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

• 88, enabling its stable isolation and subsequent affordance of the spirocyclic indole-derived imine product 92 (Scheme 19, path b). The suppression of Wagner–Meerwein rearrangement was attributed to the lower Lewis acidity of PPh₃ relative to NFSI, which emerged as the critical determinant in this

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

• furfural to succinic acid in 88% yield under mild conditions using modified hydrophilic acidic metal-free graphene oxide (GO) as solid acid catalyst and H2O2 as an oxidant [151]. The suitable acidity of the SO3H group on the graphene oxide support is crucial for the selectivity of the oxidation. The use of

• flow reactor. The moderate acidity and the hierarchical tube-type porous nature of SBA-15, as well as the adsorption energy on the surface of 10Cu–5Ni/SBA-15 catalyst, are the key parameters for giving 2-pentanone with high selectivity (78%) (Scheme 52) [180]. Wang developed a new route for the

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

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

• will review and discuss some of the stimulus responses. 2.1 pH-responsive controlled release Changes in acidity are a typical stimulus for adjusting host–guest supramolecular nanosystems. It is widely recognized that the acidity levels of various organs, tissues, and cellular compartments differ. For

• example, the acidity of tumor and inflamed tissues is distinct from that of healthy tissues, offering a potential physiological trigger for pH-responsive drug delivery. Thus, drug release can be regulated by leveraging the variations in acidity between normal and diseased cells [100]. Developing

• strides have been achieved in boosting the targeting accuracy and clinical utility of drug release mechanisms. Tumor cells are characterized by unique attributes, such as acidity, hypoxia, and altered metabolism, which set them apart from healthy cells. These distinct features underscore the importance of

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• coordination of the boron center with the remaining C2-OH group increases its acidity, thereby generating in situ an acidic catalyst for the activation of the glycosyl donor [62][63]. In this approach, the use of glycosyl phosphites of gluco- (35) and galacto- (38) configuration as donors, in combination with

• that its sufficient acidity is key to the success of the reaction. Using the 2N-Troc-protected GlcN phosphite 44 as the donor and the 4,6-O-benzylidene acetal-protected 1,2-diol 45 as the acceptor afforded the β,α-disaccharide 46 with high stereoselectivity under borinic acid catalysis [62]. In

• involves the activation of an anhydro sugar glycosyl donor 129 by the "acidic OH group" of a glycosyl 1,2-diol acceptor (generated via activation with a borinic acid catalyst possessing sufficient Lewis acidity) [62][63]. Anomeric C2-OH-unprotected lactols 45 and 36 were subjected to glycosylation with

Continuous-flow-enabled intensification in nitration processes: a review of technological developments and practical applications over the past decade

• Feng Zhou,
• Chuansong Duanmu,
• Yanxing Li,
• Jin Li,
• Haiqing Xu,
• Pan Wang and
• Kai Zhu

Beilstein J. Org. Chem. 2025, 21, 1678–1699, doi:10.3762/bjoc.21.132

• literature reported by Marziano et al. [63], the introduction of the Mc function allows the activity coefficients-based rate equation to be reformulated as Mc function-correlated rate equation, explicitly linking sulfuric acid acidity to reaction rates. Therefore, the linearized integrated form for kinetics

• analysis can be obtained from the Mc function-correlated rate equation. The linearized equation requires prior determination of two key parameters: (i) the acidity function Mc and (ii) the concentration ratio of , to resolve the values of k* and n. According to the works of Marziano et al. [64][65][66

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

• has shown clear influence of the cation in the hypophosphite salt on the effectiveness of the reductive amination. The acidity of the reaction media was a key factor affecting the equilibrium in the interaction between carbonyl compounds and amines. Intermediately acidic media is the optimal for the

• media. Finally, the combination of H3PO2 and KH2PO2 1:1 with the ratio of H2PO2− to amine 1:2 is optimal balance between solubility of reductant, acidity of the medium and stability of the reducing system providing the highest efficiency of the interaction. Under optimized reaction conditions, the

• alkali metals, such as Li, K, Rb, and Cs was studied in the reductive amination for the first time. The reactivity was strongly influenced by acidity and the nature of the alkali metal cation: under neutral conditions, the yield decreased from Na to Cs, while acidic conditions with H3PO2 reversed this

Transition-state aromaticity and its relationship with reactivity in pericyclic reactions

• Israel Fernández

Beilstein J. Org. Chem. 2025, 21, 1613–1626, doi:10.3762/bjoc.21.125

• as the relative Lewis acidity of the catalyst (measured by the Child’s method [41][42][43]), but do not follow the same trend as the energy of the LUMO(dienophile). This finding therefore challenges the traditionally used LUMO-lowering concept as the ultimate factor controlling the catalysis in these

