Experimental and DFT studies on the regioselective methanolysis of 5-azido-9-oxabicyclo[6.1.0]nonan-4-yl 4-nitrobenzoate isomers

• İlknur Polat,
• Selçuk Eşsiz and
• Emine Salamci

Beilstein J. Org. Chem. 2026, 22, 547–556, doi:10.3762/bjoc.22.40

• difference between TS1 and TS2 (4.7 kcal/mol), compared to that between TS3 and TS4 (6.9 kcal/mol), can be attributed to hydrogen-bond stabilization in TS2, indicating that conformational effects play a more dominant role than hydrogen bonding in determining transition-state stability. Mulliken charge

Recent advances in the stereoselective synthesis of distal biaxially chiral molecules

• Fanxing Zhou,
• Chen Zhang,
• Lingyu Sun,
• Yiyun Fang,
• Siming Zheng,
• Lina Hu,
• Mengyang Shen,
• Zhen Zhao,
• Wei Xu,
• Yunqiang Sun and
• Zi-Qiang Rong

Beilstein J. Org. Chem. 2026, 22, 461–479, doi:10.3762/bjoc.22.34

• potential applications in ligand and catalyst development. In a complementary direction, Smith’s group achieved the highly enantioselective synthesis of axially chiral naphthamides (Scheme 6) [47]. Their strategy employed transition-state hydrogen bonding to induce substrate deracemization, followed by

Synthesis and stereochemical analysis of dynamic planar chiral oxa[7]orthocyclophene

• Yukiho Hashimoto,
• Yuuya Kawasaki,
• Kazunobu Igawa and
• Katsuhiko Tomooka

Beilstein J. Org. Chem. 2026, 22, 436–442, doi:10.3762/bjoc.22.30

• still observed in the measurement at 5 °C, albeit only slightly. The phenyl-substituent effect on the stereochemical stability can be understood as a destabilization of the ground state due to the transannular repulsion, and a stabilization of the transition state for racemization by a conjugation

Recent advances in the cleavage of non-activated amides

• Eun-Sol Choi and
• Hyo-Jun Lee

Beilstein J. Org. Chem. 2026, 22, 352–369, doi:10.3762/bjoc.22.23

• generates the imidate-like intermediate Q. Subsequent nucleophilic attack of BuOH on the methyl group of Q leads to transition state R, accompanied by the departure of butyl methyl ether. Further attack of BuOH on the O-protonated amide, followed by an intramolecular proton transfer, furnishes transition

• intermediate anion X via the activated transition state W. Subsequent reorganization of hydrogen bonding toward the nitrogen center promotes C–N bond cleavage to give the ester product and intermediate Y. Decomposition of Y regenerates V and produces NH2Br, which is reduced at the cathode back to bromide

• (CO2) can catalyze transamidation reactions of amides by activating and stabilizing the tetrahedral transition state, which is a key intermediate (Scheme 16) [64]. Under a CO2 atmosphere, electron-deficient primary amides underwent smooth transamidation with butylamine to afford amide products 90 and

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• preferential formation of the endo-adduct (upper pathway). The predominance of exo-isomers in some cases probably reflects insufficient stabilization due to secondary orbital interactions in the transition state [43]. It should be noted separately that secondary cyclic amino acids such as azetidine-2

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