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Abstract: Using density functional theory, coupled cluster and multireference methods, dissociation energies and 3rd ionization potentials for, respectively, triply charged and neutral carbon clusters have been evaluated. The results show that the smaller C n 3+ clusters are metastable, i.e., they present a fragmentation channel with negative dissociation energy. The lowest dissociation channel always corresponds to evaporation of a singly charged carbon atom. Good agreement with available experimental data is found for most two-fragment channels. The third ionization potential of the corresponding neutral species decreases with cluster size. [ABSTRACT FROM AUTHOR]

A theoretical study of the complexes formed by carbene like Al(I), Ga(I), In(I) and Tl(I) compounds with hydrogen bond donors (HBD), XH (HCCH, HSH,HOH, HCN, HCl, HBr, HF, and HNC) have been carried out at MP2 computational level. The isolated triel(I) compounds show a negative region of the molecular electrostatic potential region associated with the triel atom suitable to interact with electron deficient groups. This region is associated to a lone pair based on the ELF analysis and to the location of the HOMO orbital. The complexes are similar to those found in nitrogen heterocyclic carbenes (NHC) with HBD. In addition, the oxidative addition reactions of those complexes to yield the corresponding valence III compounds have been characterized. The Al(III) compounds are much more stable than the corresponding Al(I) complexes. However, the stability of the triel(III) compounds decreases with the size of the triel atom and for the thallium derivatives, the Tl(I) complexes are more stable than the Tl(III) compounds in accordance with the number of the structures found in the CSD. The barrier of the TS connecting the triel(I) and triel(III) systems increases with the size of the triel atoms., (© 2024 Wiley-VCH GmbH.)

Wacker oxidations are ubiquitous in the direct synthesis of carbonyl compounds from alkenes. While the reaction mechanism has been widely studied under aerobic conditions, much less is known about such processes promoted with peroxides. Here, we report an exhaustive mechanistic investigation of the Wacker oxidation of styrene using hydrogen peroxide (H 2 O 2 ) and tert -butyl hydroperoxide (TBHP) as oxidants by combining density functional theory and microkinetic modeling. Our results with H 2 O 2 uncover a previously unreported reaction pathway that involves an intermolecular proton transfer assisted by the counterion [OTf] - present in the reaction media. Furthermore, we show that when TBHP is used as an oxidant instead of H 2 O 2 , the reaction mechanism switches to an intramolecular protonation sourced by the HO t Bu moiety generated in situ. Importantly, these two mechanisms are predicted to outcompete the 1,2-hydride shift pathway previously proposed in the literature and account for the level of D incorporation in the product observed in labeling experiments with α-d-styrene and D 2 O 2 . We envision that these insights will pave the way for the rational design of more efficient catalysts for the industrial production of chemical feedstocks and fine chemicals., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

A study involving the use of Mg-MeOH for the double reductive cleavage of both N-S and C-S bonds in a series of 11 benzo-fused cyclic sulfonamides is reported. Examples where the sulfonamide nitrogen atom is part of a pyrrolidine ring effectively undergo reduction, as long as a methoxy substituent is not para -positioned in the aromatic ring, relative to the sulfonyl group. In contrast, if the nitrogen atom is contained within an aromatic ring (pyrrole or indole), the presence of a para -methoxy substituent does not prohibit reduction. If deuterated methanol is used, aromatic ortho- deuterium incorporation was observed. To better understand how structure affects reactivity, density functional theory calculations were performed using three functionals. Results using CAM-B3LYP were found to best correlate with experimental observations, and these demonstrate the impact that the different aromatic substitution patterns and types of N-atom have on the lowest unoccupied molecular orbital (LUMO) energies and adiabatic electron affinities.

Invited for this month's cover picture is the group of Dr. Cristina Trujillo at the Trinity Biomedical Sciences Institute in Dublin (Ireland) and Prof. Ibon Alkorta at the CSIC in Madrid (Spain). The cover picture shows the possibility of reversibly storing hydrogen using metallic compounds as reactants to produce H 2 gas and metallic dimers. Computational studies have been carried out to investigate these processes, as shown in the concept art by the Schrödinger equation. It was found that the formation and release of H 2 is energetically favorable. These results are a promising starting point for further research of using coinage metals for storing hydrogen in light compounds. Read the full text of their Full Paper at 10.1002/open.202100108., (© 2021 Wiley-VCH GmbH.)

Herein we report the discovery of a new photochemical cascade process through a flow-based strategy for intercepting diradicals generated from simple alkenes. This continuous process delivers a series of unprecedented polycyclic reaction products. Exploring the scope of this novel process revealed that this approach is general and affords a variety of structurally complex reaction products in high yields (up to 81%), short reaction times (7 min) and high throughputs (up to 5.5 mmol h -1 ). A mechanistic rationale is presented that is supported by computations as well as isolation of key intermediates whose identity is confirmed by X-ray crystallography. The presented photochemical cascade process demonstrates the discovery of new chemical reactivity and complex chemical scaffolds by continuously generating and intercepting high-energy intermediates in a highly practical manner., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

In the present paper, we report the quantitative evaluation of the electron density shift (EDS) maps within different complexes. Values associated with the total EDS maps exhibited good correlation with different quantities such as interaction energies, E int , intermolecular distances, bond critical points, and LMOEDA energy decomposition terms. Besides, EDS maps at different cutoffs were also evaluated and related with the interaction energies values. Finally, EDS maps and their corresponding values are found to correlate with E int within systems with cooperative effects. To our knowledge, this is the first time that the EDS has been quanitatively evaluated.

