Knoevenagel condensation of 4,5- and 1,8-diazafluorenes

• Darya S. Cheshkina,
• Christina S. Becker,
• Alina A. Sonina and
• Maxim S. Kazantsev

Beilstein J. Org. Chem. 2026, 22, 803–812, doi:10.3762/bjoc.22.62

• with ketones resulted in unique di(pyridin-2-yl)methylene)-9H-diazafluorenes being electron-deficient ligands and functional materials. Keywords: acidic conditions; diazafluorene; diazafluorenylidene; Knoevenagel condensation; protonation; Introduction Diazafluorenylidene derivatives were reported to

• react at all – only starting compounds were quantitatively evaluated from all reactions (Scheme 2, Table 1). To rationalize this observation, we hypothesized that the protonation of nitrogens leads to electrostatic repulsion between the protonated diazafluorene and the iminium cation (vide infra

• mesomeric effect. On the other hand, diazafluorenes are potentially capable of reversible protonation by acetic acid, which is a competing process decreasing the equilibrium concentration of the enamine form (Scheme 2). Furthermore, an electrostatic repulsion between the protonated diazafluorene (1A/1A’ or

Halogenated azobenzene acrylates: from efficient solution photoswitching to stable solid-state photochromic materials

• Martina Vachtlová,
• Michaela Fecková,
• Vítězslav Zima,
• Jan Podlesný,
• Milan Klikar,
• Oldřich Pytela,
• Patrik Pařík,
• Jakub Opršal,
• Eliška Juhaňáková,
• Veronika Chrtová and
• Filip Bureš

Beilstein J. Org. Chem. 2026, 22, 782–794, doi:10.3762/bjoc.22.60

• fluorescence intensity linearly dependent on the temperature [19][20]. Priimagi et al. reported thermal sensors based on the simple azobenzenes B1–3 by exploiting the dependence of the protonation rate on the temperature, which is accompanied by a color change [21]. Four different azobenzenes C1–4 were used as

Synthesis of heterocycles based on azomethine ylides from α-amino acids (or amines) and carbonyl compounds

• Ekaterina V. Berezhnaya,
• Alexander I. Ponyaev,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2026, 22, 705–741, doi:10.3762/bjoc.22.55

• by the formation of N,N-complex I. Water then promotes the desilylation step, leading to metallodipole II, which undergoes cycloaddition with a dipolarophile to form metalated adduct III. Final protonation leads to free pyrrolidine (Scheme 34). In [3], Mendoza and colleagues developed a universal

Harnessing light energy with molecules

• Grace G. D. Han,
• Mogens Brøndsted Nielsen and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2026, 22, 680–682, doi:10.3762/bjoc.22.52

• junction at ambient conditions and hence be used as an 8-bit operation unit. Molecular photoswitches are also interesting for temperature sensing applications. Thus, in their publication, Priimagi and co-workers [14] show a strong temperature-dependence of azobenzene protonation in 1,2-dichloroethane

Experimental and DFT studies on the regioselective methanolysis of 5-azido-9-oxabicyclo[6.1.0]nonan-4-yl 4-nitrobenzoate isomers

• İlknur Polat,
• Selçuk Eşsiz and
• Emine Salamci

Beilstein J. Org. Chem. 2026, 22, 547–556, doi:10.3762/bjoc.22.40

• each elementary reaction step along these routes were computed. The acid-mediated ring-opening reaction in the isomeric epoxides 9, initiated by protonation, can follow two possible pathways – either along the intermediate 12 or along the intermediate 15. There is a possibility of two products being

Ring contraction and ring expansion reactions in terpenoid biosynthesis and their application to total synthesis

• Nicolas Kratena,
• Nicolas Heinzig and
• Peter Gärtner

Beilstein J. Org. Chem. 2026, 22, 289–343, doi:10.3762/bjoc.22.21

• the activation of the diphosphate group and ionisation) [25][37] and Class II (ionisation by olefin or epoxide protonation via a carboxylic acid in the active site) [26][38][39] and their reactions thus are mediated by carbocations and olefins, through careful preorganisation of the linear substrate

