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

• free energy transition barrier can be framed in terms of contributions from polarization and organization by the catalyst/system. Typical catalysis modes using macrocycle cavities performing (non-specific) hydrophobic substrate binding. (A) Macrocycles that confine two reagents close together to alter

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

• compounds N3, N4, and I1–I4. The activation enthalpy (ΔH‡) and activation entropy (ΔS‡) in the thermal reaction were determined from the intercept and slope. Using these values, the experimental activation free energy (ΔG‡(exp)), the k value, and the half-life (t1/2) at 298 K were calculated and the results

• 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

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

• , with other easily accessible parameters. We first calculated the Gibbs free energy of formation (ΔGcalc) of the HB complexes of HB donors with trimethylphosphine oxide (Me3PO), which models n-Bu3PO as a hydrogen bond acceptor, and compared these values with experimental data. We realized that such an

• 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

• the HB complex with tri-n-butylphosphine oxide at 298 K in anhydrous CD3CN. The Kd for 6b was not determined due to the formation of non-HB-mediated adducts (Figure S34 in Supporting Information File 1). The corresponding experimental Gibbs free energy of binding (ΔGexp) is calculated based on the Kd

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

• ° and C–I bond lengths of 2.1 Å (I–CH2CF3) and 3.2 Å. Finally, a 37.8 kcal/mol activation energy between XB-2 and B for path 1 was calculated. On the other hand, path 2 had a much lower Gibbs free energy of activation of 24.3 kcal/mol, where the angle of attack from 1a to 2a’ was found at approximately

• -mediated and SN2 reaction mechanisms. Ultimately, the nudged elastic band climbing image (NEB-CI) method predicted the SN2 pathway to be favoured, and transition state optimization showed this to possess a Gibbs free energy of activation of 24.3 kcal/mol. This report shows the ease with which sulfoxonium

Surprising acidity for the methylene of 1,3-indenocorannulenes?

• Shi Liu,
• Märt Lõkov,
• Sofja Tshepelevitsh,
• Ivo Leito,
• Kim K. Baldridge and
• Jay S. Siegel

Beilstein J. Org. Chem. 2024, 20, 3144–3150, doi:10.3762/bjoc.20.260

• for a CpH-PAH like BFC or FIC in DMSO? From the initial structural analogy to fluorene there is a substantial 8 pKa unit difference, which is nearly 11 kcal/mol in ambient reaction free energy. Computations (B97-D/def2-TZVPP(THF)//B97-D/def2-TZVPP(THF)) also predict pKa values of 14.4 and 14.3 for FIC

• ]. Electronic and thermal free energy differences between neutral and anion were compared to a reference pentafluorophenylfluorene, and subsequently converted to pKa values by dividing by 1.36. Visualization and analysis of structural and property results were obtained using Avogadro [35]. Our group develops

Controlled oligomerization of [1.1.1]propellane through radical polarity matching: selective synthesis of SF₅- and CF₃SF₄-containing [2]staffanes

• Jón Atiba Buldt,
• Wang-Yeuk Kong,
• Yannick Kraemer,
• Masiel M. Belsuzarri,
• Ansh Hiten Patel,
• James C. Fettinger,
• Dean J. Tantillo and
• Cody Ross Pitts

Beilstein J. Org. Chem. 2024, 20, 3134–3143, doi:10.3762/bjoc.20.259

• , alternatively, INT1 could be added to another equiv of 1 via TS2 to form INT2. Although formation of 4 is notably more thermodynamically favorable than INT2 (ΔΔG = −9.2 kcal/mol), a small difference in activation free energy is predicted (ΔΔG‡ = −1.4 kcal/mol). This, at least in part, provides an explanation as

• here that the free energy of activation is lower for chlorination, albeit only by 0.4 kcal/mol. This is consistent with the notion that the kinetic preference can be overcome by increasing the concentration of 1 relative to CF3SF4Cl. In the second product-determining step, Cl atom abstraction by INT5

• challenges in the synthesis of [n]staffanes using excess [1.1.1]propellane (1). (Bottom) selective synthesis of [2]staffanes bearing the SF5 (2) and CF3SF4 (3) groups (this work). Computed free energy profile for the oligomerization of [1.1.1]propellane (1) following SF5 radical addition at PWPB95-D4/def2

