Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• involves the regioselective nucleophilic attack of allylaluminum C on tosyl cyanide, which proceeds at the γ-position via six-membered ring transition state D, leading to the formation of the desired nitrile product. Transition state D is responsible for the E-selectivity observed in trisubstituted allenes

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• later stages of the catalytic cycle, are less likely to racemize without bond breaking. The barrier to pyramidal inversion has been found to be 15.1 kcal·mol−1. Berry rotation itself proceeds via a tetragonal pyramid as transition-state structure and does therefore not occur here. A second isocyanide

• bond. One of the most important quantities which allows comparison with experimental data is enantioselectivity. The most favorable TS 9-10 is that which leads to the "S"-configured product, when the substrate is Z-hydrazone. Product of opposite handedness is reached via a transition state, 1.0

• kcal·mol−1 higher in energy, resulting in a theoretical ee value of 74% (at 263 K), if pure Z-hydrazone would be used and under the assumption of kinetic reaction control. In contrast, the E-hydrazone gives preferably the "R" product (with a theoretical ee value of 64%). The transition state which gives

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

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• ligand L3 and the allylic electrophile 35. In contrast, a si-face attack leads to a higher-energy transition state due to significant steric repulsion. Enantioselective hydroallylation of vinyltrifluoromethyl compounds The direct functionalization of 1-trifluoromethylalkenes 38 through copper catalysis

• transition states: an open transition state TS7 facilitated by LiOt-Bu and a closed transition state TS6 without base assistance (Scheme 17a). The significant energy difference between these pathways (ΔΔG‡ = 4.3 kcal/mol) strongly favors the open transition state TS7 mechanism, attributed to reduced steric

• energy compared to (S,S)-TS9. Both transition states demonstrated a lithium center's coordination involving bromide, benzoate, and ligand oxygen atoms. The (S,R)-TS8 transition state exhibited a significantly shorter Li–Br interaction distance (2.81 Å compared to 3.74 Å in (S,S)-TS9), offering

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• organized polarization rather than “confinement,” specifically positing that oriented electric fields rule transition-state stabilization for many reactions [33][34][35]. These fields stabilize charge redistribution during a reaction, usually at a small locus of each substrate molecule. It follows

• groups) with little [73], if any, transition-state binding [36][80][81]. Thus, these macrocycles depend on the catalytic concept of organization; polarization is a minor contributor. Size-exclusion and regioselective outcomes are possible [56][82][83][84][85], and symmetric arrays of chiral units (like

• generated large electrostatic effects by functionalizing the capsule exteriors with charged groups (Figure 4D) [136][137]. Observed rate accelerations for capsule-promoted nucleophilic substitution reactions demonstrate significant enthalpic stabilization of the transition state attributable due to the

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

• pathway through an associative transition state to form the equatorial glycoside, 7. Surprisingly, recent evidences show that typical homogeneous glycosylation reactions in organic solution shift more towards the SN2 end of the mechanistic spectrum [32][33][34], with some exceptions [35]. The kinetic

Effect of substitution position of aryl groups on the thermal back reactivity of aza-diarylethene photoswitches and prediction by density functional theory

• Misato Suganuma,
• Daichi Kitagawa,
• Shota Hamatani and
• Seiya Kobatake

Beilstein J. Org. Chem. 2025, 21, 242–252, doi:10.3762/bjoc.21.16

• transition state for N1–N4 and I1–I4 using various functionals in combination with a 6-31G(d) basis set. The theoretical activation free energy (ΔG‡(calc)) at 298 K was determined as the difference in the sum of electronic energy and thermal free energy correction between the closed-ring isomer and the

• transition state (see Tables S7–S14 in Supporting Information File 1). Table 2 shows the differences in ΔG‡ between the theoretical value obtained by DFT calculations and the experimental value, i.e., ΔG‡(calc) − ΔG‡(exp). The B3LYP and M05 functionals underestimated the ΔG‡ value, while the BMK, CAMB3LYP

Nickel-catalyzed cross-coupling of 2-fluorobenzofurans with arylboronic acids via aromatic C–F bond activation

• Takeshi Fujita,
• Haruna Yabuki,
• Ryutaro Morioka,
• Kohei Fuchibe and
• Junji Ichikawa

Beilstein J. Org. Chem. 2025, 21, 146–154, doi:10.3762/bjoc.21.8

• in a formal oxidative addition to form benzofuranylnickel(II) fluorides F, which then undergo transmetallation with arylboronic acids 2 to produce intermediates G (Scheme 5, path b). Alternatively, a direct transition from E to G via transition state H is also possible (Scheme 5, path c). Ultimately