A theoretical study of the complexes formed by Ag 2 and Cu 2 with different molecules, XH (FH, ClH, OH 2 , SH 2 , HCN, HNC, HCCH, NH 3 and PH 3 ) that can act as hydrogen-bond donors (Lewis acids) or regium-bond acceptors (Lewis bases) was carried out at the CCSD(T)/CBS computational level. The heteronuclear diatomic coinage molecules (AuAg, AuCu, and AgCu) have also been considered. With the exception of some of the hydrogen-bonded complexes with FH, the regium-bonded binary complexes are more stable. The AuAg and AuCu molecules show large dipole moments that weaken the regium bond (RB) with Au and favour those through the Ag and Cu atoms, respectively., (© 2020 Wiley-VCH GmbH.)

The geometry, energy and electron density properties of the 1:1, 1:2 and 1:3 complexes between cyclic (Py-M) 3 (M = Au, Ag and Cu) and halide ions (F - , Cl - and Br - ) were studied using Møller Plesset (MP2) computational methods. Three different configurations were explored. In two of them, the anions interact with the metal atoms in planar and apical dispositions, while in the last configuration, the anions interact with the CH(4) group of the pyrazole. The energetic results for the 1:2 and 1:3 complexes are a combination of the specific strength of the interaction plus a repulsive component due to the charge:charge coulombic term. However, stable minima structures with dissociation barriers for the anions indicate that those complexes are stable and (Py-M) 3 can hold up to three anions simultaneously. A search in the CSD confirmed the presence of (Pyrazole-Cu) 3 systems with two anions interacting in apical disposition.

The anticancer drug candidates 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative exhibited nanomolar in-vitro activity against prostate cancer cells advanced prostate cancer (PC3) and micromolar inhibition of mammalian thioredoxin reductase. Encouraging maximum tolerable dose experiments led to human prostate cancer subcutaneous xenograft experiments; 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative were applied twelve times at two doses in groups of n = 5 PC3 to tumor-bearing NMRI:nu/nu mice. 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative at the dose of 10 and 20 mg/kg showed good tolerability, while no significant body weight loss was seen in both groups. In particular, for the drug 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate the tumor growth inhibition suggested to be dose dependent, reflected by the respective optimal T/C values of 0.45 at the dose of 10 mg/kg and of 0.31 at the dose of 20 mg/kg. By contrast, the 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative treated groups showed no indication for dose-dependent antitumoral activity, as reflected by the optimal T/C values of 0.44 for the 10 mg/kg and for the 20 mg/kg treated mice. Immunohistochemical experiments involving Ki67 staining of tumor tissue showed that both compounds reduced PC3 cell proliferation against the difficult to treat advanced human prostate tumors derived from PC3.

A computational study of the iodide discrimination by different neutral and cationic iodotriazole halogen bonding hosts was carried out by means of Density Functional Theory. The importance of the size of the scaffold was highlighted and its impact observed in the binding energies and intermolecular X···I distances. Larger scaffolds were found to reduce the electronic repulsion and increase the overlap between the halide electron lone pair and the corresponding I-C antibonding orbital, increasing the halogen bonding interactions. Additionally, the planarity plays an important role within the interaction, and can be tuned using hydroxyl to perform intramolecular hydrogen bonds (IMHB) between the scaffold and the halogen atoms. Structures with IMHB exhibit stronger halogen bond interactions, as evidenced by the shorter intramolecular distances, larger electron density values at the bond critical point and more negative binding energies., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

In this manuscript the different noncovalent interactions established between (HYCN) 2 dimers (Y=S, Se and Te) have been studied at the MP2 and CCSD(T) level of theory. Several homodimers have been taken into account, highlighting the capacity of these compounds to act both as electron donor and acceptor. The main properties studied were geometries, binding energy (E b ), and molecular electrostatic potential (MEP). Given the wide application of chalcogen bonds, and more specifically of cyano-chalcogen moieties in molecular recognition, natural bond orbital (NBO), "atoms-in-molecules" (AIM), and electron density shift (EDS) analysis were also used to analyse the different noncovalent interactions upon complexation. The presence of hydrogen, chalcogen and dipole-dipole interactions was confirmed and their implications on molecular recognition were analysed., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The stationary points for the reaction between the CO 2 and nine different phosphatranes molecules have been characterized by means of MP2 computational methods. Two minima structures have been located: a pnicogen bonded complex where one of the oxygen atoms of CO 2 acts as electron donor and an adduct that presents a covalent P-C linkage. The corresponding transition state structure linking the two minima has also been characterized. In gas phase, the pnicogen bonded complex is more stable than the corresponding adduct except in one case. In contrast, the inclusion of the solvent effect (toluene and THF), reverts the stability, being in all cases the different adducts more stable than the pnicogen bonded complexes. The electronic properties of the systems have been analysed with the Quantum Theory of Atoms in Molecules (QTAIM) and Electron Density Shift (EDS) methods., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Intramolecular interactions have been proven to be the key to conformational control in drug-design. While chalcogen interactions have been shown to be present in certain ligands of the GK-GKRP target protein, in the present study, intramolecular chalcogen interactions through selenium are found to be even more promising since they form stronger interactions. Also, the flexibility/rigidity of the carbon backbone of the corresponding ligands is crucial in the conformational stability.

