Tet. Lett. in press 2018


O. Dada, G. Sánchez-Sanz, M.Tacke, X. Zhu,

Synthesis and anticancer activity of novel NHC-gold(I)-sugar complexes

Gold(I) complexes containing stabilising ligands such as phosphines or N-heterocyclic carbenes (NHCs) are known to be inhibitors of the enzyme thioredoxin reductase (TrxR) and therefore act as potential apoptosis-inducing anticancer drug candidates. The conjugation of biomolecules overexpressed in cancer cells to the gold complexes makes them semi-targeted metabolites. Auranofin, an anti-arthritis agent, encompasses this property and exhibits anti-tumour activities. The synthesis, characterization and biological evaluation of four novel N-heterocyclic carbene-gold(I)-thiosugar complexes derived from glucose, lactose and galactose is reported. The reactions of 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) chloride (NHC∗-Au-Cl) with pre-synthesized glycosyl thiols under mildly basic conditions gave the desired NHC-Au-thiosugar complexes in high to excellent yields (79–91%). The complexes retain the strong and redox-active Au-S bond contained in Auranofin. All complexes showed good solubility in biological media and were tested against the NCI 60 cancer cell panel for cytotoxicity. The synthesized NHC∗-Au derivatives showed good activity in the medium to low micromolar region, while complex 2 showed activity in the low micromolar to nanomolar region against the tested cell lines. To provide a theoretical structure of 4, computational calculations were carried out based on the crystal structures of NHC-Au-SCN and NHC-Au-S-C6H4OMe.

Org. Lett. 20, 2948, 2018


R. McCourt, F. Denes, G. Sánchez-Sanz, E. Scanlan

Rapid Access to Thiolactone Derivatives Through Radical-Mediated Acyl-Thiol-Ene and Acyl-Thiol-Yne Cyclisation

A new synthetic approach to thiolactones that employs an efficient acyl thiol–ene (ATE) or acyl thiol–yne (ATY) cyclization to convert unsaturated thiocarboxylic acid derivatives into thiolactones under very mild conditions is described. The high overall yields, fast kinetics, high diastereoselectivity, excellent regiocontrol, and broad substrate scope of these reaction processes render this a very useful approach for diversity-oriented synthesis and drug discovery efforts. A detailed computational rationale is provided for the observed regiocontrol.

Biophys. Chem. 238, 16, 2018


G. Sánchez-Sanz, D. Crowe, A. Nicholson, A. Fleming, E. Carey, F. Kelleher

Conformational studies of Gram-negative bacterial quorum sensing acyl homoserine lactone (AHL) molecules: the importance of the n→pi* interaction

A 1H NMR study shows the presence of intermolecular hydrogen bonds for AHLs in CDCl3 solution. A detailed computational study of the structure of AHLs and the relative stability between the extended conformations (X) and those showing n→p* 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.

J. Phys. Chem. A,122, 1369, 2018


G. Sánchez-Sanz, C. Trujillo

Improvement of Anion Transport Systems by Modulation of Chalcogen Interactions: The influence of solvent

A series of potential anion transporters, dithieno[3,2-b;2′,3′-d]thiophenes (DTT), involving anion-chalcogen interactions have been studied analysing 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. In order to enhance the chalcogen interaction between the DTT derivatives and the anion, increasing the anion transporter capacity, bisisothioazole moiety was considered, i. e. the s-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 s-hole and therefore the interaction between the chalcogen and anion. Finally, different anions were analysed within the complexes finding that F and NO3would be the best candidate to form complexes and possibly displace other anions such as Clor Br.

J. Phys. Chem. A, 121, 8995, 2017


G. Sánchez-Sanz, C. Trujillo, I. Alkorta and J. Elguero

Enhancing Intramolecular Chalcogen Interactions in 1-Hydroxy-8-YH-Naphthalenes Derivatives

Forty-two peri-substituted naphthalenes presenting chalcogen weak interactions have been studied. They correspond to O···Y interactions, Y being O, S and Se. While the O atom bear H or CH3 substituents (OH and OCH3 groups), the Y atom is substituted by H, F and CN in order to explore the effect of these electron-donating and electron-withdrawing substituents on the chalcogen bond strength. The effect of F and CH3 substituents on positions ortho/para (2,4,5,7 of the naphthalene ring) was also studied. Optimizations were carried out at the MP2/augl-cc-pVDZ and binding energies at the MP2/aug-cc-pVTZ followed by an MP2/CBS estimation. The main properties studied were geometries, energies (Eb, Eiso and Edef), the Molecular Electrostatic Potential (MEP), Electron density shifts and NBO E(2) energies and the relationship between these properties.

Phys. Chem. Chem. Phys., 19, 20647, 2017


G. Sánchez-Sanz, C. Trujillo, I. Alkorta and J. Elguero

Modulation of in:out and out:out conformations in [X.X'.X"] Phosphatranes by Lewis Acids

A theoretical study of the [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. It has been found that in:out structures are more stable in larger systems i.e. in [4.4.3]:X and [4.4.4]:X than in [3.3.3]:X and [4.3.3]:X. 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.

Bioorg. Med. Chem., 25, 4285, 2017


D. Crowe, A. Nicholson, A. Fleming, E. Carey G. Sánchez-Sanz, and F. Kelleher

Conformational studies of Gram-negative bacterial quorum sensing 3-oxo N-acyl homoserine lactone molecules

In their 1H NMR spectra in CDCl3 3-oxo-N-acyl homoserine lactones (OHLs) show significant downfield chemical shifts of the amide Nsingle bondH 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 Nsingle bondH to the 3-oxo group. The 1H 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 CDCl3 and 6.5–7.2% in CD3CN. 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.

Eur. J. Med. Chem.,138, 38, 2017


A. Flood, C. Trujillo, G. Sánchez-Sanz, B. Kelly, B. Twamley, C. Muguruza, L. F. Callado, and I. Rozas

Thiophene/Thiazole-Benzene Replacement on Guanidine Derivatives Targeting α2 -Adrenoceptors

Searching for improved antagonists of α2-adrenoceptors, a thorough theoretical study comparing the aromaticity of phenyl-, pyridinyl-, thiophenyl- and thiazolylguanidinium derivatives has been carried out [at M06-2X/6–311++G(p,d) computational level] confirming that thiophene and thiazole will be good ‘ring equivalents’ to benzene in these guanidinium systems. Based on these results, a small but chemically diverse library of guanidine derivatives (15 thiophenes and 2 thiazoles) were synthesised to explore the effect that the bioisosteric change has on affinity and activity at α2-adrenoceptors in comparison with our previously studied phenyl derivatives. All compounds were tested for their α2-adrenoceptor affinity and unsubstituted guanidinothiophenes displayed the strongest affinities in the same range as the phenyl analogues. In the case of cycloakyl systems, thiophenes with 6-membered rings showed the largest affinities, while for the thiazoles the 5-membered analogue presented the strongest affinity. From all the compounds tested for noradrenergic activity, only one compound exhibited agonistic activity, while two compounds showed very promising antagonism of α2-adrenoceptors.

Molecules, 22, 227, 2017


G. Sánchez-Sanz, I. Akorta, J. Elguero

Theoretical study of intramolecular interactions in peri-substituted naphthalenes: chalcogen and hydrogen bonds  

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 has been carried out. The systems with a OH:Y hydrogen bond are the most stable ones followed by those with a chalcogen O:Y interaction, being those with a YH:O hydrogen bond (Y = S and Se) the least stable ones. The electron density values at the hydrogen bond critical points indicate that they have partial covalent character. The Natural Bond Orbital (NBO) analysis shows stabilization due to 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 have been used to compare the experimental and calculated results.

J. Phys. Chem. A., 121, 1362, 2017


Janet E. Del Bene, I. Akorta, J. Elguero, G. Sánchez-Sanz

Lone-Pair Hole on P: P···N Pnicogen Bonds Assisted by Halogen Bonds 

Ab initio MP2/aug’-cc-pVTZ calculations have been performed on the binary complexes XY:PH3 for XY = ClCl, FCl, and FBr; and PH3:N-base for N-base = NCH, NH3, NCF, NCCN, and N2; and the corresponding ternary complexes XY:PH3: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 PH3:N-base which 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 PH3 a better electron-pair acceptor through its lone-pair hole, leading to stable ternary complexes XY:PH3:N-base. The halogen bonds in ClCl:PH3 and ClCl:PH3: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:PH3:N-base appears to be stronger than that bond in FBr:PH3:N-base, which is stronger than the P…N bond in the corresponding ClCl:PH3: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 1xJ(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, 1xJ(P-Cl) approaches the value of 1J(P-Cl) for the cation +(Cl-PH3). The coupling constants 1pJ(P-N) are small and with one exception, are greater in ClCl:PH3:N-base complexes compared to FCl:PH3:N-base, despite the shorter P-N distances in the latter.

Struct. Chem., 28, 345, 2017


C. Trujillo, G. Sánchez-Sanz, I. Akorta, J. Elguero

An insight on the aromatic changes in closed shell icosagen, tetrel and pnictogen phenalenyl derivatives 

A computational study of the aromatic and antiaromatic characteristics of charged phenalenyl (PLY+1 andPLY-1) upon replacement of the central carbon atom by icosagen (B, Al and Ga), tetrel (Si and Ge) and pnictogen (N, P and As) atoms comprising systems in which the icosagen and pnictogen derivatives considered are neutral while the tetrel ones are anions or cations, has been carried out at the B3LYP/6-311++G(d,p) computational level. By substitution, two different kinds of structures have been obtained, one planar (N and B) and another one bowl-shaped depending on the size of the central atom. In terms of aromaticity, the substitution of the central C atom causes a loss of the aromatic character in all cases as indicated by NICS (Nucleus-Independent Chemical Shifts) profiles and NICS values on the 0.001 a.u. isosurface. Regarding the charge, PLY+1 present larger electron delocalisation than PLY–1, phenomenon associated with aromaticity. Furthermore, the current density maps for those planar systems corroborate NICS findings, showing anticlockwise currents in PLY+1 (like in benzene) but clockwise in PLY-N0 and PLY-B0, indicating aromatic and antiaromatic behaviour respectively.