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

• . Transition-state calculations gave insight into possible reaction pathways. CPA C48-activated substrates react and rearomatization of the benzene ring leads to the intermediate Int-66. In the presence of an oxidant, axially chiral product 213 is formed. Otherwise, nitrogen-initiated intramolecular

Synthesis, structure and π-expansion of tris(4,5-dehydro-2,3:6,7-dibenzotropone)

• Yongming Xiong,
• Xue Lin Ma,
• Shilong Su and
• Qian Miao

Beilstein J. Org. Chem. 2025, 21, 1–7, doi:10.3762/bjoc.21.1

• the colorless crystal, two of these [5]helicenoid moieties display P and M helix structures respectively, whereas the third moiety (colored in light blue) adopts a structure with approximate plane symmetry, recognized as a transition state for the enantiomerization of helicenes. The central benzene

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

• organocatalyst acts as a Lewis base forming an enamine which raises the HOMO energy of the dienophile, while the thiourea moiety acts as a Lewis acid, lowering the LUMO level of the diene (Scheme 1). A confined transition state is formed providing a high enantiocontrol of the reaction. In 2016, Shi and co

• concerted mechanism which could be explained by the transition state depicted in Scheme 16: the chiral phosphoric acid could act as a bifunctional catalyst; the OH group acts as a Brønsted acid activating the 1-azadiene, while the phosphoryl oxygen atom activates the enecarbamates as a Lewis base. In order

• activating both the azadiene and the 3-vinylindole by hydrogen-bonding interactions. However, from this transition state two possible reaction pathways could explain the observed end product. While in path a, a concerted reaction involving an inverse electron demand aza-Diels–Alder reaction could happen, a

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• , into the O–H bonds of diacid 6a (Scheme 5). Apparently, in this case, the reaction proceeds through a less sterically congested transition state. Diacyl chloride 2a was also reacted with sodium azide as nucleophile at room temperature giving dicarbonyl azide 12 in 85% yield (Scheme 6). Conclusion Two

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

• proposal was operative, owing to its lower-energy barrier; however, the saddle point geometries identified at this low level of theory were not close enough to the true transition state geometries to meet convergence criteria. Thus, using the guidance of the PES scans, A, XB-2, and B were subjected to the

• nudged elastic band climbing image (NEB-CI) method using Orca 5.0.1 at the PBE/def2-SVP D4 level of theory in the CPCM solvation model (see also section 4.2 in Supporting Information File 1) [51][52][53][54][55][56]. Both climbing images were subjected to transition state optimization and successfully

• 160° with equal C–I bond lengths of 2.5 Å in the transition state. The significantly lower activation energy allowed us to conclude that the SN2 mechanism was the more favourable pathway. Conclusion In conclusion, we have developed a direct polyfluoroalkylation reaction of sulfoxonium ylides. The

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

• nitrogen atoms that can form nitrogen–hydrogen (N–H) bonds. Therefore, the general mechanism for HER using a metal-free porphyrin involves inner core nitrogen atoms, which keep protons in proximity and lowers the activation barrier. Dihydrogen is then produced by prearranging the transition state of

• adopts a 1,3-alternate conformation and binds simultaneously to the epoxide O-atom and iodide anion via (NH···O and NH···I) hydrogen-bonding interactions. The TBA countercation is bound to the O-atom of the epoxide ring with hydrogen bonds and is situated away from the I− anion. This crucial transition

• state stabilizes the anionic species generated during the reaction pathway and facilitates a backside attack of I− on the epoxide thus resulting in the initial ring opening (Figure 4b). Apart from acting as an organocatalyst, calix[4]pyrrole 11 has been used for the promotion of cuprous chloride

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

• the two transformations. Studies directed toward a better understanding of possible transition-state structures and the design of new catalysts to improve the results are currently underway in our laboratories. A potential energy surface (PES) for the proposed mechanism for (a) isomerization of

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

• five to seven-membered cyclic compounds [47]. Arylation reactions using diaryliodonium salts can occur through four distinct mechanisms. First, the arylation can occur under metal-free conditions, involving the formation of a three-membered ring transition state through ligand coupling, leading to the

• formation of the Nu–Ar product and aryl iodide [21]. Second, the arylation can take place in the presence of a metal catalyst via oxidative addition, followed by reduction elimination [48][49]. Thirdly, it proceeds through a ligand-coupled arylation which involves a five-membered transition state to yield

Mechanochemical difluoromethylations of ketones

• Jinbo Ke,
• Pit van Bonn and
• Carsten Bolm

Beilstein J. Org. Chem. 2024, 20, 2799–2805, doi:10.3762/bjoc.20.235

• , proceeding through a five-membered transition state. To clarify the mechanism, two experiments were conducted. In the first one, 2-acetonaphthone with a trideuteromethyl group (1i-d3) was subjected to the standard reaction conditions. Two products were obtained: First, 3i-d2 containing a CF2H group, and

