An HF and DFT ab initio Study on the Mechanism of ortho‐Directed Lithiation of Hydric and Nonhydric Aromatic Compounds Incorporating Aggregation and Discrete Solvation: The Role of N,N,N′,N′‐Tetramethylethane‐1,2‐diamine (TMEDA) in Lithiation Reactions

An HF and DFT ab initio study was set up to decipher the roles of aggregation and solvation in the ortho‐directed lithiation of aromatics (hydric and nonhydric), as well as to shed light on the much debated question of precomplexation in the mechanism of lithiation. Ab initio (HF/6‐31‐G*) calculations on the lithiation of non‐hydric aromatics have uncovered several competitive routes operating as a function of the aggregation state of the organolithium base used. Specifically, two competitive routes were found for the lithiation of the anisole model 2 by organolithium dimers 1‐dim , namely the so‐called cyclic‐dimer and open‐dimer routes, whereas, for organolithium tetramers 1‐tet , the corresponding cyclic route is the only one operative, and, for monomers 1‐mon , several optional routes seem to be available. Precomplexation is, in all cases, a requirement. According to the computational data presented, the mysterious rate acceleration experimentally observed for lithiations carried out in TMEDA can be assigned to an aggregation effect on the intermediate open‐dimer species, which subsidiarily give rise to several so‐called s‐monomer routes, of which the dimerization‐driven s‐monomer route s‐m_3b is the one having the lowest energy barrier. The relevant species characteristic of both the open‐dimer and s‐monomer routes are the so‐called open dimers, i.e., high‐energy intermediates (actually, spiro dimeric aggregates), resulting from cleavage‐induced associative complexation of the aromatic substrate upon the fully solvated organolithium dimer. DFT calculations (B3LYP/6‐31+G*) also revealed that the peri‐lithiation (i.e., Li at C(8)) of 1‐naphthol model 3 is a slow process taking place preferentially through the open‐dimer route.     

Interactions of Molecules with cis and trans Double Bonds: A Theoretical Study of cis‐ and trans‐2‐Butene

Noncovalent interactions of cis‐ and trans‐2‐butene, as the smallest model systems of molecules with cis and trans double bonds, were studied to find potential differences in interactions of these molecules. The study was performed using quantum chemical methods including very accurate CCSD(T)/CBS method. We studied parallel and displaced parallel interactions in 2‐butene dimers, in butane dimers, and between 2‐butene and saturated butane. The results show the trend that interactions of 2‐butene with butane are the strongest, followed by interactions in butane dimers, whereas the interaction in 2‐butene dimers are the weakest. The strongest calculated interaction energy is between trans‐2‐butene and butane, with a CCSD(T)/CBS energy of ?2.80 kcal mol^?1. Interactions in cis‐2‐butene dimers are stronger than interactions in trans‐2‐butene dimers. Interestingly, some of the interactions involving 2‐butene are as strong as interactions in a benzene dimer. These insights into interactions of cis‐ and trans‐2‐butene can improve understanding of the properties and processes that involve molecules with cis and trans double bonds, such as fatty acids and polymers.     

Comparison of ground and excited state polarizabilities of thiophene,cyclopentadiene, and fulvene oligomers and their cyano substituted derivatives—Ab initio study

Ab Initio study of the ground and excited state polarizabilities of thiophene, fulvene, and cyclopentadiene based conducting oligomers and their cyano derivatives have been performed using the restricted Hartree–Fock (RHF) and the configuration interaction singles (CIS) approaches, respectively, with 3‐21G* basis set. For comparison purposes, for some small oligomers (monomers and dimers), higher basis sets (6‐31G*, 6‐31+G*, aug‐cc‐pVTZ) were also employed in the computations of polarizabilities. The trends in polarizability as a function of oligomer length were investigated. For all systems, the RHF polarizability increases as n^1.2–1.3 as n gets larger and the CIS polarizability increases as n^1.4–1.6 for n less than seven or eight rings and then increases approximately linearly with n for larger n. For the thiophene based systems the dependence of the polarizability on bond length alternation (BLA) along the backbone of the oligomers was also investigated using the RHF, density functional (DFT), and CIS theories (with 3‐21G* basis set). For thiophene dimer, we also performed RHF/aug‐cc‐pVTZ calculations of polarizabilities versus BLA. We found that the polarizability is largest when BLA is near zero (for both ground and excited states), which correlates with the lowest excitation energy. Comparison with experimental results has been made where possible. © 2007 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 45: 1983–1995, 2007     