Lett. Drug Des. Discov., 14, 125, 2017


W. Walther, O. Dada, C. O’Beirne, I. Ott, G. Sánchez-Sanz, C. Schmidt, C.Werner, X.Zhu and M.Tacke

In Vitro and In Vivo Investigations into the Carbene Gold Chloride and Thioglucoside Anticancer Drug Candidates NHC-AuCl and NHC-AuSR

The anticancer drug candidate 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) chloride (NHC-AuCl) and its 2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl-1’-thiolate derivative (NHC-AuSR), which is a potential ligand for glucose transporters, were tested on the NCI 60 cancer cell panel in vitro. NHC-AuCl and NHC-AuSR showed very good activity against a wide range of human cancer cell lines inclusive renal cell cancer with similar average GI50 values of 1.78 and 1.95 μM, respectively. This encouraged maximum tolerable dose (MTD) experiments in mice, where MTD values of 10 mg/kg for NHC-AuCl and 7.5 mg/kg for NHC-AuSR were determined with single injections to groups of 2 mice. In the following tumor xenograft experiment NHC-AuCl and NHC-AuSR were given at MTD in 6 injections to two cohorts of 6 CAKI-1 tumor-bearing NMRI:nu/nu mice, while a control cohort of 6 mice was treated with solvent only. NHC-AuCl at the dose of 10 mg/kg and NHC-AuSR at the lower dose of 7.5 mg/kg induced both low toxicities in the form of abdominal swelling but no significant body weight loss was seen in both groups. The tumor volume growth reduction was significant and almost identical; optimal T/C values of 0.47 were observed on day 19 for NHC-AuCl and on day 29 for NHC-AuSR. Immunohistochemistry for the proliferation marker Ki-67 and the angiogenesis marker CD31 did not show significant changes due to NHC-AuCl or NHC-AuSR treatment in the animals. However, thioredoxin reductase (TrxR) inhibition with IC50 values of 1.5 μM for NHC-AuCl and 3.1 μM for NHC-AuSR seem to indicate that apoptosis induction through elevated oxidative stress is the main mechanism for the two gold compounds.

Inorganics, 4, 36, 2016


A. Molloy, G. Sánchez-Sanz, D. G. Gilheany

PP-Rotation, P-inversion and metathesis in diphosphines studied by DFT calculations: comments on some literature conflicts

The potential energy surface for internal rotation about the phosphorus-phosphorus bond was calculated at the PCMDCM/B3LYP/6-311++G(d,p) computational level for a set of eight symmetrical, unsymmetrical and P-stereogenic diphosphines; H4P2, Me4P2, (CF3)4P2, Ph4P2, Me2P-P(CF3)2, Me2P-PPh2, and the meso- and dl-isomers of Me(CF3)P-PMe(CF3) and MePhP-PMePh. Certain trends in the data were elucidated and compared with conflicting data from the literature regarding the relative population of anti and gauche rotational isomers. The pyramidal inversion barriers (stereomutation barriers in P-stereogenic cases) for the same set of diphosphines was estimated through the inversion transition states and also compared to literature values. Finally, the Me4P2 + (CF3)4P2 → 2 Me2(CF3)2Pmetathesis reaction was also explored to evaluate its feasibility versus inversion. The finding of larger barriers inthe metathesis than in the inversion rules in favour of an inversion mechanism for the stereomutation of P-stereogenic diphosphines.

New J. Chem, 40, 9060, 2016


D. Quiñonero, A. Bauzá, G. Sánchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero

Weak interactions within nitryl halide heterodimers

A theoretical study of nitryl halide heterodimers has been carried out by means of SCS-RI-MP2 and CCSD(T) at the complete basis set (CBS) calculations. For this purpose, 66 heterodimers have been characterized as minima and arranged in six groups depending on the interactions involved and geometrical arrangements. The CCSD(T)/CBS interaction energies vary between –0.6 and –11.1 kJ mol–1. The heavier the halogen atoms the larger the interaction energies are. Natural bond orbital (NBO) and “atoms-in-molecules” (AIM) theories were used to analyze the complexes, confirming the presence of halogen, chalcogen, and π-hole interaction bonds. The largest charge-transfer energy contributions are found for halogen bonded complexes (up to 29.1 kJ mol–1). Moreover the physical nature of the interactions has been studied by means of SAPT calculations, concluding that dispersion is the major source of attraction, although electrostatics is important in halogen bonded complexes.

PLoS Comput. Bio. 12, e1005051, 2016


G. Sánchez-Sanz, B. Tywoniuk, D. Matallanas, D. Romano, L. Nguyen, B. N. Khodolenko, E. Rosta, W. Kolch, N.-V. Buchete

SARAH Domain-mediated MST2-RASSF Dimeric Interactions

RASSF enzymes act as key apoptosis activators and tumour 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 hetero-dimerization, 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 analyse both computationally and experimentally the interactions of MST2 SARAH domains with a series of synthetic peptides particularly designed to bind to it, and demonstrate that our approach can be used to design new anti-cancer drugs. 

Tetrahedron, 72, 4690, 2016


G. Sánchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero

Aromatic changes in isoelectronic derivatives of phenalenyl radicals by central carbon replacement

A computational study of the aromatic characteristics of phenalenyl (PLY) upon replacement of the central carbon atom by Si, Ge, N, P, As, B, Al and Ga atoms comprising isoelectronic series with different charges (0, +1, –1) has been performed at the B3LYP/6-311++G(d,p) level. Two different geometries have been obtained, one planar and another one bowl-shaped. PLY derivatives exhibit a loss of the aromatic character in all cases indicated by NICS (Nucleus-Independent Chemical Shifts) values. These aromatic features are also in agreement with the pyramidalisation undergone by the central atom. The current density maps for those planar systems corroborate NICS findings. These variations in the aromaticity have been rationalised in terms of charge localisation. Harmonic oscillator model of aromaticity (HOMA) and para-delocalisation indices (PDI) have been used to evaluate the electron density delocalisation. HOMA values do not correlate with NICS but PDI indices follow the same trend than NICS.

Comput. Theor. Chem. 1090, 171, 2016


G. Sánchez-Sanz, C. Trujillo, I. Alkorta

Structure, binding energy and chiral discrimination in oxathiirane homodimers.

Oxathiirane (XHCSO) homodimers bonded by hydrogen bonds (HB) and chalcogen bonds (YB) were studied at the Møller-Plesset (MP2) computational level. Binding energies obtained at the Coupled-Cluster level up to the Complete Basis Set limit [CCSD(T)/CBS] indicate that HB complexes present stronger binding modes than the YB ones.  In terms of chiral discrimination energy, R,S complexes are favored over R,R ones with the exceptions of SiCl3 and SiF3 derivatives. Natural Bond Orbital (NBO) results are in agreement with the interaction energies in the case of the HB complexes, but could not discriminate between R,R and R,S in the YB complexes. The lack of correlation between molecular electrostatic values on the 0.001 a.u. and binding energies, in addition to the discrepancies between Atoms in Molecules (AIM) and NBO results may suggest that the electrostatics is not the dominant term in the interaction energy. This was corroborated by the Localized Molecular Orbital Energy Decomposition Analysis (LMOEDA) calculations which showed that the exchange and dispersion terms are the most important attractive components for all the complexes studied, contributing up to 50.6 and 42.5% to the total attractive forces respectively.

Theor. Chem. Acc. 135,140, 2016


G. Sánchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero

Competition between intramolecular hydrogen and pnictogen bonds in protonated systems

A theoretical study of the competition between hydrogen (HB) and pnictogen bonds (ZB) in three different families of compounds, (Z)-1,2-disubstituted ethenes (Eth), 1,2-disubstituted benzenes (Phe) and 1,8-disubstituted naphthalenes (Naph), with a charged group, ZH3+ and a neutral one, Z'H2 (Z, Z' = N, P, As) as interacting moieties, has been carried out. In those structures with a NH3+ motif, intramolecular hydrogen bond structures are minima while pnictogen interactions are transition states. The opposite is true for PH3+ and AsH3+ moieties. An analysis of isodesmic energies (Eiso), interaction energies (Eb) and deformation energies (Edef), shows than in Eth derivatives, the most stable compound corresponds to P+–N ZB while in the Phe and Naph ones, the N+–N HB interaction presents the largest negative isodesmic energy. Also, Eth and Phe derivatives show negative Eiso values for all the compounds under study, however in some cases of Naph derivatives positive isodesmic energies have been found. The Atoms in Molecules (AIM) analysis of the electron density, Natural Bond Orbital (NBO) second order orbital energies and electron density shift maps (EDS) have been used to better understand these intramolecular interactions.  

Biophys. J. 110 (Suppl. 1) , 379a, 2016


A. Crowe, G. Sánchez-Sanz, B. Tywoniuk, Denis. C. Shields, N.-V. Buchete

Coarse Master Equation-Based Analysis of N-Methylation and Temperature Effects on the Dynamics of Cyclic Peptides

Cyclosporin A (CsA) is a cyclic peptide widely used as an important immunosuppressant drug to prevent organ rejection following transplants. It is eleven residues in length, cyclized head-to-tail and is multiply N-methylated and largely hydrophobic, which makes it an excellent template for drug design. This study elucidates the important effects of N-methylation and temperature on the conformational dynamics, and specifically in altering the intramolecular hydrogen bond geometries of N-methylated cyclic peptides, such as CsA. We have run several normal and high-temperature molecular dynamics (MD) simulations of CsA and of a de-methylated variant (dCsA) whereby all backbone N-methyl groups have been removed. We have found that the numerous N-methyl sites introduce a large degree of conformational specificity to CsA by modulating the formation of intramolecular hydrogen bonds. Geometric measures such as cross-sectional distances, solvent accessible surface area (SASA), and intramolecular hydrogen bonding are used to explore and compare the conformational ensemble of CsA and dCsA. We use data-driven methods to cluster the conformational states, providing an increasingly automatic method of state identification. Representative structures are analyzed further using a coarse master equation-based kinetic analysis method. This formalism can be used for a systematic comparison of the conformational dynamics of cyclic peptides in MD simulations in explicit water, under various conditions, quantifying the mechanisms and effects of N-methylation and the T-dependence.

Phys. Chem. Chem. Phys. 18, 9148, 2016


G. Sánchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero 

Modulating Intramolecular P···N Interactions

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 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 strengthen the P•••N pnictogen bond, evidenced by increasing the 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 function and charge transfer corroborate the evolution of the P•••N strength upon substitution.

