Accuracy of Different Electronic Basis Set Families for Anharmonic Molecular Vibrations: A Comprehensive Benchmark Study.

In this work, the accuracy and convergence of different electronic basis set families for the computation of anharmonic molecular vibrational spectroscopic calculations are benchmarked. A series of 39 different basis sets from different families following their hierarchy are assessed on VSCF and VSCF-PT2 algorithms with commonly used MP2 and DFT based B3LYP-D potentials for a set of molecular systems. Such an effort has been validated in a previous work ( J. Phys. Chem. A 2020, 124, 9203-9221) with split-valence basis sets for fundamentals and intensities. Here, fundamental transitions, vibrationally excited states, and intensities are compared with the experimental data to estimate the accuracy for a series of Jensen, Dunning, Calendar, Karlsruhe, and Sapporo basis set families. The convergence of basis sets are also compared with the large ANO basis set. Comprehensive statistical error analysis in terms of accuracy and precision was carried out to assess the performance of each basis set. It is observed that the improvement for the calculated harmonic and anharmonic values from the smaller basis sets to the medium (i.e., triple-ξ) is considerable. Beyond this, from medium to large basis sets, the convergence is slow and mostly posits nearly converged values. Basis sets with and without diffuse functions offer characteristically different accuracies and convergence patterns. Finally, recommendations are given on the choice of basis set chosen as black-box which can balance between accuracy and computational time, estimation of the errors, and their selections especially for large molecules.

Performance of Vibrational Self-Consistent Field Theory for Accurate Potential Energy Surfaces: Fundamentals, Excited States, and Intensities.

The performance of vibrational structure calculations beyond harmonic approximation in the framework of the vibrational self-consistent field method with second-order perturbation corrections (VSCF-PT2) is investigated in conjunction with very accurate potential energy surfaces (PESs) given by various coupled-cluster electronic structure theories. The quality of anharmonic calculations depends on the accuracy of the underlying multidimensional PES obtained from its functional form, which is given by the level of electronic structure theory. Two such highest levels of typical coupled-cluster electronic structure methods, CCSD and the ″gold standard″ CCSD(T), along with their variants such as CCD, CR-CCL (completely renormalized CR-CC(2,3) approach), and CCSD(TQ) are tested for the construction of accurate anharmonic potentials without any fitting or ad hoc scaling and using cc-pVTZ basis sets. The accuracy of VSCF-PT2 theory in comparison to experimental values is tested for a series of 16 molecules with 135 fundamental bands, 64 overtones, and combination bands and also for 39 intensities. It is found that CCD and CCSD bind the potential tighter than CCSD(T) and the computed VSCF-PT2 transitions are more blue-shifted showing higher deviation from the experiment. In general, VSCF-PT2 results computed at the CCSD(T) potential offer a good cost/accuracy ratio, with the mean absolute deviation and the mean absolute percentage error with the experiment being ∼16 cm-1 and 1.38, respectively, for fundamentals. Additionally, while the CR-CCL and CCSD(TQ) methods offer similar levels of accuracies as compared to CCSD(T), the former offers a better accuracy/cost ratio than the latter and is a suitable alternative to CCSD(T).

Comprehensive Benchmark Results for the Accuracy of Basis Sets for Anharmonic Molecular Vibrations.

The accuracy and convergence of a series of commonly used split-valence electronic basis sets are systematically investigated for the anharmonic molecular vibrational spectroscopic calculations using the second-order perturbative corrected vibrational self-consistent field theory. A series of 18 split-valence basis sets with increasing flexibility is assessed in conjunction with MP2 and density functional theory (DFT)-based dispersion-corrected B3LYP potentials and applied to a set of molecular systems with different electronic and vibrational characteristics. The computed fundamental transitions and intensities are compared with the experimental values to assess the accuracy of different basis sets. Comparisons with high levels of Dunning basis sets, aug-cc-pVQZ along with def2-TZVPP and aug-pc-2 type basis sets, are also tested to check the convergence. A full statistical error analysis has been performed, assessing the success and failure of each basis set in terms of both accuracy and precision. The general statement "the bigger the basis, the better the results" is not strictly followed for bigger basis sets that are nearly converged to the adiabatic ab initio limit. It is found that the basis set hierarchy holds good for minimal basis sets up to polarized double-ζ basis sets. Beyond that, the improvements in comparison to experimental results or with very high end aug-cc-pVQZ and others are found rather slow. Finally, a prescription regarding the choice of a basis set for a suitable balance between accuracy and the computational time is given, which can be further used to investigate specific normal modes and large molecules as a blackbox.

