Fully Automated Quantum‐Chemistry‐Based Computation of Spin–Spin‐Coupled Nuclear Magnetic Resonance Spectra

We present a composite procedure for the quantum‐chemical computation of spin–spin‐coupled ¹H NMR spectra for general, flexible molecules in solution that is based on four main steps, namely conformer/rotamer ensemble (CRE) generation by the fast tight‐binding method GFN‐xTB and a newly developed search algorithm, computation of the relative free energies and NMR parameters, and solving the spin Hamiltonian. In this way the NMR‐specific nuclear permutation problem is solved, and the correct spin symmetries are obtained. Energies, shielding constants, and spin–spin couplings are computed at state‐of‐the‐art DFT levels with continuum solvation. A few (in)organic and transition‐metal complexes are presented, and very good, unprecedented agreement between the theoretical and experimental spectra was achieved. The approach is routinely applicable to systems with up to 100–150 atoms and may open new avenues for the detailed (conformational) structure elucidation of, for example, natural products or drug molecules.     

A general,most basic rule for ion dissociation: Protonated molecules

Contrary to the common but potentially misleading belief that when a protonated molecule is excited, it is its most stable protomer that will mandatorily dissociate, we demonstrate herein that, when rationalizing or predicting the chemistry of such ions, we should always search for the most labile protomer. This “most labile protomer” rule, based on the mobile proton model, states therefore that when a protonated molecule is heated, during ionization or by collisions for instance, the loosely bonded proton (H⁺) can acquire enough energy to detach itself from the most basic site of the molecule and then freely “walk through” the molecular framework to eventually find, if available, another protonation site, forming other less stable but more labile protomers, that is, protomers that may display lower dissociation thresholds. To demonstrate the validity of the “most labile protomer” rule as well as the misleading nature of the “most stable protomer” rule, we have selected several illustrative molecules and have collected their ESI(+)-MS/MS. To compare energies of precursors and products, we have also performed PM7 calculations and elaborated potential energy surface diagrams for their possible protomers and dissociation thresholds. We have also applied the “most labile protomer” rule to reinterpret—exclusively via classical charge-induced dissociation cleavages—several dissociation processes proposed for protonated molecules. In an accompanying letter, we have also applied a similar “most labile electromer” rule to ionized molecules.     

Solvent effect on the tautomers' stabilities of protonated N,N‐dimethylnitrosamine: The role of hydrogen bonds network

DFT calculations have been applied in order to study the free energies of the structures corresponding to the three different protonation sites of N,N‐dimethylnitrosamine (DMNA). The solvent effect has been taken into account through the study of clusters consisting of protonated DMNA and up to four explicit water molecules, either in the absence or in the presence of a continuum (CPCM) solvation model. Addition of water molecules has been done by a careful screening procedure through which all important hydrogen bonds are likely to be considered. Protonation of DMNA makes all their lone pairs no longer available for hydrogen bond formation with water molecules, such that hydrogen bonds have been observed, for almost all structures, only between water molecules and between one water molecule and the protonated DMNA, in this latter case intermediated by the proton. The stabilities of the solvated structures are governed not only by the number of hydrogen bonds but also by the positions of the water molecules involved in these bonds, as well as by which of them donate or accept H atoms. Our results indicate that oxygen protonation is the most favorable one, regardless of the presence of water molecules. In vacuum protonation at the N‐amino ( 2a ) is approximately as favorable as protonation at the N nitroso ( 2c ). However, in water the former protonation is by far the less favorable one. Our best estimates for the ΔG values in bulk solvent are: ΔG( 2a ) ≈ 17.9, ΔG( 1c ) ≈ 4.3, and ΔG( 2c ) ≈ 4.9 kcal/mol.     

Behaviors of Leucine and Isoleucine in Ion Mobility‐Quadrupole Time of Flight Mass Spectrometry

In this study, ion mobility separation coupled with tandem mass spectrometry (IM‐tandem MS) was utilized to investigate the ionization behaviors of two amino acids including leucine and isoleucine. Under the electrospray ionization (ESI) mode, two protonation sites in each molecular sturcture caused two forms of protomer. One arose from the amino being protonated (amino‐protomer) and the other from the carboxyl being protonated (carboxyl‐protomer). In the two‐dimensional (drift time, m/z) spectrum, the protomers had the same mass, but the distinguishable drift times and fragmentation patterns. For the characterization purpose, the theoretical collision cross section (CCS) values of the protomers were calculated and proven to be consistent with the experimental. Moreover, the quantified relationship between the amino acids and their protomers was evaluated. It showed that the abundance of the carboxyl‐protomer was proportional to the concentration of the amino acid, whereas that of the amino‐protomer did not have the same trend. Under the atmospheric pressure chemical ionization (APCI) mode, only the carboxyl‐protomer was observed. In addition, the amino‐protomer and the cluster ions observed under ESI were absent completely. The results demonstrate that the ionization mode impacts heavily on the ionization behaviors of leucine and isoleucine not only on the form of therir protomers but also on the quantified relationship.     