A theoretical study of the regium and hydrogen bonds (RB and HB, respectively) in Au 2 :HX complexes has been carried out by means of CCSD(T) calculations. The theoretical study shows as overall outcome that in all cases the complexes exhibiting RB are more stable that those with HB. The binding energies for RB complexes range between -24 and -180 kJ ⋅ mol -1, whereas those of the HB complexes are between -6 and -19 kJ ⋅ mol -1 . DFT-SAPT also indicated that HB complexes are governed by electrostatics, but RB complexes present larger contribution of the induction term to the total attractive forces. 197 Au chemical shifts have been calculated using the relativistic ZORA Hamiltonian., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A theoretical study has been carried out at the M062X/6-311++G(d,p) computational level to search for a rationale on ligands' affinity toward α 2 -adrenoceptors by estimating the nature and strength of intramolecular hydrogen bonds potentially formed (by means of the QTAIM and NBO approaches) as well as the degree of deviation from planarity that could be observed in some of the compounds. Four different families have been studied: thiophen-2-yl, 3-carboxylatethiophen-2-yl esters, 3-cyanothiophen-2-yl, and 2-thiazolyl guanidinium derivatives. In the case of the thiophen-2-yl guanidines not substituted in the 3 position, nonplanarity was always observed, whereas in the thiazole series, intramolecular hydrogen bonds were identified between the guanidinium and the thiazole ring forcing the systems to planarity. Regarding the carboxylic esters, two different rotamers were found: quasi-planar and quasi-perpendicular systems with very similar energy. Both of these isomers can form different nets of intramolecular hydrogen bonds and other types of noncovalent interactions. Different physicochemical properties such as basicity, solubility, or lipophilicity were calculated for these systems, but no correlation to the degree of planarity was found. However, when comparing the α2-ARs affinity with the planarity of the molecules, a trend appears in the thiophen-2-yl guanidinium series indicating that lack of planarity seems to be optimal for α2-ARs engagement.

A theoretical study of a variety of cyclohexane-based anion transporters interacting with the chloride anion has been conducted using density functional theory. The calculations have been performed in the gas phase but also, in order to describe the solvation effects on the interaction, two different solvents-chloroform and dimethylsulfoxide-have been taken into account. Gas-phase interaction energies within the complexes are found to be up to 400 kJ/mol, while, when solvent effects are considered, the interaction energy values decreased drastically concomitantly with an elongation in the interatomic distances. Atoms in molecules and natural bond analysis corroborate the trends found for the intermolecular energies and Cl···H distances, suggesting strong donations from the Cl - anion into the σ*H-N antibonding orbitals, as well as with noncovalent interaction plots showing large areas of electron density overlap within the chloride anion surroundings.

A series of silyl and germanium complexes containing halogen atoms (fluorine and chlorine atoms) and exhibiting tetrel bonds with Lewis bases were analyzed by means of Møller-Plesset computational theory. Binding energies of germanium derivatives were more negative than silicon ones. Amongst the different Lewis bases utilized, ammonia produced the strongest tetrel bonded complexes in both Ge and Si cases, and substitution of the F atom by Cl led to stronger complexes with an ethylene backbone. However, with phenyl backbones, the fluorosilyl complexes were shown to be less stable than the chlorosilyl ones, but the opposite occurred for halogermanium complexes. In all the cases studied, the presence of a hydroxyl group enhanced the tetrel bond. That effect becomes more remarkable when an intramolecular hydrogen bond between the halogen and the hydrogen atom of the hydroxyl group takes places.

Ten novel N -heterocyclic carbene gold(I) complexes derived from lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride) are reported here with full characterisation and biological testing. (1,3-Dibenzyl-4,5-diphenylimidazol-2-ylidene)gold(I) chloride (NHC*-AuCl) ( 1 ) was modified by substituting the chloride for the following: cyanide ( 2 ), dithiocarbamates ( 3 ⁻ 5 ), p -mercaptobenzoate derivatives ( 12 ⁻ 14 ) and N -acetyl-l-cysteine derivatives ( 15 ⁻ 17 ). All complexes were synthesised in good yields of 57⁻78%. Complexes 2 , 12 , 13 , and 14 were further characterised by X-ray crystallography. Initial evaluation of the biological activity was conducted on all ten complexes against the multidrug resistant MCF-7 topo breast cancer, HCT-116 wt , and p53 knockout mutant HCT-116 -/- colon carcinoma cell lines. Across the three cell lines tested, mainly single-digit micromolar IC 50 values were observed. Nanomolar activity was exhibited on the MCF-7 topo cell line with 3 displaying an IC 50 of 0.28 μM ± 0.03 μM. Complexes incorporating a Au⁻S bond resulted in higher cytotoxic activity when compared to complexes 1 and 2 . Theoretical calculations, carried out at the MN15/6⁻311++G(2df,p) computational level, show that NHC* is the more favourable ligand for Au(I)-Cl when compared to PPh₃.

