Unraveling aromaticity: the dual worlds of pyrazole, pyrazoline, and 3D carborane

• Zahra Noori,
• Miquel Solà,
• Clara Viñas,
• Francesc Teixidor and
• Jordi Poater

Beilstein J. Org. Chem. 2025, 21, 412–420, doi:10.3762/bjoc.21.29

• of aromaticity. Therefore, relying solely on NICS can be misleading, and other computational indicators, along with experimental or structural data, should be used to accurately assess aromaticity. Keywords: 3D aromaticity; carborane; density functional theory; NICS ambiguity; pyrazole

• highly aromatic systems with highly negative NICS values (−25 to −30 ppm), although it can also happen with lower values. Thus, relying solely on NICS can be misleading, and other computational indicators, as well as experimental or structural data, should be considered. Computational Details All

Identification and removal of a cryptic impurity in pomalidomide-PEG based PROTAC

• Bingnan Wang,
• Yong Lu and
• Chuo Chen

Beilstein J. Org. Chem. 2025, 21, 407–411, doi:10.3762/bjoc.21.28

• instability, where the cleavage of the phthalimide and glutarimide rings comprises the major metabolic pathways [9][10]. Computational analysis confirms that C1, C3, C2’, and C4’ are the most electrophilic sites of thalidomide (Figure 4). As expected, introducing a fluorine atom to C4 activates it toward SNAr

• the PEG chain on the relative retention time of 8 and 9 on HPLC. Supporting Information Supporting Information File 18: Computational details, general experimental information, synthetic procedures, compound characterization data, and copies of NMR spectra. Funding This work is supported by the NIH

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• is not only difficult but is also defective in principle. This dynamic continuum has also been depicted by an elaborate computational simulation report by Fu et al. in 2021 [41] which was a major follow-up of the work by Crich and co-workers in 2018 [29]. In general cases, the axial glycosides also

Synthesis, structure, ionochromic and cytotoxic properties of new 2-(indolin-2-yl)-1,3-tropolones

• Yurii A. Sayapin,
• Eugeny A. Gusakov,
• Inna O. Tupaeva,
• Alexander D. Dubonosov,
• Igor V. Dorogan,
• Valery V. Tkachev,
• Anna S. Goncharova,
• Gennady V. Shilov,
• Natalia S. Kuznetsova,
• Svetlana Y. Filippova,
• Tatyana A. Krasnikova,
• Yanis A. Boumber,
• Alexey Y. Maksimov,
• Sergey M. Aldoshin and
• Vladimir I. Minkin

Beilstein J. Org. Chem. 2025, 21, 358–368, doi:10.3762/bjoc.21.26

• ://www.ccdc.cam.ac.uk/data_request/cif. Computational methods Quantum chemical calculations were performed using the Gaussian 09 software package [34] with hybrid functional PBE0 [35][36] and 6-311+G (d,p) basis set. Solvent effects were modeled by using polarizable continuum model (PCM) [37] within the integral

Antibiofilm and cytotoxic metabolites from the entomopathogenic fungus Samsoniella aurantia

• Rita Toshe,
• Syeda J. Khalid,
• Blondelle Matio Kemkuignou,
• Esteban Charria-Girón,
• Paul Eckhardt,
• Birthe Sandargo,
• Kunlapat Nuchthien,
• J. Jennifer Luangsa-ard,
• Till Opatz,
• Hedda Schrey,
• Sherif S. Ebada and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 327–339, doi:10.3762/bjoc.21.23

• the samples and the control group was assessed through a two-tailed Student's t-test. The level of statistical significance was set at p < 0.05. The examination was conducted utilizing GraphPad Prism 9® (GraphPad Software, San Diego, CA, USA). Computational details The distribution of conformers was

Synthesis and characterizations of highly luminescent 5-isopropoxybenzo[rst]pentaphene

