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

• selective mono- or di-nitration and facilitates late-stage C–H nitration of biorelevant molecules, with DFT/mechanistic studies revealing synergistic 'nitro effect' and 'methyl effect' underlying the reactivity [7]. Jia et al. developed dinitro-5,5-dimethylhydantoin (DNDMH) as an efficient arene nitration

• process hazards through the evaluation of thermal safety parameters and DFT calculations revealed catalytic and solvent effects of ionic liquids in nitration [9]. In addition, researchers have focused on improving nitration processes through process intensification strategies by integrating advanced

Influence of the cation in hypophosphite-mediated catalyst-free reductive amination

• Natalia Lebedeva,
• Fedor Kliuev,
• Olesya Zvereva,
• Klim Biriukov,
• Evgeniya Podyacheva,
• Maria Godovikova,
• Oleg I. Afanasyev and
• Denis Chusov

Beilstein J. Org. Chem. 2025, 21, 1661–1670, doi:10.3762/bjoc.21.130

• . The remedy for Parkinson’s disease, piribedil, was obtained in high yield. The plausible mechanism of the elaborated process was proposed and supported by DFT calculations. Keywords: amines; DFT; hypophosphites; reductive amination; role of cations; Introduction Sodium hypophosphite, NaH2PO2, is one

• the DFT calculations (Scheme 5, Figure 2). Firstly, reductive amination of an aldehyde started from a nucleophilic addition of the amine to the carbonyl group of the aldehyde. In the presence of acid, this step could occur via acidic catalysis involving a protonation step of an amine (Step_2) or

• weakly nucleophilic secondary ammonium cation to the carbonyl group occurred with ΔEa = 11.5 kcal/mol (TS2→3). In recent DFT [39] and experimental [40] studies on the reductive amination reaction it was postulated that this protonation of amine played a key role in the catalytic cycle especially in the

Catalytic asymmetric reactions of isocyanides for constructing non-central chirality

• Jia-Yu Liao

Beilstein J. Org. Chem. 2025, 21, 1648–1660, doi:10.3762/bjoc.21.129

• cyclization of functionalized phenyl isocyanides, guided by DFT calculations (Scheme 2b) [29]. Three types of isocyanides (10–12) were evaluated in reactions with aryl iodides, affording indole-fused N-heteroaryl scaffolds 13–15, featuring either a C–C or C–N stereogenic axis, in moderate-to-high yields with

• identified. While the employment of L9 afforded endo-selective [3 + 2] cycloadducts 60, using Trost ligand L10 resulted in a complete reversal to the exo-cycloadducts 61. DFT calculations were performed and indicated that these two ligands act in different ways in the cyclization process, providing

On the aromaticity and photophysics of 1-arylbenzo[a]imidazo[5,1,2-cd]indolizines as bicolor fluorescent molecules for barium tagging in the study of double-beta decay of ¹³⁶Xe

• Eric Iván Velazco-Cabral,
• Fernando Auria-Luna,
• Juan Molina-Canteras,
• Miguel A. Vázquez,
• Iván Rivilla and
• Fernando P. Cossío

Beilstein J. Org. Chem. 2025, 21, 1627–1638, doi:10.3762/bjoc.21.126

• Abstract In this paper, the behavior of a bicolor fluorescent indicator for the detection of barium cations formed by double-beta decay of 136Xe is analyzed by means of computational tools. Both DFT and TDDFT permit to understand the origin of the bicolor fluorescent signal emitted by 1-arylbenzo[a]imidazo

• concluded that the aromatic character of the fluorophore is better described as the combination of two aromatic subunits integrated in the polycyclic system. Different DFT functional are used to analyze the photochemical behavior of this family of sensors. It is concluded that PBE0 and M06 functionals

• decoupling between the para-phenylene and benzo[a]imidazo[5,1,2-cd]indolizine components that results in a blue shift upon Ba2+ coordination. Keywords: aromaticity; DFT-TDDFT calculations; double-beta decay; fluorescent sensors; polycyclic arenes; Introduction Double beta-decay [1] is a radioactive decay