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

• conditions also supported the generation of the radical anion [67]˙−. Furthermore, the authors used thermodynamic theoretical calculations to investigate catalytic steps, finding that the protonation of [67]˙− to generate [67-H] is thermodynamically favored (free energy of +2.39 kcal mol−1) over its

• reduction to highly energetic dianion [67]2− (free energy of +36.3 kcal mol−1). Combining experimental and theoretical observations, the authors proposed the most favorable hydrogen generation mechanism to be E–P–E–P; where E stands for reduction and P means protonation (Figure 19). Acid protonates the

Synthesis and antimycotic activity of new derivatives of imidazo[1,2-a]pyrimidines

• Dmitriy Yu. Vandyshev,
• Daria A. Mangusheva,
• Khidmet S. Shikhaliev,
• Kirill A. Scherbakov,
• Oleg N. Burov,
• Alexander D. Zagrebaev,
• Tatiana N. Khmelevskaya,
• Alexey S. Trenin and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2024, 20, 2806–2817, doi:10.3762/bjoc.20.236

• and 7a are formed (Scheme 4). Although intermediate 7a has a lower activation energy (∆G = −0.23 kcal/mol), further recyclization processes are not possible due to the positive free energy change (∆G > 0). In this context, the formation of the final product is only possible to proceed via intermediate

• irreversible process, given that it is thermodynamically challenging to revert the formed target product 4a to the original starting substances or the corresponding intermediate 6a (∆G(4a→6a) = + 4.04 kcal/mol). Meanwhile, a minimal difference in the free energy of intermediates 6a and 7a may facilitate their

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

• catalytic reaction (δE) is considered. King et al. [48] introduced the concept of the energy span of a simulated catalytic cycle by defining it as the difference between the highest and lowest free energy stationary points [49][50]. More precisely, the energy span can be defined using Equation 6, where Ti

• axis represents the free energy of the first stationary point of the selected pair and the y axis represents the free energy of the other stationary point of the pair. According to the volcano plots, the best theoretically predicted catalysts are those nearest to the lowest predicted δE values

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

• in a chloroform solution, using the polarizable continuum model (PCM) [75]. A natural bonding orbital (NBO) analysis was performed to study the effects of hyperconjugation from C–F antibonding orbitals [76]. First, dipole moments, enthalpy and Gibbs free energy differences between 1C4 and 4C1 chair

• are nearly degenerate. In solution, the picture is much clearer: the 4C1 structure is always lower in enthalpy and Gibbs free energy, which corresponds with the experimental measurements. One can see that the gap between the two structures tends to decrease as the halogen becomes larger (the minor

• described the synthesis and conformational analysis of halogenated pyran analogues of ᴅ-talose. All analogues adopt standard 4C1-like conformations both in solution and in the solid-state. The conformations were corroborated using DFT calculations by looking at the energy, enthalpy and Gibbs’ free energy

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

• by observing the influence of substituents on a reaction outcome. However, Hammett parameters have shown to not fully describe observed trends. Therefore, complementary representations capturing other properties of a molecule have been derived (vide infra) [28]. While traditional linear free energy

• Drawing inspiration from linear free energy relationships, MLR models, pioneered by Norrby and co-workers [83] and later further developed by Sigman and co-workers [69][82], are commonly used for the prediction of enantioselectivity. In such models, the substrates, catalysts, and other relevant reaction

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• . (a) Strain-promoted azide–alkyne cycloaddition between DBA 5 and benzyl azide and (b) 1H NMR spectral change at 30 °C in CDCl3. Arrhenius plots of the rate constants for the reaction between 5 and benzyl azide in CDCl3. Proposed reaction mechanism for the formation of compound 6a. Free energy

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

Divergent role of PIDA and PIFA in the AlX₃ (X = Cl, Br) halogenation of 2-naphthol: a mechanistic study

• Kevin A. Juárez-Ornelas,
• Manuel Solís-Hernández,
• Pedro Navarro-Santos,
• J. Oscar C. Jiménez-Halla and
• César R. Solorio-Alvarado

Beilstein J. Org. Chem. 2024, 20, 1580–1589, doi:10.3762/bjoc.20.141

• values as Gibbs free energy at 298 K and 1 atm. All our calculations were performed in the gas phase. Then, the solvent effects were included according to the polarizable continuum model via the solvent model density (SMD) option considering Truhlar’s model [36][37][38][39][40] and MeCN as the solvent

