Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• multiple stereocenters, including contiguous quaternary carbons. As a result, the carboborative ring contraction reaction is conveniently used for structural modification of natural products containing a cyclohexene ring and in the synthesis of new compounds to increase their activity, metabolic stability

The high potential of methyl laurate as a recyclable competitor to conventional toxic solvents in [3 + 2] cycloaddition reactions

• Ayhan Yıldırım and
• Mustafa Göker

Beilstein J. Org. Chem. 2025, 21, 2389–2415, doi:10.3762/bjoc.21.184

• criteria (availability, price, recyclability, grade, synthesis, toxicity, biodegradability, performance, stability, flammability, storage, renewability) with a view to defining the concept of green solvents [71]. Methyl laurate, predicted as the main potential green solvent in this study, fulfils almost

• solvent in a wide range of organic reactions that necessitate elevated temperatures. Furthermore, the oxidative stability index of methyl laurate at temperatures of 80 °C and 110 °C is greater than 40 (h), and the oxidation onset temperature is 198.5 °C which is better than those of methyl oleate [105

Conformational effects on iodide binding: a comparative study of flexible and rigid carbazole macrocyclic analogs

• Guang-Wei Zhang,
• Yong Zhang,
• Le Shi,
• Chuang Gao,
• Hong-Yu Li and
• Lei Xue

Beilstein J. Org. Chem. 2025, 21, 2369–2375, doi:10.3762/bjoc.21.181

• interplay between conformational selection and induced-fit mechanisms in isomeric systems remains underexplored. Cram’s preorganization theory [13] posits that prestructured hosts with minimized solvation exhibit enhanced binding stability. Recent advances [14][15][16] highlight the pivotal role of

• synergistic binding mechanism driven by cavity complementarity, and the energy of the PBG–iodide complex is lower than that of the WDG–iodide complex, it indicates that PBG forms a thermodynamically more stable complex with iodide ions compared to WDG. This stability difference arises from the distinct

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

• -stilbenes have 5-membered rings fused to the carbon–carbon double bond, are more photostable, and undergo reversible photoisomerization with higher efficiency (Figure 2) [75]. Notably, their cis isomer exhibits higher thermal stability than that of other commonly used photoswitches, such as azobenzene. This

• . However, most photoswitchable rotaxanes developed to date have been designed for use in organic solvents or non-biological environments. To fully harness their potential in biomedical and biotechnological settings, it is essential to establish new design principles that ensure biocompatibility, stability

• motion of [2]rotaxane based on a stiff-stilbene photoswitch. Figure 13 was reproduced with permission of The Royal Society of Chemistry, from [81] (“Toward bidirectional photoswitchable colored photochromic molecules with visible light stability” by T.-G. Zhan et al., Chem. Commun., vol. 54, issue 67

Halogenated butyrolactones from the biomass-derived synthon levoglucosenone

• Johannes Puschnig,
• Martyn Jevric and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2025, 21, 2297–2301, doi:10.3762/bjoc.21.175

• sofosbuvir (2). Fluorination at C2 in the nucleoside results in metabolic stability and resistance to hydrolysis as it destabilizes the formation of a C1 oxocarbenium ion [5][6]. Trifluoromethylated γ-butyrolactones also find applications as antiviral agents, for example, lactone 4 which has activity against

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

• confirmed that the cyclization pathways were controlled by the influence of substituents on the stability of the intermediates. This work expanded the scope of gold-catalyzed reactions through systematic cycloisomerization studies of 1,6-enynes and an ethyl 4-oxocyclohexanecarboxylate-derived 1,7-enyne. In

• , whereas internal alkynes favored the 8-endo-dig pathway due to steric constraints and carbocation stability. This strategy facilitated efficient and selective synthesis of macrocyclic amines, with precise ring size control via substituent modulation. In 2021, Liu group reported a BiCl3-mediated

• ligands could enhance catalytic activity and efficiency while enabling fine control over chemo-, regio-, stereo-, and enantioselectivity of reactions. Ligands enhance both the thermal/chemical stability and solubility profiles of catalysts in specific reaction media. Thus, ligands function as a regulatory

Thiadiazino-indole, thiadiazino-carbazole and benzothiadiazino-carbazole dioxides: synthesis, physicochemical and early ADME characterization of representatives of new tri-, tetra- and pentacyclic ring systems and their intermediates

• Gyöngyvér Pusztai,
• László Poszávácz,
• Anna Vincze,
• András Marton,
• Ahmed Qasim Abdulhussein,
• Judit Halász,
• András Dancsó,
• Gyula Simig,
• György Tibor Balogh and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2220–2233, doi:10.3762/bjoc.21.169