• →5 ring contraction can be found in the family of spirocyclic C15-sesquiterpenes, such as β-vetivone B (11, see Scheme 2B) [57][58][59][60]. The linear precursor farnesyl pyrophosphate (9) is first cyclised by germacrene A synthase (GAS) to its name-bearing product 10. From here, protonation by

• is initiated via protonation of geranylgeranyl pyrophosphate (GGPP, 12) at the terminal olefin with CpPS (= Clitopilus passeckeranis pleuromutilin synthase), forming the decalin system 12a. A cascade of 1,2-shifts delivers the carbocation 12b which undergoes ring contraction and elimination to give

Arene activation via π-bond localization: concepts and opportunities

• Paul Meiners,
• Julian J. Melder and
• Tobias Morack

Beilstein J. Org. Chem. 2026, 22, 257–273, doi:10.3762/bjoc.22.19

• during subsequent electrophilic addition. Although the trifluorotoluene complex exists as a mixture of its two coordination diastereomers, the pronounced electronic asymmetry of the molybdenum fragment channels protonation to a single η2-arenium intermediate. This enables nucleophilic addition of a

• sulfone complex of W(0) (Scheme 3A) [60]. As established previously [61], protonation of η2-arene ligands bearing electron-withdrawing substituents generates reactive arenium intermediates that react with nucleophiles to furnish disubstituted η2-cyclohexadiene complexes. A second protonation/nucleophilic

• protonated by mild acids to form thermally robust arenium complexes (Figure 11B). This remarkable basicity underscores the exceptional electron-donating power of the {Cr(CO)3}2− and {Mn(CO)3}− units, which stabilize dearomatized, cationic intermediates without auxiliary tethers. Beyond protonation and

Base-promoted deacylation of 2-acetyl-2,5-dihydrothiophenes and their oxygen-mediated hydroxylation

• Vladimir G. Ilkin,
• Margarita Likhacheva,
• Igor V. Trushkov,
• Tetyana V. Beryozkina,
• Vera S. Berseneva,
• Vladimir T. Abaev,
• Wim Dehaen and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2026, 22, 192–204, doi:10.3762/bjoc.22.13

• led to the intermediate A. Elimination of ethyl/methyl acetate from intermediate A afforded anion B. The latter reacted in ethanolic solution with molecular oxygen [52] with the formation of peroxide anion C. The protonation of anion C with proton sources (residual water or/and solvent or 3a can serve

Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• sequential electron transfer and protonation, enabling regioselective partial dearomatization that is difficult to achieve under hydrogenation conditions. Likewise, hydride reagents – including NaBH3CN, DIBAL-H, and other aluminum or borohydride derivatives – have been widely employed for the selective

• protonation during reduction or an isomerization event. Kinetic translocation of the double bond to the correct position enabled an intramolecular Heck reaction, a transformation originally developed by Fukuyama (Scheme 12) [78]. Hydrogenation of (−)-tabersonine to (−)-decahydrotabersonine by Catherine

Synthesis and applications of alkenyl chlorides (vinyl chlorides): a review

• Daniel S. Müller

Beilstein J. Org. Chem. 2026, 22, 1–63, doi:10.3762/bjoc.22.1

• , Scheme 24) towards further protonation – often proceeding via more stabilized tertiary carbocation intermediates (for example: 153 is more stable compared to initially formed alkenyl cation 152, Scheme 24) [91]. This protonation pathway commonly leads to the formation of gem-dichloride species 151, which

Thiazolidinones: novel insights from microwave synthesis, computational studies, and potentially bioactive hybrids

• Luan A. Martinho,
• Victor H. J. G. Praciano,
• Guilherme D. R. Matos,
• Claudia C. Gatto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2025, 21, 2618–2636, doi:10.3762/bjoc.21.203