Synthesis of optically active folded cyclic dimers and trimers

• Ena Kumamoto,
• Kana Ogawa,
• Kazunori Okamoto and
• Yasuhiro Morisaki

Beilstein J. Org. Chem. 2025, 21, 1603–1612, doi:10.3762/bjoc.21.124

• spectra were simulated by time-dependent density functional theory (TD-DFT) calculations (TD-MN15/6-31G(d)//MN15/6-31G(d). The calculated rotatory strengths of (Sp)-6 and (Sp)-7 were plotted with their observed CD spectra in Figure 3A and 3B, respectively, and the calculated CD spectra are shown in

• ). Molecular orbitals of (Sp)-6 and (Sp)-7 in their ground and excited states were calculated using DFT and TD-DFT calculations (Figures S20–S23, Supporting Information File 1). In both molecules, the orbitals were localized to part of the π-conjugation systems rather than the whole system in the ground and

• excited states due to the twisted structures by the π-stacked [2.2]paracyclophane moieties. The CPL behaviors of (Sp)-6 and (Sp)-7 were investigated by TD-DFT calculations; namely, the electric transition dipole moment (μ), magnetic transition dipole moment (m), and the angle (θ) between μ and m in the S1

Thermodynamic equilibrium between locally excited and charge transfer states in perylene–phenothiazine dyads

• Issei Fukunaga,
• Shunsuke Kobashi,
• Yuki Nagai,
• Hiroki Horita,
• Hiromitsu Maeda and
• Yoichi Kobayashi

Beilstein J. Org. Chem. 2025, 21, 1577–1586, doi:10.3762/bjoc.21.121

• synthesized and characterized (Figure 1). Their photophysical properties were comprehensively examined by steady-state and time-resolved emission and absorption spectroscopy. Furthermore, time-dependent density functional theory (TD-DFT) calculations were performed to support the experimental findings

• shown in Supporting Information File 1. Energy levels and steady-state optical properties Time-dependent density functional theory (TD-DFT) calculations were performed to gain insights into the electronic structures of Pe–PTZ derivatives at B3LYP/6-31+G(d,p) level of theory (Figure 2) [18]. The

• absorption bands derived from the Pe moiety between 390 and 450 nm. A broad absorption feature around 320 nm, whose intensity increased with the number of TPA groups, was also observed. The increase in the absorption with the increase in the number of TPA groups is reproduced by TD-DFT calculations (Figure

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

• hypothesis that the rotational barrier of the benzamidine changes upon protonation, density functional theory (DFT) calculations were performed for the C–N and C–N/C–C rotations of the molecular form and of the protonated 2-bromo-N,N,6-trimethylbenzimidamide as a model compound (Figure 2). Several transition

• 0.6 Å and 0.3–0.4 Å, respectively. This result indicates that protonation has a greater impact on the local minimum structures, as the p orbital of the nitrogen atom in the NMe₂ moiety and the C=N π orbital are located in the same plane, allowing for effective conjugation between them. The DFT study

• details, see Supporting Information File 1). The NMR and HPLC experiments clearly indicate that protonation of the amidine moiety increases the rotational barrier of the C–N bond, a result which is consistent with our DFT study. Since it was found that the E/Z isomers of amidine could be isolated as a TFA

Synthesis of an aza[5]helicene-incorporated macrocyclic heteroarene via oxidation of an o-phenylene-pyrrole-thiophene icosamer

• Yusuke Matsuo,
• Aoi Nakagawa,
• Shu Seki and
• Takayuki Tanaka

Beilstein J. Org. Chem. 2025, 21, 1561–1567, doi:10.3762/bjoc.21.119

• aza[5]helicene-incorporated macrocyclic structure (Figure 4). In the solid-state, the distance between the two aza[5]helicene moieties was found to be 3.185 Å, closely consistent with the DFT-optimized value of 3.136 Å (see Supporting Information File 1). The average dihedral angles between the o

