Machine learning-guided strategies for reaction conditions design and optimization

• Lung-Yi Chen and
• Yi-Pei Li

Beilstein J. Org. Chem. 2024, 20, 2476–2492, doi:10.3762/bjoc.20.212

• compute reaction enthalpy for particular types of reactions [30], this approach often demands significant computational resources to determine accurate TSs and activation energies. The complexity increases further when considering the impacts of solvents and catalysts, which means that large-scale

• -scale global models, descriptors with longer feature lengths and higher computational efficiency, such as the first four methods, are preferred. However, for small-scale local models, QM features can offer more compact and accurate information, but they require sampling and optimizing the 3D conformers

• -driven approaches in chemistry. A community dedicated to openly sharing data and findings will likely accelerate innovation and enhance the robustness of ML tools. Moreover, computational models that integrate theoretical chemistry and ML could unlock deeper insights into poorly understood or complex

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• (trifluoromethylphenyl) group with other fluorinated aromatics (86–90) showed a gradual decrease in ee (92% ee in 90 to 68% ee in 86 and 88) depending on the degree of fluorination. Computational modelling for the 3,5-bis(trifluoromethylphenyl) catalyst 78 revealed that π-stacking interactions of the 4-pyrene group with

• ]-rearrangement of ene-aldimines 149, catalysed by the BINOL-derived chiral phosphoric acid (CPA) (R)-151 (Scheme 31) [46]. DFT computational analysis suggested that the reaction proceeds via a complex cascade that involves the fragmentation of ene-aldimine 149 to form an imine methylene cation, which in turn

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• and reliable development is highly desirable [16]. In the spirit of accelerated discovery, the development of organocatalysts has been augmented with computational catalyst design [17][18]. Multiple programs for automated catalyst simulation have been developed in the last decade. Notable examples

• reduce the number of required experiments. As such, these methods contribute to the acceleration of catalyst discovery, for example through high-throughput virtual screening. Predating these computational techniques is the desire to understand and explain experimental outcomes in organic chemistry with

• data is paramount for predictive modelling. Depending on the problem at hand, different sources of data are available (Figure 1). Apart from experimental data, the creation of large amounts of in silico data is possible with sufficient computational resources [31][32]. While this approach is useful in

Synthesis and reactivity of the di(9-anthryl)methyl radical

• Tomohiko Nishiuchi,
• Kazuma Takahashi,
• Yuta Makihara and
• Takashi Kubo

Beilstein J. Org. Chem. 2024, 20, 2254–2260, doi:10.3762/bjoc.20.193

• Research Areas (A) (Grant Number JP20H05865, T. K.), and by research grant from The Murata Science Foundation (T. N.). Quantum chemical calculations were performed at the Research Center for Computational Science, Okazaki, Japan (Project: 23-IMS-C212 and 24-IMS-C214). This work was the result of using

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• substituents has a lower Ea than DBA with electron-donating substituents. DFT calculations The reaction mechanism was investigated by computational calculations. The reaction mechanism between 5 and benzyl azide was supported by the ωB97X-D/6-31G(d,p) calculations with the CH2Cl2 polarizable continuum model

Heterocycle-guided synthesis of m-hetarylanilines via three-component benzannulation

• Andrey R. Galeev,
• Maksim V. Dmitriev,
• Alexander S. Novikov and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2024, 20, 2208–2216, doi:10.3762/bjoc.20.188

• with heterocyclic substituents, acetone and various amines has been developed. The success of this three-component reaction is governed by the electron-withdrawing ability of the heterocyclic substituent in the 1,3-diketone, which can be evaluated with computational Hammett constants. As a rule-of

Finding the most potent compounds using active learning on molecular pairs

• Zachary Fralish and
• Daniel Reker

Beilstein J. Org. Chem. 2024, 20, 2152–2162, doi:10.3762/bjoc.20.185

• through iterative design. Beyond pharmaceutical design, we expect these methods to be easily deployable for other chemical endeavors to support material design and prioritization. Although pairwise methods like ActiveDelta exhibit increased computational costs during active learning given the

• complex computational architectures with improved hit retrieval rates in place of faster, but less effective, architectures should continue to be a good choice for most real-world projects. In the future, subsampling techniques may be employed to reduce computational costs and even potentially improve

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

• online software ProTox 3.0 for computational toxicity assessment of the products as their LD50 values. The tested compounds mainly belong to the 4th class of acute oral toxicity with 300 < LD50 ≤ 2000 mg/kg. In addition, we used MolPredictX (https://www.molpredictx.ufpb.br) [46] to evaluate potential

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• numerous biological processes, ranging from cellular recognition to immune response modulation. Understanding the intricate details of these interactions is crucial for deciphering the molecular mechanisms underlying various physiological and pathological conditions. Computational techniques have emerged