Brief. Bioinform., 17, 593, 2016


G. Sánchez-Sanz, D. Matallanas, L. K. Nguyen, B. N. Khodolenko, E. Rosta, W. Kolch, N.-V. Buchete

MST2-RASSF Protein-Protein Interactions Through SARAH Domains

The detailed, atomistic-level understanding of molecular signaling along the tumor-suppressive Hippo signaling pathway, which 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 MST1 and MST2 – modulated through both homo- and hetero-dimerization (e.g., interactions with 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 review 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 controlling cell apoptosis. Here, we focus on recent studies highlighting the special role being played by the specific interactions between the helical 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.

ChemPhysChem,17, 395, 2016


C. Trujillo, G. Sánchez-Sanz

Study of the π-π Stacking Interactions and Aromaticity in Polycyclic Aromatic Hydrocarbons and DNA/RNA Bases Complexes 

We have analysed the interactions and aromaticity electron density delocalisation observed in π-π  complexes between phenalenyl radical and acenaphthylene, and the DNA and RNA nucleobases (adenine, guanine, cytosine, thymine and uracil). Interaction energies have been obtained a M06–2X /6–311++G(2df,p) in gas phase and PCM-Water conditions. In both cases, Phe and Ace, the complexes formed with guanine are the most stable one.  Atoms in molecules (AIM) and Natural Bond Orbital (NBO) results reveal weak  π-π interactions between both interacting moieties, characterised by bond critical points between C•••C and C•••N atoms. Nucleus Independent Chemical Shifts (NICS) indicate a retaining of the aromatic character of the monomers in the outer region of the complex. FLU indexes reveal a loss of the electron delocalisation upon complexation in all cases except guanine complexes. Nevertheless, the interface region reveals large negative NICS values which cannot be associated to increase of the aromaticity or electron density delocalisation, but to magnetic couplings of both molecules leading to unrealistic description of the aromatic behaviour in that region.

New J. Chem, 39, 6791, 2015


C. Trujillo, G. Sánchez-Sanz, I. Alkorta, J. Elguero

Halogen, Chalcogen and Pnictogen Interactions in (XNO2)2 Homodimers (X = F, Cl, Br, I)

A theoretical study of the XNO2 homodimers (X = F, Cl, Br and I) has been carried out by means of the Møller-Plesset (MP2) methodology. Twenty-two different minimum structures have been found, involving pnictogen, chalcogen and halogen bonds. MP2 interaction energies range between –0.4 to –17.5 kJ•mol–1. Atoms in Molecules (AIM) and Natural Bond Orbital (NBO) approaches have been used to analyse the nature of the interaction within both monomers, obtaining good correlations between Laplacian values and bond distances. NBO E(2) orbital interaction energies are found to be up to 39.0 kJ•mol–1. Charge transfer between monomers are in agreement with those in AIM and NBO findings, showing the highest charge transferred in those asymmetric dimers which involve pure halogen bonds. Symmetry Adapted Perturbation Theory (SAPT-DFT) results show that the interactions are driven by the dispersion term, followed by the electrostatic one. The induction term present the lowest contribution with the exception of complexes 1 and 5 of the iodine derivative in which Ei(2) shows the maximum contribution to the total forces.

Phys. Chem. Chem. Phys, 17, 14961, 2015


G. Sánchez-Sanz, C. Trujillo, I. Rozas, I. Alkorta

Influence of fluoro and cyano substituents in the aromatic and antiaromatic characteristics of cyclooctatetraene

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.

ChemPhysChem,16, 2140, 2015


C. Trujillo, G. Sánchez-Sanz, I. Alkorta, J. Elguero

Computational study of proton transfer in 3(5)-hydroxypyrazole tautomers assisted by water

The tautomerism of 3(5)-hydroxypyrazole has been studied at the B3LYP, CCSD and G3B3 computational levels, including gas phase, PCM-Water solvent effects, and proton transfer assisted by water molecules. To understand the propensity of tautomerization, hydrogen-bonded acidity and basicity of neutral species have been approached by means of Platts equations. B3LYP data reveals acidity alpha-values within 0.33 and 0.71, while basicity beta-values lay between 0.22-0.58. Tautomerism processes are highly dependent on the solvent environment, and we have found a significant reduction of the transition barriers upon solvation. In addition, the inclusion of a single water molecule to assist the proton transfer considerably decreases the barriers between tautomers. While the second water molecule reduces those barriers, its effect is less appreciable than in the first one. Neutral species present more stable minima than anionic and cationic species, but relatively similar transition barriers than anionic tautomers.

Comput. Theor. Chem. 1053, 305, 2015


G. Sánchez-Sanz, C. TrujilloI. Alkorta, J. Elguero

Theoretical study of cyanophosphines: Pnicogen vs. dipole-dipole interactions

Cyanophosphine derivative dimers, [HXP(CN)]2 with X = H, F and Cl,  have been characterized by means of CCSD(T)/aug’-cc-pVTZ//MP2/aug’-cc-pVTZ computational level calculations. Different interactions have been found upon complexation, such as hydrogen bonds, pnicogen bonds and dipole···dipole interactions. The intermolecular distances range between 2.84 and 3.53 Å and the binding energies between –34.7 and –3.6 kJ•mol–1. Compounds with dipole···dipole interactions present shorter contact distances and larger (more negative) binding energies than those with pure P···P pnicogen bonds. Electron density shift maps show larger variations in compounds with dipole···dipole interactions than in those with pure pnicogen ones, in line with the energetic results. However, NBO analysis suggests that the complexes with P···P pnicogen bonds, in special those with XP···PX (X = F, Cl) show E(2) orbital interaction energies much larger than the dipole···dipole ones. 

J. Heterocycl. Chem. 52, 336, 2015

DOI: 10.1002/jhet.1955

R. Aggarwal, V. Kumar, G. Singh, D. Sanz, R. M. Claramunt,  I. Alkorta, G. Sánchez-Sanz, J. Elguero

An NMR and Computational Study of Azolo[a]pyrimidines with Special Emphasis on Pyrazolo[1,5-a]pyrimidines

The reaction of 3(5)-amino-5(3)-hydrazinopyrazole, a bifunctional compound, with  3-oxo-3-phenylpropanenitrile and two of its p-substituted derivatives affords 2,5-diaryl-7-aminopyrazolo[1,5-a]pyrimidines. A mechanism for this unexpected reaction involving the formation of hydrazine is proposed. The position of the aryl substituents on the bicyclic ring has been established by the combined use of NMR and DFT calculations. Moreover, the chemical shifts have been calculated, and some general rules have been withdrawn.

Tetrahedron, 71, 826, 2015


G. Sánchez-Sanz

Aromatic behaviour of benzene and naphthalene upon pnictogen substitution

A thorough study of the structural and aromatic properties of derivatives of benzene and naphthalene where one or more -CH- groups have been substituted by a nitrogen, phosphorous or arsenic atom has been carried out at B3LYP/6-311++G(d,p) level. Relative energies between isomers range from 5.0 to 294 kJ mol-1 finding the largest relative energies in compounds with nitrogen substitutions. In general, most of the compounds show to be planar with a few exceptions which exhibit twisted structures. Wiberg bond indexes as well as bond distances indicate that in almost all the cases the bond nature is benzene-like. Aromatic characteristics have been addressed calculating NICS values, profiles, isosurfaces and HOMA indexes. NICS(1) and (2) present values close to those of benzene showing aromatic behaviour, confirmed by NICS profiles and 3D NICS isosurfaces. HOMA indexes obtained for those compounds with reported parameterized bonds are in agreement with their corresponding aromatic nature.

ChemPhysChem, 15, 3493, 2014


C. TrujilloG. Sánchez-Sanz, I. Alkorta, J. Elguero

A computational study of 3-azonia-, 3-phosphonia- and 3-arsonia- spiro[2.2]pentanes and related three-membered heterocycles

A theoretical study, using ab initio MP2/6-311++G(d,p) computational level, has been carried out to characterize several heterocyclic spiro[2.2]pentanes cations, with N, P and As as spiro atoms. The strain and relative stability of the spiropentanes has been obtained through isodesmic reactions. NICS values and 3D NISC isosurfaces have shown σ-aromatic characteristics, similar to those found in cyclopropane. The interaction with the Cl– anion, resulting in four different stationary structures has been studied and characterized by means of the Atoms in Molecules (AIM) methodology, and it has been found Cl-pnicogen, Cl-H and Cl-C interactions have. Amongst them, the most stable structure in all cases corresponds to the 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 3-boranuidaspiro[2.2]pentane anion has been considered, resulting in the formation of a new compound through the cleavage of the carbon rings of both reactants.

J. Phys. Chem. A. 118, 5540, 2014


 M. Marín-LunaG. Sánchez-Sanz, P. O'Sullivan, I. Rozas

Guanidine complexes of Platinum: a theoretical study

We aim to design dual anticancer agents combining a guanidine-based DNA minor groove binder and a cisplatin-like Pt moiety. Hence, to understand the complexation between Pt and the guanidine or guanidinium moiety, we have calculated the complexes of model Nphenylguanidine/ ium derivatives with PtCl3‾ and PtCl2 in different coordinating modes (mono- and bidentate), with different N atoms of the guanidine/ium moiety and using the B3LYP/6-31+G** and LANL2DZ mixed basis set. Calculated interaction and relative energies, analysis of the electron density and examination of the orbital interactions indicate that the most stable type of complex is a monodentate interaction etween PtCl3‾ and guanidinium established through one of the NH2 groups. Next, we optimised the structure of three bis-guanidinium diaromatic systems developed in our group as DNA minor groove binders and their complexation with PtCl3‾ finding that the formation of Pt complexes of these minor groove binders is favourable and would produce stable monodentate coordinated systems.

Chem. Eur. J. 20, 10360, 2014


C. TrujilloG. Sánchez-Sanz, I. Karpaviciene, U. Jahn, I. Cikotiene, L. Rulisek

Divergent Pathways and Competitive Mechanisms of Metathesis Reactions Between 3-Arylprop-2-inyl esters and Aldehydes:  An Experimental and Theoretical Study

Mechanistic studies on the BF3•Et2O catalyzed reaction between 3-arylprop-2-ynyl esters and aldehydes were performed using isotopic labeling experiments and quantum chemical calculations. The reactions are shown to proceed either via classical alkyne-carbonyl metathesis route, or via 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 adducts (MBHA), unavailable via traditional MBH reactions, or (E)- and (Z)-α,β-unsaturated ketones. 18O-Labeling studies suggested the existence of two different reaction pathways to the products. These pathways were further examined by quantum-chemical calculations employing the DFT(wB97XD)/6-311+G(2d,p) method together with the conductor-like screening model for realistic solvation (COSMO-RS). Using the wB97XD functional, the accuracy of the computed data is estimated to be 1 2 kcal.mol 1 as 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 is 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.