• metabolic stability of the most promising derivatives was also determined using human liver microsomes. Keywords: early ADME characterization; Fischer indole cyclization; heterocycles; indoles; lead-likeness; new ring systems; physicochemical characterization; Introduction Considering the published

• physicochemical characterization, we conducted standardized metabolic stability assessments on pooled human liver microsome (HLM) isolates of the primary and secondary lead compounds identified during the solubility and permeability studies. The measured values are summarized in the last column of Table 2 and

• regarding their physicochemical and ADME parameters. Based on literature analogy with related compounds, furthermore on calculated properties, and results from kinetic solubility, in vitro membrane permeability and metabolic stability measurements, a tetracyclic derivative, 2,4-dimethyl-2,7,8,9,10,11

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

• of levulinic acid-derived molecules. The same group later reported a more active heterogeneous catalyst, Ru–MnOx/Al2O3, providing 2-butanol with yields up to 98.8% [242]. Conversion to 2-methyltetrahydrofuran: 2-Methyltetrahydrofuran is a promising biofuel with high energy density, high stability and

Solar thermal fuels: azobenzene as a cyclic photon–heat transduction platform

• Jie Yan,
• Shaodong Sun,
• Minghao Wang and
• Si Wu

Beilstein J. Org. Chem. 2025, 21, 2036–2047, doi:10.3762/bjoc.21.159

• [35][36][37][38][39][40][41]. Notably, the utilization of azobenzene-based materials in solar thermal storage applications is gaining considerable attention due to their advantages in low synthesis cost, facile molecular design, exceptional cycling stability, and superior fatigue resistance [6][8

• transition behavior, achieving high gravimetric energy densities (300–400 J/g) with long-term storage stability (Figure 6d). Grossman and Durgun proposed methods for incorporating azobenzenes into macrocyclic structures [82]. Their computational models indicated that the molecular rings connecting the

• -molecule azobenzene derivatives achieve gravimetric energy densities of 300–400 J/g with long-term storage stability. However, solvent dependence or steric hindrance in multiazobenzene units remains an inherent challenge dictated by material type. These materials show promising applications in device

Synthesis of N-doped chiral macrocycles by regioselective palladium-catalyzed arylation

• Shuhai Qiu and
• Junzhi Liu

Beilstein J. Org. Chem. 2025, 21, 1917–1923, doi:10.3762/bjoc.21.149

• rings. In the molecular arrangement, a pair of enantiomers exists in each cell for MC3 (Figure 2d). Considering the C–C single bonds between the π-subunits, isomerization among different molecular configurations might occur via rotations. To further investigate the conformational stability of MC3

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• terminal aromatic rings [17]. Despite lacking asymmetric stereogenic centers, this nonplanar scaffold exhibits intrinsic P/M chirality due to the helical arrangement of the π-extended skeleton. Renowned for their high thermal stability and structural rigidity, chiral helicenes have emerged as prominent

• conducted a thorough evaluation of the stability of the helical chirality across the synthesized quinohelicenes, indicating a high racemization barrier. In 2024, our group further extended the CPA-catalyzed sequential Povarov reaction and aromatization strategy by using 2-vinylphenols 14 as the olefin

• , thermal stability studies demonstrated high configurational stability of these planarly chiral macrocycles, a critical feature that enhances their potential for future utility. In 2023, Zhao and co-worker reported the asymmetric synthesis of planarly chiral paracyclophanes through either catalytic kinetic

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

• conjugated with the chromophore structure, will influence its absorption spectrum and stability [4]. The solvent will also affect the properties, as it can stabilise or destabilise either the ground or the excited state, resulting in a red- or blue shift of the spectra. The thermal half-life (t1/2) measures

• strongly overlapped, resulting in a less efficient switching. Conversely, di-ortho-chlorinated 9f has lower thermal stability because of the steric clash with the bulky chlorine substituents (Figure 5). An interesting study shows how the Z-isomer thermal lifetime changes between two phenylazoindole

• substituted products 35e–g [51]. Examples Because of their red-shifted absorption and inverse stability, diazocines are suitable substitutes for azobenzenes in biological environments. Light with longer wavelengths can penetrate biological media, such as tissue, more effectively, and is less harmful to living

[3 + 2] Cycloaddition of thioformylium methylide with various arylidene-azolones in the synthesis of 7-thia-3-azaspiro[4.4]nonan-4-ones

