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

• of interest is the selectivity (either enantio- or diastereoselectivity), which is predicted as the difference in energies between the selectivity-governing transition states ∆∆G‡ (Figure 3). Whereas the application of the above described representations and models to such problems is rather modern

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• curcumins 1 with arylidenemalonate 2 can be explained in terms of the relative stereochemistry of the substituents in the enolate arising from the first Michael addition (Figure 3). Comparison of the two possible transition states TSI and TSII for second Michael addition suggests that a severe 1,3-allylic

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• to be driven by stabilizing non-covalent interactions. Specifically, the carbonyl O in N2-s-cis shows NCIs with one of the benzene rings of PPh3 as well as a hydrogen bond-like NCI with a H-atom of the electrophilic methyl. Thus, the partitioning between transition states favor the N2-pathway over

• system (Figure 10). Under conditions A, deprotonation and cesium coordination were heavily favored by 11.1 kcal/mol (18(N-H)). Transition states 18-N2-Cs and 18-N1-Cs were found leading to N1- and N2-products, respectively. NCIs between the cesium cation with the ester and sulfonate oxygens, and

• heavily favored in complex with Cs+ by 20.6 kcal/mol under conditions A, and 13.6 kcal/mol under conditions B. Transition states were found for the reaction of 21 under both conditions (see Supporting Information File 1). However, in this case, neither chelation nor other NCIs resulted in an energy

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

• PIDA/AlCl3, 1:2). Overall, we characterized four transition states along the reaction coordinates for both pathways. Although the PIFA-assisted mechanism follows a similar route to that described in Figure 1 until the formation of the active chlorinating species, in this case, the formation of TS2

• AlBr3 (Figures S5 and S6, Supporting Information File 1). Calculations indicated that each of these pathways proceeds along four transition states. Moreover, we found that the coordination of AlBr3 to I-2 to form TS2 has the highest energy barrier (determining step, ΔG‡ for TS2 53.3 kcal/mol) in the

• presence of PIDA. Meanwhile, formation of TS3 (ΔG‡ = 21.3 kcal/mol) is the limiting step of the mechanism in the presence of PIFA. Then, in the presence of the PIFA/AlBr3 system, bromination of 2-naphthol is the energetically most favored pathway. Although all these reactions occur through four transition

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

• chemically-induced cationic cyclization mechanisms, we performed quantum chemical calculations [mPW1PW91/6–31+G(d/p)/SMD(chloroform)] [13][14][15][16][17][18][19][20] to obtain the relative free energies of the cationic intermediates and transition states that interconvert them, as well as the relative free

• higher free energy barriers of 38.0 and 38.8 kcal mol−1, respectively, to react through their associated chair–boat Cope transition states (Figure S11, Supporting Information File 1). In addition, the resulting products were predicted to be approximately 10 kcal mol−1 higher in free energies than the

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

• the minimum geometries are reported, as no transition states were obtained because the carbocation ring formation is a spontaneous process. Moreover, it is noteworthy that for each cation optimized, we examined several other conformers (specifically rotamers), but these were of higher energy than the

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• vicinal proton. These results suggested that the formation of the allylic cation occurred readily from alcohols 15 and 18; however, the transition states leading to the rearrangement products were inaccessible and so only chloride addition occurred. The generation of the rearrangement products from the

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• linear or nearly linear transition states [76]. Isotope effects can also be maximized when the acid strength is the same on both sides of the reaction [77]. On the one hand, small variations observed here with different substrates and ligands could reflect the modulation of acidity from the presence of

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

• cubic box of 30 Å side. The k-point sampling was performed through the Gamma–Pack scheme with one point. Transition states were obtained through the climbing image version of the nudged elastic band algorithm [32] and dimer method [33]. These structures showed a single imaginary frequency or with some

• -TEM images and movies will provide us a deeper understanding of fullerene coalescence processes in peapods. Computational Methods The Amsterdam Density Functional (ADF) code [21][22] was used for the electronic structure calculations and to optimize reactants, products, intermediates and transition