Phys. Chem. Chem. Phys. 16, 15900, 2014


G. Sánchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero

Intramolecular pnicogen interactions in phosphorus and arsenic analogues of proton sponges

A computational study of the intramolecular pnicogen bond in 1,5- and 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 reasonable good agreement with the crystal structures found in the CSD search, in special those of the halogen derivatives. Isodesmic reactions where the 1,8-bis-subtituted derivatives are compared to monosubstituted derivatives have been calculated, indicating that the 1,8 derivatives are more stable than the monosusbtituted 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.

J. Phys. Chem. A, 118, 1527, 2014


I. Alkorta, G. Sánchez-Sanz, J. Elguero J.E. Del Bene

Pnicogen Bonds between X=PH3 (X = O, S, NH, CH2) and Phosphorus and Nitrogen Bases. 

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 31P decrease in the complexes relative to the corresponding monomers. 1pJ(P–N) and 1pJ(P–P) values correlate best with the corresponding P–N and P–P distances as a function of the nature of the base. 1J(P–A) values do not correlate with P–A distances. Rather, the absolute values of 1J(P–O), 1J(P–S), and 1J(P–N) decrease upon complexation. Decreasing 1J(P–A) values correlate linearly with increasing complex binding energies. In contrast, 1J(P–C) values increase upon complexation and correlate linearly with increasing binding energies.

J. Phys. Condensed Matter, 25, 415504, 2013


A. J. Salkeld, M. F. Reid, J-P. R. Wells, G. Sánchez-Sanz, L. Seijo and Z. Barandiarán. 

Effective-Hamiltonian parameters for ab initio energy-level calculations of SrCl2 :Yb2+ and CsCaBr3:Yb2+.

Calculated energy levels from recent ab initio studies of the electronic structure of SrCl2:Yb2+ and CsCaBr3:Yb2+ are fitted with a semi-empirical 'crystal-field' Hamiltonian, which acts within the model space 4f14 + 4f135d + 4f136s. Parameters are obtained for the minima of the potential energy curves for each energy level and also for a range of anion–cation separations. The parameters are compared with published parameters fitted to experimental data and to atomic calculations. The states with significant 4f136s character give a good approximation to the impurity-trapped exciton states that appear in the ab initio calculations.

J. Phys. Chem. B. 117, 11608, 2013

DOI: 10.1021/jp407339v

F. Blanco, B. Kelly, G. Sánchez-Sanz, C. Trujillo, I. Alkorta , J. Elguero , I. Rozas

Non-Covalent Interactions: Complexes of Guanidinium with DNA and RNA Nucleobases

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.

Phys. Chem. Chem. Phys. 15, 14310, 2013

DOI: 10.1039/c3cp52312h

G. Sanchez-Sanz, C. Trujillo, M. Solimannejad, I. Alkorta, J. Elguero

Orthogonal interactions between nitryl derivatives and electron donors: pnictogen bonds

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.

Tetrahedron, 69, 7333, 2013


G. Sánchez-Sanz, C. Trujillo, I. Rozas, J. Elguero

A theoretical study on the aromaticity of benzene and related derivatives incorporating a C–Ctriple bond; length of mdashC–C fragment

Dedicated to Professor Ibon Alkorta on the occasion of his 50th anniversary

Continuing with our interest in aromaticity, we have studied the influence that replacement of formal C–C single bonds by C–Ctriple bond; length of mdashC–C fragments, in a series of mono- (cyclobutadiene, benzene, and cyclooctatetraene) and fused-carbocycles (naphthalene and azulene), has in their properties, focusing mostly on NMR and aromaticity. We have analyzed the effect of such substitution not only in the aromaticity of the different structures, but also in the influence of low and high spin states by means of NICS values over the rings and 3D NICS isosurfaces. We have found that, in most of the cases, the substitution induces a loss of aromaticity in singlet states (both restricted and unrestricted) that can be recovered when triplet states are taken into account.

Comp. Rend. Chim. 16, 937, 2013

DOI: 10.1016/j.crci.2013.05.016

D. Sanz, R. M. Claramunt, F. Mathey, I. Alkorta, G. Sánchez-Sanz, J. Elguero

Intermolecular spin–spin coupling constants between 31P atoms

This paper reports the study by NMR spectroscopy and ab initio methods of the structure of 3,4-dimethyl-1-cyanophosphole and its dimer. The dimer presents a P...P interaction of the pnictogen type due to the presence ofs-holes. NMR of the monomer was recorded in CDCl3 solution while NMR of the dimer corresponds to the solid state (CPMAS) experiments. The 2pJPP spin–spin coupling constan thas not been measured, but calculated at the B3LYP level. AIM, NBO and ELF methodologies have been used to describe the electronic structure of the dimer

J. Mol. Struct. 108, 138, 2013

DOI: 10.1016/j.molstruc.2013.04.069

C. Trujillo, G. Sánchez-Sanz, I. Alkorta, J. Elguero, O. Mó, M. Yáñez

Resonance assisted hydrogen bonds in open-chain and cyclic structures of malonaldehyde enol: A theoretical study

In 1989 Gilli, Bellucci, Ferretti and Bertolasi introduced the notion of Resonance Assisted Hydrogen Bonding (RAHB) one of the most fruitful concepts in structural chemistry. After reviewing our previous contributions to this topic, the present work analyzes theoretically this concept especially in non-cyclic structures. Geometries, electron densities and Laplacian at the bond critical points, cooperativity through many body interaction energies, deformation energies as well as NMR properties (chemical shifts and 2hJOO coupling constants) are used for the discussion.

J. Phys. Chem. A, 117, 3133, 2013

DOI: 10.1021/jp401480y

J. E. Del Bene, I. Alkorta, G. Sanchez-Sanz, J. Elguero

Phosphorus As a Simultaneous Electron-Pair Acceptor in Intermolecular P···N Pnicogen Bonds and Electron-Pair Donor to Lewis Acids

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. 31P absolute chemical shieldings increase in LA:H2FP:NFH2complexes 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 1pJ(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.

ChemPhysChem, 14, 1656, 2013

DOI: 10.1002/cphc.201300145

G. Sanchez-Sanz, I. Alkorta, C. Trujillo, J. Elguero

Intramolecular Pnicogen Interactions in PHF(CH2)nPHF (n=2–6) Systems

A computational study of the intramolecular pnicogen bond in PHF[BOND](CH2)n[BOND]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.

Z. Phys. Chem. 227, 821, 2013

DOI: 10.1524/zpch.2013.0367

J. E. Del Bene, I. Alkorta, G. Sanchez-Sanz, J. Elguero

Ab Initio Study of Cooperative Effects in Complexes X:HBO:Z, with X, Z=LiH, HNC, HF, HCN, HCl, ClF, and HBO: Structures, Binding Energies, and Spin-Spin Coupling Constants across Intermolecular Bonds

A systematic ab initio investigation has been carried out to determine the structures, binding energies, and spin-spin coupling constants of ternary complexes X:HBO:Z for X, Z=LiH, HNC, HF, HCN, HCl, ClF, and HBO. All complexes X:HBO:Z are linear with C∞v symmetry, except for HCl:HBO:Z and ClF:HBO:Z which have Cs symmetry, thereby reflecting the structures of the corresponding X:HBO and HBO:Z complexes. Cooperative effects on energies are synergistic in all ternary complexes. The enhanced binding energies of complexes X:HBO:Z correlate with the binding energies of the X:HBO and HBO:Z complexes. Coupling constants 1J(B-H) and 2hJ(B-A) across B-H···A hydrogen bonds correlate with the B-A distance, and exhibit synergistic effects due to the presence of Z. 1hJ(H-A) indicates that these bonds have little proton-shared character. Coupling constants across D-H···O hydrogen bonds, H-Li···O lithium bonds, and F-Cl···O halogen bonds are also sensitive to the synergistic effects arising from the presence of X. D-H···O hydrogen bonds in ternary complexes are traditional (normal) hydrogen bonds.

J. Phys. Org. Chem. 26, 378, 2013

DOI: 10.1002/poc.3099

I. Rozas, G. Sanchez-Sanz, I. Alkorta, J. Elguero
Solvent effects on guanidinium-anion interactions and the problem of guanidinium Y-aromaticity

We have calculated the complexes formed by guanidine/guanidinium and HCl/Cl, HNO3/NO3 and H2SO4/HSO4 both in the gas and aqueous Polarizable Continuum Model (PCM) phase to understand the effect that solvation has on their interaction energies. In the gas phase, the cation–anion complexes are much more stable than the rest; however, when PCM-water is considered, this energetic difference is not as large due to the extra stabilization that the ions suffer when in aqueous solution. All the complexes were analyzed in terms of their AIM and NBO properties. In all cases, water solvation seems to “dampen” those properties observed in the gas phase. The values of Nucleus Independent Chemical Shift (NICS)(1) and NICS(2) indicate a huge influence of the proximity of the carbon atom for short distances; thus, the 3D NICS values on the van der Waal isosurfaces have been used to evaluate the possible Y-aromaticity of the guanidinium system. The isosurface in this system is more similar to cyclohexane than to benzene as indication of poor aromaticity.

CrystEngComm, 15, 3178, 2013

DOI: 10.1039/C2CE26786A

I. Alkorta, G. Sánchez-Sanz, J. Elguero

Linear free energy relationships in halogen bonds

Four models of halogen bonds were used to quantify this bond using the DFT B97D/6-311+G(d) computational level: para-substituted iodobenzenes, para- and meta-substituted bromobenzenes complexed with three simple Lewis bases (NH3, NCH and CNH), 1-bromo-4-substituted-bicyclo[2.2.2]octanes with NH3 and 3- and 4-substituted pyridines complexed with BrCl and BrF. In addition, the combination of the para-substituted bromobenzenes with the 4-substituted pyridines has been studied. A total of 459 complexes have been optimized and are discussed in the present article. The energetic and geometric results have been analyzed based on the properties of the substituents and the isolated molecules involved in the interaction. The Hammett–Taft parameters provide reasonable correlations with the interaction energies. However, excellent correlations are obtained in all the cases when the electrostatic properties of the two molecules involved in the interaction are considered (R2 > 0.99).

