct detection of a regioselective proton signal enhancement of a molecule \(\)-cyclodextrin) dissolved in water resulting from cross-polarization between laser-polarized xenon and protons.

Anionic rearrangement of deprotonated cyproconazole pesticide in the gas phase

Analysis of the deprotonated cyproconazole pesticide prepared in the gas phase shows that under NICI (negative ion chemical ionization) NH 3 and/or ND 3 chemical ionization conditions, these species are produced by a regioselective proton abstraction pathway. This deprotonation orientation is evidenced from the low energy collision dissociations of [M − H] − which gives diagnostic product ions that are characteristic of the location of the negative charge. The relative abundance of fragment ions has been investigated using the energy resolved mass spectrometry breakdown. It is demonstrated that these activated dissociations are due to various competitive pathways. Furthermore, the molecular anion isomerization into an ion–dipole complex (by means of a charge-promoted cleavage) takes place prior to direct fragmentations. This isomerization process reflects the close acidity of the neutral partner and competes with other more conventional pathways. The evolution of the relative abundance of both the complementary ions arise from the ion–dipole complex and displayed a complementary dependence trend in the recorded collision-induced dissociation spectra independently of other daughter ions. This shows a competitive formation of the complex ion–dipole versus other described fragmentation pathways. The use of high resolution measurements as well as the ND 3 gas phase labeling allowed us to evidence the proposed decomposition mechanisms.

Regioselective protonation of ferrocene in superacid and formation of a C—H—Fe bond. An experimental and theoretical study of the structure and dynamics of the ferrocenonium ion

Protonation of ferrocene has been suggested to take place on carbon (exo-protonation) or iron (endo-protonation). However, experiments have not been conclusive because of interfering exchange reactions. Now low-temperature protonation of ferrocene and [2H10]-ferrocene in superacid and direct observation of the carbocation by 1H NMR at low temperature shows only primary protonation and that it exclusively takes place in an endo-fashion. Studies by DFT calculations using B3LYP hybrid functional indicate the presence of an intramolecular nonlinear C—H—Fe bond and that the proton might be delocalized between carbon and iron. Potential energy barriers for degenerate rearrangements of the hydride bridged carbocation are low, suggesting that the proton might be delocalized between all 10 carbons and iron. The NMR results are consistent with such an interpretation.Key words: regioselective, protonation, superacid, ferrocenonium ion.

Regioselective protonation of ferrocene in superacid and formation of a C—H—Fe bond. An experimental and theoretical study of the structure and dynamics of the ferrocenonium ion

Regioselective protonation of ferrocene in superacid and formation of a C—H—Fe bond. An experimental and theoretical study of the structure and dynamics of the ferrocenonium ion