• , the ΦF value was modest (0.072), which is lower than those of related aza[n]helicene analogs [27][28]. The fluorescence lifetime (τ) was determined by biexponential decay model fitting as 0.65 and 3.2 ns. DFT calculation was conducted to investigate the electronic structure. The HOMO and HOMO−1 are

• heteroarene 5. Supporting Information Supporting Information File 14: Experimental procedures, characterization data of all products, copies of 1H and 13C NMR spectra, optical data, and DFT calculation results. Supporting Information File 15: Crystallographic Information File for compound 4. Supporting

Azobenzene protonation as a tool for temperature sensing

• Antti Siiskonen,
• Sami Vesamäki and
• Arri Priimagi

Beilstein J. Org. Chem. 2025, 21, 1528–1534, doi:10.3762/bjoc.21.115

• = 98–144 nm) between compounds 1–3 and their protonated counterparts (1H+–3H+; Figures S16–S18 in Supporting Information File 1). The experimental results are enticing from the applications point of view but offer little insight into details of the azobenzene–acid interactions. DFT calculations were

• polar aprotic solvent such as DCE, we assume the formation of CIP, as supported by computational results. This discussion focuses on compound 3, which showed most promising characteristics for temperature sensing, including a larger red-shift upon protonation and a broader sensing range. DFT

• obtained, irrespective of initial acid concentration (Supporting Information File 1, Table S10). This suggests that upon protonation, 3 forms an ion pair with two MSA molecules (3H+MSA−MSA), as supported also by DFT calculations. Assuming the 1:2 stoichiometry between 3 and MSA, the reaction thermodynamics

Highly distinguishable isomeric states of a tripodal arylazopyrazole derivative on graphite through electron/hole-induced switching at ambient conditions

• Himani Malik,
• Sudha Devi,
• Debapriya Gupta,
• Ankit Kumar Gaur,
• Sugumar Venkataramani and
• Thiruvancheril G. Gopakumar

Beilstein J. Org. Chem. 2025, 21, 1496–1507, doi:10.3762/bjoc.21.112

• memory. A pre-optimized two-layer graphite was used from the library data as provided in the Quantumwise DFT package. The lattice parameters for graphite are, a = 2.4612 Å, b = 2.4612 Å, c = 6.709 Å, and α = 60°. Molecular orbitals were obtained from the calculations performed using the Gaussian 03

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

• nucleophilic substitution of the thus generated alkoxide to form an oxygen-containing five-membered ring. At least, density functional theory (DFT) calculations support that the nucleophilic attack of methylenetriphenylphosphorane to the exo-methylene unit is slightly favorable over reaction with the carbonyl

• signals due to the exo-methylene groups overlapped with the solvent signal in CD2Cl2. The thus obtained activation barriers of 3 and 5 were 11 and 12 kcal mol–1 at 263 and 253 K, respectively (Figure S27 in Supporting Information File 1). Previous DFT calculations at the B3LYP/6-31G(d) level of theory

• suggested that the bathtub conformation of CBBC 1 is slightly unfavorable than the figure-eight conformation by 2.4 kcal mol−1 [21]. On the other hand, the current DFT calculations suggest that the bathtub conformation of bis-olefin 5 is rather favorable by 0.3 kcal mol−1, which is in accordance with 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

• stabilization of the azo tautomer and making possible long range proton transfer to the quinolyl nitrogen atom. Keywords: azo dyes; E/Z isomerization; DFT; NMR; photochemistry; proton transfer; tautomerism; UV–vis; Introduction Azo compounds have long been utilized as dyes in industries such as textiles

• free energies changes the ratios between these three tautomers, but does not change the overall situation in respect of the tautomerism. These theoretical results, obtained at the M06-2X DFT level, can be validated in several ways. The usual theoretical approach is to compare them to higher level of

•  1, while the relative Gibbs’ free energies are very near to the CCSD(T). Since this comparison does not answer the question about the reliability of the DFT data for 1, it can be relied to a compound that is well-studied before. Compound 3 is a well-known tautomeric compound, a backbone of a large