• as powerful tools that can help in drawing, building and visualising complex biomolecules and provide insights into their dynamic behaviour at atomic and molecular levels. This review provides an overview of the main computational tools useful for studying biomolecular systems, particularly glycans

• simulations and analyse the corresponding results. The presented computational toolbox represents a valuable resource for researchers studying protein–glycan interactions and incorporates advanced computational methods for building, visualising and predicting protein/glycan structures, modelling protein

Allostreptopyrroles A–E, β-alkylpyrrole derivatives from an actinomycete Allostreptomyces sp. RD068384

• Marwa Elsbaey,
• Naoya Oku,
• Mohamed S. A. Abdel-Mottaleb and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2024, 20, 1981–1987, doi:10.3762/bjoc.20.174

• , Japan Computational Chemistry Lab, Department of Chemistry, Faculty of Science, Ain Shams University, 11566 Abbassia, Cairo, Egypt 10.3762/bjoc.20.174 Abstract Five new β-alkylpyrrole derivatives, allostreptopyrroles A–E (1–5), were isolated from the culture broth of Allostreptomyces RD068384. Their

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• Pengcheng Lu Luis Juarez Paul A. Wiget Weihe Zhang Krishnan Raman Pravin L. Kotian Department of Discovery Chemistry, BioCryst Pharmaceuticals Inc., Discovery Center of Excellence, 2100 Riverchase Center Building 200, Suite 200 Birmingham, AL, 35244, USA Department of Computational Chemistry and

Hetero-polycyclic aromatic systems: A data-driven investigation of structure–property relationships

• Sabyasachi Chakraborty,
• Eduardo Mayo Yanes and
• Renana Gershoni-Poranne

Beilstein J. Org. Chem. 2024, 20, 1817–1830, doi:10.3762/bjoc.20.160

• on a range of electronic molecular properties of PASs. Keywords: computational chemistry; database; dataset; π-conjugated; polycyclic aromatic hydrocarbons; polycyclic aromatic systems; Introduction Polycyclic aromatic systems (PASs) – molecules made up of fused aromatic rings – are among the most

• PAS chemical space is with data-driven methods, which have proven in the last few years to be extremely successful at uncovering underlying structure–property relationships. To enable such exploration, we initiated the COMPAS Project (COMputational database of PASs), the first database dedicated to

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• steroids 124a–e, adducts 125a–d and 126a–e were easily obtained as single diastereomers via a Pictet–Spengler condensation with coumarins A and B (used as fluorophores) under acidic conditions (Scheme 35). Computational binding studies of compound 126c in the ligand-binding pocket of enzyme 17β-HSD5

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty

• Weimao Zhong and
• Vinayak Agarwal

Beilstein J. Org. Chem. 2024, 20, 1635–1651, doi:10.3762/bjoc.20.146

• publicly available which are typically 5 Mbp in size. Computational mining these genomes with antiSMASH reveals that these bacteria, though not endowed with the biosynthetic prowess of actinomycetes, do still possess BGCs encoding NRPS-derived peptides, polyketides, RiPPs, and siderophores [4][147]. A

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• methods are evaluated as single-point calculations or optimization and frequency calculations. For comprehensive details, refer to Supporting Information File 1, section “Benchmark study - computational methods”. Hereafter, we check the geometries for imaginary frequencies and use the total thermal energy

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

• Evgen V. Govor,
• Vasyl Naumchyk,
• Ihor Nestorak,
• Dmytro S. Radchenko,
• Dmytro Dudenko,
• Yurii S. Moroz,
• Olexiy D. Kachkovsky and
• Oleksandr O. Grygorenko

Beilstein J. Org. Chem. 2024, 20, 1604–1613, doi:10.3762/bjoc.20.143

• -component reactions are very effective for the generation of synthetically tractable ultra-large chemical space [30][31][32]. Such virtual but readily accessible (REAL) compound libraries demonstrated excellent performance in early drug discovery programs when combined with modern computational tools such

• the relatively high computational costs of this method, we randomly selected 50,000 compounds to represent each database. The dimension reduction algorithm uses molecular features as the starting inputs to generate a few coordinates (in this case, t-SNE1 and t-SNE2) reflecting the probability of the

Divergent role of PIDA and PIFA in the AlX₃ (X = Cl, Br) halogenation of 2-naphthol: a mechanistic study

• Kevin A. Juárez-Ornelas,
• Manuel Solís-Hernández,
• Pedro Navarro-Santos,
• J. Oscar C. Jiménez-Halla and
• César R. Solorio-Alvarado

Beilstein J. Org. Chem. 2024, 20, 1580–1589, doi:10.3762/bjoc.20.141

• influence of PIDA and PIFA in the chlorination and bromination reactions. Interestingly, we found an excellent agreement between the theoretical predictions and the experimental results. Results and Discussion Computational details The equilibrium geometry of reagents and products, the stationary points

