A mechanochemical approach to access the proline–proline diketopiperazine framework

• Nicolas Pétry,
• Hafid Benakki,
• Eric Clot,
• Pascal Retailleau,
• Farhate Guenoun,
• Fatima Asserar,
• Chakib Sekkat,
• Thomas-Xavier Métro,
• Jean Martinez and
• Frédéric Lamaty

Beilstein J. Org. Chem. 2017, 13, 2169–2178, doi:10.3762/bjoc.13.217

• = 2.153 Å, H···OMe = 1.925 Å; see 16a-solv in Figure 2). 16a-solv was computed to be less stable than 16a by ΔG = 9.3 kcal mol−1. This higher Gibbs free energy was due only to entropic factors as 16a-solv was computed to be more stable than 16a by ΔE = −4.0 kcal mol−1. Interestingly, upon interaction with

Molecular recognition of N-acetyltryptophan enantiomers by β-cyclodextrin

• Spyros D. Chatziefthimiou,
• Mario Inclán,
• Petros Giastas,
• Athanasios Papakyriakou,
• Konstantina Yannakopoulou and
• Irene M. Mavridis

Beilstein J. Org. Chem. 2017, 13, 1572–1582, doi:10.3762/bjoc.13.157

• of the β-CD–D-NAcPhe complex, is not possible due to the bulkier indole group of D-NAcTrp that fills the cavity. This unfavorable environment might be a factor that forbids the formation of a β-CD–D-NAcTrp dimer structure. The difficulty in crystallizing the β-CD–D-NAcTrp may arise from a higher free

• energy barrier of crystal nucleation compared to other competing processes in solution at room temperature, but under the higher temperature and pressure conditions of the hydrothermal cell the presence of D-NAcTrp or of the complex β-CD–D-NAcTrp may influence the initial crystal nuclei which eventually

Framing major prebiotic transitions as stages of protocell development: three challenges for origins-of-life research

• Ben Shirt-Ediss,
• Sara Murillo-Sánchez and
• Kepa Ruiz-Mirazo

Beilstein J. Org. Chem. 2017, 13, 1388–1395, doi:10.3762/bjoc.13.135

• draw conclusions and try to make generalizations when we still lack the relevant empirical results (e.g., on the initial set of coupling mechanisms that could transform external sources of free energy into a system’s own means – and sustain, in this way, the first forms of autonomous functionality [46

G-Protein coupled receptors: answers from simulations

• Timothy Clark

Beilstein J. Org. Chem. 2017, 13, 1071–1078, doi:10.3762/bjoc.13.106

• context, the most important advantage of metadynamics is that it gives a free-energy profile of the process being simulated [27]. This means that we can obtain complete free-energy profiles along the binding path for both ligands and IBPs [39]. This, in turn, allows us to validate the simulations by

• functional bias and activate one or other of the two alternative paths. Metadynamics simulations have proven to be able to determine the bias, or lack of it, by considering the change in ligand-binding free energy between the binary ligand–receptor complex and the alternative ternary complexes with either

• the G-protein α-subunit or β-arrestin. We define two free-energy differences: The ligand bias can be determined from these energies according to Table 1 [39]. Thus, the simulations allow not only the calculation of the free energy of binding for unknown ligands but also the functional bias

Conformational study of L-methionine and L-cysteine derivatives through quantum chemical calculations and ³J_HH coupling constant analyses

• Weslley G. D. P. Silva,
• Carolyne B. Braga and
• Roberto Rittner

Beilstein J. Org. Chem. 2017, 13, 925–937, doi:10.3762/bjoc.13.94

• ). Calculated parameters (ωB97X-D/aug-cc-pVTZ) for the conformers of 1 and 2. Relative Gibbs free energy (ΔG) and electronic energy with ZPE corrections (ΔE) are given in kcal mol−1, populations (P) in % and dihedral angles in degrees. Experimental and calculated 1H NMR data for the compound 1 in different

Nucleophilic and electrophilic cyclization of N-alkyne-substituted pyrrole derivatives: Synthesis of pyrrolopyrazinone, pyrrolotriazinone, and pyrrolooxazinone moieties

• Işıl Yenice,
• Sinan Basceken and
• Metin Balci

Beilstein J. Org. Chem. 2017, 13, 825–834, doi:10.3762/bjoc.13.83

• second step, the iodide anion, which already exists in the reaction media attacks the protonated methoxy group and removes the methyl group from the structure to yield the corresponding pyrrolooxazinone skeleton 19c. The formation of 19c is quite exergonic with a Gibbs free energy of 52.52 kcal/mol in

How and why kinetics, thermodynamics, and chemistry induce the logic of biological evolution

