Accurate Computation of Aqueous pKas of Biologically Relevant Organic Acids: Overcoming the Challenges Posed by Multiple Conformers, Tautomeric Equilibria, and Disparate Functional Groups with the Fully Black-Box pK-Yay Method.

The use of static electronic structure calculations to compute solution-phase pKas offers a great advantage in that a macroscopic bulk property could be computed via microscopic computations involving very few molecules. There are various sources of errors in the quantum chemical calculations though. Overcoming these errors to accurately compute pKas of a plethora of acids is an active area of research in physical chemistry pursued by both computational as well as experimental chemists. We recently developed the pK-Yay method in our attempt to accurately compute aqueous pKas of strong and weak acids. The method is fully black-box, computationally inexpensive, and is very easy for even a nonexpert to use. However, the method was thus far tested on very few molecules (only 16 in all). Herein, in order to assess the future applicability of pK-Yay, we study the effect of multiple conformers, the presence of tautomers under equilibrium, and the impact of a wide variety of functional groups (derivatives of acetic acid with substituents at various positions, dicarboxylic acids, aromatic carboxylic acids, amines and amides, phenols and thiols, and fluorine bearing organic acids). Starting with more than 1000 conformers and tautomers, this study establishes that overall errors of ∼ 1.0 pKa units are routinely obtained for a majority of the molecules. Larger errors are noted in cases where multiple charges, intramolecular hydrogen bonding, and several ionizable functional groups are simultaneously present. An important conclusion to emerge from this work is that, the computed pKas are insensitive (difference <0.5) to whether we consider multiple conformers/tautomers or only choose the most stable conformer/tautomer. Further, pK-Yay captures the stereoelectronic effects arising due to differing axial vs equatorial pattern, and is useful to predict the dominant acid-base equilibrium in a system featuring several equilibria. Overall, pK-Yay may be employed in several chemical applications featuring organic molecules and biomonomers.

Intrinsic vs Reaction-Driven Fluxionality in Transition-Metal Oxide Clusters: What Does Probing the Dynamics of M3O6- (M = Mo and W) Reacting with H2O Teach Us?

Fluxionality is an important concept in cluster science, with far reaching implications in the area of catalysis. The interplay between intrinsic structural fluxionality and reaction-driven fluxionality though is underexplored in the literature and is a topic of contemporary interest in physical chemistry. In this work, we present an easy-to-use computational protocol combining ab initio molecular dynamics simulations with static electronic structure computations to ascertain the role of intrinsic structural fluxionality in the course of fluxionality occurring due to a chemical reaction. The reactions of structurally well-defined M3O6- (M = Mo and W) with water─which were originally used in the literature to illustrate the significance of reaction-driven fluxionality in transition-metal oxide (TMO) clusters, were chosen for this study. Besides probing the nature of fluxionality, this work provides the timescale for the key proton-hop step in the fluxionality pathway and further attests to the significance of hydrogen bonding in both stabilizing the key intermediates as well as driving forward the reactions of M3O6- (M = Mo and W) with water. The approach presented in this work becomes valuable given that the use of molecular dynamics alone may not help us in accessing some metastable states whose formation involves an appreciable energy barrier. Similarly, merely obtaining a slice of the potential energy surface via static electronic structure calculations will not be helpful in probing the different types of fluxionality. Hence, there is the need for a combined approach to study fluxionality in structurally well-defined TMO clusters. Our protocol may also serve as a starting point in the analysis of much more complicated fluxional chemistry happening on surfaces wherein the recently developed "ensemble of metastable states" approach to catalysis is deemed to be particularly promising.

Gem-dimethyl peptide nucleic acid (α/ß/γ-gdm-PNA) monomers: synthesis and the role of gdm-substituents in preferential stabilisation of Z/E-rotamers.

The flexible backbone of aminoethylglycine (aeg) PNA upon substitution becomes sterically constrained to enable conformational pre-organization for preferential binding to DNA or RNA. The bulky gem-dimethyl (gdm) substituent on carbons adjacent to the t-amide sidechain either at Cα (glycyl) or Cß/Cγ (aminoethylene) sides may influence the Z/E rotamer ratio arising from a restricted rotation around the t-amide bond. Employing 2D NMR (NOESY), it is shown here that the Cα-gdm-PNA-T monomer exhibits exclusively the Z-rotamer, while the Cß-gdm-PNA-T monomer shows only the E-rotamer. The unsubstituted aeg-PNA-T and Cγ-gdm-PNA-T monomers display a mixture of Z/E rotamers. The rotamers with t-amide carbonyl pointing towards the gem-dimethyl group always prevailed. The results are supported by computational studies that suggested that the preferred rotamers are the outcome of a net energetic benefit from the stabilising n-π* interactions of carbonyls (amide backbone and t-amide sidechain), and C-HO interactions and the destabilising steric clash of gem-dimethyl groups with the t-amido methylene group. The E-rotamer structure in Cγ-gdm is also characterised by X-ray crystallography. The exclusive E-rotamer for the Cß-gdm monomer seen in solution here is the first such example among several modified PNA monomers. Since the conformation of the sidechain is important for inducing base stacking and effective base pairing, the exclusive E-rotamer in the Cß-gdm monomer may have significance in the properties of the derived PNA : DNA/RNA duplexes with all E-rotamers.