Analytical gradients of the second‐order Møller–Plesset energy using Cholesky decompositions

An algorithm for computing analytical gradients of the second‐order Møller–Plesset (MP2) energy using density fitting (DF) is presented. The algorithm assumes that the underlying canonical Hartree–Fock reference is obtained with the same auxiliary basis set, which we obtain by Cholesky decomposition (CD) of atomic electron repulsion integrals. CD is also used for the negative semidefinite MP2 amplitude matrix. Test calculations on the weakly interacting dimers of the S22 test set (Jure?ka et al., Phys. Chem. Chem. Phys. 2006, 8, 1985) show that the geometry errors due to the auxiliary basis set are negligible. With double‐zeta basis sets, the error due to the DF approximation in intermolecular bond lengths is better than 0.1 pm. The computational time is typically reduced by a factor of 6–7. © 2013 Wiley Periodicals, Inc.     

Perylene Bisimide Dimer Aggregates: Fundamental Insights into Self‐Assembly by NMR and UV/Vis Spectroscopy

A novel perylene bisimide (PBI) dye bearing one solubilizing dialkoxybenzyl and one bulky 2,5‐di‐tert‐butylphenyl substituent was synthesized and its aggregation behavior was analyzed by NMR and UV/Vis spectroscopy in various chloroform/methylcyclohexane (MCH) solvent mixtures. In the presence of no less than 10 vol % chloroform, exclusive self‐assembly of this PBI dye into π‐stacked dimers was unambiguously confirmed by means of both concentration‐dependent ¹H NMR and UV/Vis spectroscopic experiments. Based on ROESY NMR, a well‐defined π‐stacked dimer structure was determined and further corroborated by molecular modeling studies. By varying the solvent composition of chloroform and MCH, the solvent effects on the Gibbs free energy of PBI dimerization were elucidated and showed a pronounced nonlinearity between lower and higher MCH contents. This observation could be related to a further growth process of dimers into larger aggregates that occurs in the absence of chloroform, which is required to solvate the aromatic π surfaces. With the help of a single‐crystal structure analysis for a related PBI dye, a structural model could be derived for the extended aggregates that are still composed of defined π–π‐stacked PBI dimer entities.     

F2 dimer: Improved intermolecular potential energy surface using ab initio calculations

A computational study on the intermolecular potential energy of 44 different orientations of F₂ dimers is presented. Basis set superposition error (BSSE) corrected potential energy surface is calculated using the supermolecular approach at CCSD(T) and QCISD(T) levels of theory. The interaction energies obtained using the aug‐cc‐pVDZ and aug‐cc‐pVTZ basis sets are extrapolated to the complete basis set limit using the latest extrapolation scheme. The basis set effect is checked and it is found that the extrapolated intermolecular energies provide the best compromise between the accuracy and computational cost. Among 1320 energy points of F₂–F₂ system covering more relative orientations, the most stable structure of the dimers was obtained with a well depth of ?146.62 cm^?1 that related to cross configuration, and the most unstable structure is related to linear orientation with a well depth of ?52.63 cm^?1. The calculated second virial coefficients are in good agreement with experimental data. The latest extrapolation scheme of the complete basis set limit at the CCSD(T) level of theory is used to determine the intermolecular potential energy surface of the F₂ dimer. Comparing the results obtained by the latest scheme with those by older schemes show that the new approach provides the best compromise between accuracy and computational cost.     