• Islam S. Marae,
• Jingyun Tan,
• Rengo Yoshioka,
• Zakaria Ziadi,
• Eugene Khaskin,
• Serhii Vasylevskyi,
• Ryota Kabe,
• Xiushang Xu and
• Akimitsu Narita

Beilstein J. Org. Chem. 2025, 21, 270–276, doi:10.3762/bjoc.21.19

• BPP 2 and BPP-OiPr 3. Supporting Information Supporting Information File 114: Experimental and computational details, X-ray crystallography, synthesis and characterization of new compounds, additional PL, mass, and NMR spectra, and theoretical calculations. Acknowledgements We appreciate the help

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

• results demonstrate the reliability of this relatively efficient computational approach for predicting the HB donation ability of CF2H-containing molecules. We further conducted natural bond orbital (NBO) [56] second-order perturbation analysis [57] to estimate the interaction energies (ELP→σ*) of the

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• been performed based on DOE methodologies, with the objective of maximizing the yield of the reaction product. However, these techniques are not well suited to find the global optimal conditions and scale exponentially with the number of variables. Computational approaches that rely on optimization

• algorithms offer more efficient ways to obtain the optimal conditions, without requiring an exponential number of experiments per variable to be optimized. Early examples of chemical reaction conditions optimization through computational approaches focused on the application of black-box optimization

Chemical glycobiology

• Elisa Fadda,
• Rachel Hevey,
• Benjamin Schumann and
• Ulrika Westerlind

Beilstein J. Org. Chem. 2025, 21, 8–9, doi:10.3762/bjoc.21.2

• . [12] in the context of photoswitchable ligands to the lectin LecA. Staying in the theme of lectin characterization, Lundstrøm et al. study the glycan binding profile of CMA1 originating from melon [13]. A time that sees great opportunities in computational biology also breeds innovative applications

• in the glycosciences. A key aspect is the modelling of protein–glycan interactions. Marcisz et al. study the power of umbrella sampling in distinguishing the interactions between different glycosaminoglycans and their receptors [14]. Nieto-Fabregat et al. provide a detailed overview on computational

• experimental and computational efforts, developing a neural-network-based approach for the interpretation of glycan structures from their vibrational fingerprints [17]. We anticipate that this diverse collection of reports across the entire spectrum of the chemical sciences cements the readers’ understanding

Direct trifluoroethylation of carbonyl sulfoxonium ylides using hypervalent iodine compounds

• Radell Echemendía,
• Carlee A. Montgomery,
• Fabio Cuzzucoli,
• Antonio C. B. Burtoloso and
• Graham K. Murphy

Beilstein J. Org. Chem. 2024, 20, 3182–3190, doi:10.3762/bjoc.20.263

• deprotonation would complete the pathway. The alternative mechanistic proposal is an SN2 reaction [40][41][42] between 1a and the iodonium ion 2a’, which directly furnishes B without invoking halogen bonded adducts. To assess which of these mechanistic possibilities was more probable, we turned to computational

• easily available 2,2,2-trifluoroethyl(mesityl)iodonium triflate reagent enabled the straightforward trifluoroethylation of diverse sulfoxonium ylides under mild conditions and short reaction times. Various computational strategies were also employed to differentiate between competing halogen bond

• Information File 32: Experimental part, NMR spectra, computational details and crystallgraphic data. Acknowledgements We would like to acknowledge the Schipper lab at the University of Waterloo for providing access to the microwave reactor used in this study. We would also like to acknowledge Boris Ragula

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

• is more nuanced [10][11]. Subsequently, literature and computational examples reveal a leitmotif for CpH-PAH-based redox-active carbon-rich materials. Results and Discussion From competitive titrations against 9-C6F5-fluorene (pKa = 28.14 in CH3CN) [12][13] and (4-Me-C6F4)(C6H5)CHCN (pKa = 26.98 in

• , however, using them in reverse. The standard uncertainty estimates of the pKa values of FIC and BFC in DMSO are 0.8 pKa units. Synthesis Material used to measure the acidity of compounds BFC and FIC was prepared previously by methods reported in reference [9]. Computational methods The structural and

