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

• rates and to make precise predictions using ML models. Traditionally, the optimization of a chemical reaction, the development of kinetic models, and optimization of analytical characterization parameters are undertaken independently. With this approach, many overlapping tasks are performed in parallel

• , thus leading to long lead times and inefficient personnel allocation. To overcome these issues, Sagmeister et al. [72] developed a dual modelling approach using a single platform that seamlessly integrates the calibration of PAT, reaction optimization, kinetic modelling, and parametrizes a process

• , using a scientific programming language called Julia, the collected data can be fitted to the kinetic model parameters, and in silico optimization of the reaction parameters can be performed. Machine-learning-driven optimization of chemical reactions Historically, optimization of chemical reactions has

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• calculations also revealed that due to kinetic control the activation of the C2 carbon of the dienolate is preferred vs the C4 atom, therefore only one regioisomer is observed. Additionally, the asymmetric IEDADA reaction could be performed at a higher scale (1 mmol) leading to the synthesis of the

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

• here that the free energy of activation is lower for chlorination, albeit only by 0.4 kcal/mol. This is consistent with the notion that the kinetic preference can be overcome by increasing the concentration of 1 relative to CF3SF4Cl. In the second product-determining step, Cl atom abstraction by INT5

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

• concluded that both the presence of hydrogen-bond donor moieties (pyrrolic –NH groups) and a basic β-substituent are necessary to make the compound catalytically active. Further, authors have performed 1H NMR binding and kinetic studies and suggested that the reaction mechanism involves a simultaneous

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

• ][15][16][17][18][19], the separation of which is by no means trivial [20] (Scheme 1). Nonetheless, substituents at the carbon atom indicated by γ (R2) of these reagents have been shown to bias the metallotropic rearrangement and/or the kinetic reactivity of the competing regioisomeric intermediates

• propargyltrichlorosilane [35][36] (Scheme 2). Other notable asymmetric catalytic approaches to prepare α-allenic alcohols (R2 = H) include the Corey–Bakshi–Shibata reduction of allenyl ketones [37], enzymatic [38][39][40], non-enzymatic [41] kinetic resolution of racemic α-allenic alcohols, and asymmetric 1,4

Extension of the π-system of monoaryl-substituted norbornadienes with acetylene bridges: influence on the photochemical conversion and storage of light energy

• Robin Schulte,
• Dustin Schade,
• Thomas Paululat,
• Till J. B. Zähringer,
• Christoph Kerzig and
• Heiko Ihmels

Beilstein J. Org. Chem. 2024, 20, 3061–3068, doi:10.3762/bjoc.20.254

• that the triplet energy of 1i is significantly lower than 2.4 eV and even triplet sensitizers with lower triplet energies than that of [Ru(phen)3](PF6)2 could be employed for this reaction, which might even allow red light-driven switching. In addition to these kinetic studies, the photoisomerization

• intersystem crossing (ISC), internal conversion (IC), or quenching by structural relaxation, etc. Finally, the half-life, t1/2, of the quadricyclane derivatives 2h–l,n was determined by kinetic analysis of the thermally induced cycloreversion to the corresponding norbornadiene derivatives 1h–l,n at 60 °C

Cyclodextrin-based rotaxanes for polymer materials: challenge on simultaneous realization of inexpensive production and defined structures

• Yosuke Akae

Beilstein J. Org. Chem. 2024, 20, 3026–3049, doi:10.3762/bjoc.20.252

• reported the pseudorotaxane equilibrium observed by mixing α-CD and the axle molecules bearing methylpyridinium moieties on their ends, where the bigger rim of CD (the head side) was likely to include the dumbbell (Figure 8A) [71][72]. Concurrently, Komiyama and co-workers performed the kinetic analysis of

• , and its dynamic nature was comprehensively clarified by thermodynamic analysis. This motivated us to integrate this motif into the polymer system. Further details of the thermodynamic analyses with the actual kinetic parameters are discussed in the original articles [46][47]. To integrate this motif

• after the de-crosslinking of the gel. In addition to the qualitative observation by the naked eye, the quantitative kinetic analysis of this decrosslinking was conducted by fluorescence spectroscopy. Such a quantitative study became possible thanks to the defined rotaxane structure, which supported the

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• -exchanged Montmorillonite K10 [63] were presented (Scheme 19). Chemical and kinetic data confirm that the mechanisms of the described processes are probably of a radical nature with the formation of MOO-t-Bu complexes [61]. The proposed pathway of the peroxidation is shown on the example of 9-substituted

4,6-Diaryl-5,5-difluoro-1,3-dioxanes as chiral dopants for liquid crystal compositions

• Maurice Médebielle,
• Peer Kirsch,
• Jérémy Merad,
• Carolina von Essen,
• Clemens Kühn and
• Andreas Ruhl