Pathways for the Formation of Formamide, a Prebiotic Biomonomer: Metal-Ions in Interstellar Gas-Phase Chemistry.

The chemistry occurring in the interstellar medium (ISM) is an active area of contemporary research. New aspects of interstellar chemistry are getting unraveled regularly. In this context, the role of metal-ions in the chemistry occurring in the ISM is not well-studied so far. Herein, we highlight the role of metal-ions in interstellar chemistry. For this purpose, we choose the problem of gas-phase formamide formation in interstellar molecular clouds. Formamide is a key biomonomer and contains the simplest peptide [-(C═O)-NH-] linkage. With its two electronegative atoms ("O" and "N"), it provides an excellent platform to probe the role of the metal-ions. The metal-ions chosen are Na+, K+, Al+, Mg+, and Mg2+-all of them present in the ISM. The metal-ions are studied in three different forms as bare positively charged ions, as hydrated metal-ions co-ordinated with a molecule of water, and when the metal-ions are part of a neutral covalent molecule. With the aid of electronic structure calculations [CCSD(T) and DFT methods], we study different gas-phase pathways which result in the generation of interstellar formamide. Throughout our study, we find that metal-ions lower the barriers (with Mg+, Mg++, and Al+ offering maximal stabilization of the transition states) and facilitate the reactions. The chemical factors influencing the reactions, how we consider the putative conditions in the ISM, the astrochemical implications of this study, and its connection with terrestrial prebiotic chemistry and refractory astrochemistry are subsequently presented. Based on our results, we also recommend the detection of two new closed-shell molecules, NH2CH2OH (aminomethanol) and CH2NH2+ (iminium ion), and two open-shell molecules, CONH2 (carbamyl radical) and HCONH (an isomer of carbamyl radical), in the ISM.

pK-Yay: A Black-Box Method Using Density Functional Theory and Implicit Solvation Models to Compute Aqueous pKa Values of Weak and Strong Acids.

The concept of pKa is very important in chemistry and biology. Over the past two decades, electronic structure calculations have made huge strides toward becoming reliable counterparts to experiments in determining solution-phase pKa values. However, invariably, the computation of pKa values involves the use of methods whose error bars are intrinsically larger (definitely >2 kcal/mol with density functionals) than the accuracy desired for the estimation of pKa values (<1 or 1.5 pKa units). This scenario presents an ample scope for innovation in developing systematic error cancellation methods even today. In this work, we have developed the pK-Yay method. It is a user-friendly black-box method used to compute aqueous pKa values of strong and weak acids employing routinely used and computationally inexpensive density functionals and implicit solvation models. It does not require the use of any explicit solvent molecule or modifying any other parameter in an electronic structure program. As part of evaluating the method, a comprehensive test set of 26 weak and strong organic and mineral acids covering 35 pKa units (20 to -15) was assembled. The detailed description of the method, its performance with different functionals (ωB97X-D performed best for organic acids with a mean absolute error (MAE) of 0.8 pKa units, and B2-PLYP performed best for strong acids with an MAE of 1.6 pKa units), the strengths and limitations in the present version, and a future scope to improve the accuracy and reduce its empirical nature are presented herein.

Theoretical Investigation of a Vital Step in the Gas-Phase Formation of Interstellar Ammonia NH2+ + H2 → NH3+ + H.

A crucial step in the gas-phase formation of ammonia in the interstellar medium (ISM) is the reaction of NH2+ with molecular hydrogen. Understanding the electronic structure of the participating species in this reaction and the evaluation of the rate coefficients at interstellar temperatures are, therefore, critical to gain new insights into the mechanisms of formation of interstellar ammonia. We present here the first theoretical results of the rate coefficients of this reaction as a function of temperatures relevant to the ISM, computed using transition-state theory. The results are in reasonable agreement with recent experimental data. This exothermic reaction features a tiny barrier which is primarily a consequence of zero-point energy corrections. The results demonstrate that quantum mechanical tunneling and core-electron correlations play significant roles in determining the rate of the reaction. The noteworthy failure of popular density functionals to describe this reaction is also highlighted.