• aromatic hydrocarbon acidities I. Results of pKa measurements in acetonitrile. Acknowledgements High-performance computational work was carried out using the supercomputer at SPST Tianjin University. Funding Experimental work at Tartu was carried out using the instrumentation at the Estonian Center of

Controlled oligomerization of [1.1.1]propellane through radical polarity matching: selective synthesis of SF₅- and CF₃SF₄-containing [2]staffanes

• Jón Atiba Buldt,
• Wang-Yeuk Kong,
• Yannick Kraemer,
• Masiel M. Belsuzarri,
• Ansh Hiten Patel,
• James C. Fettinger,
• Dean J. Tantillo and
• Cody Ross Pitts

Beilstein J. Org. Chem. 2024, 20, 3134–3143, doi:10.3762/bjoc.20.259

• truncated after incorporation of two bicyclopentane (BCP) units. Synthetic and computational studies suggest this phenomenon can be attributed to alternating radical polarity matching. In addition, single-crystal X-ray diffraction (SC-XRD) data reveal structurally interesting features of the CF3SF4

• activation alone. Overall, our results suggest that this alternating polarity matching effect is subtle and subject to mitigation yet can lead to desirable products if employed thoughtfully. Lastly, following our synthetic and computational studies, accessing a CF3SF4-containing [2]staffane in good yield and

• synthetic and computational study demonstrates that selective one-pot syntheses of [2]staffanes can be achieved when employing reagents that serve as radical sources of "extreme" electron-withdrawing groups (e.g., SF5 or CF3SF4), which impact relative philicities of the bicyclopentyl radical intermediates

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• combination of computational and experimental methods to study the electrocatalytic activity of the hydrogen evolution reaction (HER) catalyzed by free base 5,10,15-tris(pentafluorophenyl)corrole (98) [112]. Their work showed that using p-toluenesulfonic acid as the proton source, 98 was able to produce

Enantioselective regiospecific addition of propargyltrichlorosilane to aldehydes catalyzed by biisoquinoline N,N’-dioxide

• Noble Brako,
• Sreerag Moorkkannur Narayanan,
• Amber Burns,
• Layla Auter,
• Valentino Cesiliano,
• Rajeev Prabhakar and
• Norito Takenaka

Beilstein J. Org. Chem. 2024, 20, 3069–3076, doi:10.3762/bjoc.20.255

• % yield with 61:39–92:8 enantiomeric ratios. Furthermore, possible mechanisms of propargyl–allenyl isomerization of propargyltrichlorosilane were computationally investigated. Keywords: α-allenic alcohol; computational chemistry; Lewis base catalysis; organocatalysis; propargyltrichlorosilane

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• ]. Last but not least, predicted polyketide structures can be synthesized in a streamlined and automated fashion by using a microfluidic device reported by Burke and co-workers [84][85]. As such, the necessary computational and synthetic tools are all in place to examine the PK chemical space and to

Tailored charge-neutral self-assembled L₂Zn₂ container for taming oxalate

• David Ocklenburg and
• David Van Craen

Beilstein J. Org. Chem. 2024, 20, 3007–3015, doi:10.3762/bjoc.20.250

• Information Supporting Information File 2: Synthetic protocols, characterization data, NMR spectra, guest binding investigations, data fitting, and computational modeling details. Funding The authors are grateful for financial support by the Fonds der Chemischen Industrie (FCI) through a Liebig grant and the

Structure and thermal stability of phosphorus-iodonium ylids

• Andrew Greener,
• Stephen P. Argent,
• Coby J. Clarke and
• Miriam L. O’Duill

Beilstein J. Org. Chem. 2024, 20, 2931–2939, doi:10.3762/bjoc.20.245

• in this decomposition, which will be elucidated with future computational studies. It was, however, found that the torsion angle φ (or ‘hypervalent twist’) between the plane of the arene substituent and the hypervalent 3-centre-4-electron bond was instrumental: When the arene ring was locked in the