Theoretical investigation of the proton affinities of benzazoles in the gas phase and in solution

The ground‐state equilibrium geometries of benzothiazole, benzoxazole, and benzimidazole were optimized at the density functional theory (DFT)/6‐31G** level of theory. Proton affinities on each of the possible sites in the studied series of compounds have been calculated at the DFT/6‐31G**/6‐311++G** level. The results indicate clearly that N‐site protonation is strongly favored over X‐site protonation (X = NH, O, S) for the series studied. Correlation of the computed proton affinities to the energy (E_HOMO) of the highest occupied MO in the gas phase and in solution has been explored and discussed. A comprehensive investigation of the effect of solvent on the process of protonation of the studied compounds has been performed. Different dielectric continuum models (i.e., Onsager, PCM, and IPCM) have been tested; their performance and range of applicability are reported and discussed. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Combined use of tandem mass spectrometry and computational chemistry to study 2H‐chromenes from Piper aduncum

Natural 2H‐chromenes were isolated from the crude extract of Piper aduncum (Piperaceae) and analyzed by electrospray ionization tandem mass spectrometry (ESI‐MS/MS) applying collision‐induced dissociation. Density functional theory (DFT) calculations were used to explain the preferred protonation sites of the 2H‐chromenes based on thermochemical parameters, including atomic charges, proton affinity, and gas‐phase basicity. After identifying the nucleophilic sites, the pathways were proposed to justify the formation of the diagnostic ions under ESI‐MS/MS conditions. The calculated relative energy for each pathway was in good agreement with the energy‐resolved plot obtained from ESI‐MS/MS data. Moreover, the 2H‐chromene underwent proton attachment on the prenyl moiety via a six‐membered transition state. This behavior resulted in the formation of a diagnostic ion due to 2‐methylpropene loss. These studies provide novel insights into gas‐phase dissociation for natural benzopyran compounds, indicating how reactivity is correlated to the intrinsic acid‐base equilibrium and structural aspects, including the substitution pattern on the aromatic moiety. Therefore, these results can be applied in the identification of benzopyran derivatives in a variety of biological samples.     

Chemoselective Borane‐Catalyzed Hydroarylation of 1,3‐Dienes with Phenols

A B(C₆F₅)₃‐catalyzed hydroarylation of a series of 1,3‐dienes with various phenols has been established through a combination of theoretical and experimental investigations, affording structurally diverse ortho‐allyl phenols. DFT calculations show that the reaction proceeds through a borane‐promoted protonation/Friedel–Crafts pathway involving a π‐complex of a carbocation–anion contact ion pair. This protocol features simple and mild reaction conditions, broad functional‐group tolerance, and low catalyst loading. The obtained ortho‐allyl phenols could be further converted into flavan derivatives using B(C₆F₅)₃ with good cis diastereoselectivity. Furthermore, this transformation was applied in the late‐stage modification of pharmaceutical compounds.     

Thioacetanilide at 120 K

The title compound, C₈H₉NS, has four symmetry‐independent molecules in the asymmetric unit. These molecules link into two independent infinite N—H...S hydrogen‐bonded chains in the a‐axis direction with graph‐set notation C₂²(8). The NH—CS group adopts a trans conformation and forms a dihedral angle of about 50° with the phenyl ring. The intermolecular hydrogen‐bond energy calculated by the density functional theory (DFT) method is −14.95 kJ mol⁻¹. The correlation between the IR spectrum of this compound and the hydrogen‐bond energy is also discussed. This molecular system is of interest because of its biological function.     

Probing gas adsorption in MOFs using an efficient ab initio widom insertion Monte Carlo method

We propose a novel biased Widom insertion method that can efficiently compute the Henry coefficient, K_H, of gas molecules inside porous materials exhibiting strong adsorption sites by employing purely DFT calculations. This is achieved by partitioning the simulation volume into strongly and weakly adsorbing regions and selectively biasing the Widom insertion moves into the former region. We show that only few thousands of single point energy calculations are necessary to achieve accurate statistics compared to many hundreds of thousands or millions of such calculations in conventional random insertions. The methodology is used to compute the Henry coefficient for CO₂, N₂, CH₄, and C₂H₂ in M‐MOF‐74(M = Zn and Mg), yielding good agreement with published experimental data. Our results demonstrate that the DFT binding energy and the heat of adsorption are not accurate enough indicators to rank the guest adsorption properties at the Henry regime. © 2016 Wiley Periodicals, Inc.     