Catalyst-Controlled Structural Divergence: Selective Intramolecular 7-endo-dig and 6-exo-dig Post-Ugi Cyclization for the Synthesis of Benzoxazepinones and Benzoxazinones.

Metal catalyzed post-Ugi cyclization of bis-amides is reported in this study. Exposure of bis-amides to Pd(II) catalyst triggered the formation of seven-membered benzoxazepinones. This investigation established that changing the catalyst to a Echavarren's gold(I) turned off cyclization to seven member ring and turned on 6-exo-dig annulations to afford family of six-membered benzoxazinones. To support the proposed mechanisms, quantum chemical based density functional theory calculations have been performed and validated. This novel method obtained molecular complexity up to four modular inputs and divergence of two different skeletons. 2D NMR spectroscopic techniques and single crystal X-ray diffraction established the proposed structures.

Intrinsic structure of pentapeptide Leu-enkephalin: geometry optimization and validation by comparison of VSCF-PT2 calculations with cold ion spectroscopy.

The intrinsic structure of an opioid peptide [Ala2, Leu5]-leucine enkephalin (ALE) has been investigated using first-principles based vibrational self-consistent field (VSCF) theory and cold ion spectroscopy. IR-UV double resonance spectroscopy revealed the presence of only one highly abundant conformer of the singly protonated ALE, isolated and cryogenically cooled in the gas phase. High-level quantum mechanical calculations of electronic structures in conjunction with a systematic conformational search allowed for finding a few low-energy candidate structures. In order to identify the observed structure, we computed vibrational spectra of the candidate structures and employed the theory at the semi-empirically scaled harmonic level and at the first-principles based anharmonic VSCF levels. The best match between the calculated "anharmonic" and the measured spectra appeared, indeed, for the most stable candidate. An average of two spectra calculated with different quantum mechanical potentials is proposed for the best match with experiment. The match thus validates the calculated intrinsic structure of ALE and demonstrates the predictive power of first-principles theory for solving structures of such large molecules.

Azo-dyes based small bifunctional molecules for metal chelation and controlling amyloid formation.

Chemical tools are needed to discover new effective drugs for tackling multifaceted complex neurodegenerative diseases like Alzheimer's disease (AD). Multifunctional nature of two compounds, 5-((4-nitro-phenyl)diazenyl)quinolin-8-ol (HL1) and 4-((4-nitrophenyl)diazenyl)benzene-1,3-diol (HL2) is reported w.r.t. their ability to bind Cu2+ ions and amyloid aggregates related to AD. HL1 and HL2 have half congo-red type azo-stilbene structural framework incorporated with metal chelating groups, designed to chelate metal ions from metal-amyloid species. Metal binding studies of HL1 and HL2 are established by the methods of Job's Plot, UV-vis spectra with metal ions and stability constant determination. In addition, their metal complexes are isolated, purity checked by elemental analysis, spectroscopically characterized and their structural analyses were obtained from DFT based calculations including binding energy determination. Chicken egg white Lysozyme (CEWL) was used as a model peptide for fibrillation studies. HL1 is found as an excellent colorimetric sensor for amyloid fibrils. Inhibitory effect of HL1 and HL2 and their isolated metal complexes L1-Cu and L2-Cu on CEWL fibrillation was studied using ThT and ANS fluorescence assay along with TEM imaging. In addition, the cell toxicity studies on these compounds suggest that although azo dyes may be non-toxic but having a nitro-substitution lead to significant cell toxicity. Overall, these results suggest that this new class of multifunctional small molecules can interact with amyloids as well as metal ions and could be potential anti-aggregation metal chelating agents.