How an early or late transition state impacts the stereoselectivity of tetrahydropyran formation by intramolecular oxa-Michael addition.

The intramolecular oxa-Michael addition giving tetrahydropyrans has been examined experimentally using both acidic and basic catalysis. With acidic catalysis, the diequatorial product is exclusively obtained in a kinetically controlled reaction in all cases. Under basic conditions at low temperature, the reaction is again under kinetic control, but formation of the axial-equatorial isomer is generally favoured with an (E)-Michael acceptor, although isomerisation to the diequatorial isomer is observed at higher temperatures. Computationally, it is found that the acid catalysed reaction has a late transition state and the kinetic favouring of the diequatorial isomer has a steric explanation. In contrast, under strongly basic conditions, an early transition state is found. Electrostatic effects are likely to be the main contributor to the stereoselectivity for the (E)-isomer and steric interactions for the (Z)-isomer.

Metal-Ion- and Hydrogen-Bond-Mediated Interstellar Prebiotic Chemistry: The First Step in the Formose Reaction.

The formose reaction, which offers a feasible chemical pathway for the prebiotic synthesis of sugars, is a well-studied reaction for over two hundred and 50 years. Yet huge knowledge gaps exist even in the very first step of the formose reaction. In this work, we provide a new and otherwise unintuitive reaction pathway for the gas-phase conversion of formaldehyde to glycolaldehyde (the first step in the formose reaction) occurring in the interstellar medium (ISM). Employing electronic structure calculations (CCSD(T) and DFT methods), we exhaustively probe the role of various metal ions and small molecules detected in the ISM to propose a new mechanism wherein metal-oxygen interactions and hydrogen bonds cooperatively facilitate an otherwise implausible chemical reaction. The reactions involving Mg2+ are throughout found to be barrierless, and those featuring Al+ ions are noted to only have a small barrier. The proton affinities of the small molecules, metal-oxygen interactions, and the extent of C-C-bond formation are found to be the significant factors that influence the barrier heights. The mechanism is also shown to be consistent with well-known experimental details in the terrestrial formose reaction (which could, however, proceed through a different mechanism). Future experimental and theoretical scope arising out of this paper are subsequently discussed.

Breaking a bottleneck: Accurate extrapolation to "gold standard" CCSD(T) energies for large open shell organic radicals at reduced computational cost.

Open Shell organic radicals are principal species involved in many diverse areas such as combustion, photochemistry, and polymer chemistry. Computational studies of such species with an accurate method like coupled-cluster with single and double and perturbative triple (CCSD(T)) may be restricted to systems of modest size due to the steep computational scaling of the method. Herein, we assess the accuracy of extrapolated CCSD(T) energies determined using the connectivity-based hierarchy (CBH) method on medium to large sized radicals. In our method, an MP2 calculation on the target radical is coupled with CCSD(T) energies of fragments determined uniquely by our hierarchy to perform accurate extrapolations. A careful assessment is done with a robust CBH-rad49 test set comprising of 49 diverse cyclic and acyclic radicals with a variety of functional groups. We demonstrate that the extrapolation method with CBH-2 or CBH-3 is sufficient to obtain sub-kcal accuracy. ROMP2 and PMP2 calculations with both Pople-style and Dunning-style basis-sets resulted in mean absolute errors for CCSD(T) extrapolation (full CCSD(T)-extrapolated CCSD(T)) within 0.5 kcal/mol. Further speedup for such CCSD(T) extrapolations are obtained with ROHF-based RI-MP2 calculations. Challenging systems with (a) high ring strain, (b) delocalized character, and (c) spin contamination are identified and analyzed in detail. Finally, we apply our extrapolation method on 10 larger radicals containing 10-15 heavy atoms, where accurate CCSD(T) energies are obtained at a fractional cost of full CCSD(T) calculations.

The successful merger of theoretical thermochemistry with fragment-based methods in quantum chemistry.