• –AlCl2 complex yields the final product 1-chloro-2-naphthol (P–Cl). The calculated mechanism for the chlorination reaction starts with coordination of a PIFA oxygen atom to aluminum chloride. This generates a highly exergonic PIFA–AlCl3 adduct. In Figure 1, the Gibbs free energy of this adduct is set as

• reaction proceeds through a stepwise mechanism. Thus, the reaction starts with the coordination of aluminum bromide to an acetate ligand in PIDA to form the PIDA–AlBr3 adduct in a highly exergonic process. Similar to the previous section, the Gibbs free energy at this point was set as 0 kcal/mol for

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

• most reliable method, it was employed to optimize the geometry and compute frequencies (to derive Gibbs free energy) for the difluorinated pyrrolidines. These computations were conducted in both the gas phase and employing an implicit DMSO solvent using SMD [22]. Subsequently, a NBO [23] analysis was

• the gas phase and implicit DMSO (in parentheses), along with the MAE compared to the CCSD/DGTZVP level. Relative Gibbs free energy (kcal⋅mol−1) for the geometry-optimized difluorinated pyrrolidines. Relative electronic energy (ΔEfull = ΔELewis + ΔEnon-Lewis) in isodesmic relationships and significant

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• enthalpy (ΔH), and stoichiometry (n). Values for free energy change (ΔG) and entropy contributions (TΔS) were derived from the equation ΔG = ΔH − TΔS = − RT ln Kd (with T = 298.15 K and R = 8.314 J mol−1K−1). General procedure I for the O-alkylation with BrCH2CH2NHBoc: A solution of glycosyl azobenzene

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

• anticipated that 1 would similarly undergo Cope rearrangement. However, when we heated 1 up to 200 °C for 5 h, we did not observe any Cope rearrangement products and we were able to recover >90% of 1. DFT calculations [mPW1PW91/6–31+G(d/p)/SMD(toluene)] on the Cope rearrangement of 2 revealed a free energy

• barrier through the chair–chair transition state of 28.1 kcal mol−1 and an overall ΔG from 2 to 10a/10b, which have the same predicted energy, of −2.0 kcal mol−1 (Figure 3B). The relative free energy barrier through the chair–boat transition state was calculated to be 36.9 kcal mol−1, but would require a

• , Supporting Information File 1). The lowest transition state for a Cope rearrangement, a chair–chair structure at 29.3 kcal mol−1, originates from a DD (down–down orientations of the methyl groups on the 10-membered ring) conformer that is 3.2 kcal mol−1 higher in free energy than the most dominant conformer

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol

• Naziha Tarannam,
• Prashant Kumar Gupta,
• Shani Zev and
• Dan Thomas Major

Beilstein J. Org. Chem. 2024, 20, 1189–1197, doi:10.3762/bjoc.20.101

• divided into three analogous sets. Below we will describe the free energy trends for the germacrene A and hedycaryol carbocations (Figure 2), while the corresponding electronic energy trends are presented in Supporting Information File 1 (Figure S1). Gibbs free energy of germacrene A–L carbocations For

• ring carbocation, E and F are 6.0 and 10.9 kcal/mol less stable than A, H is 16.0 kcal/mol above A, whereas G is the least stable (19.5 kcal/mol). For the remaining set (I–L), the free energy variation is smaller, with values ranging from 10.0 to 11.4 kcal/mol relative to A. To understand the reason

• for the difference in free energy, we analyzed the NCI plots for germacrene cations A–D. Despite being isomers, these carbocations possess quite different geometric arrangements. For instance, molecule A is more planar than the puckered B. It is clear from visual inspection of the NCI plots that B

Novel route to enhance the thermo-optical performance of bicyclic diene photoswitches for solar thermal batteries

• Akanksha Ashok Sangolkar,
• Rama Krishna Kadiyam and
• Ravinder Pawar

Beilstein J. Org. Chem. 2024, 20, 1053–1068, doi:10.3762/bjoc.20.93

• calculated employing the following equation: where Gdiene and Gphotoproduct indicate the Gibbs free energy of the bridged bicyclic diene molecule and the corresponding photoproduct. The ΔGstr was herein calculated by computing the Gibbs free energy of the diene and photoproduct using the M062X/6-311++G