High-pressure activation for the solvent- and catalyst-free syntheses of heterocycles, pharmaceuticals and esters

• Kelsey Plasse,
• Valerie Wright,
• Guoshu Xie,
• R. Bernadett Vlocskó,
• Alexander Lazarev and
• Béla Török

Beilstein J. Org. Chem. 2025, 21, 1374–1387, doi:10.3762/bjoc.21.102

• using density functional theory (DFT) with the Becke three-parameter exchange and Lee–Yang–Parr correlation (B3LYP) functional [49], along with the 6–311++G(d,p) basis set for gas-phase calculations of all compounds. After completing the molecular geometry optimizations, vibrational frequency

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

• loadings were necessary for ortho-substituted phenyls. Control experiments and DFT calculations revealed that the oxetane ring is formed before the tetrahydrofuran in the domino process. In 2023, Shigehisa and co-workers published a new cycloisomerisation strategy for the construction of oxetane rings from

• halogens, nitriles, alkenes and heteroaryls. On the other hand, this methodology suffers from relatively low diastereoselectivity as the dr lies between 1:1 and 2:1. DFT calculations suggested the reaction proceeds through nitrogen elimination, oxonium ylide 119 formation, homolytic cleavage and radical

• groups including esters, ketones, sulphones and heteroaryls. The mechanistic proposal, supported by DFT calculations, starts with an oxidative decarboxylation to give an aminooxetanyl radical 157. This species is in turn coupled with the aryl halide by the active Ni(0) catalyst (generated in situ by

Recent advances and future challenges in the bottom-up synthesis of azulene-embedded nanographenes

• Bartłomiej Pigulski

Beilstein J. Org. Chem. 2025, 21, 1272–1305, doi:10.3762/bjoc.21.99

• of the diverse range of azulene-embedded nanographenes discussed in this review presents a significant challenge, as many of the original studies lack comprehensive data. In numerous cases, fluorescence characteristics were not thoroughly examined, and time-dependent density functional theory (TD-DFT

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

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

• chemistry’s structural variability. Cao et al. [14] developed an automated workflow that predicts the regioselectivity of C–H activations using extensive DFT calculations on a HPC cluster using up to 600 nodes, each containing 16 Intel Xeon E5-2670 cores. They considered two possible reaction mechanisms, an

• and usability since several DFT calculations need to be run on an HPC cluster in order to make a prediction. In this study, we introduce a quantum mechanics (QM)-based computational workflow specifically developed to predict regioselectivity in C–H functionalization reactions involving directing

• pre-computed relative energies at DFT level of theory for a selection of C–H bonds that are identified using SMARTS patterns. Using this approach, we achieved an accuracy of 92% with a total runtime of less than one second. Dataset curated from Reaxys From a query in Reaxys (see Supporting Information

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

• chromatography with 30:70 EtOAc/hexanes. Product structures were confirmed by 1H and 13C NMR analysis and X-ray crystal structure analysis of 8a. Density functional theory (DFT) calculations DFT computations were conducted utilizing Gaussian 16W with the B3LYP functional and the 6-31G(d,p) basis set [21][22

Supramolecular assembly of hypervalent iodine macrocycles and alkali metals

• Krishna Pandey,
• Lucas X. Orton,
• Grayson Venus,
• Waseem A. Hussain,
• Toby Woods,
• Lichang Wang and
• Kyle N. Plunkett

Beilstein J. Org. Chem. 2025, 21, 1095–1103, doi:10.3762/bjoc.21.87

• macrocycle is electrophilic in nature. In addition, DFT results show the three outwardly projected carbonyl oxygens (formerly the carbonyl of benzoic acid) are negatively charged and can potentially bind or interact with metal cations. Figure 3 (right) shows the calculated electrostatic potential map with

• difference in binding constants as well as the isolation of two distinct molecular conformations of phenylalanine HIM 1 (Figure 1), DFT calculations were performed. The details of DFT calculations are shown in Table 1. For DFT calculations, we assigned two HIM macrocycles per LiBArF20 as found in the co

