The intramolecular stabilizing effects of O-benzoyl substituents as a driving force of the acid-promoted pyranoside-into-furanoside rearrangement

• Alexey G. Gerbst,
• Sofya P. Nikogosova,
• Darya A. Rastrepaeva,
• Dmitry A. Argunov,
• Vadim B. Krylov and
• Nikolay E. Nifantiev

Beilstein J. Org. Chem. 2025, 21, 2456–2464, doi:10.3762/bjoc.21.187

• ° correspondingly, after which the starting structures were fully optimized. Quite expectedly for galactose, the gt conformer was found to have the lowest energy. Supporting Information File 1, Table S1 contains the energies obtained for the three conformers and Figure 4C provides graphical representation of the

• -Sundralingam parameters for C1-endo and C1-exo conformations of compound 2 are given in Table 1. The resulting most stable C1-endo conformer of furanoside 2 is in agreement with the 1H,1H coupling constants that were observed for it previously [26]: 3J1,2 < 1 Hz, 3J2,3 = 1.6 Hz and 3J3,4 = 5.0 Hz. The

• corresponding torsional angles in the found conformer are measured to be approximately 90°, −101° and 129°. A possible reason for this result was determined upon the examination of the obtained structures (graphical representation is given in Figure 5A). It is clearly seen that both the pyranoside and the

Rotaxanes with integrated photoswitches: design principles, functional behavior, and emerging applications

• Jullyane Emi Matsushima,
• Khushbu,
• Zuliah Abdulsalam,
• Udyogi Navodya Kulathilaka Conthagamage and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2345–2366, doi:10.3762/bjoc.21.179

• of the DB24C8 macrocycles can control the photocyclization of the dithienylethene. For instance, when the DB24C8 is positioned at the N-methyltriazolium (MTA) site, the photocyclization rate is enhanced because the macrocycle locks the antiparallel conformer of the dithienylethene. In contrast, the

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• less favorable pathway compared to the previously employed 1,5-HAT. Initial feasibility studies revealed that the non-brominated substrate exhibited poor reactivity in the photochemical 1,6-HAT reaction (Scheme 14), as its unreactive conformer J dominated the equilibrium. In contrast, the brominated

• analogue achieved high efficiency: the bulky bromine atom sterically biased the population toward the reactive conformer I, where the benzylic C–H bond is optimally positioned for 1,6-HAT. Therefore, (S)-113 was selected as the precursor for the key photoredox reaction (Scheme 15). To prepare this, a

A m-quaterphenyl probe for absolute configurational assignments of primary and secondary amines

• Yuka Takeuchi,
• Mutsumi Kobayashi,
• Yuuka Gotoh,
• Mari Ikeda,
• Yoichi Habata,
• Tomohiko Shirai and
• Shunsuke Kuwahara

Beilstein J. Org. Chem. 2025, 21, 2211–2219, doi:10.3762/bjoc.21.168

• derivatives [41] the preferred conformation of (S)-2a can be proposed (Figure 2). In the case of the P conformer, a Newman projection along the C–N bond reveals that the bulkier substituent, the hydroxymethyl group (denoted as L), is close to a seven-membered ring, and is destabilized by steric repulsion with

• the methylene protons. In contrast, in the M conformer, the medium-sized methyl group (denoted as M) is located near the seven-membered ring, reducing the steric repulsion involving the hydroxymethyl group with the methylene protons. Moreover, considering that the phenyl ring and the ester carbonyl

• clarity. The relationship between the ACD values and excess of P conformer. Excess of P conformer (%) = ([P] − [M])/([P] + [M]) × 100, where [P] and [M] are the amounts of P and M conformers calculated by B3LYP/6-31G*, respectively. Coupling reaction of 1 and chiral primary and secondary amines. The

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

• [49]. The metastable E-diazocine exists in two conformers that can interconvert and have different absorption spectra (Scheme 10): twist (generally more stable) and chair (less stable). The spectrum of the chair conformer overlaps with the Z-isomer. Thus, to obtain better PSSs, the right conditions