A Decapeptide Hydrated by Two Waters: Conformers Determined by Theory and Validated by Cold Ion Spectroscopy.

The intrinsic structures of biomolecules in the gas phase may not reflect their native solution geometries. Microsolvation of the molecules bridges the two environments, enabling a tracking of molecular structural changes upon hydration at the atomistic level. We employ density functional calculations to compute a large pool of structures and vibrational spectra for a gas-phase complex, in which a doubly protonated decapeptide, gramicidin S, is solvated by two water molecules. Though most vibrations of this large complex are treated in a harmonic approximation, the water molecules and the vibrations of the host ion coupled to them are locally described by a quantum mechanical vibrational self-consistent field theory with second-order perturbation correction (VSCF-PT2). Guided and validated by the available cold ion spectroscopy data, the computational analysis identifies structures of the three experimentally observed conformers of the complex. They, mainly, differ by the hydration sites, of which the one at the Orn side chain is the most important for reshaping the peptide toward its native structure. The study demonstrates the ability of a quantum chemistry approach that intelligently combines the semiempirical and ab initio computations to disentangle a complex interplay of intra- and intermolecular hydrogen bonds in large molecular systems.

First-principles anharmonic quantum calculations for peptide spectroscopy: VSCF calculations and comparison with experiments.

First-principles quantum calculations for anharmonic vibrational spectroscopy of three protected dipeptides are carried out and compared with experimental data. Using hybrid HF/MP2 potentials, the Vibrational Self-Consistent Field with Second-Order Perturbation Correction (VSCF-PT2) algorithm is used to compute the spectra without any ad hoc scaling or fitting. All of the vibrational modes (135 for the largest system) are treated quantum mechanically and anharmonically using full pair-wise coupling potentials to represent the interaction between different modes. In the hybrid potential scheme the MP2 method is used for the harmonic part of the potential and a modified HF method is used for the anharmonic part. The overall agreement between computed spectra and experiment is very good and reveals different signatures for different conformers. This study shows that first-principles spectroscopic calculations of good accuracy are possible for dipeptides hence it opens possibilities for determination of dipeptide conformer structures by comparison of spectroscopic calculations with experiment.

Mechanistic studies of malonic acid-mediated in situ acylation.

We have previously introduced an easy to perform, cost-effective and highly efficient acetylation technique for solid phase synthesis (SPPS). Malonic acid is used as a precursor and the reaction proceeds via a reactive ketene that acetylates the target amine. Here we present a detailed mechanistic study of the malonic acid-mediated acylation. The influence of reaction conditions, peptide sequence and reagents was systematically studied. Our results show that the methodology can be successfully applied to different types of peptides and nonpeptidic molecules irrespective of their structure, sequence, or conformation. Using alkyl, phenyl, and benzyl malonic acid, we synthesized various acyl peptides with almost quantitative yields. The ketenes obtained from the different malonic acid derived precursors were characterized by in situ (1) H-NMR. The reaction proceeded in short reaction times and resulted in excellent yields when using uronium-based coupling agents, DIPEA as a base, DMF/DMSO/NMP as solvents, Rink amide/Wang/Merrifield resins, temperature of 20°C, pH 8-12 and 5 min preactivation at inert atmosphere. The reaction was unaffected by Lewis acids, transition metal ions, surfactants, or salt. DFT studies support the kinetically favorable concerted mechanism for CO2 and ketene formation that leads to the thermodynamically stable acylated products. We conclude that the malonic acid-mediated acylation is a general method applicable to various target molecules.

Conformational structures of a decapeptide validated by first principles calculations and cold ion spectroscopy.

Calculated structures of the two most stable conformers of a protonated decapeptide gramicidin S in the gas phase have been validated by comparing the vibrational spectra, calculated from first- principles and measured in a wide spectral range using infrared (IR)-UV double resonance cold ion spectroscopy. All the 522 vibrational modes of each conformer were calculated quantum mechanically and compared with the experiment without any recourse to an empirical scaling. The study demonstrates that first-principles calculations, when accounting for vibrational anharmonicity, can reproduce high-resolution experimental spectra well enough for validating structures of molecules as large as of 200 atoms. The validated accurate structures of the peptide may serve as templates for in silico drug design and absolute calibration of ion mobility measurements.