Beilstein J. Org. Chem. 2024, 20, 2940–2945, doi:10.3762/bjoc.20.246

• still remain elusive and are not well understood [29]. Recently we have become interested in the preparation of racemic [30] anti- and highly enantioenriched 2,2-difluoro-1,3-diols [30][31][32] through an acylative double catalytic kinetic resolution (DoCKR) process [33]. While the 1,3-diol motif is

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• stereocenter of the product is controlled by the catalyst. A single crystal of Cu(I) was investigated by X-ray and proved to be the dicopper complex, while the Cu(II) catalyst was revealed as mononuclear copper coordinated with two ligands. Further kinetic isotope experiments and nonlinear relationship studies

• confirmed that a copper–ligand monomer complex exists in the mechanism through nonlinear relationship experiments and kinetic studies (Scheme 17). He et al. [68] developed the regio- and enantioselective monofluoroalkylation of yne-allylic esters using fluorinated malonates as the starting materials, giving

• showed that the reaction exhibits a negative nonlinear effect, while the kinetic experiments indicate that a mono-copper catalyst might be involved in the rate-limiting step. They speculated that the observed nonlinear effect might arise from the existence of both the inactive homo-dimer of ligands and

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

• Boltzmann constant, T is the temperature in Kelvin, h is the Planck constant, and R is the gas constant. The enantiomeric excess (%ee) was calculated using Equation 2 [41]. kfav stands for the kinetic rate constant of the most favourable process, and kdefav stands for the rate constant of the less

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

• could CLSM observe the initial kinetic self-sorting of gelators, but it also showed that the homogenous mixture of NFs and CFs can undergo a higher level of self-sorting, resulting in macroscopic phase separation (Figure 4). To gather a three-dimensional surface profile of a material, AFM utilises a

• understanding of the kinetic processes probed by such in situ investigations are essential to understanding the relationship between gel structure and their bulk properties [71]. As discussed previously, scattering provides bulk-averaged information that is a statistical average of the structures across the

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• amide at both the oxygen and the nitrogen, however, the ΔG‡ value for the latter was lower by 2.5 kcal·mol−1. This demonstrates a clear kinetic preference for formation of the five-membered ring over the seven-membered one [19]. Subsequent deprotonation of 11 leads to tertiary amide 12. Upon cyclization

• , the iodane moiety in 12 is eliminated by an intramolecular attack by the amide nitrogen to form the aziridinium 13. Finally, ring-opening by SN2 attack of trifluoroacetate leads to the final product 14 [20]. In this case, the kinetic pyrrolidine product is obtained due to the electron-withdrawing

Phenylseleno trifluoromethoxylation of alkenes

• Clément Delobel,
• Armen Panossian,
• Gilles Hanquet,
• Frédéric R. Leroux,
• Fabien Toulgoat and
• Thierry Billard

Beilstein J. Org. Chem. 2024, 20, 2434–2441, doi:10.3762/bjoc.20.207

• oxygen atom which disfavors the episelenonium opening with the CF3O− anion in the closest position to the oxygen atom. It is noteworthy that the regioisomeric ratio of terminal alkenes (2e, 2i) evolved with the reaction time. The amount of the kinetic terminal regioisomer (anti-Markovnikov – 2e’, 2i

• ’) decreases with time in favor of the thermodynamic Markovnikov regioisomer (2e, 2i). This phenomenon cannot occur for products 2g and 2h because the kinetic and thermodynamic products are the same. This observation confirms the existence of an equilibrium between the episelenonium and the final products 2

Homogeneous continuous flow nitration of O-methylisouronium sulfate and its optimization by kinetic modeling

• Jiapeng Guo,
• Weike Su and
• An Su

Beilstein J. Org. Chem. 2024, 20, 2408–2420, doi:10.3762/bjoc.20.205

• its control difficult and risky. In this paper, a homogeneous continuous flow microreactor system was developed for the nitration of O-methylisouronium sulfate under high concentrations of mixed acids, with a homemade static mixer eliminating the mass transfer resistance. In addition, the kinetic

• modeling of this reaction was performed based on the theory of NO2+ attack, with the activation energy and pre-exponential factor determined. Finally, based on the response surface generated by the kinetic model, the reaction was optimized with a conversion of 87.4% under a sulfuric acid mass fraction of

• 94%, initial reactant concentration of 0.5 mol/L, reaction temperature of 40 °C, molar ratio of reactants at 4.4:1, and a residence time of 12.36 minutes. Keywords: continuous flow; kinetic modeling; nitration; reaction optimization; static mixer; Introduction The demand for high-quality

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

• for the resolution of chiral amines [28]. However, it was not until 2004 that they were recognised as efficient chiral Brønsted acid organocatalysts for asymmetric Mannich reactions [29]. Malkov and co-workers revealed [30] that (R)-TRIP can act as a very efficient catalyst for the kinetic resolution