A 1 H NMR study shows the presence of intermolecular hydrogen bonds for AHLs in CDCl 3 solution. A detailed computational study of the structure of AHLs and the relative stability between the extended conformations (X) and those showing n → π* interactions (np) have been carried out by means of DFT calculations. Solvent effects have been shown to be very important when stabilising np conformations, particularly with polar solvents. This was shown by the shortening of C⋯O intramolecular distances and the increase in the relative energies favouring the np conformation with the dielectric constant of the solvent. The charge transfer between the O donor and the acceptor carbonyl group, assessed by second order perturbation energies, E(2), also shows an increase in the E(2) values with the dielectric constant of the solvent., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A series of potential anion transporters, dithieno[3,2-b;2',3'-d]thiophenes (DTT), involving anion-chalcogen interactions have been studied by analyzing the interaction energy, geometry, and charge transfer. It was found that gas phase calculations show very negative interaction energies with short anion-chalcogen distances, but when solvent effects are considered, the interaction energy values decreased drastically concomitantly with an elongation on the interatomic distances. To enhance the chalcogen interaction between the DTT derivatives and the anion, increasing the anion transporter capacity, bisisothioazole moiety was considered; i.e., the σ-hole of the chalcogen atom was modulated by substitution of the adjacent carbon by a nitrogen atom in the S-C axis, increasing the depth of the σ-hole and therefore the interaction between the chalcogen and anion. Finally, different anions were analyzed within the complexes, finding that F - and NO 3 - would be the best candidates to form complexes and possibly displace other anions such as Cl - or Br - .

Forty-two peri-substituted naphthalene derivatives presenting chalcogen weak interactions were studied. They correspond to O···Y interactions, Y being O, S, and Se. While the O atom bears H or CH 3 substituents (OH and OCH 3 groups), the Y atom is substituted by H, F, and CN to explore the effect of these electron-donating and electron-withdrawing substituents on the chalcogen bond strength. The effect of F and CH 3 substituents on positions ortho/para (2,4,5,7 of the naphthalene ring) was also studied. Optimizations were performed at the MP2/aug-cc-pVDZ, and binding energies were performed at the MP2/aug-cc-pVDZ followed by an MP2/CBS estimation. The main properties studied were geometries, energies (E b , E iso , and E def ), the molecular electrostatic potential, electron density shifts, natural bond order E(2) energies, and the relationship between these properties.

In their 1 H NMR spectra in CDCl 3 3-oxo-N-acyl homoserine lactones (OHLs) show significant downfield chemical shifts of the amide NH proton when compared to the parent N-acyl homoserine lactones (AHLs). NMR spectroscopic and DFT calculation studies have shown that this is most likely due to the presence of a stabilising intramolecular H-bond from the NH to the 3-oxo group. The 1 H NMR spectra also show evidence for the enol tautomers and that the amount of enol present for a range of OHLs is 4.1-4.5% in CDCl 3 and 6.5-7.2% in CD 3 CN. In contrast, DFT calculations show that the lowest energy enol tautomer and the keto tautomer are of equal energy in the gas phase, but that the keto tautomer is more stable in chloroform, acetonitrile and water solution. The calculations also show that there is no evidence for any n→π ∗ or C5H-bonding interactions being present in either the lowest energy keto or enol tautomer of the OHLs in solution or the gas phase, which is in contrast to the reported solid-state structure., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A theoretical study of [X.X'.X'']phosphatrane:Lewis acid complexes has been carried out in order to analyze how the in:out and out:out conformations can be modulated by the interaction with Lewis acids (LA). It has been found that in:out structures are more stable in larger systems i.e. in [4.4.3]:LA and [4.4.4]:LA than in [3.3.3]:LA and [4.3.3]:LA. The results obtained for the relative energies in conjunction with electron density properties showed that upon complexation, in:out conformers become more stable with the increasing acidity of the corresponding Lewis acid. In fact, the binding energies found for in:out complexes are larger than those obtained for out:out complexes. The complexes with the largest relative energy favoring the in:out structure correspond to those with charged Lewis acids, followed by the complexes with ClF. In all cases, the complexes are cooperative, reaching a maximum value of 168.5 kJ mol -1 for the [4.3.3]:F + complex.

Ab initio MP2/aug'-cc-pVTZ calculations have been performed on the binary complexes XY:PH 3 for XY = ClCl, FCl, and FBr; and PH 3 :N-base for N-base = NCH, NH 3 , NCF, NCCN, and N 2 ; and the corresponding ternary complexes XY:PH 3 :N-base, to investigate P···N pnicogen bond formation through the lone-pair hole at P in the binary complexes and P···N pnicogen-bond formation assisted by P···Y halogen bond formation through the σ-hole at Y. Although the binary complexes PH 3 :N-base that form through the lone-pair hole have very small binding energies, they are not equilibrium structures on their potential surfaces. The presence of the P···Y halogen bond makes PH 3 a better electron-pair acceptor through its lone-pair hole, leading to stable ternary complexes XY:PH 3 :N-base. The halogen bonds in ClCl:PH 3 and ClCl:PH 3 :NCCN are traditional halogen bonds, but in the remaining binary and ternary complexes, they are chlorine- or bromine-shared halogen bonds. For a given nitrogen base, the P···N pnicogen bond in the ternary complex FCl:PH 3 :N-base appears to be stronger than that bond in FBr:PH 3 :N-base, which is stronger than the P···N bond in the corresponding ClCl:PH 3 :N-base complex. EOM-CCSD spin-spin coupling constants for the binary and ternary complexes with ClCl and FCl are also consistent with the changing nature of the halogen bonds in these complexes. At long P-Cl distances, the coupling constant 1x J(P-Cl) increases with decreasing distance but then decreases as the P-Cl distance continues to decrease, and the halogen bonds become chlorine-shared bonds. At the shorter distances, 1x J(P-Cl) approaches the value of 1 J(P-Cl) for the cation + (Cl-PH 3 ). The coupling constants 1p J(P-N) are small and, with one exception, are greater in ClCl:PH 3 :N-base complexes compared to that in FCl:PH 3 :N-base, despite the shorter P-N distances in the latter.