• and photoproduct and ΔT is the difference in thermal contribution to the Gibbs free energy (M062X/6-311++G**) of the two photoisomers. The thermal back reaction (TBR) barrier is the energy barrier that the photoproduct must overcome to revert back into the parent isomer for continuing the

Tandem Hock and Friedel–Crafts reactions allowing an expedient synthesis of a cyclolignan-type scaffold

• Viktoria A. Ikonnikova,
• Cristina Cheibas,
• Oscar Gayraud,
• Alexandra E. Bosnidou,
• Nicolas Casaretto,
• Gilles Frison and
• Bastien Nay

Beilstein J. Org. Chem. 2024, 20, 162–169, doi:10.3762/bjoc.20.15

• energy, with a difference of Gibbs free energy with oxocarbenium 7 (39.2 kcal/mol) and 7’ (35.8 kcal/mol) incompatible with the reaction conditions. We therefore ruled out this possibility and suggest that aldehyde 3 is the main intermediate in this transformation (Scheme 3). Interestingly, the 1

• dihydronaphthalene 4. One-pot conversion of substrate 1 into 1-aryltetraline structure 6, and the proposed mechanism for its formation. Free-energy profile of the hypothesized [1,5]-sigmatropic hydrogen shift between 7 and 7’, (IEFPCM(CH2Cl2)-M06/6-311++G(2d,2p)//M06/6-31G(d,p) level of theory). Scope of substrates

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• -order kinetics, indicating a bimolecular process. Furthermore, their findings elucidated a compelling linear free-energy relationship between the rate constants and electronic characteristics of the para-substituents of the DCV electrophiles, implying a dipolar, zwitterionic mechanism. The researchers

Electron-beam-promoted fullerene dimerization in nanotubes: insights from DFT computations

• Laura Abella,
• Gerard Novell-Leruth,
• Josep M. Ricart,
• Josep M. Poblet and
• Antonio Rodríguez-Fortea

Beilstein J. Org. Chem. 2024, 20, 92–100, doi:10.3762/bjoc.20.10

• settings) is also predicted to be formed. Free energy difference between the two isomers, estimated in the gas phase, is somewhat reduced when increasing temperature (see Supporting Information File 1, Table S1). Therefore, the molar fraction of (1-Cs)•+@CNT would increase slightly at higher temperatures

• simulation technique that allowed us to explore the free energy surface in a fast and efficient way. In particular, we performed Car–Parrinello metadynamics simulations by choosing collective variables (CVs) that describe the formation and breaking of C–C bonds in the interdimer region (see Computational

• carbon atoms of one C60 molecule (those of contiguous hexagon and pentagon) with respect to nine carbon atoms in the other C60, all of them in the interdimer region (see Supporting Information File 1). Choosing this single CV, we aim to rapidly and efficiently explore the region of the free energy

Studying specificity in protein–glycosaminoglycan recognition with umbrella sampling

• Mateusz Marcisz,
• Sebastian Anila,
• Margrethe Gaardløs,
• Martin Zacharias and
• Sergey A. Samsonov

Beilstein J. Org. Chem. 2023, 19, 1933–1946, doi:10.3762/bjoc.19.144

• GAG properties, especially protein recognition specificity and multipose binding. We found that the binding free energy landscape in the proximity of the GAG native binding pose is complex and implies the co-existence of several binding poses. The sliding of a GAG chain along a protein surface could

• multipose character of GAG binding and the polarity of the binding poses of these periodic molecules. In the present work, all-atom MD simulations are conducted to study the dynamics of the protein–GAG complexes, and are complemented by free energy analysis. The free energy analysis of the protein–GAG

• analysis of the contacts between protein and GAG molecules established in the course of the simulation. Binding free energy calculations MM/GBSA (molecular mechanics generalized born surface area) model igb = 2 [48] from AMBER20 was used for free energy calculations on the trajectories obtained from RS

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

• (С-6), 143.51 (С-4), 129.63 (С-3), 103.54 (С-3a), 38.35 (NСH3), 22.65 (CH3 in Ac); HRESIMS–TOF ( m/z): [M + Na]+ calcd for C8H10N6ONa, 229.0808; found, 229.0815; Anal. calcd for C8H10N6O: C, 46.60; H, 4.89; N, 40.76; found, C, 46.65; H, 4.85; N, 40.86. Gibbs free energy diagram (B3LYP/6-311++G(d,p