• -substituted aldimines. This was later addressed by the same researchers [15], who developed an organocatalytic kinetic resolution of secondary boronates to furnish bench-stable homochiral (S)-35. The latter were then employed in the asymmetric allylation of in situ-formed primary aldimines 37, leading

• directly to the unprotected chiral (S,Z)-homoallylic amines 38 in high yields and with an excellent retention of the enantiopurity (Scheme 8B). The method remains the only direct Z-selective crotylation to attain enantioenriched unprotected homoallylic amines, and the only example of an effective kinetic

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• ][5]. The transient impact of kinetic energy, channeled into the reaction, facilitates overcoming the constraints inherent in equilibrium models. Thus, employing limited substrates could potentially yield diverse products through a simple alteration of conditions, compared to solvent-based methods [6

• for unconventional reaction pathways by exploiting kinetic energy to surpass equilibrium constraints. This methodology presents several advantages over conventional solvent-based approaches, including the potential for diverse product formation with limited substrates and the development of

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

• , the interest to describe the influence of substrate or catalyst structures on the rate or selectivity of a reaction is well-established and led among others to the introduction of Hammett parameters to relate chemical structures to both kinetic and thermodynamic reaction properties [28] (Figure 4). As

• enantioselectivities of a kinetic resolution of benzyl alcohols and an enantiodivergent fluorination of allylic alcohols, observing good correlations for both reactions. Since then, the proposed NCI descriptors have been successfully applied to multiple different reactions, such as an allenoate Claisen rearrangement

• have also been used to predict the Mayr–Patz nucleophilicity parameter N, which estimates the nucleophilicity of a nucleophile based on experimentally measured kinetic data. The MLR models are used to predict N for more than 1200 nucleophiles, enabling the prediction of N for further nucleophiles [98

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• significantly enhanced metabolic stability, a key parameter for property-based design efforts. Keywords: deuterated aldehydes; deuterated formamides; deuterated isocyanides; DHPs; kinetic isotope effect; Leuckart–Wallach; microsomal stability; multicomponent reactions; Introduction Multicomponent reactions

• drug-like compounds with synthetic ease [5][6]. In recent years use of deuterium in drug discovery has expanded beyond mechanistic and tracer studies to deuterium incorporation in small molecules in attempts to hijack the deuterium kinetic isotope effect to induce longer drug t1/2 and greater systemic

• this position was thought a reasonable approach to extend drug t1/2 through exploitation of the kinetic isotope effect underpinned by the C–D bond being slightly shorter and stronger than a C–H bond. Such site-specific labeling was hypothesized to slow CYP3A4 metabolism. To evaluate the hypothesis

Cell-free protein synthesis with technical additives – expanding the parameter space of in vitro gene expression

• Tabea Bartsch,
• Stephan Lütz and
• Katrin Rosenthal

Beilstein J. Org. Chem. 2024, 20, 2242–2253, doi:10.3762/bjoc.20.192

• , batch-to-batch reproducibility, and reliable kinetic modelling of the system [10][11]. Furthermore, the transferability of CFPS screening results to the cells is limited but important, as in vivo production is often required for preparative scale applications [11][12]. To date, the description of CFPS

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

• . Synthesis of DBA 5. Mechanical properties of PVA-N3 before and after crosslinking. Supporting Information Supporting Information File 70: Experimental section and kinetic study of the reaction of compound 5 and benzyl azide. Funding This work was partially supported by NEDO (grant number 23200050-0), the

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

• difficult to synthesise but remains stable, forming the support around it is advisable [67]. Another limitation of the encapsulation method is that the size of the pore openings in the support must be smaller than the kinetic size of the immobilised catalyst [77]. Covalent tethering is a method of bonding

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

• character of TsO− and triphenylphosphine oxide, precluding any thermodynamic versus kinetic arguments for regioselectivity. Conclusion We have established highly regioselective N1- and N2-alkylations of methyl 5-bromo-1H-indazole-3-carboxylate from diverse commercially available alcohols with excellent

Electrochemical radical cation aza-Wacker cyclizations

• Sota Adachi and
• Yohei Okada

Beilstein J. Org. Chem. 2024, 20, 1900–1905, doi:10.3762/bjoc.20.165

• representative radical cation precursors that are widely used to realize the formation of unique bonds. The respective radical cations are trapped by various nucleophiles under radical and/or ion control, where kinetic and/or thermodynamic effects are expected to be dominant. Typical examples that clearly show

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

• diaryliodonium triflates such as 8 and 9 [13]. They studied a model reaction with 2-aminopyridine (1), p-tolualdehyde (10) and cyclohexyl isocyanide (11) both experimentally (by binding and kinetic studies) and theoretically (by density functional theory (DFT) calculations) (Scheme 5). Catalyst 8 was found to be

• no loss of activity after 30 days. On the other hand, reusability seemed problematic, as significant decrement in yield was observed after the second cycle. Kinetic target-guided synthesis (KTGS) has emerged as a promising strategy in drug discovery [24]. It relies on a drug target serving as a