A theoretical study of the peri interactions, both intramolecular hydrogen (HB) and chalcogen bonds (YB), in 1-hydroxy-8YH-naphthalene, 1,4-dihydroxy-5,8-di-YH-naphthalene, and 1,5-dihydroxy-4,8-di-YH-naphthalene, with Y = O, S, and Se was carried out. The systems with a OH:Y hydrogen bond are the most stable ones followed by those with a chalcogen O:Y interaction, those with a YH:O hydrogen bond (Y = S and Se) being the least stable ones. The electron density values at the hydrogen bond critical points indicate that they have partial covalent character. Natural Bond Orbital (NBO) analysis shows stabilization due to the charge transfer between lone pair orbitals towards empty Y-H that correlate with the interatomic distances. The electron density shift maps and non-covalent indexes in the different systems are consistent with the relative strength of the interactions. The structures found on the CSD were used to compare the experimental and calculated results.

RASSF enzymes act as key apoptosis activators and tumor suppressors, being downregulated in many human cancers, although their exact regulatory roles remain unknown. A key downstream event in the RASSF pathway is the regulation of MST kinases, which are main effectors of RASSF-induced apoptosis. The regulation of MST1/2 includes both homo- and heterodimerization, mediated by helical SARAH domains, though the underlying molecular interaction mechanism is unclear. Here, we study the interactions between RASSF1A, RASSF5, and MST2 SARAH domains by using both atomistic molecular simulation techniques and experiments. We construct and study models of MST2 homodimers and MST2-RASSF SARAH heterodimers, and we identify the factors that control their high molecular stability. In addition, we also analyze both computationally and experimentally the interactions of MST2 SARAH domains with a series of synthetic peptides particularly designed to bind to it, and hope that our approach can be used to address some of the challenging problems in designing new anti-cancer drugs., Competing Interests: The authors have declared that no competing interests exist.

The detailed, atomistic-level understanding of molecular signaling along the tumor-suppressive Hippo signaling pathway that controls tissue homeostasis by balancing cell proliferation and death through apoptosis is a promising avenue for the discovery of novel anticancer drug targets. The activation of kinases such as Mammalian STE20-Like Protein Kinases 1 and 2 (MST1 and MST2)-modulated through both homo- and heterodimerization (e.g. interactions with Ras association domain family, RASSF, enzymes)-is a key upstream event in this pathway and remains poorly understood. On the other hand, RASSFs (such as RASSF1A or RASSF5) act as important apoptosis activators and tumor suppressors, although their exact regulatory roles are also unclear. We present recent molecular studies of signaling along the Ras-RASSF-MST pathway, which controls growth and apoptosis in eukaryotic cells, including a variety of modern molecular modeling and simulation techniques. Using recently available structural information, we discuss the complex regulatory scenario according to which RASSFs perform dual signaling functions, either preventing or promoting MST2 activation, and thus control cell apoptosis. Here, we focus on recent studies highlighting the special role being played by the specific interactions between the helical Salvador/RASSF/Hippo (SARAH) domains of MST2 and RASSF1a or RASSF5 enzymes. These studies are crucial for integrating atomistic-level mechanistic information about the structures and conformational dynamics of interacting proteins, with information available on their system-level functions in cellular signaling., (© The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

A computational study of the intramolecular pnictogen bond in 8-phosphinonaphthalen-1-amine derivatives (1-NX2, 8-PX2 with X = H, F, Cl, Br, CH3, CN and NC), proton sponge analogues, has been carried out to determine their structural and geometric parameters, interaction energies and electronic properties such as the electron density of the intramolecular interaction. Our results show that substitution of H atoms in the PH2 group by electron withdrawing groups on the Lewis acid moiety strengthens the P···N pnictogen bond, evidenced by the increasing electron density values at the bond critical point and by shorter distances. However, substitutions on the Lewis base moiety (NX2) show weaker P···N interactions than when the substitution is done on the Lewis acid counterpart (PX2). Nevertheless, in all cases, pnictogen bonds are enhanced upon substitution with respect to the parent 1-NH2, 8-PH2 system. Second-order orbital interaction energies, electron density maps, electron delocalization functions and charge transfer corroborate the evolution of the P···N strength upon substitution.