CONSPECTUS: Quantum chemistry and electronic structure theory have proven to be essential tools to the experimental chemist, in terms of both a priori predictions that pave the way for designing new experiments and rationalizing experimental observations a posteriori. Translating the well-established success of electronic structure theory in obtaining the structures and energies of small chemical systems to increasingly larger molecules is an exciting and ongoing central theme of research in quantum chemistry. However, the prohibitive computational scaling of highly accurate ab initio electronic structure methods poses a fundamental challenge to this research endeavor. This scenario necessitates an indirect fragment-based approach wherein a large molecule is divided into small fragments and is subsequently reassembled to compute its energy accurately. In our quest to further reduce the computational expense associated with the fragment-based methods and overall enhance the applicability of electronic structure methods to large molecules, we realized that the broad ideas involved in a different area, theoretical thermochemistry, are transferable to the area of fragment-based methods. This Account focuses on the effective merger of these two disparate frontiers in quantum chemistry and how new concepts inspired by theoretical thermochemistry significantly reduce the total number of electronic structure calculations needed to be performed as part of a fragment-based method without any appreciable loss of accuracy. Throughout, the generalized connectivity based hierarchy (CBH), which we developed to solve a long-standing problem in theoretical thermochemistry, serves as the linchpin in this merger. The accuracy of our method is based on two strong foundations: (a) the apt utilization of systematic and sophisticated error-canceling schemes via CBH that result in an optimal cutting scheme at any given level of fragmentation and (b) the use of a less expensive second layer of electronic structure method to recover all the missing long-range interactions in the parent large molecule. Overall, the work featured here dramatically decreases the computational expense and empowers the execution of very accurate ab initio calculations (gold-standard CCSD(T)) on large molecules and thereby facilitates sophisticated electronic structure applications to a wide range of important chemical problems.

An overlooked yet ubiquitous fluoride congenitor: binding bifluoride in triazolophanes using computer-aided design.

Despite its ubiquity during the binding and sensing of fluoride, the role of bifluoride (HF2(-)) and its binding properties are almost always overlooked. Here, we give one of the first examinations of bifluoride recognition in which we use computer-aided design to modify the cavity shape of triazolophanes to better match with HF2(-). Computational investigation indicates that HF2(-) and Cl(-) should have similar binding affinities to the parent triazolophane in the gas phase. Evaluation of the binding geometries revealed a preference for binding of the linear HF2(-) along the north-south axis with a smaller Boltzmann weighted population aligned east-west and all states being accessed rapidly through in-plane precessional rotations of the anion. While the (1)H NMR spectroscopy studies are consistent with the calculated structural aspects, binding affinities in solution were determined to be significantly smaller for the bifluoride than the chloride. Computed geometries suggested that a 20° tilting of the bifluoride (stemming from the cavity size) could account for the 25-fold difference between the two binding affinities, HF2(-) < Cl(-). Structural variations to the triazolophane's geometry and electronic modifications to the network of hydrogen bond donors were subsequently screened in a stepwise manner using density functional theory calculations to yield a final design that eliminates the tilting. Correspondingly, the bifluoride's binding affinity (K ∼ 10(6) M(-1)) increased and was also found to remain equal to chloride in the gas and solution phases. The new oblate cavity appeared to hold the HF2(-) in a single east-west arrangement. Our findings demonstrate the promising ability of computer-aided design to fine-tune the structural and electronic match in anion receptors as a means to control the arrangement and binding strength of a desired guest.

C vs N: which end of the cyanide anion is a better hydrogen bond acceptor?

The ability of the C and N ends of the cyanide anion (CN(-)) as acceptors of hydrogen bonds, an experimentally difficult problem, has been computationally examined in this study. Structures obtained in our previous work involving cyanide binding within the cavity of a triazolophane macrocycle (Chem.-Eur. J. 2011, 17, 9123-9129) were used to analyze the problem. Three different approaches involving (a) breakdown of the triazolophane into smaller components, (b) population analyses, and (c) ion-dipole analyses helped demonstrate that the N terminus of cyanide is a slightly better hydrogen bond acceptor than the C terminus even though it is not the site of protonation or covalent bond formation. This outcome reflects a competition between the preference for noncovalent interactions at the nitrogen and covalent bond formation at the carbon.

Improving physical properties via C-H oxidation: chemical and enzymatic approaches.

Physicochemical properties constitute a key factor for the success of a drug candidate. Whereas many strategies to improve the physicochemical properties of small heterocycle-type leads exist, complex hydrocarbon skeletons are more challenging to derivatize because of the absence of functional groups. A variety of C-H oxidation methods have been explored on the betulin skeleton to improve the solubility of this very bioactive, yet poorly water-soluble, natural product. Capitalizing on the innate reactivity of the molecule, as well as the few molecular handles present on the core, allowed oxidations at different positions across the pentacyclic structure. Enzymatic oxidations afforded several orthogonal oxidations to chemical methods. Solubility measurements showed an enhancement for many of the synthesized compounds.