Specific Noncovalent Association of Chiral Large‐Ring Hexaimines: Ion Mobility Mass Spectrometry and PM7 Study

Ion mobility mass spectrometry and PM7 semiempirical calculations are effective complementary methods to study gas phase formation of noncovalent complexes from vaselike macrocycles. The specific association of large‐ring chiral hexaimines, derived from enantiomerically pure trans‐1,2‐diaminocyclohexane and various isophthaldehydes, is driven mostly by CH–π and π–π stacking interactions. The isotrianglimine macrocycles are prone to form two types of aggregates: tail‐to‐tail and head‐to‐head (capsule) dimers. The stability of the tail‐to‐tail dimers is affected by the size and electronic properties of the substituents at the C‐5 position of the aromatic ring. Electron‐withdrawing groups stabilize the aggregate, whereas bulky or electron‐donating groups destabilize the complexes.     

Mechanism of the Deprotonation Reaction of Alkyl Benzyl Ethers with n‐Butyllithium

Kinetic study of the α‐lithiation of benzyl methyl ether (BME) by nBuLi has revealed that increasing the concentration of the organolithium compound does not necessarily increase the reactivity, and this is a consequence of the reactivities of the different nBuLi aggregates present in solution. We propose a dimer‐based mechanism, in which a pre‐complexation step is a key process for substrates bearing a donor oxygen atom that can interact with the lithium cation to form mixed dimers. For these studies, we have developed a system based on UV/Vis spectroscopy that allows kinetic measurements to be conducted at ?80 °C under argon.     

Electronic structure and conformation of aniline and meta‐chloroaniline dimers

Poly(aniline) is a subject of considerable scientific and technological interest. Its homologs such as poly(m‐chloroaniline) potentially offer similar physical‐chemical properties. In this work we present a comparative theoretical study between aniline and the m‐chloroaniline species at several levels of theory. To envisage the possible mechanism of polymerization, we have obtained geometries and electronic structures for the monomers and dimers as well as the corresponding cations and dications. Based on the monomer‐optimized geometries, atomic charges, bond orders, and spin densities, a head‐to‐tail coupling in the electrochemical polymerization is suggested. We have also calculated band gaps and ionization potentials. For the cationic dimers of aniline and m‐chloroaniline, the highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) energy difference has a smaller value, and oxidation at specific sites may be observed. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 78: 99–111, 2000     

Calculation of free energy landscapes: A histogram reweighted metadynamics approach

We present an efficient method for the calculation of free energy landscapes. Our approach involves a history‐dependent bias potential, which is evaluated on a grid. The corresponding free energy landscape is constructed via a histogram reweighting procedure a posteriori. Because of the presence of the bias potential, it can be also used to accelerate rare events. In addition, the calculated free energy landscape is not restricted to the actual choice of collective variables and can in principle be extended to auxiliary variables of interest without further numerical effort. The applicability is shown for several examples. We present numerical results for the alanine dipeptide and the Met‐Enkephalin in explicit solution to illustrate our approach. Furthermore, we derive an empirical formula that allows the prediction of the computational cost for the ordinary metadynamics variant in comparison with our approach, which is validated by a dimensionless representation. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011     

Chiral Hexa‐ and Nonamethylene‐Bridged Bis(L‐Leu‐oxalamide) Gelators: The First Oxalamide Gels Containing Aggregates with a Chiral Morphology