• Addy Pross and
• Robert Pascal

Beilstein J. Org. Chem. 2017, 13, 665–674, doi:10.3762/bjoc.13.66

• /persistence, rather than on free energy, that offers a basis for understanding the evolutionary process. Furthermore, a threshold distance from equilibrium, leading to irreversibility in the reproduction cycle, is needed to switch the directive for evolution from thermodynamic to DKS. The present report

• ][47][48][49][50][51][52][53][54] also favours a kinetic approach rather than a thermodynamic one, since there is no direct relationship between Gibbs free energy of reactions and kinetic barriers [37]. Indeed, the most significant flaw in attempts to derive natural selection from thermodynamics is

• that the kinetic behaviour of complex systems can hardly be deduced from data governing free energy minima, data which ignores the free energy barrier heights separating reactants and products. Organic chemists are fully cognisant of the fact that kinetic barriers cannot usually be deduced from

Conjecture and hypothesis: The importance of reality checks

• David Deamer

Beilstein J. Org. Chem. 2017, 13, 620–624, doi:10.3762/bjoc.13.60

• ]. There are several advantages to using evaporation in this regard. First, simply concentrating potential reactants adds significant free energy to a system that can be used to drive condensation reactions [23]. Furthermore, if amphiphilic compounds are present they can organize and concentrate reactants

Dimerization reactions of aryl selenophen-2-yl-substituted thiocarbonyl S-methanides as diradical processes: a computational study

• Michael L. McKee,
• Grzegorz Mlostoń,
• Katarzyna Urbaniak and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 410–416, doi:10.3762/bjoc.13.44

• . This reaction has a free energy of the transition state of 15.7 kcal/mol (TS1) and is spontaneous by −35.5 kcal/mol (Figure 2). In an alternative reaction, two molecules of thiocarbonyl ylide 8 initially form a complex 15, which is bound by 4.5 kcal/mol (∆H (THF, 298 K)) and subsequently converts over

• electronegative nature of Se in the five-membered ring increases the spin density on the adjacent C(2) atom. Therefore, from the perspective of spin density, the formation of the six-membered ring 13 should be preferred. With respect to the most stable conformer 12E, the free energy barrier of the reaction

• leading to 13 is 22.3 kcal/mol (12E → 12G → TS4 → 13). The alternative pathway, which results in the formation of the new C–C bond via 12E → 12H → TS5 → 14 has a higher free energy of the transition state of 23.7 kcal/mol. The lowest free energy barrier was found for the coupling of the two C(2) atoms

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

• Salvatore V. Giofrè,
• Santa Cirmi,
• Raffaella Mancuso,
• Francesco Nicolò,
• Giuseppe Lanza,
• Laura Legnani,
• Agata Campisi,
• Maria A. Chiacchio,
• Michele Navarra,
• Bartolo Gabriele and
• Roberto Romeo

Beilstein J. Org. Chem. 2016, 12, 2793–2807, doi:10.3762/bjoc.12.278

• 3D plots. Free energy profiles for the cycloaddition reaction of the two isomers Z (A) or E (B) of dipolarophile 8 with nitrone 4, considering both the endo (N, black) or exo (X, red) path. Compound 6e reduces cancer cell proliferation. Treatment of SH-SY5Y, HT-29 and HepG2 cells with 6e in a range

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

• methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein–ligand docking, pharmacophore modeling and QSAR techniques are reviewed. Keywords: ADME; computer-aided drug design; docking; free energy; high-throughput screening; LBDD; lead optimization

• functions are obtained by using data from experimentally determined structures and fitting this information to parameters. The idea here is that the binding free energy is calculated as the weighted sum of terms that are uncorrelated. These terms can be the number of hydrogen bonds, hydrophobic effect, and

• different types of contacts and their types etc. Regression analysis is usually done to obtain weights of the terms using experimental target–ligand complexes with known binding free energy data [122]. Unlike knowledge-based scoring functions, which are obtained by directly converting frequency of

Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of β-isoxazolyl- and β-imidazolyl enamines with nitrile oxides

• Ilya V. Efimov,
• Marsel Z. Shafikov,
• Nikolai A. Beliaev,
• Natalia N. Volkova,
• Tetyana V. Beryozkina,
• Wim Dehaen,
• Zhijin Fan,
• Viktoria V. Grishko,
• Gert Lubec,
• Pavel A. Slepukhin and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2016, 12, 2390–2401, doi:10.3762/bjoc.12.233

• around the double bond, and found to be 38.09 kcal∙mol−1 above 1a_1 in free energy. Calculations of the suggested mechanisms (Scheme 3) performed for E-isomer 1a_1 and nitrile oxide 6a allowed localizing a concerted transition state for both, observed and not observed regioisomers 3 and 8, respectively

