Screwing the helical chirality through terminal peri-functionalization

• Devesh Chandra,
• Sachin and
• Upendra Sharma

Beilstein J. Org. Chem. 2026, 22, 205–212, doi:10.3762/bjoc.22.14

• phosphine oxide and the nitro-functionalized oxa[5]helicene. This ion-pairing interaction was also studied using NMR titration and Job’s plot analysis. The transition state depicted in Figure 3 was found to be most favorable providing the product with M-configuration. Looking ahead, these strategies may

Advances in Zr-mediated radical transformations and applications to total synthesis

• Hiroshige Ogawa and
• Hugh Nakamura

Beilstein J. Org. Chem. 2026, 22, 71–87, doi:10.3762/bjoc.22.3

• for the success of the reaction. DFT calculations suggested that in the transition state (TS1), a Cl–π interaction between the chlorine atom on the zirconocene catalyst and the aromatic ring of the substrate facilitated rapid halogen atom transfer (XAT), generating a radical at the C3 position of

• potential and stabilizing the radical pathway. The DFT calculations are shown in Scheme 13A. The activation barrier for the XAT process was calculated to be ΔG‡ = 8.0 kcal/mol, indicating that this process can proceed spontaneously around room temperature. Moreover, the transition state (TS1) suggested the

Reactivity umpolung of the cycloheptatriene core in hexa(methoxycarbonyl)cycloheptatriene

• Dmitry N. Platonov,
• Alexander Yu. Belyy,
• Rinat F. Salikov,
• Kirill S. Erokhin and
• Yury V. Tomilov

Beilstein J. Org. Chem. 2026, 22, 64–70, doi:10.3762/bjoc.22.2

• hydrogen, conversely, induces the i-chlorination. Besides the obvious steric influence, the ester group slightly reduces the negative charge at the nucleophilic center (Figure 3) and can also influence the electronegative transition state in terms of orbital overlap. Additionally, we considered the

Mechanistic insights into hydroxy(tosyloxy)iodobenzene-mediated ditosyloxylation of chalcones: a DFT study

• Jai Parkash,
• Sangeeta Saini,
• Vaishali Saini,
• Omkar Bains and
• Raj Kamal

Beilstein J. Org. Chem. 2025, 21, 2703–2715, doi:10.3762/bjoc.21.208

• while the 6-31G+(d,p) was used for remaining other atoms. The geometries of all ground state and transition state structures are optimized using the above specified basis sets and exchange-correlation functional. The effect of solvent was also taken into account using the SMD implicit solvation model

• . The solvent considered for the present study was dichloromethane (CH2Cl2). Frequency calculations were performed for all optimized structures to confirm the stationary point and transition state. Intrinsic reaction coordinate (IRC) calculations were carried out to validate the transition states. The

• . Effect of substituent group present on the migrating aryl ring on relative free energies (G) and relative potential energies (E) of the transition state, intermediates and product for the reaction pathway leading to formation of β,β-ditosyloxy ketones. The energies are reported relative to the reactant

Recent advances in total synthesis of illisimonin A

• Juan Huang and
• Ming Yang

Beilstein J. Org. Chem. 2025, 21, 2571–2583, doi:10.3762/bjoc.21.199

• . However, subsequent density functional theory (DFT) calculations by the Tantillo group on rearrangements of potential biosynthetic precursors revealed that structure 10 corresponds to a transition state rather than a stable intermediate of the 1,2-alkyl migration [27]. Their study further indicated that

Rapid access to the core of malayamycin A by intramolecular dipolar cycloaddition

• Yilin Liu,
• Yuchen Yang,
• Chen Yang,
• Sha-Hua Huang,
• Jian Jin and
• Ran Hong

Beilstein J. Org. Chem. 2025, 21, 2542–2547, doi:10.3762/bjoc.21.196

• undesired stereochemistry at C3 due to a possible chair-like transition state like 10a (Scheme 2B). This phenomenon is consistent with the observations from previous syntheses [31][35][36]. We anticipated that late-stage epimerization might invert the configuration once the acyl group is revealed at the C2

Synthesis of the tetracyclic skeleton of Aspidosperma alkaloids via PET-initiated cationic radical-derived interrupted [2 + 2]/retro-Mannich reaction

• Ru-Dong Liu,
• Jian-Yu Long,
• Zhi-Lin Song,
• Zhen Yang and
• Zhong-Chao Zhang

Beilstein J. Org. Chem. 2025, 21, 2470–2478, doi:10.3762/bjoc.21.189

• formation of IN1. The radical cation IN1 served as the reference point for DFT investigations. As illustrated in Figure 2a, facilitated by a favorable radical cation–π interaction [31], IN1 proceeds to the first radical addition transition state (TS1), with an energy barrier of 8.3 kcal/mol. This leads to

• undergo reductive SET in the presence of [FCNIr(II)Pic]−. This leads to the regeneration of [FCNIr(III)Pic] to complete the catalytic cycle and formation of the final product via proton transfer. Intrinsic reaction coordinate (IRC) analysis showed the reaction coordinate connecting the transition state