On Ethylene Polymerisation with Aluminium and Scandium Complexes: DFT and Post‐HF Calculations

Summary: The performance of Density Functional Theory (DFT) methods in predicting ethylene polymerisation and/or oligomerisation activity in selected aluminium and scandium based complexes was studied using both DFT and post‐Hartree‐Fock CCSD(T) calculations. Whereas previous reports have drawn attention to the underestimation of the barrier for the β‐hydrogen termination process for a few aluminium based species, we found that the same holds for the corresponding scandium complexes. New, however, is the observation that apart from underestimating the energy barrier connected to β‐hydrogen termination, the insertion of ethylene is also severely underestimated by the DFT methods applied compared to post‐Hartree‐Fock calculations up to the CCSD(T) level.

Structure of the diketiminate complex referred to in the text.     

Producing DFT/MM enzyme reaction trajectories from SCC‐DFTB/MM driving forces to probe the underlying electronics of a glycosyltransferase reaction

The SCC‐DFTB/MIO/CHARMM free energy surface for a glycosyltransferase, TcTS, is benchmarked against a DFT/MM reaction trajectory using the same CHARMM MM force field ported to the NWChem package. The popular B3LYP functional, against which the MIO parameter set was parameterized is used to optimize TS structures and run DFT reaction dynamics. A novel approach was used to generate reaction forces from a SCC‐DFTB/MIO/CHARMM reaction surface to drive B3LYP/6‐31G/MM and B3LYP/6‐31G(d)/MM reaction trajectories. Although TS structures compare favorably, differences stemming primarily from a minimal basis set approximation prevented a successful 6‐31G(d) FEARCF reaction dynamics trajectory. None the less, the dynamic evolution of the B3LYP/6‐31G/MM‐computed electron density provided an opportunity to perform NBO analysis along the reaction trajectory. Here, we illustrate that a successful ab initio reaction trajectory is computationally accessible when the underlying potential energy function of the semi‐empirical method used to produce driving forces is sufficiently close to the ab initio potential. © 2017 Wiley Periodicals, Inc.     

Site‐Specific Acid–Base Properties of Tenoxicam

The Hammett approach, as a new deductive tool, was introduced to characterize the otherwise inaccessible minor protonation pathway of tenoxicam ( 1 ), the non‐steroidal anti‐inflammatory drug. A total of eight compounds, constituting a systematic series of side chain‐substituted analogues of tenoxicam and piroxicam ( 2 ), were synthesized and studied in terms of acid? base properties and Hammett constants to identify the ideal replacement of the unprotonated pyridin‐2‐yl group, a key moiety in both molecules. Hammett constants of the phenyl substituents have been found to be in a linear correlation with the experimental log K values of the enolate sites, the basic moiety of the extended conjugated system in this family of piroxicam derivatives. Then, a similar correlation was observed for the analogous tenoxicam derivatives. After identifying the 2‐aza Hammett constant of the pyridin‐2‐yl group and the corresponding log K value, the site‐specific acid–base properties of tenoxicam could be quantitated. This novel method is assessed to be a fine‐tuning tool to find the ideal substituent by using analogue‐based deductive method to obtain site‐specific constants of the minor protonation/deprotonation pathway in drugs and biomolecules. The tenoxicam microconstant values indicate that the enolate moiety is of extremely low basicity (reflected by the =3.70 and =1.09 values), which can, however, be interpreted in terms of the peculiar ring system and the overwhelming electron‐withdrawing effects of the adjacent heteroatoms. A diagram depicting the pH‐dependent distribution of 1 microspecies is also presented.     