We analysed the interactions and aromaticity electron-density delocalisation observed in π-π complexes between the phenalenyl radical and acenaphthylene, and the DNA and RNA nucleobases (adenine, guanine, cytosine, thymine and uracil). Interaction energies are obtained at the M06-2X/6-311++G(2df,p) computational level for gas phase and PCM-water conditions. For both the phenalenyl radical and acenaphthylene, the complexes formed with guanine are the most stable ones. Atoms in molecules and natural bond orbital results reveal weak π-π interactions between both interacting moieties, characterized by bond critical points between C⋅⋅⋅C and C⋅⋅⋅N atoms. Nucleus independent chemical shifts (NICS) indicate the retention of the aromatic character of the monomers in the outer region of the complex. The fluctuation indexes reveal a loss of electron delocalisation upon complexation for all cases except guanine complexes. Nevertheless, the interface region shows large negative NICS values, which is not associated with an increase of the aromaticity or electron-density delocalisation, but with magnetic couplings of both molecules, leading to an unrealistic description of the aromatic behaviour in that region., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The tautomerism of 3- and 5-hydroxypyrazole is studied at the B3LYP, CCSD and G3B3 computational levels, including the gas phase, PCM-water effects, and proton transfer assisted by water molecules. To understand the propensity of tautomerization, hydrogen-bond acidity and basicity of neutral species is approached by means of correlations between donor/acceptor ability and H-bond interaction energies. Tautomerism processes are highly dependent on the solvent environment, and a significant reduction of the transition barriers upon solvation is seen. In addition, the inclusion of a single water molecule to assist proton transfer decreases the barriers between tautomers. Although the second water molecule further reduces those barriers, its effect is less appreciable than the first one. Neutral species present more stable minima than anionic and cationic species, but relatively similar transition barriers to anionic tautomers., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An exhaustive and systematic study of the structural and electronic properties of cyclooctatetraene (COT) upon substitution of hydrogen atoms by fluoro and cyano groups has been carried out in order to analyse the influence of both substituents on the aromaticity. We found that C-C distances decrease with fluoro substitution while in cyano derivatives the opposite happens. All the compounds retain their original structural type, with the exception of the cyano derivatives;thus, compounds 25CN6T, 27CN6T and 30CN8T show boat-like structure, whereas compounds 20CN5T, 26CN6T, and 29CN7T present twisted structures. Regarding the relative energies of those compounds with the same number of substitutions, it was found that compounds where the X groups were more separated among them were the most stable ones. Inversion barriers (ΔETS) were found to increase with the number of substitutions; in the case of fluoro derivatives these barriers have a two-fold, increase compared to the parent compound while in the cyano ones a three-fold increase was observed. The aromatic character based on the NICS values, was found to increase in the ground singlet states and in the transition states of both fluoro and cyano derivatives. For triplet states, a decrease of the aromatic behaviour was found upon substitution. NICS profiles and 3D NICS isosurfaces confirm such findings. Finally, HOMA indexes corroborate the aromatic changes described by the NICS values, although, no good correlations between both quantities were found.

A theoretical study at the ab initio MP2/6-311++G(d,p) level of theory is carried out to characterize several heterocyclic spiro[2.2]pentane cations with N, P, and As as spiro atoms. The strain and relative stability of the spiropentanes are obtained through isodesmic reactions. Nucleus-independent chemical shifts (NICS) and 3D NICS isosurfaces show σ-aromatic characteristics, similar to those found in cyclopropane. The interaction with the Cl(-) anion, which results in four different stationary structures, is studied and characterized by means of the atoms in molecules methodology, and Cl⋅⋅⋅pnicogen, Cl⋅⋅⋅H, and Cl⋅⋅⋅C interactions are found. The most stable structure in all cases corresponds to opening of one of the three-membered rings, due to the attack of the Cl atom, and C-Cl bond formation. Furthermore, the reaction with the 3-boranuidaspiro[2.2]pentane anion results in the formation of a new compound through cleavage of one ring of both reactants., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A computational study of the intramolecular pnicogen bond in 1,8-bis-substituted naphthalene derivatives (ZXH and ZX2 with Z = P, As and X = H, F, Cl, and Br), structurally related to proton sponges, has been carried out. The aim of this paper is the study of their structural parameters, interaction energies and electronic properties such as electron density on the intramolecular interaction. The calculated geometrical parameters associated to the P···P interaction are in reasonably good agreement with the crystal structures found in a CSD search, in particular those of the halogen derivatives. Isodesmic reactions where the 1,8-bis-substituted derivatives are compared to monosubstituted derivatives have been calculated, indicating that the 1,8 derivatives are more stable than the monosubstituted ones for those cases with X-Z···Z-X and F-Z···Z-H alignments. Electron densities and Laplacians at the BCP on the pnicogen interactions suggest that they can be classified as pure closed shell interactions with a partial covalent character. Electron density shift maps are consistent with the results for intermolecular pnicogen interactions. Relationships between interatomic distance and electron density at the bond critical points and between interatomic distance and the orbital charge transfer stabilization energies have been found.