• states. The Perdew, Burke and Ernzerhoff (PBE) functional provided the electronic density [23]. Electrons were described with Slater-type basis functions of triple-ζ + polarization quality. We have included scalar relativistic corrections using the zeroth-order regular approximation (ZORA) formalism

Anion–π catalysis on carbon allotropes

• M. Ángeles Gutiérrez López,
• Mei-Ling Tan,
• Giacomo Renno,
• Augustina Jozeliūnaitė,
• J. Jonathan Nué-Martinez,
• Javier Lopez-Andarias,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2023, 19, 1881–1894, doi:10.3762/bjoc.19.140

• , stands for the stabilization of anionic transition states on π-acidic aromatic surfaces. Anion–π catalysis on carbon allotropes is particularly attractive because high polarizability promises access to really strong anion–π interactions. With these expectations, anion–π catalysis on fullerenes has been

• catalysis; electromicrofluidics; enolate addition; ether cyclizations; fullerenes; Introduction Anion–π catalysis was introduced ten years ago [1]. The idea is to stabilize anionic transition states on electron-deficient, π-acidic aromatic surfaces (Figure 1A). The true beginning is arguably in 2015

• polarizability [9][10][11], the dream scaffolds for induced anion–π interactions are carbon allotropes. Anionic transition states placed on C60 fullerenes 1 will drive the 60 π electrons toward the other side, thus inducing a transient macrodipole that will stabilize the same transition state that induced its

Unraveling the role of prenyl side-chain interactions in stabilizing the secondary carbocation in the biosynthesis of variexenol B

• Moe Nakano,
• Rintaro Gemma and
• Hajime Sato

Beilstein J. Org. Chem. 2023, 19, 1503–1510, doi:10.3762/bjoc.19.107

• investigated the biosynthetic pathways using DFT calculations to validate the above-mentioned aspects. Results and Discussion The detailed structures of the intermediates and transition states were elucidated by computational analysis. Interestingly, we have found an interaction between the secondary

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• site (see transition states 66 and 67, Scheme 17) [45]. In 2020, Fu and co-workers developed a novel aza-Friedel–Crafts reaction between 3-arylindoles 68 and 2-aryl-3H-indol-3-ones 69 activating the C2–H bond of the heteroaromatic ring. Chiral phosphoric acid P12 catalyzed this transformation

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• cation cis-218. On the other hand, when polysubstitution with methoxy groups is present, the cation in 216 is delocalized, inhibiting the production of cyclobutene 217. Thus, radical cyclization according to the Beckwith–Houk model [108][109] via transition states TSI and TSII would take place, leading

Supramolecular approaches to mediate chemical reactivity

• Pablo Ballester,
• Qi-Qiang Wang and
• Carmine Gaeta

Beilstein J. Org. Chem. 2022, 18, 1463–1465, doi:10.3762/bjoc.18.152

• reactants are confined in the restricted space provided by an enzyme binding pocket, the increase in local concentration, due to the proximity effect, the stabilization of intermediates and transition states cause the acceleration of the reaction. Thus, learning from natural enzymes, novel supramolecular

• capsules [5][6][8][9]. The capsules feature sizeable internal hydrophobic cavities that can accommodate large substrates and even allow bimolecular reactions to take place. In addition, they may ensure catalytic turnover. Transition states and reaction intermediates may also be stabilized in the cavities

• distributions when performed inside the containers compared to the bulk solution. As mentioned above, activation of substrates, stabilization of intermediates and transition states through intermolecular interactions was established as one of the fundamental factors of supramolecular catalysis, and among these

Experimental and theoretical studies on the synthesis of 1,4,5-trisubstituted pyrrolidine-2,3-diones

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Nguyen Ngoc Tri,
• Luc Van Meervelt,
• Nguyen Tien Trung and
• Wim Dehaen

Beilstein J. Org. Chem. 2022, 18, 1140–1153, doi:10.3762/bjoc.18.118

• reactants, intermediates, transition states, and products were optimized and are illustrated in Figure S7 in Supporting Information File 1. The relative free energy (ΔG, ΔG#) values for all species are presented in Figure 4, the reaction potential energy surface. This figure is a detailed reaction mechanism