Struct. Chem. 24, 1145, 2013


C. Trujillo, G. Sánchez-Sanz, I. Alkorta, J. Elguero

A theoretical investigation of the mechanism of formation of a simplified analog of the green fluorescent protein (GFP) from a peptide model

Theoretical calculations at the B3LYP/6-311++G(d,p) level have been carried out on the reaction path connecting a dipeptide to an imidazolinone as a model for the formation of GFP. In addition, we have studied the hydration effects on the processes, adding a water molecule to assist the cyclization. The solvent effects have been taken into account by introducing the monohydrated molecules into a solvent cavity with a polarized continuum model. Significant reductions of the energy barriers for the reaction path can be observed within the water-assisted processes. The solvent effects account for a barrier lowering of 4–5 kJ mol−1.

J. Phys. Chem. A, 117, 183, 2013

DOI: 10.1021/jp3100816

I. Alkorta, G. Sanchez-Sanz, J. Elguero, J. E. Del Bene

Exploring (NH2F)2, H2FP:NFH2, and (PH2F)2 Potential Surfaces:Hydrogen Bonds or Pnicogen Bonds?

An ab initio MP2/aug’-cc-pVTZ study has been carried out to identify local minima on the (NH2F)2, H2FP:NFH2, and (PH2F)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, (NH2F)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, (PH2F)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 H2FP:NFH2surface, 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 2hJ(X–Y) across X–H···Y hydrogen bonds tend to be small, due in part to the nonlinearity of many of the hydrogen bonds. 1pJ values across a particular kind of pnicogen bond are relatively large and vary significantly but do not correlate with corresponding distances.

J. Phys. Chem. A, 116, 9205, 2012

DOI: 10.1021/jp307083g

J. E. Del Bene, I. Alkorta, G. Sanchez-Sanz, J. Elguero

Interplay of F-H...F Hydrogen Bonds and P...N Pnicogen Bonds

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. 31P and 15N chemical shieldings do not correlate with charges on P and N, respectively, but 31P shieldings correlate quadratically with the P–N distance. 1pJ(P–N) coupling constants do not correlate with the intermolecular P–N distance. However, when hydrogen bonding occurs only at P–F, 1pJ(P–N) decreases in absolute value as the P–N distance decreases, thereby approaching 1J(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.

J. Chem. Theor. Comput. 8, 2320, 2012

DOI: 10.1021/ct300399y

I. Alkorta, G. Sanchez-Sanz, J. Elguero, J. E. Del Bene

Influence of Hydrogen Bonds on the P...P Pnicogen Bond

Ab initio MP2/aug′-cc-pVTZ calculations have been carried out to investigate the influence of F–H···F hydrogen bonds on the P···P pnicogen bond in complexes nFH:(PH2F)2 for n = 1–3. The formation of F–H···F hydrogen bonds leads to a shortening of the P–P distance, a lengthening of the P–F distance involved in the hydrogen bond, a strengthening of the P···P interaction, and changes in atomic populations, NMR 31P chemical shieldings, and 1pJ(P–P) coupling constants. The magnitude of these changes depends on the number of FH molecules and their positions in the complex and are relatively modest except for complexes 2FH:(PH2F)2and 3FH:(PH2F)2 that have all FH molecules hydrogen bonded to the same F-atom. For these two complexes, 1pJ(P–P) decreases as the P–P distance decreases and approaches the value of 1J(P–P) for P2H4. The dramatic changes in these two complexes reflect the changing nature of the hydrogen bonds and the pnicogen bond. Thus, the complex 3FH:(PH2F)2 acquires ion-pair character represented as [3(FH)F:(H2P–PH2F)+], and the P···P pnicogen bond acquires significant covalent character. These changes are observed to a lesser extent in 2FH:(PH2F)2.

Comput. Theor. Chem. 994, 64, 2012

DOI: 10.1016/j.comptc.2012.06.004

B.Kelly,  G. Sanchez-Sanz, F. Blanco, I. Rozas

Cation–π vs. π–π interactions: Complexes of 2-pyridinylguanidinium derivatives and aromatic systems

We have theoretically studied, using PCM–water solvation, the cation–π and π–π complexes established by the biologically relevant 5-substituted 2-pyridinylguanidinium derivatives and electron-rich and electron-depleted aromatic systems (benzene and (hexafluoro)benzene). In condensed phase using PCM–water and M06-2X/6-311++G(d,p) different cation–π and π–π complexes were found. The interactions established within these complexes have been analyzed by means of the Atoms in Molecules and Natural Bond Orbital approaches and electron density difference maps have been calculated. Finally, the effect of the cation–π and π–π complexation on the aromaticity of pyridine, benzene and hexafluorobenzene was evaluated by calculating the corresponding aromaticity indexes, NICS0, 1 and 2 as well as the NICS on the 0.001 a.u. isodensity surface.

Comput. Theor. Chem. 994, 81, 2012

DOI: 10.1016/j.comptc.2012.06.019

C. Trujillo, G. Sanchez-Sanz, I. Alkorta, J. Elguero

Thermodynamic and hydrogen-bond basicity of phosphine oxides: Effect of the ring strain

A theoretical study of acidity and hydrogen bond acceptor properties of tetrahedric phosphine oxide derivatives have been carried out by means of MP2 computational methods. The results obtained for the mentioned complexes have been compared with the analogous ones of trimethylphosphine oxide. The strain decreases the complexation energy with metallic atoms as well as the thermodynamic and hydrogen bond acceptor (HBA) ability of the tetrahedric derivatives.

ARKIVOC ii, 85, 2012


I. Alkorta, G. Sanchez-Sanz, C. Trujillo, J. Elguero, R. M. Claramunt

A theoretical study of the parent NH-benzazoles (benzimidazoles,indazoles and benzotriazoles): geometries, energies, acidity and basicity, NMR properties and molecular electrostatic potentials

The three parent N H-benzazoles, benzimidazole, indazole and benzotriazole, have been studied theoretically at the B3LYP/6-311++G(d,p) level. Optimized geometries have been compared with those obtained by X-ray crystallography, energ ies with studies about tautomerism, acidbase properties with pKas, and chemical shifts with those reported in the literature. As aromaticity probe, Schleyer's Nuclear Independent Chemical Shifts (NICS) were used and represented in two 3D isosurfaces of the electron density.

Phys. Chem. Chem. Phys. 14, 11468, 2012

 DOI: 10.1039/C2CP41230F

 G. Sánchez-Sanz , I. Alkorta , J. Elguero , M. Yañez, O. Mó

Strong interactions between copper halides and unsaturated systems: new metallocycles? Or the importance of deformation

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.

Tetrahedron, 68, 6548, 2012

DOI: 10.1016/j.tet.2012.05.056

G. Sanchez-Sanz, I. Alkorta, C. Trujillo, J. Elguero

A theoretical NMR study of the structure of benzynes and some of their carbocyclic and heterocyclic analogs

This work reports the theoretical study of the aromaticity of a series of carbocycles (benzene, cyclohexane, bent and planar cyclooctatetraene) and heterocycles (pyridine, furan, thiophene,  pyrrole) and their didehydro forms (arynes and hetarynes). As aromaticity probe Schleyer's NICS  were used and represented in two 3D isosurfaces of the electron density. The spatial 3D  representation of the NICS is shown to be a powerful tool to visualize the aromaticity (or its  absence) of different molecules.

Phys. Chem. Chem. Phys. 14, 9880, 2012

DOI: 10.1039/C2CP40949F

G. Sanchez-Sanz , C. Trujillo , I. Alkorta, J. Elguero
Weak interactions between hypohalous acids and dimethylchalcogens

The complexes formed between dimethylchalcogens X(CH3)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–HO contact. The most stable complexes of IOH and BrOH acids present halogenchalcogen interactions with interaction energies, Ei, 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.

Chem. Phys. Lett. 538, 14, 2012

DOI: 10.1016/j.cplett.2012.04.039

J. E. Del Bene, I. Alkorta, G. Sanchez-Sanz, J. Elguero

Homo- and heterochiral dimers (PHFX)2, X = Cl, CN, CH3, NC: To what extent do they differ?

Ab initio MP2/aug’-cc-pVTZ calculations have been performed to determine if intermolecular P–P distances, Z–P–P angles, binding energies, 31P chemical shieldings, or EOM–CCSD spin–spin coupling constants can differentiate between corresponding C2 (homochiral) and Ci (heterochiral) dimers (PHFX)2, X = Cl, CN, CH3, NC. With one exception, Ci isomers have shorter P–P distances than corresponding C2 isomers. Neither binding energies, Z–P–P angles, chemical shieldings, nor spin–spin coupling constants 1pJ(P–P) exhibit patterns which distinguish between corresponding C2 and Ci isomers. 1pJ(P–P) values correlate linearly with P–P distances, so that experimental values of 1pJ(P–P) could be used to extract intermolecular P–P distances.

Chem. Phys. Lett. 538, 5, 2012

DOI: 10.1016/j.cplett.2012.04.034

J. E. Del Bene, I. Alkorta, G. Sanchez-Sanz, J. Elguero

Variations in the structures and binding energies of binary complexes with HBO

Ab initio MP2/aug’-cc-pVTZ calculations have been carried out to determine the structures and binding energies of binary complexes formed by HBO with a series of small molecules A. Three different types of structures have been identified, which depend on the nature of A. In one structure A:HBO, HBO acts as a weak proton donor. In the second HBO:A, HBO is a relatively strong base. The third type of complex A||HBO has HBO and A in an approximately parallel arrangement. The dipole moment of A influences both the type of complex formed and its binding energy.

J. Phys. Chem. A 116, 5199, 2012

DOI: 10.1021/jp300540z

M. Solimannejad, V. Ramezani, C. Trujillo, I. Alkorta, G. Sanchez-Sanz, J. Elguero

Competition and Interplay between sigma-Hole and pi-Hole Interactions: A Computational Study of 1:1 and 1:2 Complexes of Nitryl Halides (O2NX) with Ammonia

 Quantum calculations at the MP2 cc-pVTZ, MP2 aug-cc-pVTZ, and CCSD(T) cc-pVTZ levels have been used to examine 1:1 and 1:2 complexes between O2NX (X = Cl, Br, and I) with NH3. The 1:1 complexes can easily be differentiated using the stretching frequency of the N–X bond. Thus, those complexes with σ-hole interaction show a blue shift of the N–X bond stretching whereas a red shift is observed in the complexes along the π-hole. The SAPT-DFT methodology has been used to gain insight on the source of the interaction energy. In the 1:2 complexes, the cooperative and diminutive energetic effects have been analyzed using the many-body interaction energies. The nature of the interactions has been characterized with the atoms in molecules (AIM) and natural bond orbital (NBO) methodologies. Stabilization energies of 1:1 and 1:2 complexes including the variation of the zero point vibrational energy (ΔZPVE) are in the ranges 7–26 and 14–46 kJ mol–1, respectively.