Mechanistic studies of the reaction between 3-arylprop-2-ynyl esters and aldehydes catalyzed by BF3 ⋅Et2 O were performed by isotopic labeling experiments and quantum chemical calculations. The reactions are shown to proceed by either a classical alkyne-carbonyl metathesis route or an unprecedented addition-rearrangement cascade. Depending on the structure of the starting materials and the reaction conditions, the products of these reactions can be Morita-Baylis-Hillman (MBH) adducts that are unavailable by traditional MBH reactions or E- and Z-α,β-unsaturated ketones. (18) O-Labeling studies suggested the existence of two different reaction pathways to the products. These pathways were further examined by quantum chemical calculations that employed the DFT(wB97XD)/6-311+G(2d,p) method, together with the conductor-like screening model for realistic solvation (COSMO-RS). By using the wB97XD functional, the accuracy of the computed data is estimated to be 1-2 kcal mol(-1) , shown by the careful benchmarking of various DFT functionals against coupled cluster calculations at the CCSD(T)/aug-cc-pVTZ level of theory. Indeed, most of the experimental data were reproduced and explained by theory and it was convincingly shown that the branching point between the two distinct mechanisms is the formation of the first intermediate on the reaction pathway: either the four-membered oxete or the six-membered zwitterion. The deep mechanistic understanding of these reactions opens new synthetic avenues to chemically and biologically important α,β-unsaturated ketones., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to investigate the pnicogen bonded complexes formed between the acids O═PH3, S═PH3, HN═PH3, and H2C═PH3 and the bases NH3, NCH, N2, PH3, and PCH. All nitrogen and phosphorus bases form complexes in which the bases are lone pair electron donors. The binding energies of complexes involving the stronger bases NH3, NCH, and PH3 differentiate among the acids, but the binding energies of complexes with the weaker bases do not. These complexes are stabilized by charge transfer from the lone pair orbital of N or P to the σ*P═A orbital of X═PH3, where A is the atom of X directly bonded to P. PCH also forms complexes with the X═PH3 acids as a π electron donor to the σ*P═A orbital. The binding energies and the charge-transfer energies of the π complexes are greater than those of the complexes in which PCH is a lone pair donor. Whether the positive charge on P increases, decreases, or remains the same upon complex formation, the chemical shieldings of (31)P decrease in the complexes relative to the corresponding monomers. (1p)J(P-N) and (1p)J(P-P) values correlate best with the corresponding P-N and P-P distances as a function of the nature of the base. (1)J(P-A) values do not correlate with P-A distances. Rather, the absolute values of (1)J(P-O), (1)J(P-S), and (1)J(P-N) decrease upon complexation. Decreasing (1)J(P-A) values correlate linearly with increasing complex binding energies. In contrast, (1)J(P-C) values increase upon complexation and correlate linearly with increasing binding energies.

Considering that guanidine-based derivatives are good DNA minor groove binders, we have theoretically studied, using the Polarizable Continuum model mimicking water solvation, the complexes formed by the biologically relevant guanidinium cation and the DNA and RNA nucleobases (adenine, guanine, cytosine, thymine, and uracil). The interactions established within these complexes both by hydrogen bonds and by cation-π interactions have been analyzed by means of the Atoms in Molecules and Natural Bond Orbital approaches. Moreover, maps of electron density difference have been produced to understand the cation-π complexes. Finally, the NICS and three-dimensional NICS maps of the cation-π complexes have been studied to understand the effect of the guanidinium cation on the aromaticity of the nucleobases.

Pnictogen complexes between nitryl derivatives (NO2X, X = CN, F, Cl, Br, NO2, OH, CCH, and C2H3) and molecules acting as Lewis bases (H2O, H3N, CO, HCN, HNC and HCCH) have been obtained at the MP2/aug-cc-pVTZ computational level. A total of 53 minima have been located. Their energy, geometry, DFT-SAPT energy terms, electronic properties (NBO, AIM, ELF, and NCI) and NMR shieldings have been calculated and analyzed. Finally, a search in the CSD database has been carried out, showing a large number of similar interactions in crystallographic structures.

A computational study of the intramolecular pnicogen bond in PHF-(CH2)n-PHF (n=2-6) systems was carried out. For each compound, two different conformations, (R,R) and (R,S), were considered on the basis of the chirality of the phosphine groups. The characteristics of the closed conformers, in which the pnicogen interaction occurs, were compared with those of the extended conformer. In several cases, the closed conformations are more stable than the extended conformations. The calculated interaction energies of the pnicogen contact, by means of isodesmic reactions, provide values between -3.4 and -26.0 kJ mol(-1). Atoms in molecules and electron localization function analysis of the electron density showed that the systems in the closed conformations with short P···P distances have a partial covalent character in this interaction. The calculated absolute chemical shieldings of the P atoms showed an exponential relationship with the P···P distance. In addition, a search in the Cambridge crystallographic database was carried out to detect those compounds with a potential intramolecular pnicogen bond in the solid phase., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ab initio MP2/aug'-cc-pVTZ calculations have been performed to investigate the structures and energies of binary complexes LA:PH2F and LA:PH3 and of ternary complexes LA:H2FP:NFH2 and LA:H3P:NH3 in which the pnicogen-bonded P atom also acts as an electron-pair donor to a Lewis acid (LA), for LA = BH3, NCH, ClH, FH, FCl, and HLi. Hydrogen bonds, halogen bonds, and dative covalent bonds are found at P in some cases, depending on the nature of the Lewis acid. HLi forms a lithium bond with P only in the binary complex HLi:PH3. The binding energies of ternary complexes exhibit a classical synergistic effect, although the computed cooperativity may be overestimated due to neglect of the interaction of the Lewis acid with NH2F or NH3 in some cases. The hydrogen-bonding Lewis acids appear to have little effect on the strength of the P···N bond, while the remaining Lewis acids strengthen the pnicogen bond. (31)P absolute chemical shieldings increase in LA:H2FP:NFH2 complexes relative to the corresponding LA:PH2F complexes as the positive charge on P decreases, while chemical shieldings decrease in LA:H3P:NH3 relative to the corresponding LA:PH3 complexes as the positive charge increases. Absolute values of (1p)J(P-N) spin-spin coupling constants in complexes LA:H2FP:NFH2 decrease as the P-N distance decreases. It appears that this behavior is associated with the presence of a second intermolecular interaction, whether electron-donation by P or hydrogen bond formation at P-F.