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

• solvent polarity results in a decrease in rate constants. This phenomenon is attributed to the lower polarity of the transition state in comparison to that of the initial compounds [61]. Furthermore, these methods often require harsh reaction conditions, prolonged reaction times, and laborious

• ]. The 28:72 exo/endo (cis/trans) isomer ratio (Table 1, entry 9), obtained in this cycloaddition reaction indicates that the endo transition state is more stable, and that the thermodynamically more stable trans isomer is the major product in the reaction proceeding diastereoselectively through this

• transition state (Scheme 2). Meanwhile, the diastereomeric ratio of interest can be determined by integrating the 1H NMR spectra, in particular by selecting the appropriate signal pairs (one from each diastereomer) belonging to the respective cycloaddition product. An example of these selected protons (trans

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

• configuration exert pronounced effects on reaction pathways. These substrate-specific geometric parameters directly dictate transition state formation during ring closure. Recent advances demonstrated that deliberate manipulation of angle strain and configuration enabled divergent skeletal outcomes under

Asymmetric total synthesis of tricyclic prostaglandin D2 metabolite methyl ester via oxidative radical cyclization

• Miao Xiao,
• Liuyang Pu,
• Qiaoli Shang,
• Lei Zhu and
• Jun Huang

Beilstein J. Org. Chem. 2025, 21, 1964–1972, doi:10.3762/bjoc.21.152

• a single diastereomer (Table 1, entry 4). To explain this diastereoselectivity, we hypothesize that the C–O bond, which occupies an axial position in the proposed transition state TS-1, could avert an additional hyperconjugative interaction (σ*C-O/π) that renders the reacting C=C bond electron

• connection of C8 and C12 in compound 21 could be realized through a photoredox-catalyzed radical cyclization of unactivated alkene-substituted β-ketoester 27. This reaction was expected to involve a 5-exo-trig radical cyclization via transition state TS-3 [38], in which the diastereoselectivity could be

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• with the desired C6 chiral center was constructed via intermediate 229, where the sulfinyl group induced K+–oxygen chelation to form a six-membered transition state prior to protonation from the less hindered face. Acid-mediated epimerization at C9 of 230 yielded compound 231, which was transformed

Preparation of spirocyclic oxindoles by cyclisation of an oxime to a nitrone and dipolar cycloaddition

• Beth L. Ritchie,
• Alexandra Longcake and
• Iain Coldham

Beilstein J. Org. Chem. 2025, 21, 1890–1896, doi:10.3762/bjoc.21.146

• stereoisomer has the ring-junction NC–H bond, the imide carbonyls, and the oxindole carbonyl all cis to one another across the two newly formed rings. This must arise from a preference for an exo transition state that places the incoming maleimide away from the oxindole carbonyl. The cascade chemistry allows

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

• CPA-catalyzed cyclization of INT-E through the dual hydrogen bonding activation transition state TS-1 afforded the eight-membered heterocycle INT-F with a stereogenic center. Through the elimination of aniline 73, the saddle-shaped dibenzo[1,5]diazocine 72 was produced via a central-to-inherent

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

• rest of the molecule. The transition state for the thermal back-isomerisation of 72 is planar in case of electron-donating groups and twisted for electron-withdrawing groups; the latter isomerise faster than the former (Scheme 23, top). The planar transition state is also favoured in polar and protic

• -position give hypsochromic shifts and shorten the thermal half-life by stabilising the transition state 73’ (Scheme 23, bottom) [63]. Synthesis The classic synthesis of indigo is achieved via Baeyer–Drewsen synthesis reacting 2-nitrobenzaldehyde (74) and acetone in basic medium (Scheme 24, top) [91]. Since

• transition state E-inversion (Scheme 32A). The addition of ring strain between the stator and the rotor (Scheme 34, right) was found to affect the thermal half-life depending on the ring size [109]. Too small (n = 3) 108a and too large rings (n > 5) 108d–f force the E-isomer in a less stable conformation and

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

• based on NO2+. The intrinsic kinetics model based on NO2+ can be established as shown in Table 3. According to the Brønsted–Bjerrum rate law (transition-state theory) [62], the overall rate equation based on NO2+ can be transferred into an activity coefficients-based rate equation. According to the

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

• Israel Fernandez Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040-Madrid, Spain 10.3762/bjoc.21.125 Abstract The influence of transition-state aromaticity on the barrier heights of concerted pericyclic reactions is summarized herein. To

• other than aromaticity govern the barrier heights of these pericyclic reactions. Keywords: activation barrier; activation strain model; aromaticity; computational chemistry; transition state; Introduction Aromaticity is arguably one of the most fundamental and extensively studied concepts in chemistry

• further support to the barrier-lowering effect induced by the aromaticity of the transition state. While the purported ‘‘aromatic stabilization’’ is mainly established based on comparisons to transition states of alternative stepwise reaction routes, its extension to highly related processes following

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

• axially chiral anilines [10][11] and a triazine molecule [9]. In particular, protonation of a remote basic site in N–C axially chiral anilines significantly increases the rotational barrier by attenuating resonance stabilization in the transition state. One important issue in this field is the development