Comput. Theor. Chem. 991, 124, 2012

DOI: 10.1016/j.comptc.2012.04.007

G. Sanchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero

Electron density shift description of non-bonding intramolecular interactions

A new methodology is described for the study of the electron density shift in intramolecular interactions. The methodology has been tested in an intermolecular complex and compared to the electron density shift obtained as the difference between the complex and the isolated monomers. The molecular fragmentation procedures and its application to hydrogen bonds, chalcogen–chalcogen interactions, nitrogen–boron interactions, dihydrogen interactions and silicon–nitrogen interactions are described. A careful selection of the fragmentation scheme is necessary in order to describe correctly the electron density shift in the intramolecular interactions. For this reason, different orders of fragmentation have been studied and analyzed pointing out the problems and limitations which are inherent to the methodology. It has been found that this methodology is a new tool which provides a good qualitative description of the electron density shift within the interacting region between two or more contacts, in both inter and intramolecular contacts with a reasonable low computational cost.

Struct. Chem. 23, 1245, 2012

DOI: 10.1007/s11224-012-9991-4

I. Alkorta, L. M. Azofra, G. Sanchez-Sanz, J. Elguero

A theoretical study of six-membered rings containing the -N=S-S=N- motif

The sulfur electronic structure allows for the existence of hypervalent molecules that were discussed as early as 1939 by Schomaker and Pauling. In the present paper, we report a theoretical study of three hypothetical possible six-membered rings that contain the –N=S–S=N– motif carried out at the MP2/aug-cc-pVDZ level. Three minima have been found, of which two of them are six-membered rings with all covalent bonds. Since they do not have a planar structure, we have calculated the aromaticity index NICS through the symmetry axis perpendicular to the mid-plane and at various points in space. Benzene, cyclohexane, and 1,2,5-thiadiazole have served as points of comparison.

J. Phys. Chem. A, 116, 3056, 2012

DOI: 10.1021/jp300763d

J. E. Del Bene, I. Alkorta, G. Sánchez-Sanz, J. Elguero

Structures, Binding Energies, and Spin-Spin Coupling Constants of Geometric Isomers of Pnicogen Homodimers (PHFX)2, X = F, Cl, CN, CH3, NC

Ab initio MP2/aug′-cc-pVTZ calculations have been carried out to determine the structures and binding energies of homodimers (PHFX)2 for X = F, Cl, CN, CH3, and NC. Geometric isomers of these complexes with Ci symmetry exist, which are differentiated in terms of the nature of the atoms (F–P···P–F, H–P···P–H, or A–P···P–A, with A being the atom of X directly bonded to P), which approach a nearly linear alignment. Of these, isomers having F–P···P–F linear are the most stable. Binding energies, intermolecular distances, and EOM-CCSD spin–spin coupling constants are sensitive to both the nature of X and the atoms that assume the linear alignment.

J. Mol. Struct., 1015,138, 2012


P. López-Tarifa, G. Sánchez-Sanz, I. Alkorta, J. Elguero, D. Sanz, A. Perona, R. M. Claramunt

The tautomeric structures of 3(5),3′(5′)-azopyrazole [(E)-1,2-di(1H-pyrazol-3(5)-yl)diazene)]: The combined use of NMR and electronic spectroscopies with DFT calculations

An azo derivative of 1H-pyrazole has been chosen to study the information obtained from different techniques for determining the structure of a non-crystalline compound in the solid-state and in solution. Syn–antiisomerism of the azo group, prototropic tautomerism of the 1H-pyrazole and rotation about the pyrazole–azo group resulted in 20 structures that were analyzed. Energy calculations, 13C and 15N chemical shifts, 1H–1H coupling constants and electronic spectra reduced the 20 possible structures to only one, the 3,3′-Z,Z-anti-azopyrazole.

J. Phys. Chem. A, 116, 2300, 2012

DOI: 10.1021/jp211451y

I. Alkorta, G. Sánchez-Sanz, J. Elguero, J.E. Del Bene

FCl:PCX Complexes: Old and New Types of Halogen Bonds

MP2/aug′-cc-pVTZ calculations have been performed to investigate the halogen-bonded complexes FCl:PCX, for X = NC, CN, F, H, CCH, CCF, CH3, Li, and Na. Although stable complexes with a F–Cl···P halogen bond exist that form through the lone pair at P (configuration I), except for FCl:PCCN, the more stable complexes are those in which FCl interacts with the C≡P triple bond through a perturbed π system (configuration II). In complexes I, the nature of the halogen bond changes from traditional to chlorine-shared and the interaction energies increase, as the electron-donating ability of X increases. The anionic complex FCl:PC has a chlorine-transferred halogen bond. SAPT analyses indicate that configuration I complexes with traditional halogen bonds are stabilized primarily by the dispersion interaction. The electrostatic interaction is the most important for configuration I complexes with chlorine-shared halogen bonds and for configuration II complexes except for FCl:PCNa for which the induction term is most important. The F–Cl stretching frequency is red-shifted upon complexation. EOM-CCSD/(qzp,qz2p) spin–spin coupling constants have been obtained for all FCl:PCX complexes with configuration I. 1J(F–Cl) decreases upon complexation. 2XJ(F–P) values are quadratically dependent upon the F–P distance and are very sensitive to halogen-bond type. 1XJ(Cl–P) tends to increase as the Cl–P distance decreases but then decreases dramatically in the chlorine-transferred complex FCl:PC as the Cl–P interaction approaches that of a covalent Cl–P bond. Values of 1J(F–Cl) for configuration II are reduced relative to configuration I, reflecting the longer F–Cl distances in II compared to those of the neutral complexes of I. Although the F–P and Cl–P distances in configuration II complexes are shorter than these distances in the corresponding configuration I complexes,2XJ(F–P) and 1XJ(Cl–P) values are significantly reduced, indicating that coupling through the perturbed C–P π bond is less efficient. The nature of F–P coupling for configuration II is also significantly different, as evidenced by the relative importance of PSO, FC, and SD components.

Struct.Chem. 23, 873, 2012

DOI: 10.1007/s11224-012-9947-8

I. Alkorta, G. Sanchez-Sanz, C. Trujillo, L. M. Azofra, J. Elguero

A theoretical reappraisal of the cyclol hypothesis

Theoretical calculations at the B3LYP/6-31G(d) level have been carried out on the isomerization of cyclic-tri-glycine into the corresponding tri-cyclol. The results confirmed that the cyclol hypothesis was untenable both from a thermodynamic as well as from a kinetic point of view.

Struct. Chem. 23, 847, 2012

DOI: 10.1007/s11224-011-9931-8

M. Solimannejad, M. Gharabaghi, I. Alkorta, G. Sanchez-Sanz
A theoretical study of 1:1 and 1:2 complexes of acetylene with nitrosyl hydride
Ab initio calculations at MP2 computational level using aug-cc-pVTZ basis set were used to analyze the interactions between 1:1 and 1:2 complexes of acetylene and nitrosyl hydride. The structures obtained have been analyzed with the atoms in molecules and the density functional theory–symmetry adapted perturbation theory methodologies. Four minima were located on the potential energy surface of the 1:1 complex. Twenty-four different structures have been obtained for the 1:2 complexes. Five types of interactions are observed, CH···O, CH···N, NH···π hydrogen bonds and orthogonal interactions between the π clouds of triple bond, or the lone pair of oxygen with the electron-deficient region of the nitrogen atom. Stabilization energies of the 1:1 and 1:2 clusters including basis set superposition error and ZPE are in the range 3–8 and 6–17 kJ mol−1 at MP2/aug-cc-pVTZ computational level, respectively. Blue shift of NH bond upon complex formation in the ranges between 18–30 and 20–96 cm−1 is predicted for 1:1 and 1:2 clusters, respectively. The total nonadditive energy in the 1:2 cluster, calculated as the sum of the supermolecular nonadditive MP2 energy and the three-body dispersion energy, presents values between −1.48 and 1.20 kJ mol−1.

ChemPhysChem, 13, 496, 2012

DOI: 10.1002/cphc.201100830

G. Sánchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero
Intermolecular Weak Interactions in HTeXH Dimers (X=O, S, Se, Te): Hydrogen Bonds, Chalcogen-Chalcogen Contacts and Chiral Discrimination
A theoretical study of the HTeXH (X=O, S, Se and Te) monomers and homodimers was carried out by means of second-order Møller-Plesset perturbation theory (MP2) computational methods. In the case of monomers, the isomerization energy from HTeXH to H2Te=X and H2X=Te (X=O, S, Se, and Te) and the rotational transition-state barriers were obtained. Due to the chiral nature of these compounds, homo and heterochiral dimers were found. The electron density of the complexes was characterized with the atoms-in-molecules (AIM) methodology, finding a large variety of interactions. The charge transfer within the dimers was analyzed by means of natural bond orbitals (NBO). The density functional theory-symmetry adapted perturbation theory (DFT-SAPT) method was used to compute the components of the interaction energies. Hydrogen bonds and chalcogen–chalcogen interactions were characterized and their influence analyzed concerning the stability and chiral discrimination of the dimers.

Mag. Reson. Chem. 50, 246, 2012

DOI: 10.1002/mrc.2868

D. Sanz, R, M. Claramunt, I. Alkorta, G. Sanchez-Sanz, J. Elguero

The structure of glibenclamide in the solid state

The structure of glibenclamide, 5-chloro-N-(2-{4-[(cyclohexylamino)carbonyl] aminosulfonyl}phenyl) ethyl)-2-methoxybenzamide, an important antidiabetic drug, has been studied both in solution and in the solid state by a combination of NMR spectroscopy and theoretical calculations. The possibility that glibenclamide suffers a tautomerization under melting to afford a desmotrope was rejected.

J. Heteroc. Chem. 49, 1257, 2012

 DOI: 10.1002/jhet.1076

N. Fresno, R. Pérez-Fernández, M. L. Jimeno, I. Alkorta, G. Sánchez-Sanz, J. Elguero, J. E. Del Bene.

Multinuclear NMR Characterization of Cyanuric Fluoride (2,4,6-Trifluoro-1,3,5-triazine)

Although 2,4,6-trifluoro-1,3,5-triazine, C3F3N3, is a highly symmetrical molecule, its NMR parameters can be obtained by reducing its symmetry through the introduction of 14N/15N and 12C/13C isotopomers. Experimental and computed chemical shifts of cyanuric fluoride have been obtained for 13C, 15N, and 19F. Spin-spin coupling constants have been measured and compared with previous experimental data and with the complete set of computed EOM-CCSD coupling constants.