• should be chosen to favour the twist conformer [50]. Each form exists in two enantiomers. The E-enantiomers cannot interconvert directly without first converting to the other conformer [51]. Regarding the substitutions on the aromatic rings, it has been reported that electron-donating groups tend to red

• soluble in water. For C- and S-diazocine, the absorption band separation of the two isomers is lower in polar solvents, resulting in worse PSS. In particular, for the S-diazocine it was found that the E-chair conformer was bathochromically shifted with increasing polarity of the solvent until completely

Thermodynamics and polarity-driven properties of fluorinated cyclopropanes

• Matheus P. Freitas

Beilstein J. Org. Chem. 2025, 21, 1742–1747, doi:10.3762/bjoc.21.137

• electron delocalization effects. Among the difluorocyclopropanes, the stability order is 1.1 > 1.2-t. > 1.2-c., highlighting the destabilizing influence of 1,2-syn-diaxial repulsion in the 1.2-c. isomer. A similar interaction is observed in cis-1,3-difluorocyclobutane, where the diaxial conformer is

Structural analysis of stereoselective galactose pyruvylation toward the synthesis of bacterial capsular polysaccharides

• Tsun-Yi Chiang,
• Mei-Huei Lin,
• Chun-Wei Chang,
• Jinq-Chyi Lee and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2025, 21, 1671–1677, doi:10.3762/bjoc.21.131

• , and the immunological properties may base on R/S-configuration. However, precisely controlling the formation of R- and S-isomers and identifying the correct conformer can be challenging due to the structural similarities between these two isomers. Researchers have recently developed strategies to

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

• temperature. These are attributable to the mixture of conformers with the figure-eight conformation as minor and the bathtub conformation as major conformer with a ratio of ca. 1:7. The obtained temperature-dependent 1H NMR data were subjected to the van't Hoff plot, affording an enthalpy ΔH and an entropy ΔS

• conformation (Sa,Sa)-A is feasible with a small activation barrier of 9.9 kcal mol−1. The figure-eight conformer (M,M)-B untwists to adopt an achiral conformation C with the exo-alkene units rotated inwards in opposite directions. These conformational changes are almost identical to those of CBBC 1. However

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

• K does not change it much (Table 1, the italicized values). The calculated energy barrier of process from 1KE to 1KK in acetonitrile (37 kcal/mol in Table 1) is relatively high and this process should be slow in the NMR time scale. The conclusion from these calculations is that the major conformer

• is a result of fast exchange between 1E and 1KE and the minor conformer can be attributed to 1KK. The measured carbon spectrum of 1 in CD3CN at 243 K (Figure S8 in Supporting Information File 1) supports this assignment as well. The HSQC spectrum (Figure S9 in Supporting Information File 1) helps in

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

• , and the conformer corresponding to the centroid of each cluster is retained. The remaining conformers of each complex are optimized using GFN1-xTB in the implicit solvent model ALPB with parameters for CH2Cl2[21][22]. After each optimization, the geometry of the complex is analysed to determine

• within a plane. Once all calculations for all conformers of all complexes are completed, the complex with the overall lowest-energy conformer is selected, and its corresponding reaction site is considered the most likely to react. All complexes that have conformers within a defined energy threshold of

• the overall lowest-energy conformer are considered to correspond to potential reaction sites; for this study, we choose a threshold of 1 kcal·mol−1. When several complexes with conformers within the energy threshold are found and the corresponding reaction site differs between the complexes, we allow

A versatile route towards 6-arylpipecolic acids

• Erich Gebel,
• Cornelia Göcke,
• Carolin Gruner and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 1104–1115, doi:10.3762/bjoc.21.88

• evident by an antiperiplanar coupling of the axially positioned H6 with 3J(H6,H5,pro-S) = 11.7 Hz and a gauche coupling with 3J(H6,H5,pro-R) = 3.3 Hz. The major diastereomer, assigned as (2R,6S)-9 was found as a mixture of conformers in solution (Figure 2a). Like for (2R,6R)-9, one conformer of (2R,6S)-9

• (2R,6S)-11, with only one set of 1H NMR signals, and, hence, one conformer. In addition, for the unprotected (2R,6S)-11 the coupling constants 3J(H6,H5,pro-R) = 12.8 Hz for proton H6 and 3J(H2,H3,pro-R) = 12.9 Hz for proton H2 indicate diaxial couplings, which in return confirms a flip to the more