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

• Shuai Qiu,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2016, 12, 2293–2297, doi:10.3762/bjoc.12.222

• + 2] annulation between 5H-thiazol-4-ones and nitroalkenes [10]. In this stepwise process, the use of 3,5-dichlorophenyl as the substituent group of the urea in catalyst V would remarkably increase the free energy difference between R- and S-selection in the first Michael addition step, and also

• decreases the free energy of the second formal Mannich reaction, thus improving the reaction rate and chemoselectivity of the [4 + 2] cycloaddition. To extend the usefulness of this reaction, we demonstrate that the adduct can be efficiently reduced with borane. As shown in Scheme 2, 3a was readily reduced

An effective one-pot access to polynuclear dispiroheterocyclic structures comprising pyrrolidinyloxindole and imidazothiazolotriazine moieties via a 1,3-dipolar cycloaddition strategy

• Alexei N. Izmest’ev,
• Galina A. Gazieva,
• Natalya V. Sigay,
• Sergei A. Serkov,
• Valentina A. Karnoukhova,
• Vadim V. Kachala,
• Alexander S. Shashkov,
• Igor E. Zanin,
• Angelina N. Kravchenko and
• Nina N. Makhova

Beilstein J. Org. Chem. 2016, 12, 2240–2249, doi:10.3762/bjoc.12.216

• , because the corresponding endo-transition state would require more energy of activation, as it would result in an electrostatic repulsion between the cis carbonyls thus increasing the free energy of activation [46][47]. As expected, the azomethine ylide adds at the double bond of 1a–c from that side in

Experimental and theoretical insights in the alkene–arene intramolecular π-stacking interaction

• Valeria Corne,
• Ariel M. Sarotti,
• Carmen Ramirez de Arellano,
• Rolando A. Spanevello and
• Alejandra G. Suárez

Beilstein J. Org. Chem. 2016, 12, 1616–1623, doi:10.3762/bjoc.12.158

• derivative. Vinyl region of the 1H NMR spectra of 6a–d in CDCl3 at 300 K. Vinylic region of the low temperatures 1H NMR spectra of 6a in CDCl3. M06-2X/6-31+G(d) Gibbs free energy profiles (in kcal/mol) computed for the conformational equilibriums of 6a–c. Comparison of the M06-2X/6-31+G(d) energy profiles

Methylpalladium complexes with pyrimidine-functionalized N-heterocyclic carbene ligands

• Dirk Meyer and
• Thomas Strassner

Beilstein J. Org. Chem. 2016, 12, 1557–1565, doi:10.3762/bjoc.12.150

• ) and 12 (in CH3CN). Synthesis of complex 13. Possible pathways of methyl trifluoroacetate formation starting from complex 13. Synthesis of complex 14 by conversion of complex 13 with iodobenzene bistrifluoroacetate. Synthesis of the [((pym)^(NHC-R))PdII(CH3)2] complex 15. Calculated free energy

Ring-whizzing in polyene-PtL₂ complexes revisited

• Oluwakemi A. Oloba-Whenu,
• Thomas A. Albright and
• Chirine Soubra-Ghaoui

Beilstein J. Org. Chem. 2016, 12, 1410–1420, doi:10.3762/bjoc.12.135

• can be found elsewhere [21]. The Gibbs free energy difference between the two structures is small: 4.1 kcal/mol (2.4 kcal/mol for L = PH3). This is in accord with four structures of (Ph3C3)M(PPh3)2+ X− where M = Ni, Pd, and Pt and X− = ClO4 and PF6, which show a progressive movement of the ML2 unit

• fragment orbital can interact with b2 to form an η3 complex as shown in 13. An η5 geometry, 14, will be favored using the empty e”1 orbital. The computed Gibbs free energy difference between the two is very small, namely 1.5 kcal/mol favoring η3. A recent search of the Cambridge crystallographic database

• point calculations. Analytical frequencies were computed to determinate the nature of the stationary points. The Gaussian 09 software suite [34] was used in all of the calculations. The plots of the molecular structures utilized CYLview [35]. For brevity we will report the structures and Gibbs free

On the mechanism of imine elimination from Fischer tungsten carbene complexes

• Philipp Veit,
• Christoph Förster and
• Katja Heinze

Beilstein J. Org. Chem. 2016, 12, 1322–1333, doi:10.3762/bjoc.12.125

• first-order rate-law with a Gibbs free energy of activation of ΔG‡298K = 112 kJ mol−1. Three proposed mechanistic pathways are taken into account and supported by detailed (time-dependent) densitiy functional theory [(TD)-DFT] calculations. The preferred pathway is initiated by an irreversible CO