J. Phys. Chem. A, 115, 13724, 2011


J. E. Del Bene, I. Alkorta, G. Sánchez-Sanz and J. Elguero

Structures, Energies, Bonding, and NMR Properties of Pnicogen Complexes H2XP:NXH2 (X= H, CH3 , NH2 , OH, F, Cl)

Ab initio calculations have been carried out in a systematic investigation of P···N pnicogen complexes H2XP:NXH2 for X ═ H, CH3, NH2, OH, F, and Cl, as well as selected complexes with different substituents X bonded to P and N. Binding energies for complexes H2XP:NXH2 range from 8 to 27 kJ mol–1 and increase to 39 kJ mol–1 for H2FP:N(CH3)H2. Equilibrium structures have a nearly linear A–P–N arrangement, with A being the atom directly bonded to P. Binding energies correlate with intermolecular N–P distances as well as with bonding parameters obtained from AIM and SAPT analyses. Complexation increases 31P chemical shieldings in complexes with binding energies greater than 19 kJ mol–1. One-bond spin–spin coupling constants 1pJ(N–P) across the pnicogen interaction exhibit a quadratic dependence on the N–P distance for complexes H2XP:NXH2, similar to the dependence of 2hJ(X–Y) on the X–Y distance for complexes with X–H···Y hydrogen bonds. However, when the mixed complexes H2XP:NX′H2 are included, the curvature of the trendline changes and the good correlation between 1pJ(N–P) and the N–P distance is lost.

Mol. Phys., 109, 2543, 2011


G. Sánchez-Sanz, I. Alkorta, and J. Elguero.

Theoretical study of the HXYH dimers (X,Y=O,S,Se). Hydrogen bonding and chalcogen-chalcogen interactions. 

A theoretical study of the HXYH (X, Y = O, S and Se) monomers and dimers has been carried out by means of MP2 computational methods. For the monomers, isomerization (H2X=Y//HXYH) and rotational transition state barriers have been calculated. Additionally, the molecular electrostatic potential of the isolated monomers has also been analysed. Due to the chiral nature of these compounds, homo and heterochiral dimers have been explored. The number of minima found for the dimers range between 13 and 22. The electron density of the complexes has been characterized with the Atoms in Molecules (AIM) methodology finding a large variety of interactions. The DFT-SAPT method has been used to analyse the components of the interaction energies. Concerning chalcogen–chalcogen interactions, although the most stable minima are formed through hydrogen bonds (especially if OH groups are present in the molecules) as the size of the atoms involved in the interaction increase, the chalcogen–chalcogen contacts become more important.

Chem. Phys. Lett., 512, 184, 2011


J. E. Del Bene, I. Alkorta, G. Sánchez-Sanz and J. Elguero.

31P-31P Spin-spin Coupling Constans for Pnicogen Homodimers.

Ab initio calculations have been carried out in a systematic investigation of pnicogen homodimers (PH2X)2, for X = F, OH, NC, NH2, CCH, CN, CH3, H, and BH2. Complex binding energies range from 7 to 34 kJ mol−1, which is within the range observed for neutral hydrogen-bonded complexes. One-bond spin–spin coupling constants across the pnicogen interaction 1pJ(P–P) exhibit a quadratic dependence on the P–P distance, similar to the dependence of 2hJ(X–Y) on the X–Y distance for complexes with X–H⋯Y hydrogen bonds. Thus, computed values of 1pJ(P–P) could be used to extract P–P distances from experimentally measured coupling constants.

Comput. Theor. Chem., 947, 37, 2011


G. Sánchez-Sanz, I. Alkorta, and J. Elguero

A theoretical study of the conformation of 2,2-bifuran,2,2-bithiophene, 2,2-bitellurophene and mixed derivates: chalcogen-chalcogen interactions or dipole-dipole effects. 

Using as models 2,2′-biheterocycles (furan, thiophene, selenophene, tellurophene) the possibility of stabilizing effects due to the proximity of two chalcogen atoms (O, S, Se, Te) was explored. The geometries of the ground states were compared satisfactorily with the available experimental results. The torsional barriers through planar and orthogonal transition states were calculated and discussed in function of the nature of the chalcogen atoms. Special attention was devoted to dipole moments that were calculated by a vector summation with good results.

Tetrahedron, 67, 7316, 2011


G. Sánchez-Sanz, I. Alkorta, and J. Elguero

Isomerization barriers in bis(4H-thiopyran) and in bithioxanthenes. 

The inversion and rotation mechanisms for the isomerization of Feringa’s bithioxanthenes existing in two conformations, up/up and up/down, have been calculated at the B3LYP/6-31G(d) and B3LYP/6-311++G(d,p) levels. The inversion mechanism that maintains the double bond nature of the central bond is a classical one but the rotation mechanisms that break the double bond to form a biradical needs to explore the singlet and triplet states. To do this we have removed the four fused phenyl rings of bithioxanthene and calculated at the CASSCF and CASPT2 levels bis(4H-thiopyran) proving that B3LYP calculations yield reasonable results for the rotation barriers.

J. Phys. Chem. A, 115, 12124, 2011


C. Trujillo, G. Sánchez-Sanz , I. Alkorta and J. Elguero.

Simultaneous Interactions of Anions and Cations with Cyclohexane and Adamantane: Aliphatic Cyclic Hydrocarbons as Charge Insulators.

With ab initio MP2 computational methods, a theoretical study has been carried out to characterize the interaction between aliphatic cyclic hydrocarbons, as models of molecular hydrocarbon monolayers, with cations (Li+, Na+, and K+), anions (F, Cl, and Br), and both simultaneously in opposite faces of the hydrocarbons. In addition, the energetic barrier for the cation crossing through the hydrocarbon ring has been calculated. The hydrocarbons chosen for this study are cyclohexane (C6H12) and adamantane (C10H16). The energies obtained for the M+:hydrocarbon:X complexes indicate positive cooperativity in the cases where the hydrocarbon is cyclohexane while diminutive effects are found in the adamantane complexes. The density functional theory–symmetry adapted perturbation theory analysis of the interaction energies shows that the most important term in the complexes with cations is the induction, while in the complexes with anion and with cations and anions simultaneously the most important term is the repulsion-exchange one. The electron density of the complexes has been analyzed using the atoms in molecules methodology and provides some insight to the electron transfer within the complexes.

Int. J. Mass Spect., 299, 20, 2011


G. Sánchez-Sanz, S. Díaz-Tendero, M. Alcamí and F. Martín.

Theoretical study of the stability of small triply charged carbon clusters Cn3+ (n=3-12).

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 Cn3+ 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.

J. Chem. Phys., 133, 114509, 2010


G. Sánchez-Sanz, L. Seijo, and Z. Barandiarán.

Yb2+ -doped SrCl2 Electronic structure of impurity states and impurity-trapped excitons.

First-principles electronic structure calculations of the excited states of Yb2+-doped SrCl2 crystals up to 65000cm1 reveal the existence of unexpected excited states with double-well potential energy surfaces and dual electronic structure lying above and very close in energy to the 4f135manifold, with which they interact strongly through spin-orbit coupling. The double-well energy curves result from avoided crossings between Yb-trapped exciton states (more stable at short Yb–Cl distances) and 4f136s impurity states (more stable at long Yb–Cl distances); the former are found to be preionization states in which the impurity holds the excited electron in close lying empty interstitials located outside the YbCl8 moiety. Spin-orbit coupling between the double-well states and the lower lying 4f135d impurity states spreads the dual electronic structure character to lower energies and, hence, the instability of the divalent oxidation state is also spread. To some extent, the dual electronic structure (impurity-trapped exciton–impurity state) of some excited states expresses and gives support to hypotheses of interaction between Yb2+ and Yb3+ pairs proposed to understand the complex spectroscopy of the material and conciliates these hypotheses with interpretations in terms of the existence of only one type of Yb2+ defect. The results presented confirm the presence of impurity states of the 4f136s configuration among the 4f135manifolds, as proposed in literature, but their energies are very different from those assumed. The Yb-trapped excitons found in this chloride host can be seen as precursors of the luminescent Yb-trapped excitons characterized experimentally in the isomorphous SrF2 crystals.

J. Chem. Phys., 133, 114506, 2010


G. Sánchez-Sanz, L. Seijo, and Z. Barandiarán.

Electronic spectra of Yb2+ -doped SrCl2.

The absorption and emission spectra of Yb2+-doped SrCl2 have been calculated on the basis of ab initio quantum chemical calculations which consider recently found, unexpected excited states with double-well energy curves and complex electronic structure, resulting from avoided crossings between Yb-trapped excitons and Yb impurity states, which influence prominent spectral features. The root mean square deviation and largest absolute error of the calculated energy levels are 394 and 826cm1, respectively. The YbCl8 moiety breathing mode vibrational frequencies and bond lengths of the lowest states are consistent with observed vibrational progressions and energy shifts induced by uniaxial compression. Photoionization is predicted above 49000cm1 as a consequence of the spin-orbit induced spreading of the Yb-trapped exciton character in the upper part of the spectrum and three new emission bands are predicted with origins at about 33 800, 36 400, and 43600cm1. The electron correlation methods used overestimate the relative stabilization of the 4f14ground state and this leads to a constant error of the whole absorptionspectrum of about 3500cm1 (23%–7%). Although this energy shift is customarily considered an adjustable parameter, it is a nonparametric, direct product in an ab initio route which shows the limitations on the proper representation of differential correlation between the 4fN.

Chem. Phys. Lett., 498, 226, 2010


G. Sánchez-Sanz, Z. Barandiarán, L. Seijo,

Energy level shifts in two-step spin–orbit coupling ab initio calculations

We point out a problem with two-step spin–orbit ab initio calculations in which the energy levels of spin–orbit free Hamiltonians are shifted as a means to including dynamic correlations at low cost in small spin–orbit configuration interaction calculations. The usual shifts driven by the energy order of the states can lead to anomalous results when avoided crossings exist with significant change of wave function character, which take place at different nuclear positions in the configurational spaces of the first and the second steps. In these cases, the shifts of the spin–orbit free energy levels must be assigned according to the characters of the wave functions.