• ). Analysing the 1H NMR spectra of reduction product (2R,6S)-13 reveals a very similar pattern to the previously discussed Suzuki–Miyaura product (2R,6S)-9 with one significant distinction. The signals of both protons H2 and H6 of the first conformer (2R,6S)-13I in comparison to the second one (2R,6S)-13II are

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

• previously isolated in crystalline form in two different molecular conformations [18]. In conformer I (Figure 2, bottom), all three benzyl groups are oriented towards the interior of the macrocycle. In contrast, conformer II (Figure 2, top) features two benzyl groups projecting inward and one benzyl group

• 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

• . Alternative view of the crystal structure of the HIM 1 and LiBArF20 complex. BArF20 anion is omitted for clarity. Nitrogen, oxygen, iodine, and lithium atoms are denoted by light blue, red, purple, and lavender color, respectively. Conformer II displays two benzyl groups projected in and one benzyl group

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

• rotamers have different energies. When the C–F bonds are aligned gauche, the vacant σ* orbital of each C–F bond is able to mix with the filled σ orbital of an adjacent C–H bond, and this hyperconjugative interaction stabilises the gauche conformer (III, Figure 2). The anti conformer does not benefit from

• ) bond, such that the endo orientation of the C–F bond (as depicted in I, Figure 6) is lower in energy than the exo conformer (not shown). This is an example of the anomeric effect [77]. The anomeric effect can be visualised perhaps most clearly when the ether moiety is embedded within a small ring [78

• hyperconjugative interactions can take place (i.e., σC–H → σ*C–F and σC–H → σ*C–O, with the former likely to be stronger). This is only a subtle effect, with the gauche conformer just ≈0.3 kcal·mol−1 lower in energy than the anti conformer (not shown) [86], but it can nevertheless have a significant impact upon

Deep-blue emitting 9,10-bis(perfluorobenzyl)anthracene

• Long K. San,
• Sebastian Balser,
• Brian J. Reeves,
• Tyler T. Clikeman,
• Yu-Sheng Chen,
• Steven H. Strauss and
• Olga V. Boltalina

Beilstein J. Org. Chem. 2025, 21, 515–525, doi:10.3762/bjoc.21.39

• . Interestingly, only one conformer is observed, with both perfluorobenzyl groups pointing in the same direction (instead of the opposite directions) on the ANTH core, in contrast with the earlier reported by us presence of two different conformers of perfuorobenzylated corannulene in the single crystal, which

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

• strong reinforcement of the geometrically preferred C5 conformer by coinciding pyridyl groups with “out” carbonyls. The result is a lowering of symmetry from D3h to CS. While observations of symmetry-lowering are commonplace in controlled environments [47][264][293][335][366][367][368][369], we believe

• positions of the two active carboxylic acid groups in cages such as 1, there are several levels of tuning possible in terms of the rigidity. Hexapyridine cage 2 is calculated (and observed) to exist exclusively (>99.9%) in the C13 conformer (Figure 8B and Figure 9A) [41]. Since the amide groups rarely

• conformers C5, C9, C10, C12, and C13. (B) Organocatalysis performed by cage 2 (which exists exclusively in the C13 conformer) is a clear example of polarization and organization. The data for cage 1 suggest cavity height (balanced flexibility) is important for the catalytic rate. Supporting Information

Antibiofilm and cytotoxic metabolites from the entomopathogenic fungus Samsoniella aurantia

• Rita Toshe,
• Syeda J. Khalid,
• Blondelle Matio Kemkuignou,
• Esteban Charria-Girón,
• Paul Eckhardt,
• Birthe Sandargo,
• Kunlapat Nuchthien,
• J. Jennifer Luangsa-ard,
• Till Opatz,
• Hedda Schrey,
• Sherif S. Ebada and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 327–339, doi:10.3762/bjoc.21.23

• on forces and step size. The IEFPCM solvent model [33] was used to simulate the solvent effects of methanol and frequency calculations were used to determine the conformers as minima. Conformers 4.5 kcal/mol above the lowest energy conformer and double conformers were discarded. Time-dependent DFT