An ab initio MP2/aug'-cc-pVTZ study has been carried out to identify local minima on the (NH(2)F)(2), H(2)FP:NFH(2), and (PH(2)F)(2) potential surfaces, to characterize the types of interactions which stabilize the complexes found at these minima, and to evaluate their binding energies. With one exception, (NH(2)F)(2) complexes are stabilized by N-H···N or N-H···F hydrogen bonds. Only one complex, that with the smallest binding energy, has a pnicogen N···N bond. In contrast, (PH(2)F)(2) complexes are stabilized by P···P or P···F pnicogen bonds or by an antiparallel alignment of the dipole moment vectors of the two monomers, but not by hydrogen bonds. The most stable complex has an F-P···P-F alignment which approaches linearity. Both hydrogen-bonded and pnicogen-bonded complexes exist on the H(2)FP:NFH(2) surface, with the most stable being the pnicogen-bonded complex with F-P···N-F approaching a linear arrangement. Charge transfer transitions from a lone pair on a P, N, or F atom in one molecule to an antibonding σ* orbital of the other stabilize these complexes. These transitions are most important for complexes with pnicogen bonds. Although net charge transfer occurs in complexes in which the two monomers are inequivalent, charges on N and P do not correlate with N and P absolute chemical shieldings. Rather, these shieldings also reflect charge distributions and overall bonding patterns. EOM-CCSD two-bond spin-spin coupling constants (2h)J(X-Y) across X-H···Y hydrogen bonds tend to be small, due in part to the nonlinearity of many of the hydrogen bonds. (1p)J values across a particular kind of pnicogen bond are relatively large and vary significantly but do not correlate with corresponding distances.

Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to investigate the influence of F-H···F hydrogen bonds on the P···N pnicogen bond in complexes nFH:(H2FP:NFH2) for n = 1-2, and a selected complex with n = 3. The NBO analysis indicates that the N(lp) → P-Fσ* charge-transfer transition has a much greater stabilizing effect than the P(lp) → N-Fσ* transition. When hydrogen bonding occurs at P-F, charge transfer associated with the pnicogen bond and the hydrogen bond are in the same direction but are in opposite directions when hydrogen bonding occurs at N-F. As a result, the formation of F-H···F hydrogen bonds at P-F leads to shorter P···N distances, increased strength of P···N bonds, and synergistic energetic effects; hydrogen bonding at N-F has opposite effects. (31)P and (15)N chemical shieldings do not correlate with charges on P and N, respectively, but (31)P shieldings correlate quadratically with the P-N distance. (1p)J(P-N) coupling constants do not correlate with the intermolecular P-N distance. However, when hydrogen bonding occurs only at P-F, (1p)J(P-N) decreases in absolute value as the P-N distance decreases, thereby approaching (1)J(P-N) for H2P-NH2. However, the P···N bond in 3FH:(H2FP:NFH2) has little covalent character, unlike the P···P bond in the corresponding complex 3FH:(PH2F)2.

The complexes formed by CuF with CC double and triple bonds have been studied at the MP2 and CCSD(T) computational levels. The interaction of CuF with acetylene, ethylene and their fluoro derivatives is very strong, with interaction energies close to those of conventional covalent bonds. Hence, these complexes could be actually viewed as a new kind of metallocycles, with significantly strong Cu-C linkages. All electronic indexes analyzed by means of the AIM, ELF and NBO formalisms, indicate that the strength of the interaction should increase with the number of fluorine substituents in both series of compounds. Surprisingly, however, although both series of compounds exhibit the same bonding arrangements, they follow opposite stability trends and the expected increase of the interaction energies with the number of fluorine substituents is only observed in the acetylene series. The reason for this unexpected behavior is once more associated with the effects triggered by the distortion of the interacting subunits. Deformation not only has a direct energetic cost but dramatically affects the intrinsic properties of the interacting systems.

The complexes formed between dimethylchalcogens X(CH(3))(2) (X = S, Se, and Te) and hypohalous acids YOH (Y = F, Cl, Br, and I) have been studied at the MP2/aug'-cc-pVTZ computational level, five minima structures being located. Two of them correspond to hydrogen bonds (HB), another two to halogen bonds (XB) with the chalcogen acting as an electron donor, the last one showing a C-H···O contact. The most stable complexes of IOH and BrOH acids present halogen···chalcogen interactions with interaction energies, E(i), up to -49 kJ mol(-1). In the case of the ClOH and FOH molecules, the hydrogen bonded complexes are more stable with interaction energies between -27 and -34 kJ mol(-1). Linear correlations between the molecular electrostatic potential (MEP) stationary points at the van der Waals surface and the interaction energy have been found. The contribution of the different energy terms to the total interaction energy was analyzed by means of the DFT-SAPT theory finding that the electrostatic attractive term is dominant in the complexes with HB and XB, excepting a few cases in which the dispersion and induction terms become more important than the electrostatic one.