• LAs [66] (Table 2). As expected, we found that the reduction of the activation barrier (up to ca. 25 kcal/mol) directly correlates with the relative Lewis acidity of the catalyst. In addition, the process becomes more and more asynchronous as the acidity of the catalyst increases, which strongly

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

• is assumed. Stronger electron donation gives rise to larger red-shift, and hence more pronounced color changes, upon protonation, as illustrated in Figure 1C. Figure 1D illustrates the shift in protonation equilibrium with increasing acidity when MSA is added to DCE solution of 3 at 25 °C. Due to the

• strong acidity of MSA, moderate polarity of DCE, and the electron-donating substituents of 3, only 76 equivalents of acid (3.08 mM) is needed for nearly full protonation as indicated by the almost complete disappearance of the absorption peak at 360 nm. Similar data for compounds 1 and 2 in MSA/DCE

Tautomerism and switching in 7-hydroxy-8-(azophenyl)quinoline and similar compounds

• Lidia Zaharieva,
• Vera Deneva,
• Fadhil S. Kamounah,
• Nikolay Vassilev,
• Ivan Angelov,
• Michael Pittelkow and
• Liudmil Antonov

Beilstein J. Org. Chem. 2025, 21, 1404–1421, doi:10.3762/bjoc.21.105

• influenced by the structural variations and the environment (temperature, solvent properties, acidity and presence of other molecules). The E/Z isomerization of the azodyes, caused by light irradiation [12][13][14] or electrochemically [15][16], has paved the way for the development of innovative materials

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• after deprotonation of a suitably functionalised ether at the α-carbon. Therefore, a stabilising group must be incorporated to control regioselectivity of the deprotonation as well as to increase the acidity of the α-hydrogen. Mordini et al. showed that even weakly stabilising groups such as phenyl

Enhancing chemical synthesis planning: automated quantum mechanics-based regioselectivity prediction for C–H activation with directing groups

• Julius Seumer,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2025, 21, 1171–1182, doi:10.3762/bjoc.21.94

• activation, called concerted metal deprotonation (CMD) [5][6][7]. In a concerted mechanism, the Pd atom of the catalyst forms a sigma bond to an aromatic carbon, which increases the acidity of the adjacent (alpha) proton. This allows for the simultaneous abstraction of this proton by a carboxylate ligand. A

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• reduction of the H-bond-donor acidity of the hydroxy group of 58. (See section 6, which focuses on carbonyl compounds, for a further explanation of the predicted conformation of 58.) Finally, two structural variations on the hydroxy group should be mentioned. First, if the hydroxy group is acylated (i.e

Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• ][101][102][103][104]), or with a carbanion generated by a strong base in an Ugi/Dieckmann cyclization [105]. In all these cases, the glyoxylate derivative incorporates two carbon atoms into the final product, thus serving as a C2-building block. Similarly, the ester group increases the acidity of the

Study of the interaction of 2H-furo[3,2-b]pyran-2-ones with nitrogen-containing nucleophiles

• Constantine V. Milyutin,
• Andrey N. Komogortsev and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2025, 21, 556–563, doi:10.3762/bjoc.21.44

• that, the use of 3-fold excess of amine 2a led to the same results. Apparently, the stability of salt 3a is connected with high acidity of the starting furanone 1a and its recovery is only possible under the action of strong acids (HCl, H2SO4). Further, we investigated the chemical behavior of

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• terminal alkynes did not result in the desired N-acyl amidine 10l. Based on the substrate scope of acetylenes, the authors noted that the lower acidity of terminal acetylenes led to a diminished formation of the copper acetylide intermediate. Based on several mechanistic experiments and density functional

Quantifying the ability of the CF₂H group as a hydrogen bond donor

• Matthew E. Paolella,
• Daniel S. Honeycutt,
• Bradley M. Lipka,
• Jacob M. Goldberg and
• Fang Wang

Beilstein J. Org. Chem. 2025, 21, 189–199, doi:10.3762/bjoc.21.11

• established methods, including 1H NMR-based hydrogen bond acidity determination, UV–vis spectroscopy titration with Reichardt's dye, and 1H NMR titration using tri-n-butylphosphine oxide as a hydrogen bond acceptor. Our experiments reveal that the direct attachment of the CF2H group to cationic aromatic

• by hydrogen bond acidity [47][48] which is derived from the 1H NMR chemical shift difference of a given proton in DMSO-d6 and CDCl3, the CF2H group is generally a stronger donor than the methyl group but substantially weaker than the OH or amide NH groups [19][20]. These results collectively indicate

• that, although the CF2H group mimics hydroxy or thiol groups, it is a generally less effective hydrogen bond donor. Given that the HB donation ability of a particular functional group usually increases with increasing Brønsted acidity [49] we chose to incorporate the CF2H group into the backbone of N

Surprising acidity for the methylene of 1,3-indenocorannulenes?