Quantifying the ability of the CF₂H group as a hydrogen bond donor

• Matthew E. Paolella,
• Daniel S. Honeycutt,
• Bradley M. Lipka,
• Jacob M. Goldberg and
• Fang Wang

Beilstein J. Org. Chem. 2025, 21, 189–199, doi:10.3762/bjoc.21.11

• HB complex. Values for ΔGcalc were then calculated as the weighted average of the free energy of each HB complex as in which PMe3PO···HB,a and PMe3PO···HB,b are the percent populations of the HB complex of Me3PO with the donor conformer a and b, respectively; PMe3PO | HB,a and PMe3PO | HB,b are the

• percent populations of Me3PO and the corresponding HB donor conformer as two non-interacting molecules (see Supporting Information File 1 for details). We found a strong linear correlation between ΔGexp and ΔGcalc obtained at the PCM(MeCN)-M06-2X/6-31+G(d,p) level of theory (Figure 5 and Figure 6A). These

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• the two conformers of hydrazones 3e and 3f (see Supporting Information File 1) is in accordance with the E stereoisomers. Furthermore, another correlation is observed for one conformer involving the NH of the imine on one side and the α-proton and the CH2 of the Cbz of the phenylalanine on the other

• . This correlation is present for one conformer (anti) and not for the other (syn), and this observation is similar for hydrazones 3e and 3f (see Supporting Information File 1). Based on these experimental data we can hypothesize the geometry of the two conformers of hydrazones 3e and 3f is E,syn and E

• not the enamine. As for the hydrazones 3e and 3f, we assumed that the hydrazones 6e and 6f were obtained as a mixture of conformers, E,syn and E,anti (Scheme 4). Surprisingly, the ratio of each conformer differs for hydrazones 6e (ratio 77:23) and 6f (ratio 52:48). The last cyclization step was based

Synthesis and conformational analysis of pyran inter-halide analogues of ᴅ-talose

• Olivier Lessard,
• Mathilde Grosset-Magagne,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2024, 20, 2442–2454, doi:10.3762/bjoc.20.208

• stated above, all analogues exhibit a gt conformation except for compound 17, which is a tg conformer. This information could also be extracted from Table 3 by looking at the O5–C5–C6–O6 torsion angles (Table 3, entry 1). Table 3 also highlights that there are significant intra-annular torsion angles for

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

• structure, it is important to include information from relevant conformers. To avoid losing important information from discarding conformers, Paton and co-workers [85] introduced wSterimol, which takes into account structures from the entire conformer ensemble via Boltzmann-weighting. The authors used their

• descriptors for the prediction of the enantioselectivity for several previously reported reactions, showing improved prediction performance compared to non-Boltzmann-weighted Sterimol parameters. Apart from considering parameters of the entire conformer ensemble, it has been shown that informative models can

• minimum buried volume in a conformer ensemble was identified to determine the ligation state towards a metal centre as either mono- or bis-ligated and thus providing a threshold for catalytically active ligands [87]. All of these examples demonstrate that not only the type of descriptor is important, but

Allostreptopyrroles A–E, β-alkylpyrrole derivatives from an actinomycete Allostreptomyces sp. RD068384

• Marwa Elsbaey,
• Naoya Oku,
• Mohamed S. A. Abdel-Mottaleb and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2024, 20, 1981–1987, doi:10.3762/bjoc.20.174

• : Allostreptomyces; β-alkylpyrrole; conformer; cytotoxic; DFT; 4-formylpyrrole-2-carboxylic acid; Introduction β-Alkylpyrroles are key structural motifs in biomolecules and functional organic materials [1]. For instance, β-alkylpyrroles are the main building blocks for the life-essential tetrapyrrole pigments

• and 3, their conformational ensembles, datasets of a structure and population of each conformer [25], were determined using a Spartan 24 parallel package conformational search tool (Wavefunction Inc, USA), followed by geometry optimization of the most weighted conformers (Boltzmann distribution weight