Spectrosc. Lett., 43, 393, 2010


G. Sánchez-Sanz, L. Seijo, and Z. Barandiarán.

Energy shift of the 4f 13 6s1 excited states of Yb2+ from gas phase to CsCaBr3 solid.

Ab initio calculations on Yb2+-doped CsCaBr3 show a large increase (20000 cm−1) of the 4f 14 → 4f 136s 1transitions from gas phase to CsCaBr3, due to large embedding effects originated beyond the first bromide coordination shell. The 4f 136s 1 states of (YbBr6)4- in vacuo undergo a sudden energy and electron density change at short Br-Yb distances resulting in the formation of an Yb-trapped exciton, which evolves to full ionization, making Yb(II) unstable in hexabromide coordination in gas phase. Embedding in CsCaBr3localizes the 6s electron inside the Br6 cage, which increases the 6s-Br6 repulsion and increases the energy of the 4f 136s 1 states.

J. Phys. Chem. A, 113, 12591, 2009


G. Sánchez-Sanz, L. Seijo, and Z. Barandiarán.

Energy Gaps in the 4f 13 5d1 Manifolds and Multiple Spontaneous Emissions in Yb2+ -doped CsCaBr3

Multiple spontaneous 4f135d1 → 4f14 emissions are predicted in Yb2+-doped CsCaBr3 crystals by ab initio quantum chemical calculations. Four emission bands are found at 23 900, 26 600, 34 600, and 43 900 cm−1 that should be experimentally observable at low temperatures. The first, third, and fourth bands are slow, electric dipole forbidden emissions that can be described as spin-forbidden. The second band is a fast, electric dipole-allowed emission that cannot be described as spin-allowed, but as spin-enabled; its radiative emission lifetime is 400 ns. Large energy gaps (23 900, 4600, 4000 cm−1, respectively), relative to the maximum local phonon energies calculated (around 185 cm−1), are found below the emitting levels of the slow bands, which indicates that these states should be significantly stable and multiphonon relaxation to the lower states should be negligible. A smaller gap (2600 cm−1) separates the states of the fast band, which should result in a temperature dependent competition between radiative and nonradiative decay. Differential correlation between 4f−4f and 4f−5d pairs, splitting of the 5d shell by interactions with the host, and spin−orbit effects within the 4f13 subshell, are found to be responsible for the existence of the gaps, which, in turn, split the absorption spectrum into four groups of separate bands, three of which could lie below the host absorption threshold. The quantum chemical methods employed make use of explicit wave functions expanded in terms of flexible basis sets, multiconfigurational self-consistent-field and multireference second-order perturbation methods to account for nondynamic and dynamic electron correlation, scalar and relativistic terms in the (YbBr6)4− defect cluster Hamiltonian, and quantum mechanical embedding potentials to represent the host crystal.

J. Chem. Phys., 131, 024505, 2009


G. Sánchez-Sanz, L. Seijo, and Z. Barandiarán.

Spin-forbidden and spin-enabled 4f 14 → 4f 13 5d1 transitions of Yb2+ -doped CsCaBr3.  

The lowest part of the 4f5absorption spectrum of Yb2+-doped CsCaBr3 crystals has been calculated using methods of quantum chemistry and it is presented here. A first, low-intensity band is found on the low energy side of the spectrum, followed by several strong absorption bands, in agreement with experimental observations in trivalent and divalent lanthanide ions of the second half of the lanthanide series, doped in crystals. Based on Hund’s rule, these transitions are usually interpreted as “spin-forbidden” and “spin-allowed” transitions, but this interpretation has been recently questioned in the literature. Here, a two-step relativistic method has been used which reveals the spin composition of the excited statewave functions. The forbidden band is found to be due to spin-forbidden transitions involving “high-spin” excited states because their 13T1u character is 90%. However, the allowed bands cannot be described as spin-allowed transitions involving “low-spin” excited states. Rather, they correspond to “spin-enabled” transitions because they get their intensity from limited (smaller than 45%) electric dipole enabling low-spin 1T1u character. Calculations using a spin-free Hamiltonian revealed that the difference in their electronic structures is related to the fact that the 4f135d(t2g)1manifold is split by an energy gap which separates the lowest (high-spin) 13T1u from the rest of terms, which, in turn, lie very close in energy from each other. As a consequence, the lowest spin-orbit components of 13T1are shown to remain 90% pure when spin-orbit coupling is considered, whereas a strong spin-orbit coupling exists between the remaining 4f135d(t2g)1 terms, among which the 131T1u enabling ones lie. As a result, there is a widespread electric dipole enabling 1T1u character, which, although never higher than 45%, leads to a number of spin-enabled absorption bands.

J. Chem. Phys., 127, 104308, 2007


H. Zetergren, G. Sánchez, S. Díaz-Tendero, M. Alcamí, and F. Martín

Theoretical study of the stability of multiply charged C70 fullerenes.

We have calculated the electronic energies and optimum geometries of C70q+ and C68q+fullerenes (q=014) by means of density functional theory. The ionization energies for C70 and C68 fullerenes increase more or less linearly as functions of charge, consistent with the previously reported behavior for C60 and C58 [S. Díaz-Tendero et al., J. Chem. Phys.123, 184306 (2005)]. The dissociation energies corresponding to the C70q+ → C68q+C2C70q+C68(q1)++C2+C70q+→ C68(q2)+C++C+C70q+C68(q3)++C2++C+, and C70q+C68(q4)++C2++C2+ decay channels show that C70q+ (like C60q+) is thermodynamically unstable for q6. However, the slope of the dissociation energy as a function of charge for a given decay channel is different from that of C60q+fullerenes. On the basis of these results, we predict q=17 to be the highest charge state for which a fission barrier exists for C70q+.

J. Nanosci. Nanosci., 7, 1329, 2007


M. Alcamí, G. Sánchez, S. Díaz-Tendero, Y. Wang and F. Martín

Structural patterns in fullerenes showing adjacent pentagons: C20 to C70.  

We have analyzed in detail the structure of the smallest fullerenes Cn (20 ≤ n ≤ 72) obtained in B3LYP/6-31G* calculations. All these systems, except for C60, C70, and C72, necessarily present adjacent pentagons in their structure. For the most stable classical isomers, we have studied the variation of bond distances, HOMO-LUMO gaps and enthalpies of formation with fullerene size. A classification of the bonds in 9 different motifs permits to gain insight in the factors determining the fullerene stability. A simplified model that assumes a fixed energy per bond is able to reproduce the calculated enthalpies of formation and to estimate the energy change associated with each structural motif. An extra stabilization of 30–40 kcal/mol is predicted for the fullerenes showing spherical aromaticity.

Int. J. Mass Spect., 252, 126, 2006


S. Díaz-Tendero, G. Sánchez, M. Alcamí, F. Martín, P.-A. Hervieux, M. Chabot, G. Martinet, P. Désesquelles F. Mezdari, KWohrer-Béroff, S. Della-Negra, H. Hamrita, A. LePadellec and L. Montagnon.

Fragmentation of small carbon clusters.

We report on theoretical and experimental efforts designed to understand the fragmentation of small neutral carbon clusters. Theoretically, the dissociation dynamics of Cn has been investigated using a statistical model based on the microcanonical Metropolis Monte Carlo method. In this model various structural quantities (geometries, dissociation energies, harmonic frequencies…) are required for both the parent cluster and the fragments. They have been obtained from quantum chemistry calculations for Cn up to n = 9. Experimentally, a new detection system for high velocity fragments has been recently developed allowing the fragmentation of high velocity clusters to be totally recorded. Results for the branching ratios of deexcitation of Cn with 5 ≤ n ≤ 9 formed by electron capture in high velocity Cn+–He collisions are presented. In all cases, the agreement between theory and experiment is reasonably good provided that the theoretical branching ratios are convoluted with a Cn energy distribution centered at around 10 eV.

Int. J. Mass Spect., 252, 133, 2006


S. Díaz-Tendero, G. Sánchez, P.-A. Hervieux, M. Alcamí, and F. Martín

Ionization potentials and dissociation energies of neutral, singly and doubly charged Cn fullerenes from n=20-70.

Using B3LYP density functional theory, first and second ionization potentials as well as dissociation energies for neutral, singly and doubly charged fullerenes with sizes between 20 and 70 atoms have been evaluated. Comparison with available experimental data is good except for the doubly charged species. The results show that neutral fullerenes with a magic number of atoms, namely C32, C50, C60 and C70, have the largest stability against ionization and C2 evaporation. A similar large stability is observed for the corresponding singly and doubly charged magic fullerenes, except for C32+ and C322+. Neutral and positively charged C62 is found to be rather unstable. Also, C2+ emission is shown to become competitive with C2 emission for sufficiently small doubly charged fullerenes. The origin of these and other properties is discussed in detail.

Braz. J. Phys., 36B, 529, 2006


S. Díaz-Tendero, G. Sánchez, P.-A. Hervieux, M. Alcamí, and F. Martín.

Ionization potentials, dissociation energies and statistical fragmentation of neutral and positively charged small carbon clusters. 

Dissociation energies, ionization potentials and fragmentation dynamics of neutral, singly- and doubly charged small carbon clusters have been theoretically studied with a combination of the density functional theory, the coupled cluster method and the the statistical model microcanonical Metropolis Monte Carlo. The second ionization potential decreases with the cluster size and is larger than the first one, which also decreases with the size showing oscillations. Dissociation energies also oscillate with the cluster size, being those with an odd number of atoms more stable. C3 cluster has the largest dissociation energy. The combination of a statistical treatment for the cluster fragmentation with experimental results has allowed us to evaluate the energy distribution in collisions experiments.

Chem. Phys. Lett., 416, 14, 2005


G. Sánchez, S. Díaz-Tendero, M. Alcamí and F. Martín

Size dependence of ionization potentials and dissociation energies of neutral, singly and doubly charged Cn fullerenes from n=20-70.

Dissociation energies and ionization potentials of neutral and singly-charged fullerenes have been obtained from density functional theory calculations for sizes ranging from 40 to 70 atoms. Good agreement with available experimental data has been obtained. Our results confirm that magic number fullerenes with n = 50, 60 and 70 present the largest ionization potentials and dissociation energies. We have found that the most stable isomer for n = 62 is a non-classical structure with a chain of four adjacent pentagons surrounding a heptagon, and for n = 50 is a structure of D3 symmetry that violates the pentagon adjacency penalty rule. Both unusual structures lead to the best agreement with experiment.

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