The charge transport properties of dicyanomethylene-functionalised violanthrone derivatives

• Sondos A. J. Almahmoud,
• Joseph Cameron,
• Dylan Wilkinson,
• Michele Cariello,
• Claire Wilson,
• Alan A. Wiles,
• Peter J. Skabara and
• Graeme Cooke

Beilstein J. Org. Chem. 2024, 20, 2921–2930, doi:10.3762/bjoc.20.244

• hindered charge transport. Experimental Computational Density functional theory (DFT) calculations were performed using Gaussian 09 software. Molecular geometries were initially optimised semi-empirically (AM1) and then reoptimised by DFT using the B3LYP method with the 6-311G(d,p) basis set unless stated

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

Young investigators in natural products chemistry, biosynthesis, and enzymology

• Jeffrey D. Rudolf,
• Lena Barra and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 2720–2721, doi:10.3762/bjoc.20.229

• clusters, and enzymes, development of chemical probes, biocatalysis and chemoenzymatic total synthesis, enzymatic mechanisms, and computational investigations of chemical structures and reactions. All of the major classes of natural products are represented here: nonribosomal peptides, ribosomally

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

• an asymmetric FLP and consequently an asymmetric catalyst. The subsequent study explores the asymmetric insertion of CO2 into chiral PO catalysed by the proposed in silico designed catalyst. Computational Details During the benchmark to choose the best catalyst, the reported geometries were optimised

• -D3(BJ)/def2-SVP computational level. Single point energy calculations on the optimised structures were run at the B3LYP-D3(BJ)/def2-TZVP level to obtain more accurate electronic energies. The reported free energies in this section correspond to the sum of the triple-zeta electronic energy and the

• minimise the computational costs associated with the study, the asymmetric catalyst was obtained by removing a phenyl group and exchanging the t-Bu group with a methyl group in the catalyst of Gao [28]. It appears that the capture of CO2 by the catalyst is barrierless and results in the formation of an

Deciphering the mechanism of γ-cyclodextrin’s hydrophobic cavity hydration: an integrated experimental and theoretical study

• Stiliyana Pereva,
• Stefan Dobrev,
• Tsveta Sarafska,
• Valya Nikolova,
• Silvia Angelova,
• Tony Spassov and
• Todor Dudev

Beilstein J. Org. Chem. 2024, 20, 2635–2643, doi:10.3762/bjoc.20.221

• complex is formed [11]. This suggests that hydration of CDs remains an important factor, especially given a recent study that showed how hydration history contributes to the hydration ability of α-CD [12]. Numerous experimental and computational studies have investigated the hydration of natural and

• upon heating. Conclusion Using experimental and computational methods as well as available literature data, the present study reliably estimates the number of water molecules present in γ-CD, their preferable binding position, and thermal stability. Comparison with the other cyclodextrins revealed that

• atmosphere of pure nitrogen. To ensure accuracy and reproducibility of the results the measurements were repeated multiple times, and no difference was observed between individual trials. Computational details A computational protocol similar to that used in our previous work on α-CD [13] and β-CD [14

Applications of microscopy and small angle scattering techniques for the characterisation of supramolecular gels

• Connor R. M. MacDonald and
• Emily R. Draper

Beilstein J. Org. Chem. 2024, 20, 2608–2634, doi:10.3762/bjoc.20.220

Anion-dependent ion-pairing assemblies of triazatriangulenium cation that interferes with stacking structures

• Yohei Haketa,
• Takuma Matsuda and
• Hiromitsu Maeda

Beilstein J. Org. Chem. 2024, 20, 2567–2576, doi:10.3762/bjoc.20.215

• NMR spectra of new ion pairs, details for crystal structures, and theoretical calculations. Acknowledgements Theoretical calculations were partially performed at the Research Center for Computational Science, Okazaki, Japan (Projects: 22-IMS-C077, 23-IMS-C069, and 24-IMS-C067). The synchrotron