• -donating character of the amino substituent vs the alkoxy substituent thus increasing the C(carbene)–X double bond character (X = N, O) [62][63][64] and the loss of some attractive NH…Fe interaction (H…Fe(Fc-C) = 2.98 Å) in W(CO)5(E-2) [27][54][55][56][57][58][59]. The Gibbs free energy of activation for

• between TDTS and TDI is the maximum energy span between a given intermediate and all following transition states of the cycle and can be understood as the overall Gibbs free energy of activation of the whole catalytic cycle [65]. This procedure can be translated to competing reaction paths. For pathways

Scope and mechanism of the highly stereoselective metal-mediated domino aldol reactions of enolates with aldehydes

• M. Emin Cinar,
• Bernward Engelen,
• Martin Panthöfer,
• Hans-Jörg Deiseroth,
• Jens Schlirf and
• Michael Schmittel

Beilstein J. Org. Chem. 2016, 12, 813–824, doi:10.3762/bjoc.12.80

• of 1.22 kcal mol−1 (TS-A2-A3) takes place, which furnishes the metal-bound hemiacetal in a boat conformation (A3) with a relative free energy of −7.49 kcal mol−1. Hydrolysis of A3 provides tetrahydro-2H-pyran-2,4-diol 5a. Computationally predicted A2 has a lower free energy than the hemiacetal A3

From steroids to aqueous supramolecular chemistry: an autobiographical career review

• Bruce C. Gibb

Beilstein J. Org. Chem. 2016, 12, 684–701, doi:10.3762/bjoc.12.69

• sterically hinder dimerization interfere less with an assembly as the angle between the two interfacing surfaces of a pair of cavitands increases from 0° (in a dimer) to ~70.5° (in a regular tetrahedron). This senary assembly many be higher in free energy, but because this container has a volume of four

cis–trans-Amide isomerism of the 3,4-dehydroproline residue, the ‘unpuckered’ proline

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2016, 12, 589–593, doi:10.3762/bjoc.12.57

• upon NMR investigations of the conventional methyl esters of the N-acetyl amino acids (Ac-Xaa-OMe) [38]. The equilibrium Ks-trans/s-cis constants in the model compounds were found to be: 5 – 4.97 ± 0.07, 6 – 5.45 ± 0.09, 7 – 4.31 ± 0.05 and 8 – 4.82 ± 0.03 (50 mM, D2O, 296 K). In terms of the free

• energy the 3,4-double bond increased the relative stability of the s-trans conformer by 0.2–0.3 kJ/mol, whereas the 4-CF3-group demonstrated an opposite effect of about 0.3 kJ/mol (standard error ±0.1 kJ/mol). Despite both effects being rather marginal, this indicates that the increase of the

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• , based on scoring functions, are able to tread hundred thousands of candidates in a highly approximate (and sometimes erratic) fashion, alchemical-free energy perturbation (FEP) calculations are also error prone. The predictive power of those FEPs depends on many adjustable parameters, even if the

• and promising antibacterial lead agents for treatment of serious Gram-positive infections. Settled right between very fast, but often erratic, virtual screening techniques, on the one side, and alchemical free energy perturbation calculations on the other, our protocol speed (one day per guest on a

Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

• Stephanie R. Hare and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2016, 12, 377–390, doi:10.3762/bjoc.12.41

• dynamical behavior of carbocations involved in terpene-forming reactions. In each section, we highlight important take home messages. Dynamical behavior – a brief tutorial The reactivity of a molecule often ties back to a single characteristic: its energy (in particular, its free energy). Computational and

Simple activation by acid of latent Ru-NHC-based metathesis initiators bearing 8-quinolinolate co-ligands

• Julia Wappel,
• Roland C. Fischer,
• Luigi Cavallo,
• Christian Slugovc and
• Albert Poater

Beilstein J. Org. Chem. 2016, 12, 154–165, doi:10.3762/bjoc.12.17

• calculating the energy of the acid–base equilibrium (see Scheme 2), where [Ru] is 2a or 2b, [Ru]H+ is 2a or 2b with a protonated O atom. The energy of [Ru] and [Ru]H+ is calculated in CH2Cl2 using the protocol described in the computational details sections, while for the aqueous solvation free energy of the

Synthesis and reactivity of aliphatic sulfur pentafluorides from substituted (pentafluorosulfanyl)benzenes

• Norbert Vida,
• Jiří Václavík and
• Petr Beier

Beilstein J. Org. Chem. 2016, 12, 110–116, doi:10.3762/bjoc.12.12

• Diels–Alder products (Table 1). Single-point energies of the transition states suggested that pathway a was preferred over b (difference of ca. 10–20 kJ/mol). This was further supported by comparison of Gibbs free energy values. Boltzmann distribution was used to calculate theoretical endo/exo