• (Scheme 5). The first two stages occur through the TS10, TS15 transition states with Ea values ca. 7.4 and 28.4 kcal·mol−1, respectively. The last stage is a thermodynamically favorable H-shift process with ΔG of −8.9 kcal·mol−1 which is similar to the transformation from IS9 to 10ab. In addition, we

• form an N–H bond leads to 10ab-v3 (Scheme S1, Supporting Information File 1). These processes are carried out through the TS11, TS16, and TS20 transition states with ΔG# values of 4.7, 26.9, and 7.1 kcal·mol−1, respectively. For the reaction pathway starting from 4a’, the first steps lead to

Understanding the competing pathways leading to hydropyrene and isoelisabethatriene

• Shani Zev,
• Marion Ringel,
• Ronja Driller,
• Bernhard Loll,
• Thomas Brück and
• Dan T. Major

Beilstein J. Org. Chem. 2022, 18, 972–978, doi:10.3762/bjoc.18.97

• ). We studied the inherent chemistry of the reaction leading to HP and IE using gas-phase calculations. This provided the free energy of distinct carbocation intermediates and transition states along the proposed reaction path leading to products in the gas phase. The gas phase is a natural choice as a

• A and A’ is set to zero. Bonds breaking/forming in the transition states are marked by dotted lines. All calculations were performed in the gas phase at the M06-2X/6-31G+(d,p) level of theory. Structures of intermediates C‘ and C. The distance between the double bond and the cation in intermediate C

Electroreductive coupling of 2-acylbenzoates with α,β-unsaturated carbonyl compounds: density functional theory study on product selectivity

• Naoki Kise and
• Toshihiko Sakurai

Beilstein J. Org. Chem. 2022, 18, 956–962, doi:10.3762/bjoc.18.95

• treatment with 1 M HCl produces phthalide 4 through desilylation and following lactonization of F (path d). As can be seen from Scheme 5, the cyclization of D to E is the key step for the formation of compound 6. Therefore, we calculated the intermediates (D and E) and transition states (D–E TS) for this

Synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexane via cyclopropene cycloadditions to the stable azomethine ylide derived from Ruhemann's purple

• Alexander S. Filatov,
• Olesya V. Khoroshilova,
• Anna G. Larina,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2022, 18, 769–780, doi:10.3762/bjoc.18.77

• diastereofacial stereoselectivity. Our goal was to identify the nature of transition states associated with two theoretically possible diastereomers and to find out if the experimentally observed diastereomer is more kinetically favorable than the opposite one. The reaction between 3-methyl-3-phenylcyclopropene

• optimization of both transition states TS-4-NI and TS-4'-NI corresponding to pyramidal inversion in cycloadducts 4 and 4' and two pairs of invertomers, we have found that each of the diastereomers 4 and 4' is a mixture of two easily interconverting invertomers (ΔG‡4-exo->4-endo = 1.2 kcal/mol and ΔG‡4-endo->4

• 3-methyl-3-phenylcyclopropene (2j) and corresponding DFT calculations (relative Gibbs free energy change between reagents, transition states and possible products are given in kcal/mol). Plausible mechanism of the 1,3-DC reaction of protonated Ruhemann's purple (1) with 1-chloro-2-phenylcyclopropene

A resorcin[4]arene hexameric capsule as a supramolecular catalyst in elimination and isomerization reactions

• Tommaso Lorenzetto,
• Fabrizio Fabris and
• Alessandro Scarso

Beilstein J. Org. Chem. 2022, 18, 337–349, doi:10.3762/bjoc.18.38

• the active site of the enzyme. Once bound, substrate activation is carried out by specific amino acid side chains that adorn the inner surface of the cavity by means of a combination of covalent and/or weak intermolecular interactions leading to the stabilization of intermediate species and transition