• calculated the distance between the imino carbon atom and the nitrogen atom of the NMe₂ moiety (d) for local minimum and transition-state structures (Figure 2). In the local minimum and transition state of the C–N rotation and C–N/C–C concerted rotation, protonation leads to a shortening of the C–N bond by

• double-bond nature of the C–N bond in the transition state of the C–N/C–C concerted rotation was decreased due to the twisted structure, and the activation energy varies depending on whether the amidine was protonated or in its molecular form (Figure 2). To investigate the effect of protonation on the

Wittig reaction of cyclobisbiphenylenecarbonyl

• Taito Moribe,
• Junichiro Hirano,
• Hideaki Takano,
• Hiroshi Shinokubo and
• Norihito Fukui

Beilstein J. Org. Chem. 2025, 21, 1454–1461, doi:10.3762/bjoc.21.107

• , the racemization barrier of 5 (34.8 kcal mol−1) is larger than that of CBBC 1 (33.7 kcal mol−1), which accords with the experimental results. In the transition state TS2, the exocyclic olefin unit a is close to the adjacent benzene ring b, which causes intramolecular steric repulsion to increase the

Tautomerism and switching in 7-hydroxy-8-(azophenyl)quinoline and similar compounds

• Lidia Zaharieva,
• Vera Deneva,
• Fadhil S. Kamounah,
• Nikolay Vassilev,
• Ivan Angelov,
• Michael Pittelkow and
• Liudmil Antonov

Beilstein J. Org. Chem. 2025, 21, 1404–1421, doi:10.3762/bjoc.21.105

• conventional UV–vis spectroscopy, suggesting preferable population of intramolecular hydrogen bonding stabilized E. Comparing the angles α of the E* form (13°) and the transition state between E and Ecis (60°) the former is nearer to the geometry of E, suggesting preferable population. The excitation of KE

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

Recent advances in amidyl radical-mediated photocatalytic direct intermolecular hydrogen atom transfer

• Hao-Sen Wang,
• Lin Li,
• Xin Chen,
• Jian-Li Wu,
• Kai Sun,
• Xiao-Lan Chen,
• Ling-Bo Qu and
• Bing Yu

Beilstein J. Org. Chem. 2025, 21, 1306–1323, doi:10.3762/bjoc.21.100

• activation energy modulation during transition state formation. Specifically, donor/acceptor electronic configurations in the substrate could either stabilize or destabilize the transient hybrid state, thereby thermodynamically governing the energy barrier for intermolecular HAT progression. When the partial

Enhancing chemical synthesis planning: automated quantum mechanics-based regioselectivity prediction for C–H activation with directing groups

• Julius Seumer,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2025, 21, 1171–1182, doi:10.3762/bjoc.21.94

• structure on the potential energy surface is located, which can be done straightforwardly using standard optimization algorithms. While the use of intermediate energies provides a computationally efficient alternative to explicit transition state searches, it rests on the assumption that there is a

• the transition state [10][11]. The site with the lowest reaction energy is expected to correspond to the experimentally observed reaction site. Therefore, instead of locating the structure of the transition state, the preceding palladacycle intermediate structure is generated and optimized, as shown

• theory or perform a transition state search to calculate the activation energy. With this threshold, we obtain 70% correct, 14.5% semi-correct, and 14.5% wrong predictions over the whole dataset. For six out of 17 molecules, all possible reaction sites are predicted as reaction sites within the threshold

A multicomponent reaction-initiated synthesis of imidazopyridine-fused isoquinolinones

• Ashutosh Nath,
• John Mark Awad and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 1161–1169, doi:10.3762/bjoc.21.92

• . A comprehensive DFT investigation of reactant 6 was carried out to analyze the transition state of the IMDA reaction for a Br-substituted diene and its charge distribution (Figure 2). The diene has a notable positive charge (+0.318, +0.098, 6a), (+0.334, +0.082, 6h) and (+0.316, +0.074, 6r) whereas

• calculated using the Gaussian 16 software (Figure 3) [21]. The N-acylated compound 6a has a baseline relative energy of 0 kJ/mol, while the transition state of the Diels–Alder (TS-DA) reaction presents the highest energy barrier at 1.221 kJ/mol. The DA adduct shows a little lower energy at 1.001 kJ/mol

• , indicating a smooth transition from the transition state to the product. The final dehydrative ring-opening gives products by decreasing the energy to 0.978 kJ/mol. Computational analysis indicates that the IMDA step has a high energy barrier which needs a catalyst, while the dehydrative re-aromatization

Salen–scandium(III) complex-catalyzed asymmetric (3 + 2) annulation of aziridines and aldehydes

• Linqiang Wang and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1087–1094, doi:10.3762/bjoc.21.86

• carboxylate groups followed by a ring opening of the aziridine ring, forming azomethine ylide intermediates A. The intermediates A further undergo a [2 + 3] annulation (or cycloaddition) with aldehydes 2 through endo transition state TS to generate intermediates B, which release products 3 with regeneration

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85