• lower to 0.004). Eleven and seven weighted conformers for compounds 2 and 3 were obtained, respectively, each forming equilibrium mixtures. The quantum chemical method for the calculation of conformer distribution was ωB97X-V/6-311+G(2df,2p)[6-311G*] [30]. The CPCM solvation model for methanol was used

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• given SMILES string undergoes modifications to produce a list of SMILES for each deprotonated C–H bond. We generate min(1 + 3nrot, 20) conformers for each SMILES using RDKit (v.2022.09.4) [16][17], where (nrot) represents the number of rotatable bonds. Each conformer undergoes optimization in dimethyl

• identify the lowest-energy conformer. We then conduct re-optimization in ORCA (v. 5.0.4) [22][23], using the dispersion D4-corrected DFT functional CAM-B3LYP [24][25], the Karlsruhe [26][27] triple-ζ basis set, def2-TZVPPD, and the conductor-like polarizable continuum model (CPCM) [28] as the implicit

• Finkelmann et al. [30][31] and Ree et al. [14], we utilize the automated approach to compute CM5 atomic charges from semiempirical tight-binding (GFN1-xTB [37]) calculations. We modify the workflow to enhance the accuracy of the computed CM5 atomic charges. Instead of generating a single random conformer, we

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• the impact of gauche and anomeric effects on the conformer stabilities of different stereo- and regioisomers. Initially, we conducted a benchmark assessment comparing the optimal density functional theory method with coupled cluster with single and double excitations (CCSD) calculations and

• hyperconjugative interactions [3]. However, it is noteworthy that 3-fluoropiperidine does not exhibit such a fluorine gauche effect. In this case, the axial conformer is similarly populated to the equatorial conformer, despite the favorable antiperiplanar arrangement of orbitals that would facilitate these

• delocalization is considered to be secondary [7]. However, stabilization via intramolecular hydrogen bonding does not seem to significantly impact the conformational stability of 3-fluoropiperidine. In this context, the cis-conformer, with the axial fluorine atom facing the N-hydrogen atom, is either equally or

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• energy profile is seen for protonation-induced cyclization of 1, although the 6/6/6-tricyclic C3 tertiary cation is 7.1 kcal mol−1 higher in energy than its preceding intermediate (Figure 2C). A lower energy conformer of 1 exists, but we have been unable to find the corresponding cation A1b+, which

• implies that protonation and cyclization may be concerted for that conformer (Figure S4, Supporting Information File 1). We previously transformed 2 into the trans,trans-6/6/6-tricyclic C6 alcohol 8 using mCPBA to epoxidize the C6–C7 alkene [7]. Under the same conditions, epoxidation of 1 yielded the 6,7

• [22]. An X-ray structure of 9 allowed us to solve its absolute configuration and measure the C2–C7 distance to be 3.31 Å. This distance matches reasonably well with the calculated distance, 3.36 Å, of the lowest energy conformer of 9. Calculation of the proposed 6,7-epoxy derivative of 2, which was

Unprecedented synthesis of a 14-membered hexaazamacrocycle

• Anastasia A. Fesenko and
• Anatoly D. Shutalev

Beilstein J. Org. Chem. 2023, 19, 1728–1740, doi:10.3762/bjoc.19.126

• the PBE1PBE/6-311+G(2d,p) level of theory using the DFT B3LYP/6-311++G(d,p) optimized geometries (DMSO solution) and applying a multi-standard approach [44]. The calculated shifts of sp2-atoms C-7a, C-4, C-6, C-3, and C-3a in (Z)-8 and the s-cis-conformer (with respect to the C4–N bond) of 9 were

• model showed that (Z)-8 was significantly less stable than the s-cis-conformer of 9 in DMSO solution (ΔG = 7.17 kcal/mol; 298 K, 1 atm). As we proposed, pyrazolopyrimidine 8 undergoes dimerization to produce macrocycle 5 under certain conditions (Scheme 5). The dimerization of 8 was thoroughly studied

• calculated by the GIAO method at the PBE1PBE/6-311+G(2d,p) level of theory using the DFT B3LYP/6-311++G(d,p) optimized geometries (DMSO solution) and applying a multi-standard approach [44]. It is noteworthy that, in the most stable conformer of 10, the NH2 group of the triazole ring is located between the