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• stereoisomers to influence preferred conformations when designing functional molecules. Experimental Computational details The benchmark study was conducted for 3-fluoropyrrolidine and 3-fluoropyrrolidinium cation to determine the optimal theoretical level for further investigations involving 2,3-, 2,4-, and

Predicting bond dissociation energies of cyclic hypervalent halogen reagents using DFT calculations and graph attention network model

• Yingbo Shao,
• Zhiyuan Ren,
• Zhihui Han,
• Li Chen,
• Yao Li and
• Xiao-Song Xue

Beilstein J. Org. Chem. 2024, 20, 1444–1452, doi:10.3762/bjoc.20.127

• transfer capacity and chemical stability of different cyclic hypervalent halogen reagents. Results and Discussion We selected five different skeletons and twenty common transfer groups for combination (Figure 2) and calculated their BDEs. Referring to the previous computational studies of hypervalent

• iodine [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] and the computational database of organic species by Paton and co-workers [77], geometry optimizations and single point energy calculations for homolytic BDEs are both performed using M06-2X/def2-TZVPP [78][79][80] in the gas phase

• at 298.15 K by Gaussian 16 [81]. Frequency calculations confirmed that optimized structures are minima (no imaginary frequency). The accuracy of computational BDEs of halides using M06-2X/def2-TZVPP is also evaluated and compared to experimental BDEs, demonstrating the reliability of the method (see

A comparison of structure, bonding and non-covalent interactions of aryl halide and diarylhalonium halogen-bond donors

• Nicole Javaly,
• Theresa M. McCormick and
• David R. Stuart

Beilstein J. Org. Chem. 2024, 20, 1428–1435, doi:10.3762/bjoc.20.125

• . Comparison of E(r) for XB complexes 9–12, 42–44, and 53–56. Correlation of p-character and Vs,max on X of XB donor with ΔG of XB bond. Model for ΔG based on Equation 1. Supporting Information Supporting Information File 21: Computational data. Supporting Information File 22: Coordinates of optimized

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• (S10 OD021758-01A1), and Jodie Johnson for GC–MS support. We thank Wenbo Ning for measuring the melting point of 9. Funding This work was funded in part by NIH grant R35 GM142574 (to J.D.R.), NSF grant CHE-1856416 (to D.J.T.), and NSF CHE-2020110 (to S.L.). Computational resources were provided by NSF

Diameter-selective extraction of single-walled carbon nanotubes by interlocking with Cu-tethered square nanobrackets

• Guoqing Cheng and
• Naoki Komatsu

Beilstein J. Org. Chem. 2024, 20, 1298–1307, doi:10.3762/bjoc.20.113

• (Figure 5b). Computational methods The geometry optimization and frequency analysis of Cu-nanobrackets 1a and 1b were performed at (U)ωB97X-D/6-31+G(d,p)-SDD(Cu) [30][31][32][33] level using the Gaussian 16 program [34], with calculating the pre-resonance Raman activities at 488 nm excitation wavelength

Synthesis of indano[60]fullerene thioketone and its application in organic solar cells

• Yong-Chang Zhai,
• Shimon Oiwa,
• Shinobu Aoyagi,
• Shohei Ohno,
• Tsubasa Mikie,
• Jun-Zhuo Wang,
• Hirofumi Amada,
• Koki Yamanaka,
• Kazuhira Miwa,
• Naoyuki Imai,
• Takeshi Igarashi,
• Itaru Osaka and
• Yutaka Matsuo

Beilstein J. Org. Chem. 2024, 20, 1270–1277, doi:10.3762/bjoc.20.109

• -withdrawing substituents. Computational studies with density functional theory revealed the unique vibrations of the thioketone group in FIDS. The molecular structure of FIDS was confirmed by single-crystal X-ray analysis. Bulk heterojunction organic solar cells using three evaporable fullerene derivatives

Mechanistic investigations of polyaza[7]helicene in photoredox and energy transfer catalysis

• Johannes Rocker,
• Till J. B. Zähringer,
• Matthias Schmitz,
• Till Opatz and
• Christoph Kerzig

Beilstein J. Org. Chem. 2024, 20, 1236–1245, doi:10.3762/bjoc.20.106

• Aza-H•+ (red) were computed using TD-DFT (see Supporting Information File 1 for details). These computational results, which are included in Figure 1B, align well with the experimentally observed absorption bands in the visible region, supporting our assignment. The observed behavior of the Aza-H

Competing electrophilic substitution and oxidative polymerization of arylamines with selenium dioxide

• Vishnu Selladurai and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2024, 20, 1221–1235, doi:10.3762/bjoc.20.105

• interactions are rarely reported and currently gaining interest [59]. Computational studies To comprehend the role of electron-donating and -withdrawing groups in arylamine oxidation using SeO2 as oxidant, DFT calculations were carried out on the arylamines and SeO2 using Gaussian 16 [60]. The molecular