• Daniil I. Rudik,
• Irina V. Tiushina,
• Anatoly I. Sokolov,
• Alexander Yu. Smirnov,
• Alexander R. Romanenko,
• Alexander A. Korlyukov,
• Andrey A. Mikhaylov and
• Mikhail S. Baranov

Beilstein J. Org. Chem. 2025, 21, 1791–1798, doi:10.3762/bjoc.21.141

• thermodynamically stable cis- and trans- isomers were also obtained in the reaction with azomethine ylides [20]. Finally, we performed preliminary derivatization studies of the obtained spiro-tetrahydrothiophenes. Compounds 7 and 9 demonstrated remarkable stability under both acidic and basic hydrolysis conditions

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

• , stimulus responsiveness, specific recognition and binding, and multi-target synergistic action [14][15][16]. These characteristics enable precise control of drug release and targeted drug delivery, thereby improving drug stability and bioavailability, and reducing drug toxicity and side effects

• disintegration to avert reversibility. Given the benefits of the chemical stability of most aromatic macrocycles, creating stimulus-responsive complexes usually requires the guest components to undergo stimulus-triggered changes that affect their ability to bind with the host macrocycles. The controllable

• encapsulate DOX. This structure integrates multiple non-covalent interactions, such as hydrophobic interactions and π–π stacking, endowing the micelles with both structural stability and pH responsiveness. When targeted to the tumor microenvironment (acidic pH), the core of the micelles dissociates to achieve

Unique halogen–π association detected in single crystals of C–N atropisomeric N-(2-halophenyl)quinolin-2-one derivatives and the thione analogue

• Mai Uchibori,
• Nanami Murate,
• Kanako Shima,
• Tatsunori Sakagami,
• Ko Kanehisa,
• Gary James Richards,
• Akiko Hori and
• Osamu Kitagawa

Beilstein J. Org. Chem. 2025, 21, 1748–1756, doi:10.3762/bjoc.21.138

• ) observed in their single crystals. Results and Discussion Synthesis of quinoline-2-ones (thione), their enantiomer separation and rotational stability We focused on N-(2-halophenyl)quinolin-2-ones 1 and the thione analogue 2 as alternative substrates to verify chirality- and functional group-dependent

• poor (11% ee and 9% ee) [31]. In addition, rotational stability about the C–N bond in 1a,b was not mentioned at all. We prepared racemates rac-1a,b in accordance with Scheme 1 and separated their enantiomers [(P)-1a,b and (M)-1a,b] through medium pressure liquid chromatography (MPLC) using a semi

• be isolated because of the low rotational stability [32]. Quinolinone rac-1a was converted to quinoline-thione rac-2a by reaction with Lawesson’s reagent, and subsequently, the enantiomers [(P)-2a and (M)-2a] were separated by MPLC using a chiral IH column. Unfortunately, the barrier value of

Thermodynamics and polarity-driven properties of fluorinated cyclopropanes

• Matheus P. Freitas

Beilstein J. Org. Chem. 2025, 21, 1742–1747, doi:10.3762/bjoc.21.137

• cyclopropyl ring [9]. Building on these insights, the relative stability of all possible fluorinated cyclopropanes, from mono- to perfluorocyclopropane (Figure 1), was quantum chemically evaluated in this study. Polarity-dependent properties of the most polar compound were also analyzed to inform potential

• its ability to form ion complexes and self-assemble into a stacking arrangement [12][13][14]. Therefore, understanding the energetics and polarity of fluorinated cyclopropanes is crucial for elucidating the intramolecular forces that govern the stability of molecular structures. Moreover, these

• preclude its synthesis, as the all-cis-1,2,3-trifluorocyclopropane framework has been successfully prepared in earlier studies [17]. To better understand the intramolecular interactions that govern the stability of fluorinated cyclopropanes, the sets of di-, tri-, and tetrafluorinated cyclopropane isomers

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

• , a mechanism known as HAD (H-bond-mediated aglycone delivery) [68]. The picoloyl protecting group at the remote C4–OH position has also been successfully employed to stabilize the anomeric configuration in 2,3,6-tri-O-benzylated TMS-glycoside acceptors [69]. This unusual stability of the anomeric

• configuration has been explained by the formation of a picolinium adduct, resulting from the trapping of the acidic by-product TMSOTf by the pyridine moiety of the picoloyl group during glycosylation [69]. The resulting intermediate, a picolinium-stabilized TMS-glycoside, exhibits high configurational stability