• states of the reaction with impressive accelerations, substrate, and product selectivities. The development of artificial catalytic systems able to activate substrates and to stabilize intermediate species through weak noncovalent interactions is the scope of supramolecular catalysis [1][2][3][4

Iridium-catalyzed hydroacylation reactions of C1-substituted oxabenzonorbornadienes with salicylaldehyde: an experimental and computational study

• Angel Ho,
• Austin Pounder,
• Krish Valluru,
• Leanne D. Chen and
• William Tam

Beilstein J. Org. Chem. 2022, 18, 251–261, doi:10.3762/bjoc.18.30

• optimizations of all the intermediates and transition states were carried out with the Minnesota functional M06 [69] with the double-ζ basis set def2SVP [70] and Grimme’s dispersion (GD3) [71]. Harmonic vibrational frequencies were computed to verify the nature of the stationary points. The normal modes of all

• optimization and frequency calculations. Frequency analyses and single-point energies were calculated with the M06 functional [69] with the triple-ζ basis set def2TZVP [70] with the PCM (1,4-dioxane) solvent model [72]. The Gibbs free energies of formation of the reactants, products, and transition states were

• iridium–hydride bond to form hydrometalated intermediates IN2a and IN2b (Figure 1). Two possible transition states, which exhibit a distorted Ir–H–C–C’ four-membered ring geometry, can be located. The concerning free energy barrier about IN1a to IN2a, via 1aTS2a is 8.6 kcal/mol whereas it is 4.9 kcal/mol

Efficient and regioselective synthesis of dihydroxy-substituted 2-aminocyclooctane-1-carboxylic acid and its bicyclic derivatives

• İlknur Polat,
• Selçuk Eşsiz,
• Uğur Bozkaya and
• Emine Salamci

Beilstein J. Org. Chem. 2022, 18, 77–85, doi:10.3762/bjoc.18.7

• Information Experimental section, 1H and 13C NMR spectra for all new compounds, as well as selected 2D NMR spectra and crystallographic data for compound 10 are provided. Optimized geometries of the transition states with selected interatomic distances and cartesian coordinates for computed structures are

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• this case, the nitroalkene could not be activated by hydrogen bonding via the (thio)urea moiety, however, it is also probably less sterically hindered (Figure 3a). The DFT calculated transition states support this analysis. The transition state TS-major-re-SR-cat leading to the major stereoisomer of

• sulfur stereogenic center does not play an important role in the Michael addition (Figure 3b). The stereochemical outcome of the Michael addition is dictated mainly by the configuration of the proline unit. The calculated transition states for the Michael addition with both diastereomeric catalysts (S,R

• . Catalyst design principles. DFT-calculated (PBEh-3c/def2-SV(P)//M06-2X/def2-TZVP) structures of catalyst (S,R) and (S,S)-C2, enamine between aldehyde 6c and (S,R)-C2; enamine 6c-(S,R)-C2 and hydrogen-bonded nitroalkene 9. a) Arrangements of reactants in the transition states; b) DFT-calculated (PBEh-3c

Enantioenriched α-substituted glutamates/pyroglutamates via enantioselective cyclopropenimine-catalyzed Michael addition of amino ester imines

• Zara M. Seibel,
• Jeffrey S. Bandar and
• Tristan H. Lambert

Beilstein J. Org. Chem. 2021, 17, 2077–2084, doi:10.3762/bjoc.17.134

• reported [45], for which a detailed transition state model was developed. In that study, it was determined that the reaction proceeds via several competing low-energy transition states involving both O–H and N–H enolate binding modes, E and Z enolate isomers, and a range of H-bonding and other noncovalent

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• investigated by means of DFT calculations using the reaction between enaminone 6a and phenyl azide. TS1 and TS2 have been proposed as two transition states, which then converted to IN1 and IN2 as two possible isomers. The stable final products were achieved via a cascade reaction including the elimination of

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• based on the operating transition states [37][38]. A cyclic transition state is proposed in the reaction with sodium borohydride. In this transition state, the oxygen of the sulfinyl group interacts with the boron atom, facilitating the release of the hydride, directing the attack to the Si-face of the