• aldehyde 1, activated by protonation of the oxygen atom through structure ii, forming the intermediate aldol iii. In the presence of EDDA, water elimination occurs in intermediate iv, yielding the Knoevenagel adducts 3 or 4. Synthesis of novel imidazo[1,2-a]pyridine–thiazolidinone hybrids To further

• band around 350 nm was observed. This increase can be explained by deprotonation of the structures, which facilitates solvation effects by water molecules. The cause for the tautomerism effect at acidic pH may be due to the protonation of the basic site of the amino group present in the derivatives

• -TZVPP single point calculations in CPCM water of compounds 3n and 4n in protonated, deprotonated, and neutral forms showed that there is a degree of charge transfer between a HOMO–LUMO excitation in their neutral and deprotonated forms [98]. Protonation of the nitrogen atom in the donor region shifts

Rotaxanes with integrated photoswitches: design principles, functional behavior, and emerging applications

• Jullyane Emi Matsushima,
• Khushbu,
• Zuliah Abdulsalam,
• Udyogi Navodya Kulathilaka Conthagamage and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2345–2366, doi:10.3762/bjoc.21.179

• macrocycle occurs along a thread containing fumaramide and succinic amide ester units as recognition sites, with highly fluorescent perylene bisimide and pyrene serving as stoppers [67]. The macrocycle features two pyridine units that, upon protonation, effectively quench the fluorescence of both

Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• in four steps. Subsequent conjugate addition of the lithium anion of TMS-acetonitrile to 15, followed by careful one-pot protonation of the resulting enolate with ethyl salicylate and TMS removal with CsF, gave 16 bearing three properly arranged substituents. Grignard 1,2-addition to ketone 16

Pathway economy in cyclization of 1,n-enynes

• Hezhen Han,
• Wenjie Mao,
• Bin Lin,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2025, 21, 2260–2282, doi:10.3762/bjoc.21.173

•  2, path b). In the following years, Liu and co-workers discovered that the protonation of intermediate 2 triggered its conversion to intermediate 3, which subsequently underwent oxidation with oxygen, resulting in the generation of an indenone skeleton 6 [9]. This tunability achieved efficient and

• pathway-controlled approach using tryptamine ynamides bearing Michael acceptor moieties as substrates (Scheme 27) [38][39]. Under strong Brønsted acid catalysis, protonation of the carbonyl group was achieved, which facilitated a Michael addition between the electron-rich indole C3-position and the

Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings

• Lifen Peng,
• Ting Wang,
• Zhiwen Yuan,
• Bin Li,
• Zilong Tang,
• Xirong Liu,
• Hui Li,
• Guofang Jiang,
• Chunling Zeng,
• Henry N. C. Wong and
• Xiao-Shui Peng

Beilstein J. Org. Chem. 2025, 21, 2173–2201, doi:10.3762/bjoc.21.166

• generation of 12a in Cu rod electrodes, the Cu anode was expected to liberate Cu+ into the reaction mixture. The reaction of this Cu+ with DMSO and I− afforded (DMSO)nCuI, which was coordinated with C≡C to give B. The intermediate C was obtained by cyclization of B and deprotonation. Further protonation of C

• -exo-dig N-radical addition into the C≡C bond to generate the cyclic species C. The radical anion D was then obtained via single electron reduction of C at the cathode. The subsequent protonation of D gave α-aminyl radical E [215][216][217], which was converted into the anion F by further cathodic

• reduction. The subsequent protonation of F occurred to complete the formation of 28. This approach, applying electrolyte as the proton sources, avoided the use of reductants and metal catalysts efficiently. In 2022, Guo developed an electrochemical intramolecular 1,2-amino oxygenation of alkyne to access

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• with the desired C6 chiral center was constructed via intermediate 229, where the sulfinyl group induced K+–oxygen chelation to form a six-membered transition state prior to protonation from the less hindered face. Acid-mediated epimerization at C9 of 230 yielded compound 231, which was transformed