Chiral amino acid‐ and amino alcohol‐oxalamides are well‐known as versatile and efficient gelators of various lipophilic and polar organic solvents and water. To further explore the capacity of the amino acid/oxalamide structural fragment as a gelation‐generating motif, the dioxalamide dimethyl esters 1₆Me and 1₉Me , and dicarboxylic acid 2₆OH / 2₉OH derivatives containing flexible methylene bridges with odd ( 9 ; n=7) and even ( 6 ; n=4) numbers of methylene groups were prepared. Their self‐assembly motifs and gelation properties were studied by using a number of methods (FTIR, ¹H NMR spectroscopy, CD, TEM, DSC, XRPD, molecular modeling, MMFF94, and DFT). In contrast to the previously studied chiral bis(amino acid or amino alcohol) oxalamide gelators, in which no chiral morphology was ever observed in the gels, the conformationally more flexible 1₆Me , 1₉Me , 2₆OH , and 2₉OH provide gelators that are capable of forming diverse aggregates of achiral and chiral morphologies, such as helical fibers, twisted tapes, nanotubules, straight fibers, and tapes, in some cases coexisting in the same gel sample. It is shown that the differential scanning calorimetry (DSC)‐determined gelation enthalpies could not be correlated with gelator and solvent clogP values. Spectroscopic results show that intermolecular hydrogen‐bonding between the oxalamide units provides the major and self‐assembly directing intermolecular interaction in the aggregates. Molecular modeling studies reveal that molecular flexibility of gelators due to the presence of the polymethylene bridges gives three conformations ( zz , p1 , and p2 ) close in energy, which could form oxalamide hydrogen‐bonded layers. The aggregates of the p1 and p2 conformations tend to twist due to steric repulsion between neighboring iBu groups at chiral centers. The X‐ray powder diffraction (XRPD) results of 1₆Me and 1₉Me xerogels prove the formation of p1 and p2 gel aggregates, respectively. The latter results explain the formation of gel aggregates with chiral morphology and also the simultaneous presence of aggregates of diverse morphology in the same gel system.     

Mass spectrometry detection of minor new meridianins from the antarctic colonial ascidians Aplidium falklandicum and Aplidium meridianum

Taking into account the broad biological activities found in the meridianin indole alkaloids isolated to date, we have re‐examined the organic extracts of an Antarctic collection of the tunicates Aplidium meridianum and A. falklandicum (Chordata: Ascidiacea) by HPLC in conjunction with a high‐resolution mass spectrometer (HPLC‐MS). A new set of analogs of meridianins A–G has been detected, and their structures are proposed on the basis of the molecular formulae identified by LC‐HRMS analysis using a C18 column with a gradient of water/acetonitrile and an LTQ‐FT‐MS Orbitrap detector. Remarkably, dimers derived from meridianin A and from meridianin B or E were also detected. Our findings provide further evidence of the broad variability within the meridianin‐like derivatives of this highly bioactive alkaloid family. Copyright © 2015 John Wiley & Sons, Ltd.     

Conformational Panorama and Chirality Controlled Structure–Energy Relationship in a Chiral Carboxylic Acid Dimer

Chirality recognition in dimers of tetrahydro‐2‐furoic acid (THFA) was studied in a conformer‐specific manner using rotational spectroscopy and theoretical approaches. THFA shows a strong preference for the trans‐ over the cis‐COOH configuration. Two drastically different scenarios are possible for the detectable (THFA)₂: a kinetically preferred dimer bound by feeble interactions between two trans THFAs or a thermodynamically favored dimer with a double hydrogen‐bonded ring structure between two cis subunits. To identify the conformers responsible for the extremely dense rotational spectra observed, it was essential not only to locate several hundred homo/heterochiral (THFA)₂ minima in ab initio calculations but also to evaluate the energetic connectivities among the minima. The study further reveals an interesting chirality dependent structure–energy ordering relationship. A method for enantiomeric excess (ee) determination of THFA is presented using a recently proposed chiral self‐tag approach.     

A fast method for large‐scale De Novo peptide and miniprotein structure prediction