Transformation of the gas‐phase favored O‐protomer of p‐aminobenzoic acid to its unfavored N‐protomer by ion activation in the presence of water vapor: An ion‐mobility mass spectrometry study

An ion‐mobility mass spectrometry study showed that the preferred O‐protonated form of p‐aminobenzoic in the gas phase can be converted to the thermodynamically less favored N‐protomer by in‐source collision‐induced ion activation during the ion transfer process from the atmospheric region to the first vacuum region if the humidity is high in the ion source. Upon the addition of water vapor to the nitrogen gas used to promote the solid analyte to the gas phase under helium‐plasma ionization conditions, the intensity of the ion‐mobility arrival‐time peak for the N‐protomer increased dramatically. Evidently, the ion‐activation process in the first vacuum region is able to provide the energy required to surmount the barrier to isomerize the O‐protomer to the more energetic N‐protomer. The transfer of the proton attached to the carbonyl oxygen atom of the O‐protomer to the amino group takes place by a water‐bridge mechanism. Apparently, the postionization transformations that take place during the transmission of ions from the atmospheric‐pressure ion source to the detector, via different physical compartments of low to high vacuum, play an eminent role in determining the population ratios eventually manifested at the detector.     

Study of conformational and optical rotation for the alaninamide

Six stationary points of alaninamide have been located on the potential surface energy (PES) at the B3LYP/6‐311++G(2d,2p) level of theory both in the gas phase and in aqueous solution. In the aqueous solution, to take the water solvent effect into account, the polarizable continuum model (PCM) method has been used. Accurate geometric structures and their relative stabilities have been investigated. The results show that the intramolecular hydrogen bond plays a very important role in stabilizing the global minimum of the alaninamide. Moreover, the consistent result in relative energy using high‐level computations, including the MP2 and MP3 methods with the same basis set [6‐311++G(2d,2p)], indicates that the B3LYP/6‐311++G(d,p) level may be applied to the analogue system. More importantly, the optical rotation of the optimized conformers (both in the gas phase and in aqueous solution) of alaninamide have been calculated using the density functional theory (DFT) and Hartree–Fock (HF) method at various basis sets (6‐31+G*, 6‐311++G(d,p), 6‐311++G(2d,2p) and aug‐cc‐pvdz). The results show that the selection of the computation method and the basis set in calculation has great influence on the results of the optical rotations. The reliability of the HF method is less than that of DFT, and selecting the basis set of 6‐311++G(2d,2p) and aug‐cc‐pvDZ produces relative reliable results. Analysis of the computational results of the structure parameters and the optical rotations yields the conclusion that just the helixes in molecules caused the chiral molecules to be optical active. The Boltzmann equilibrium distributions for the six conformers (both in the gas phase and in the aqueous solution) are also carried out. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

A Nexus between Theory and Experiment: Non‐Empirical Quantum Mechanical Computational Methodology Applied to Cucurbit[n]uril⋅Guest Binding Interactions

A training set of eleven X‐ray structures determined for biomimetic complexes between cucurbit[n]uril (CB[7 or 8]) hosts and adamantane‐/diamantane ammonium/aminium guests were studied with DFT‐D3 quantum mechanical computational methods to afford ΔG_calcd binding energies. A novel feature of this work is that the fidelity of the BLYP‐D3/def2‐TZVPP choice of DFT functional was proven by comparison with more accurate methods. For the first time, the CB[n] ? guest complex binding energy subcomponents [for example, ΔE_dispersion, ΔE_{electrostatic}, ΔG_solvation, binding entropy (?TΔS), and induced fit E_{deformation(host)}, E_{deformation(guest)}] were calculated. Only a few weeks of computation time per complex were required by using this protocol. The deformation (stiffness) and solvation properties (with emphasis on cavity desolvation) of cucurbit[n]uril (n=5, 6, 7, 8) isolated host molecules were also explored by means of the DFT‐D3 method. A high ρ²=0.84 correlation coefficient between ΔG_exptl and ΔG_calcd was achieved without any scaling of the calculated terms (at 298 K). This linear dependence was utilized for ΔG_calcd predictions of new complexes. The nature of binding, including the role of high energy water molecules, was also studied. The utility of introduction of tethered [‐(CH₂)_nNH₃]⁺ amino loops attached to N,N‐dimethyl‐adamantane‐1‐amine and N,N,N′,N′‐tetramethyl diamantane‐4,9‐diamine skeletons (both from an experimental and a theoretical perspective) is presented here as a promising tool for the achievement of new ultra‐high binding guests to CB[7] hosts. Predictions of not yet measured equilibrium constants are presented herein.     