Stereoselective electrochemical intramolecular imino-pinacol reaction: a straightforward entry to enantiopure piperazines

• Margherita Gazzotti,
• Fabrizio Medici,
• Valerio Chiroli,
• Laura Raimondi,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2025, 21, 1897–1908, doi:10.3762/bjoc.21.147

• methanesulfonic acid, which acts as a strong Brønsted acid to selectively protonate the imine nitrogen atoms. This protonation step increases the electrophilicity of the adjacent imine carbons by inductive effect, leading to the formation of a highly reactive diiminium intermediate 4a. When formed, compound 4a is

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

• between hydrazone and pyridine can be broken by protonation with an acid and even by metal coordination, rendering these compounds photo- and acidochromic (Scheme 31) [102]. The equilibrium can also be modulated by introducing hydrogen-bond acceptors in R1 [107] or by introducing substituents to the

Research progress on calixarene/pillararene-based controlled drug release systems

• Liu-Huan Yi,
• Jian Qin,
• Si-Ran Lu,
• Liu-Pan Yang,
• Li-Li Wang and
• Huan Yao

Beilstein J. Org. Chem. 2025, 21, 1757–1785, doi:10.3762/bjoc.21.139

• of supramolecular vesicles using WP6 and pyridine derivatives (G1) (Figure 4). This supramolecular system achieves controllable assembly and disassembly through pH responsiveness: under acidic conditions (pH 6.0), protonation of the WP6 carboxyl groups leads to vesicle disassembly; whereas in a

• hydrophobic alkyl chain core. The assembly driving force directly relies on the host–guest interaction between WP6 and FC. Further studies have shown that by regulating the deprotonation/protonation state of the WP6 carboxyl groups through pH control, the reversible dissociation and reassembly of the vesicle

Influence of the cation in hypophosphite-mediated catalyst-free reductive amination

• Natalia Lebedeva,
• Fedor Kliuev,
• Olesya Zvereva,
• Klim Biriukov,
• Evgeniya Podyacheva,
• Maria Godovikova,
• Oleg I. Afanasyev and
• Denis Chusov

Beilstein J. Org. Chem. 2025, 21, 1661–1670, doi:10.3762/bjoc.21.130

• the DFT calculations (Scheme 5, Figure 2). Firstly, reductive amination of an aldehyde started from a nucleophilic addition of the amine to the carbonyl group of the aldehyde. In the presence of acid, this step could occur via acidic catalysis involving a protonation step of an amine (Step_2) or

• protonation of an aldehyde (Step_2’). Due to the higher basicity of the secondary amine compared with the carbonyl group of benzaldehyde, protonation of dimethylamine was the main reaction pathway (30.9 vs −2.6 kcal/mol). However, it was found that the protonation of the carbonyl group led to a great

• weakly nucleophilic secondary ammonium cation to the carbonyl group occurred with ΔEa = 11.5 kcal/mol (TS2→3). In recent DFT [39] and experimental [40] studies on the reductive amination reaction it was postulated that this protonation of amine played a key role in the catalytic cycle especially in the

pH-Controlled isomerization kinetics of ortho-disubstituted benzamidines: E/Z isomerism and axial chirality

• Ryota Kimura,
• Satoshi Ichikawa and
• Akira Katsuyama

Beilstein J. Org. Chem. 2025, 21, 1568–1576, doi:10.3762/bjoc.21.120

• barriers by protonation, providing a novel approach to control the kinetics of isomerization via pH adjustment. The results showed that protonation of the amidine moiety significantly suppresses both C–N bond rotation and C–N/C–C concerted rotation, demonstrating the potential of ortho-disubstituted

• triggered by protonation and deprotonation [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. This class of molecules has the capacity to regulate three-dimensional structures and motions of molecules through simple acid–base stimuli. This provides a high degree of control over their