• and I. Without any metal coordination, DFT suggests conformer I is more stable than conformer II by ≈60 kJ/mol. However, upon complexation with Li+, both complexes 2 and 3 are remarkably similar in energy with the difference of less than 1 kJ/mol. This very small energy difference should be too small

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

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• allylic amination of acetate 12 with isatin (11a).a Supporting Information Data of thermal racemization of 7, DFT calculations for investigating racemization mechanism of 7, general methods and materials, experimental procedures and characterization data, 1H, 13C and 31P NMR spectra for 9 and 10, 1H, 13C

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• bridge cycle [36][37]. The excellent diastereoselectivity in this radical cyclization was further rationalized by DFT calculations, which suggests an energy discrepancy of the hydrogen atom transfer process from different faces of the resulting α-hydroxyl radical. Final reduction of the ketone and amide

On the photoluminescence in triarylmethyl-centered mono-, di-, and multiradicals

• Daniel Straub,
• Markus Gross,
• Mona E. Arnold,
• Julia Zolg and
• Alexander J. C. Kuehne

Beilstein J. Org. Chem. 2025, 21, 964–998, doi:10.3762/bjoc.21.80

• intensity borrowing from higher excited states, due to orbital overlap, does not explain the improved performance sufficiently, especially when comparing the oscillator strengths that can be determined using density functional theory (DFT) studies [19][20][21]. Moreover, when looking at di- or multiradicals

• to break the symmetry. Here, the molecule consists of a pentalchloro phenyl and two tribromophenyl units (PCl-TBr2M) [55], or with two p-bromotetrafluorophenyl rings (PCl-TFBr2M) (see Figure 2d–f) [52]. DFT calculations for these mixed per- and trihalophenylmethyl radicals and their orbitals show a

• . However, one can observe a loss of the vibronic features in the fluorescence signal, indicating that the emission occurs from a CT state, in agreement with the DFT orbital distribution in the ground state geometry (see Figure 2e for different orbital location in HDMO and SOMO). Interestingly, successive

Study of tribenzo[b,d,f]azepine as donor in D–A photocatalysts

• Katy Medrano-Uribe,
• Jorge Humbrías-Martín and
• Luca Dell’Amico

Beilstein J. Org. Chem. 2025, 21, 935–944, doi:10.3762/bjoc.21.76

• experimentally in the solvatochromism study of fluorescence using solvents with diverse polarities (see Supporting Information File 1, Figure S9). Indeed, the density functional theory (DFT) calculation performed at WB97XD/Def2TZVP level of theory showed the lowest value for the HOMO–LUMO energy gap in compound

• behavior is supported by the DFT studies, which suggested a better spatial separation between the HOMO and LUMO. As expected, the HOMO–LUMO energy gap followed a trend that is dependent on the electron-donating capacity of the nitrogen heterocycles and amine present in compounds 5e (2.9 eV), 5d (3.5 eV

• CT stabilization of the first excited state of the molecule [34]. This observation is further supported by the orthogonal D–A conformation calculated using DFT, which indicates a decoupled interaction between the HOMO and the LUMO (Figure 2). Moreover, compound 5e is the only member of the family in

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• thiols act as stoichiometric reductants. Mechanistic insights, elucidated through control experiments and DFT calculations, revealed that photoexcitation of diazo imide 41 triggers nitrogen extrusion (ΔG‡ = +10.0 kcal·mol−1), generating the triplet carbene intermediate Int-45. In DCM, this species

• substrates 61. At 10 °C, the catalytic system consisting of NiBr₂(diglyme), oxazoline ligand, (EtO)₃SiH, and K₃PO₄(H₂O) achieved β-selective hydroalkylation. When the temperature was raised to 100 °C, the reaction selectively produced α-branched products. DFT calculations showed that at low temperatures, the

• mechanistic experiments and DFT calculations, the authors proposed a possible mechanism for the reaction: first, DPZ is excited by light to form the excited state DPZ*, which then oxidizes bromide ions through single-electron transfer to generate corresponding radical anions. These radical anions undergo