• Shi Liu,
• Märt Lõkov,
• Sofja Tshepelevitsh,
• Ivo Leito,
• Kim K. Baldridge and
• Jay S. Siegel

Beilstein J. Org. Chem. 2024, 20, 3144–3150, doi:10.3762/bjoc.20.260

• of the first acidity constant (pKa) for BFC (27.6 in CH3CN) and FIC (27.8 in CH3CN) shows the methylene protons to be significantly more acidic than those in related cyclopentadiene (32 in CH3CN), indene (34 in CH3CN), or fluorene (37 in CH3CN) and comparable to the methine of 9

• -perfluorophenylfluorene (28.14 in CH3CN). This work reports quantitative pKa values of BFC and FIC, places those values in a broadened context of CpH-cognate hydrocarbon acidity and presents a Clar–Loschmidt graph perspective to help understand the “surprises”. Keywords: acidity; aromatic hydrocarbon; Clar sextet

• ; Loschmidt group element; molecular graph; Introduction A classic textbook tetrad linking hydrocarbon acidity to aromatic stabilization energy comprises cyclopentadiene (CpH), indene (InH), fluorene (FlH), and diphenylmethane (DPMH) [1][2], with pKa values in DMSO equal to 18 [3], 20.1 [3], 22.6 [3], and

C–C Coupling in sterically demanding porphyrin environments

• Liam Cribbin,
• Brendan Twamley,
• Nicolae Buga,
• John E. O’ Brien,
• Raphael Bühler,
• Roland A. Fischer and
• Mathias O. Senge

Beilstein J. Org. Chem. 2024, 20, 2784–2798, doi:10.3762/bjoc.20.234

• one, may have slowed down the protodeboronation process, as substrates with electron-withdrawing groups are postulated to increase the Lewis acidity of the boronic acid, which may allow an increased incidence of protodeboronation to occur. It is also known that aryl–B(Pin) complexes have a greater

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

• positions. These substituents will have two main effects on the FLP. First, they will alter the Lewis acidity and basicity of the LA and LB centres, respectively; second, they may induce steric hindrance. The first effect is perhaps the most intriguing to consider, as the acidity and basicity of the LA/LB

• centres are indicative of the FLP’s reactivity [45][46]. Thus, substituents must be selected to ensure a broad spectrum of acidity and basicity of the LA and LB. Different methods for determining these properties have been described in the literature. Because of their easy computation, the proton affinity

• [43] and fluoride ion affinity [44] were selected to compute the basicity and acidity of the systems considered. By selecting the substituents presented in Figure 4, FIAs spanning a range of 60 kcal·mol−1 and PAs spanning a range of 48 kcal·mol−1 were obtained (Figure S3, Supporting Information File 1

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• ). However, increasing acidity and using trifluoroacetic acid (Table 1, entry 17) did not improve the overall yield. We also tried microwave activation conditions since this is a known technique for reactions of this type [32], but unfortunately, we did not find any improvement in the yield (Table 1, entry

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• binding with an electron-withdrawing group. This acidity can result in stronger hydrogen bonds between the substrate and the catalyst C30, which contains a bis(trifluoromethyl)phenyl-modified squaramide moiety. This stronger interaction potentially enhances the catalyst–substrate interaction, allowing for

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• a [1,5]-H shift [19], indazolo[3’,2’:2,3]imidazo[1,5-c]quinazolin-6(5H)-one 18 (Scheme 7) [20]. The favorable host–guest interaction between 14 and the reactants (demonstrated by 2D NMR and FTIR spectroscopy as well as by scanning electron micrography), combined with the acidity of the succinyl

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• 73% yield. Mechanistically, we believe that the hemiketal protonates the azetidine before a nucleophilic attack can occur. Therefore, the ring opening is critical to the acidity of the transient hemiacetals and to the basicity of the respective azetidines, explaining the unsuccessful attempts with 3a

• . Dioxolanes 11 and 16 are inherently stable and we were unable to cleave the ketal after reaction. Thus, we investigated the feasibility to use boronic acids in the ring-opening reaction (Scheme 3c). Phenylboronic acid 17 is known to exhibit a similar acidity as the corresponding hemiketals providing a

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• facilitating HAT to produce a benzylic radical. Fluorine-atom-transfer (FAT) with Selectfluor then gave the benzyl fluoride. The low acidity of phenylacetic acids in polar aprotic solvents disfavoured decarboxylation (via an SET pathway) promoting HAT from the benzylic position. By using a mixture of 1:1 MeCN

• radical cation II. The acidity of benzylic protons is augmented after oxidation of the adjacent π-system, facilitating rapid proton transfer at this position, resulting in benzylic radical III [13][88]. Single-electron oxidation of the resulting benzylic radical is facile and expected to occur readily