• involving TMS-glycoside acceptors require consistently acidic conditions, which places special demands on the acid stability of the protecting groups employed. This approach enabled the synthesis of β,α-1,1'-linked β-mannosyl-α-glucoside 62 and its 2-azido-2-deoxy-derivative 64, using the 4,6-O-benzylidene

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

• (11%), dichloroethane (8%). and acetic acid (8%) (Figure 4b), which are particularly valued for their ability to dissolve both organic substrates while maintaining chemical stability under the reaction conditions. Notably, sulfuric acid plays a dual role – as catalyst and solvent – in these systems, a

• and presents significant mathematical complexity when dealing with intricate reaction systems. Long-term operation stability/stress testing: Ensuring long-term operational stability is a critical requirement for the practical implementation of continuous-flow nitration processes, particularly given

• in nitration systems where minor deviations can lead to thermal runaway or hazardous by-product accumulation. Therefore, conducting long-term operational stability testing becomes imperative following the development of optimized continuous-flow nitration processes to validate industrial viability

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

• pH 0) [19], and usage of an additional amount of base leads to stronger reductive properties. Moreover, the role of the cation could be critical for the thermal stability against disproportionation or aerobic oxidation of hypophosphite [38]; salts with larger cations are also more soluble in organic

• 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

Catalytic asymmetric reactions of isocyanides for constructing non-central chirality

• Jia-Yu Liao

Beilstein J. Org. Chem. 2025, 21, 1648–1660, doi:10.3762/bjoc.21.129

• ]. Encouraged by the above results, we turned our attention to biaryl lactams [49]. However, in this case, the inherent resonance stability of the amide bond makes the ring-opening process rather challenging. To solve this problem, we envisioned that a cooperative catalytic system merging silver catalysis and

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

• [1][2][3]. Initially introduced to account for the remarkable stability, low reactivity, and unique structural features of benzene and related aromatic hydrocarbons, the concept has undergone a significant evolution [4]. Since the introduction of the famous Hückel’s (4n + 2) rule [5], first clearly

• that the gain in (in-plane) aromaticity in the parent reaction is not translated into a gain in stability (i.e., a more aromatic transition structure does not translate into a lower-barrier process). Following the same methodology, the ASM of reactivity was applied then to understand the reasons behind

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

• stability of the chiral axis, amidine 1, which has identical substituents on the amidine nitrogen and thus does not generate E/Z isomers, was selected. In the chiral HPLC analysis using an acidic eluent [MeCN/H2O (containing 0.5% CF3CO2H) 20:80], the trifluoroacetate salt of amidine 1 was observed as two

• well as the C–N bond rotation the racemization rate could be controlled by the protonation of the basic amidine moiety. This result indicates the possibility of controlling the stability of the chiral axis by the basicity of the amidine, as well as the C–N bond, as mentioned above. Conclusion In

Facile synthesis of hydantoin/1,2,4-oxadiazoline spiro-compounds via 1,3-dipolar cycloaddition of nitrile oxides to 5-iminohydantoins

• Juliana V. Petrova,
• Varvara T. Tkachenko,
• Victor A. Tafeenko,
• Anna S. Pestretsova,
• Vadim S. Pokrovsky,
• Maxim E. Kukushkin and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 1552–1560, doi:10.3762/bjoc.21.118

• was employed. The substantial impact of the reaction conditions can be attributed to the stability of the dipole formed. The presence of mesomeric donor substituent (such as 4-OMe group) has been shown to render nitrile oxides more susceptible to dimerization in comparison to other dipoles [27][34

• -containing compound [38]; the stability of these compounds is contingent on the nature of the substituents bonded to the thiocarbonyl group, which reacts with nitrile oxide [41]. It has been demonstrated [7] that 1,4,2-oxathiazoles derived from thiourea are among the least stable compounds, gradually

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

• they all typically result in significant changes in the absorption spectrum and/or alter the stability of the metastable isomer. In sensing, azobenzenes have been utilized, e.g., through changes in isomerization kinetics [17][18] or colorimetric properties. The colorimetric sensors are effective for

• different azo compounds [23][24][25]. More recent work has harnessed protonation to enable red-light switching [12][13][26] and to control the stability of the cis-isomer [27][28][29]. These studies have focused on how protonation affects isomerization, with less attention given on how external stimuli

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

• thiocarbonyl S-methanides 1a and 1b, respectively, in situ generated at 45 °C in absence of any trapping reagent, were described in earlier publications [6][10][11][12][13][14][28]. In the present study, the thermal stability of the new dispiro-1,3,4-thiadiazolines 2c and 2d was tested in THF solution at a