A highly efficient in situ N-acetylation approach for solid phase synthesis.

We describe a new general N-acetylation method for solid phase synthesis. Malonic acid is used as a precursor and the reaction proceeds by in situ formation of a reactive ketene intermediate at room temperature. We have successfully applied this methodology to peptides and non-peptidic molecules containing a variety of functional groups. The reaction gave high yields compared to known acetylation methods, irrespective of the structure, conformation and sequence of the acetylated molecule. Computational studies revealed that the concerted mechanism via the ketene intermediate is kinetically favorable and leads to a thermodynamically stable acetylated product. In conclusion, our method can be easily applied to acetylation in a wide variety of chemical reactions performed on the solid phase.

Approximate first-principles anharmonic calculations of polyatomic spectra using MP2 and B3LYP potentials: comparisons with experiment.

Anharmonic vibrational spectroscopy calculations using MP2 and B3LYP computed potential surfaces are carried out for a series of molecules, and frequencies and intensities are compared with those from experiment. The vibrational self-consistent field with second-order perturbation correction (VSCF-PT2) is used in computing the spectra. The test calculations have been performed for the molecules HNO3, C2H4, C2H4O, H2SO4, CH3COOH, glycine, and alanine. Both MP2 and B3LYP give results in good accord with experimental frequencies, though, on the whole, MP2 gives very slightly better agreement. A statistical analysis of deviations in frequencies from experiment is carried out that gives interesting insights. The most probable percentage deviation from experimental frequencies is about -2% (to the red of the experiment) for B3LYP and +2% (to the blue of the experiment) for MP2. There is a higher probability for relatively large percentage deviations when B3LYP is used. The calculated intensities are also found to be in good accord with experiment, but the percentage deviations are much larger than those for frequencies. The results show that both MP2 and B3LYP potentials, used in VSCF-PT2 calculations, account well for anharmonic effects in the spectroscopy of molecules of the types considered.

A tandem in situ peptide cyclization through trifluoroacetic acid cleavage.

We present a new approach for peptide cyclization during solid phase synthesis under highly acidic conditions. Our approach involves simultaneous in situ deprotection, cyclization and trifluoroacetic acid (TFA) cleavage of the peptide, which is achieved by forming an amide bond between a lysine side chain and a succinic acid linker at the peptide N-terminus. The reaction proceeds via a highly active succinimide intermediate, which was isolated and characterized. The structure of a model cyclic peptide was solved by NMR spectroscopy. Theoretical calculations support the proposed mechanism of cyclization. Our new methodology is applicable for the formation of macrocycles in solid-phase synthesis of peptides and organic molecules.

Vibrational self-consistent field calculations for spectroscopy of biological molecules: new algorithmic developments and applications.

This review describes the vibrational self-consistent field (VSCF) method and its other variants for computing anharmonic vibrational spectroscopy of biological molecules. The superiority and limitations of this algorithm are discussed with examples. The spectroscopic accuracy of the VSCF method is compared with experimental results and other available state-of-the-art algorithms for various biologically important systems. For large biological molecules with many vibrational modes, the scaling of computational effort is investigated. The accuracy of the vibrational spectra of biological molecules using the VSCF approach for different electronic structure methods is also assessed. Finally, a few open problems and challenges in this field are discussed.

Development of a new variational approach for thermal density matrices.

A McLachlan-type variational principle is derived for thermal density matrices. In this approach, the trace of the mean square of the differences between the derivatives of the exact and model density matrices is minimized with respect to the parameters in the model Hamiltonian. Applications to model anharmonic systems in the independent particle model show that the method can provide thermodynamic state functions accurately (within 5% of the converged basis set results) and at the same level of accuracy as the results using Feynman-Gibbs-Bogoliubov variational principle at this level of approximation.