Although peptides have many biological and biomedical implications, an accurate method predicting their equilibrium structural ensembles from amino acid sequences and suitable for large‐scale experiments is still missing. We introduce a new approach—PEP‐FOLD—to the de novo prediction of peptides and miniproteins. It first predicts, in the terms of a Hidden Markov Model‐derived structural alphabet, a limited number of local conformations at each position of the structure. It then performs their assembly using a greedy procedure driven by a coarse‐grained energy score. On a benchmark of 52 peptides with 9–23 amino acids, PEP‐FOLD generates lowest‐energy conformations within 2.8 and 2.3 Å Cα root‐mean‐square deviation from the full nuclear magnetic resonance structures (NMR) and the NMR rigid cores, respectively, outperforming previous approaches. For 13 miniproteins with 27–49 amino acids, PEP‐FOLD reaches an accuracy of 3.6 and 4.6 Å Cα root‐mean‐square deviation for the most‐native and lowest‐energy conformations, using the nonflexible regions identified by NMR. PEP‐FOLD simulations are fast—a few minutes only—opening therefore, the door to in silico large‐scale rational design of new bioactive peptides and miniproteins. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

Effects of stereocomplexation on the physicochemical behavior of PLA/PEG block copolymers in aqueous solution

A series of polylactide/poly(ethylene glycol) (PLA/PEG) block copolymers were synthesized by ring‐opening polymerization of L ‐ or D ‐lactide in the presence of mono‐ or di‐hydroxyl PEG. The effects of stereocomplexation on the physicochemical behavior of PLA/PEG copolymers in aqueous solution were investigated by varying the degree of stereocomplexation or PLLA/PEG to PDLA/PEG ratio. In mixture solutions of insoluble and soluble copolymers, stereocomplexation strongly affects the solubility of the copolymers. In mixture solutions of soluble copolymers, both the size and aggregation number (N_agg) of the aggregates vary as a function of the degree of stereocomplexation. It is suggested that the size variation of the aggregates with increasing the degree of stereocomplexation is dependent on N_agg changes which are determined by two effects: the self‐adjusting of the aggregates so as to minimize the free energy and thus to increase the N_agg, and the kinetics of aggregation which tend to form more aggregates and thus to decrease the N_agg. Combination of the two opposite effects well explains the diverse variations of N_agg and size of the aggregates as a function of the degree of stereocomplexation. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2012     

Extracting information on the surface monomer unit distribution of PLGA by ToF‐SIMS

The surface chemistry of a range of random poly l‐lactide‐co‐glycolide (PLGA) materials has been investigated using XPS, static secondary ion mass spectrometry (SSIMS) and gentle secondary ion mass spectrometry (G‐SIMS). The estimated mole fraction of lactide units provided by SSIMS was in good agreement with bulk composition and appeared not to have been affected by contamination. Conversely, XPS assessment of lactide compositions was unreliable due to hydrocarbon contamination contributions. In this study, we propose a novel model to demonstrate that by using SSIMS it is possible to infer the degree of trans‐esterification for PLGA co‐polymers synthesised from a mixture of lactide and glycolide homo‐dimers. This was determined by introducing two independent parameters, the ratio of trans‐esterified bonds to the total number of ester bonds, P_T, and the lactide composition. The model has indicated that, for this set of polymers, P_T was approximately 0.25. Furthermore, we have demonstrated that G‐SIMS successfully identified the structurally important key fragments leading to direct identification. Analysis by G‐SIMS showed that the glycolic acid units from all PLGA compositions are emitted in a lower energy‐fragmentation process than lactic acid units. Copyright © 2008 John Wiley & Sons, Ltd.     

A molecular mechanics model for imatinib and imatinib:kinase binding

Imatinib is an important anticancer drug, which binds specifically to the Abl kinase and blocks its signalling activity. To model imatinib:protein interactions, we have developed a molecular mechanics force field for imatinib and four close analogues, which is consistent with the CHARMM force field for proteins and nucleic acids. Atomic charges and Lennard‐Jones parameters were derived from a supermolecule ab initio approach. We considered the ab initio energies and geometries of a probe water molecule interacting with imatinib fragments at 32 different positions. We considered both a neutral and a protonated imatinib. The final RMS deviation between the ab initio and force field energies, averaged over both forms, was 0.2 kcal/mol. The model also reproduces the ab initio geometry and flexibility of imatinib. To apply the force field to imatinib:Abl simulations, it is also necessary to determine the most likely imatinib protonation state when it binds to Abl. This was done using molecular dynamics free energy simulations, where imatinib is reversibly protonated during a series of MD simulations, both in solution and in complex with Abl. The simulations indicate that imatinib binds to Abl in its protonated, positively‐charged form. To help test the force field and the protonation prediction, we did MD free energy simulations that compare the Abl binding affinities of two imatinib analogs, obtaining good agreement with experiment. Finally, two new imatinib variants were considered, one of which is predicted to have improved Abl binding. This variant could be of interest as a potential drug. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