Access to optically active tetrafluoroethylenated amines based on [1,3]-proton shift reaction

• Yuta Kabumoto,
• Eiichiro Yoshimoto,
• Bing Xiaohuan,
• Masato Morita,
• Motohiro Yasui,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2024, 20, 2776–2783, doi:10.3762/bjoc.20.233

• , the negative charge generated on the imine carbon can be delocalized, hence the transition state is stabilized and the reaction proceeds smoothly. On the other hand, when the substituent R is an alkyl group, the negative charge generated on the imine carbon is an unstable factor, and therefore the

• transition state is not stabilized, leading to the increase of the activation energy of the reaction. As a result, the reaction does not proceed smoothly. The absolute configurations of product (S)-23c, (S)-23d, and (S)-23e were determined on the basis of their X-ray crystallographic analyses. The validity

• which is being abstracted simultaneously interacts with the carbon possessing the tetrafluoroethylene fragment. At this time, transition states TS1 or TS2 are possible, but the reaction proceeds exclusively through the transition state TS1 to avoid significant steric repulsion between the substituent R

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

• alkoxylation and alkylation products with the assistance of Lewis acid as co-catalyst (Scheme 9). Starting from four different racemic substrates, the same product 6g with 96% ee was obtained under standard conditions. This indicates that the reactions proceed through the same transition state and the

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

• free energy correction at double-zeta. The kinetics of some reactions were calculated, applying the transition state theory [40]. Within this theory, the rate constant of an elementary reaction with the free energy barrier ΔG‡ is given by Equation 1, where k is the rate constant in s−1, kB is the

• File 1). Notably, the CO2 capture exhibits a lower activation barrier compared to the capture of epoxide (+10.0 kcal·mol−1 vs +30.0 kcal·mol−1). Using transition state theory [40] as expressed in Equation 1, the rate constants were calculated for binding to either molecule at 273.0 K, resulting in k1

• mechanism leading to the (S) product presents an asymmetric TS, 1.2 kcal·mol−1 higher in energy than that of the (R) mechanism. Thus, the asymmetric catalyst enables to generate an enantiomeric excess of 95% with the (R) product being the most abundant product. Surprisingly, a transition state connecting

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

• extensive effort. This involves complex parameter optimization, meticulous validation against experimental data, and careful consideration of diverse reaction conditions and possible reaction mechanisms [28][29]. Although some studies employ transition-state (TS) theory to simulate activation energies and

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

• that the transition state was stabilized by 4.1 kcal·mol−1 by an extra molecule of trifluoroacetic acid. A similar stabilizing interaction was not identified in this case with 3a, despite significant effort, but it cannot be ruled out. The cyclization of 9 was shown to be possible by attack of the

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

• attributed to the chair-like transition state where the organoboron reagent 1 exchanges one isopropoxy group for one of the BINOL 3 oxygen atoms, whereas the free OH group of the BINOL forms a hydrogen bond to the carbonyl of substrate 2. The flanking phenyl groups on the BINOL facilitate recognition between

• -Fmoc-aryl- and -alkylimines, catalysed by a chiral disulfonimide 45 (Scheme 10). Since allyltrimethylsilane (46) belongs to the type 2 allylation reagents [33], the nucleophilic addition proceeds via an open transition state (Figure 1). Two possible mechanistic pathways were proposed, where the Fmoc

• , in the COBI–imine complex 74 it appears at 8.41 ppm, while in the imine TfOH salt 75 it shows at 9.24 ppm. This detailed NMR investigation sparked further interest in the structure of the transition state of this reaction. An analysis of the potential energy profiles of the two hypothetical pathways

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

• [92] and a phase-transfer catalysed oxidative amination reaction [93]. In the latter, NCI descriptors were both used to simplify previously existing MLR models and also led to a hypothesis of key NCIs in the transition state. Whereas these descriptors require the selection of a suitable probe model

• [96] investigated a bromocyclization catalysed by a chiral phosphoric acid (CPA) and a DABCOnium brominating reagent (Figure 6). The authors calculated transition state conformer ensembles for several flexible DABCOnium systems and performed energy decomposition analysis to separate the interactions

• develop a comprehensive model, finding that imine parameters govern the defining transition state and hence the preferred enantiomer. In a focused modelling, two separate models are constructed, one for all E- and Z-imines, respectively, finding substrate–catalyst matching is important for E- and Z-imines

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

• small about 1.18 kcal mol−1 (Supporting Information File 1, Figure S2). To investigate the activation barrier of this equilibrium, potential energy curve by changing the dihedral angle θ of one anthryl group was calculated. The transition state was calculated with the dihedral angle θ = 30.6° and the