• switches [19]. For example, hydrazone-based molecular switches undergo reversible E/Z isomerization around the C=N bond [1][2][3][4][5][6][7], with protonation significantly shifting the equilibrium. Beyond double-bond isomerization, pH stimuli have also been employed to modulate rotational barriers in

General method for the synthesis of enaminones via photocatalysis

• Paula Pérez-Ramos,
• Raquel G. Soengas and
• Humberto Rodríguez-Solla

Beilstein J. Org. Chem. 2025, 21, 1535–1543, doi:10.3762/bjoc.21.116

• bond of I is cleaved by PC1•, generating a C-centered radical II, which can be further reduced to give an enolate III, that ultimately evolves to the more stable anion IV and undergoes protonation to afford the final enaminone product 9a. Conclusion In summary, a simple and effective nickel-assisted

Azobenzene protonation as a tool for temperature sensing

• Antti Siiskonen,
• Sami Vesamäki and
• Arri Priimagi

Beilstein J. Org. Chem. 2025, 21, 1528–1534, doi:10.3762/bjoc.21.115

• changes in their absorption and photochemical properties. While azobenzene protonation has been recently used as a tool in photoswitching studies, the factors influencing protonation itself have received little attention. Here, we report a strong temperature dependence of azobenzene protonation in 1,2

• . Keywords: azobenzene; protonation; sensing; spectral changes; temperature; Introduction Molecular switches are molecules that can reversibly shift between distinct (meta)stable states in response to external stimuli such as light, pH changes, or electric fields [1]. Over the past decades, they have

• other transformations that can offer useful functionalities. These include ionization via protonation of one of the nitrogens forming the azo bond [12][13], azo–hydrazone tautomerization [14][15], and binding of analytes to side groups [16]. Such transformations depend on the azobenzene structure but

Ambident reactivity of enolizable 5-mercapto-1H-tetrazoles in trapping reactions with in situ-generated thiocarbonyl S-methanides derived from sterically crowded cycloaliphatic thioketones

• Grzegorz Mlostoń,
• Małgorzata Celeda,
• Marcin Palusiak,
• Heinz Heimgartner,
• Marta Denel-Bobrowska and
• Agnieszka B. Olejniczak

Beilstein J. Org. Chem. 2025, 21, 1508–1519, doi:10.3762/bjoc.21.113

• publications [15], or/and from secondary processes, like an intramolecular rearrangement. Taking into account the postulated basicity (and nucleophilicity) of thiocarbonyl S-methanides 1 derived from cycloaliphatic thioketones [6], the initiating step of these processes can be presented as protonation of the

Advances in nitrogen-containing helicenes: synthesis, chiroptical properties, and optoelectronic applications

• Meng Qiu,
• Jing Du,
• Nai-Te Yao,
• Xin-Yue Wang and
• Han-Yuan Gong

Beilstein J. Org. Chem. 2025, 21, 1422–1453, doi:10.3762/bjoc.21.106

• 6 exhibiting enhanced chiroptical performance and protonation-induced CPL amplification [19]. Meanwhile, Audisio’s team developed heterohelicenes via regioselective [3 + 2]-cycloadditions, with compound 7 displaying pH-responsive CPL sign inversion (|glum| = +1.1 × 10−3 at 430 nm, −1.2 × 10−3 at 585

• length. Protonation further induced red-shifted emission, with compound 14d-H+ emitting at 542 nm. However, PLQYs decreased significantly from 0.078 to 0.006 with longer helicenes. The CD spectra of 14c and 14d were found to resemble their carbohelicene analogues, underscoring the structural fidelity and

• excellent UV stability and solvent-dependent fluorescence [91]. Protonation significantly enhanced their emission intensity, and the presence of nitrogen facilitated further structural derivatization. In the same year, Alcarazo’s group reported an enantioselective gold-catalyzed synthesis of compound 78