Spectroscopic constants and molecular properties of the X2Π and a4Σ− electronic states of the SiF radical

The potential energy curves (PECs) of the X²Π and a⁴Σ^? electronic states of the SiF radical have been studied by an ab initio quantum chemical method. The calculations have been made using the complete active space self‐consistent field (CASSCF) method, which is followed by the valence internally contracted multireference configuration interaction (MRCI) approach in combination with several correlation‐consistent basis sets. The effects on the PECs by the core‐valence correlation and relativistic corrections are included. The way to consider the relativistic correction is to use the third‐order Douglas–Kroll Hamiltonian approximation. The relativistic corrections are made at the level of cc‐pV5Z basis set. The core‐valence correlation corrections are performed using the cc‐pCV5Z basis set. To obtain more reliable results, the PECs determined by the MRCI calculations are also corrected for size‐extensivity errors by means of the Davidson modification (MRCI+Q). These PECs are extrapolated to the complete basis set limit by the total‐energy extrapolation scheme. Using these PECs, the spectroscopic parameters are determined and compared with those reported in the literature. With these PECs obtained by the MRCI+Q/CV+DK+56 calculations, the vibrational levels, inertial rotation, and centrifugal distortion constants of the first 20 vibrational state of each electronic state are calculated when the rotational quantum number J equals zero. Comparison with the Rydberg‐Klein‐Rees (RKR) data shows that the present results are reliable and accurate. The molecular constants of the X²Π and a⁴Σ^? electronic states determined by the MRCI+Q/CV+DK+56 calculations should be good prediction for future laboratory experiment. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Theoretical study of excited states of DNA base dimers and tetramers using optimally tuned range‐separated density functional theory

Excited states of various DNA base dimers and tetramers including Watson‐Crick H‐bonding and stacking interactions have been investigated by time‐dependent density functional theory using nonempirically tuned range‐separated exchange (RSE) functionals. Significant improvements are found in the prediction of excitation energies and oscillator strengths, with results comparable to those of high‐level coupled‐cluster (CC) models (RI‐CC2 and EOM‐CCSD(T)). The optimally‐tuned RSE functional significantly outperforms its non‐tuned (default) version and widely‐used B3LYP functional. Compared to those high‐level CC benchmarks, the large mean absolute deviations of conventional functionals can be attributed to their inappropriate amount of exact exchange and large delocalization errors which can be greatly eliminated by tuning approach. Furthermore, the impacts of H‐bonding and π‐stacking interactions in various DNA dimers and tetramers are analyzed through peak shift of simulated absorption spectra as well as corresponding change of absorption intensity. The result indicates the stacking interaction in DNA tetramers mainly contributes to the hypochromicity effect. The present work provides an efficient theoretical tool for accurate prediction of optical properties and excited states of nucleobase and other biological systems. © 2015 Wiley Periodicals, Inc.     

Theoretical study of third‐row transition metal monofluorides

The 5d‐metal (excluding La) monofluorides were studied using second order Moller‐Plesset (MP2) perturbation theory. The basis set used was Stuttgart/Dresden (SDD) effective core potentials (ECPs). The ground state multiplicity for these dimers was obtained. The cation and anion of these dimers were also studied at the same level of theory. Relative stability, atomic charges, electron affinity, ionization potential, binding energy (BE), vibrational frequencies, and electronic configuration for these dimers were also obtained. The properties of the neutral dimers were compared with those of their anion and cation. The electronic states of each neutral dimer as well as its ions at their ground state were also defined. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011