Dual Basis Approach for Ab Initio Anharmonic Calculations of Vibrational Spectroscopy: Application to Microsolvated Biomolecules.

A dual electronic basis set approach is introduced for more efficient but accurate calculations of the anharmonic vibrational spectra in the framework of the vibrational self-consistent field (VSCF) theory. In this approach, an accurate basis set is used to compute the vibrational spectra at the harmonic level. The results are used to scale the potential surface from a more modest but much more efficient basis set. The scaling is such that at the harmonic level the new, scaled potential agrees with one of the accurate basis sets. The approach is tested in the application of the microsolvated, protected amino acid Ac-Phe-OMe, using the scaled anharmonic hybrid potential in the VSCF and VSCF-PT2 algorithms. The hybrid potential method yields results that are in good accord with the experiment and very close to those obtained in calculations with the high-level, very costly potential from the large basis set. At the same time, the hybrid potential calculations are considerably less expensive. The results of the hybrid calculations are much more accurate than those computed from the potential surface corresponding to the modest basis set. The results are very encouraging for using the hybrid potential method for inexpensive yet sufficiently accurate anharmonic calculations for the spectra of large biomolecules.

A thermal self-consistent field theory for the calculation of molecular vibrational partition functions.

A new approach for the calculation of anharmonic molecular vibrational partition functions is developed based on a separable ansatz to the thermal density matrix. The parameters appearing in the effective single particle Hamiltonians that generate the thermal density matrices are determined variationally. The resulting equations are the thermal analogs of the vibrational self-consistent field approximation. The method has the formal property that the free energy calculated by this approach is an upper bound to the exact free energy. Thermodynamic quantities calculated by this approach are generally in good agreement with the results of numerically converged calculations. This approach is more efficient than the standard sum over state approaches in that the computational resources scale with N(4) where N is the number of vibrational degrees of freedom. Thus it can be applied to fairly large systems.

Hypochlorite-Mediated Modulation of Photoinduced Electron Transfer in a Phenothiazine-Boron dipyrromethene Electron Donor-Acceptor Dyad: A Highly Water Soluble "Turn-On" Fluorescent Probe for Hypochlorite.

A highly water-soluble phenothiazine (PTZ)-boron dipyrromethene (BODIPY)-based electron donor-acceptor dyad (WS-Probe), which contains BODIPY as the signaling antennae and PTZ as the OCl- reactive group, was designed and used as a fluorescent chemosensor for the detection of OCl- . Upon addition of incremental amounts of NaOCl, the quenched fluorescence of WS-Probe was enhanced drastically, which indicated the inhibition of reductive photoinduced electron transfer (PET) from PTZ to 1 BODIPY*; the detection limit was calculated to be 26.7 nm. Selectivity studies with various reactive oxygen species, cations, and anions revealed that WS-Probe was able to detect OCl- selectively. Steady-state fluorescence studies performed at varied pH suggested that WS-Probe can detect NaOCl and exhibits maximum fluorescence in the pH range of 7 to 8, similar to physiological conditions. ESI-MS analysis and 1 H NMR spectroscopy titrations showed the formation of sulfoxide as the major oxidized product upon addition of hypochlorite. More interestingly, when WS-Probe was treated with real water samples, the fluorescence response was clearly visible with tap water and disinfectant, which indicated the presence of OCl- in these samples. The in vitro cell viability assay performed with human embryonic kidney 293 (HEK 293) cells suggested that WS-probe is non-toxic up to 10 µm and implicates the use of the probe for biological applications.

Ruthenium Catalyzed Intramolecular C-S Coupling Reactions: Synthetic Scope and Mechanistic Insight.

A ruthenium catalyzed intramolecular C-S coupling reaction of N-arylthioureas for the synthesis of 2-aminobenzothiazoles has been developed. Kinetic, isotope labeling, and computational studies reveal the involvement of an electrophilic ruthenation pathway instead of a direct C-H activation. Stereoelectronic effect of meta-substituents on the N-arylthiourea dictates the final regioselective outcome of the reaction.