Impact of replacement of the central benzene ring in anthracene by a heterocyclic ring on electronic excitations and reorganization energies in anthratetrathiophene molecules

The impact of changing the central benzene ring on the electronic excitations and reorganization energies (λ) of the anthratetrathiophene (ATT) molecules is studied by density functional theory (DFT) and time‐dependent DFT (TD‐DFT) quantum chemical calculations. The effect of changing the position of the sulfur atom at the periphery of anthracene on the optical and charge transfer properties is also studied. The calculated results suggest that the HOMO, LUMO, HOMO–LUMO energy gap, ionization potential (IP), electron affinity (EA), hole extraction potential (HEP), electron extraction potential (EEP), and reorganization energies (λ) are affected by replacing the central ring with different heterocyclic rings and the position of the sulfur atom. In addition, all molecules show good hole‐ and electron‐transport properties. This work may be helpful for future design and preparation of high‐performance charge‐transport materials.     

Predicting reactivity and stereoselectivity in the Nazarov reaction: a combined computational and experimental study

The Nazarov reaction of pentadienyl cations generated by protonation of either dienones or alkoxytrienes has been examined in detail both experimentally and by DFT calculations. In particular, calculations at the B3LYP/6‐311G** level of theory accurately predicted, and accounted for, the outcome of the Brønsted acid catalyzed electrocyclization of 4π‐electron systems in which one of the double bonds involved in the process was embedded in N‐ and S‐heterocyclic rings. Calculations showed that both heteroatoms are capable of accelerating the ring closure by stabilizing the partial positive charge which develops at C‐6 (C‐2) in the transition state, with S‐heterocyclic derivatives being more reactive than the corresponding N‐containing compounds. In general, pentadienyl cations generated by protonation of alkoxytrienes were expected to react faster than those obtained by protonation of the corresponding dienones, as the latter were stabilized by a hydrogen bond. The presence of a substituent on the heterocyclic ring significantly affects the stereoselectivity (torquoselectivity) only in the case of the N‐heterocyclic derivatives, in which a 2‐alkyl group is axially oriented, providing the cis‐2,5‐disubstituted isomer only. Instead, with substituted S‐heterocyclic compounds, the anticipated torquoselectivity was very low and, in fact, a 3:1 diastereomeric mixture between the trans and cis products was experimentally found after ring closure. For this study, the synthesis of the appropriate N‐ and S‐containing dienones and alkoxytrienes was realized to evaluate the predictivity power of the DFT computations, which was very good in all of the cases examined, both in terms of reactivity and stereoselectivity. The consistency observed between computational and experimental results, therefore, shows the usefulness of DFT calculations at the B3LYP/6‐311G** level of theory as a robust instrument for the prediction of reactivity and stereoselectivity in the Nazarov electrocyclic reaction.     

Robust Atomistic Modeling of Materials,Organometallic, and Biochemical Systems

Modern chemistry seems to be unlimited in molecular size and elemental composition. Metal‐organic frameworks or biological macromolecules involve complex architectures and a large variety of elements. Yet, a general and broadly applicable theoretical method to describe the structures and interactions of molecules beyond the 1000‐atom size regime semi‐quantitatively is not self‐evident. For this purpose, a generic force field named GFN‐FF is presented, which is completely newly developed to enable fast structure optimizations and molecular‐dynamics simulations for basically any chemical structure consisting of elements up to radon. The freely available computer program requires only starting coordinates and elemental composition as input from which, fully automatically, all potential‐energy terms are constructed. GFN‐FF outperforms other force fields in terms of generality and accuracy, approaching the performance of much more elaborate quantum‐mechanical methods in many cases.     

Nonplanar Butterfly‐Shaped π‐Expanded Pyrrolopyrroles

Large aza‐analogues of curved polycyclic aromatic hydrocarbons with a double‐helicene structure present unique features for molecular photonics. We present the preparation and characterization of three such structures. The synthesis of these heterocyclic nanographenes involves only a few high‐yield steps that use readily available starting materials. X‐ray analysis revealed that each of these new dyes has three conformational isomers: one diastereoisomer in a meso form and two enantiomers in twisted forms [(P,P)] and [(M,M)]. The low energy barriers between the conformers, however, prevent their separation by using chiral HPLC, and the NMR spectra show only one set of signals for each of these curved compounds. Density functional theory (DFT) calculations quantify the small energy difference and the small energy barriers between the chiral and meso forms, which fully supports the experimental results. Their optical absorption lacks any sensitivity to the solvent environment, whereas their fluorescence features exhibit pronounced solvatochromism. This rarely observed solvatofluorochromism of centrosymmetric molecules without either electron‐withdrawing groups or ‐donating substituents was probed by using time‐resolved spectroscopy. These studies suggest that, similar to 9,9′‐bianthryl, the nonpolar locally excited state shows negligible solvatochromism, whereas the charge‐transfer state is sensitive to solvent polarity.