Binding order of substrate and cofactor in sulfonamide monooxygenase during sulfa drug degradation: in silico studies.

For decades, sulfonamide antibiotics have been used across industries such as agriculture and animal husbandry. However, the use and inadvertent misuse of these antibiotics have resulted in the advent of sulfonamide-drug-resistant strains due to antibiotic pollution. Enzymatic bioremediation of antibiotics remains a potential emerging solution to combat antibiotic pollution. Here, we propose an enzymatic model for the degradation of sulfonamides by Microbacterium sp. We have employed a multi-pronged computational strategy involving - protein structure modelling, ligand docking and molecular dynamics simulations to decipher a plausible binding order for the enzymatic degradation of sulfonamides by the bacterial sulfonamide monooxygenase, SulX. Our results enable us to predict that this degradation is achieved through the sequential binding of the antibiotic sulfonamide followed by the reduced flavin cofactor FMNH2, thereby laying the computational foundation for further advancements in enzyme-mediated degradation of the antibiotic. We also provide a list of experiments which may be performed to verify and follow-up on our in-silico studies.Communicated by Ramaswamy H. Sarma.

New insights on photocatalytic H2 liberation from water using transition-metal oxides: lessons from cluster models of molybdenum and tungsten oxides.

Molecular hydrogen (H2) is an excellent alternative fuel. It can be produced from the abundantly present water on earth. Transition-metal oxides are widely used in the environmentally benign photocatalytic generation of H2 from water, thus actively driving scientific research on the mechanisms for this process. In this study, we investigate the chemical reactions of W3O5(-) and Mo3O5(-) clusters with water that shed light on a variety of key factors central to H2 generation. Our computational results explain why experimentally Mo3O5(-) forms a unique kinetic trap in its reaction while W3O5(-) undergoes a facile oxidation to form the lowest-energy isomer of W3O6(-) and liberates H2. Mechanistic insights on the reaction pathways that occur, as well as the reaction pathways that do not occur, are found to be of immense assistance to comprehend the hitherto poorly understood pivotal roles of (a) differing metal-oxygen and metal-hydrogen bond strengths, (b) the initial electrostatic complex formed, (c) the loss of entropy when these TMO clusters react with water, and (d) the geometric factors involved in the liberation of H2.

Application of the generalized connectivity-based hierarchy to biomonomers: enthalpies of formation of cysteine and methionine.

Computational challenges toward an accurate determination of the enthalpies of formation of amino acids are partly due to the nonavailability of systematic error-canceling thermochemical procedures for such biomonomers. Recently, we developed the connectivity-based hierarchy (CBH) to accurately compute the enthalpies of formations of organic molecules composed of main group elements. Advancing the applicability of CBH to biologically relevant molecules, we have computed the enthalpies of formation of the naturally occurring sulfur-containing amino acids cysteine and methionine which act as fertile testing grounds for the error-canceling ability of thermochemical schemes for biomolecules. We establish herein using the sophisticated error-canceling isoatomic scheme (CBH-2) that relatively inexpensive computational methods with modest basis sets can be used to accurately obtain the enthalpies of formations of the amino acids. Overall, we recommend the use of the isoatomic scheme over the currently popular isodesmic bond separation scheme in future applications in theoretical thermochemistry.

Molecular growth of PANH via intermolecular Coulombic decay.

Nitrogen-bearing polycyclic aromatic hydrocarbons (PANHs) are ubiquitous in space. They are considered precursors to advanced biomolecules identified in meteorites. However, their chemical evolution into biomolecules in photodestructive astrophysical mediums remains a paradox. Here, we show that light can efficiently initiate the molecular mass growth of PANHs. Ultraviolet-photoexcited quinoline monomers, the smallest PANH, were observed to associate and intermolecular Coulombic decay between the associating monomers formed the cations of quinoline-dimer. Molecular rearrangements in the dimer cation lead to a dominant formation of cations heavier than quinoline. The enrichment of these heavier cations over all the other cations reveals the efficiency of this route for the mass growth of PANHs in space. This mechanism also leads to a highly reactive unsaturated PANH-ring via CH loss, a hitherto unknown channel in any photon-driven process. The occurrence of this efficient pathway toward complex molecules points to a rich chemistry in dense interstellar clouds.

Connectivity-Based Hierarchy for theoretical thermochemistry: assessment using wave function-based methods.

The Connectivity-Based Hierarchy (CBH) is a generalized method we have developed recently to accurately predict the thermochemical properties of large closed-shell organic molecules-hydrocarbons as well as nonhydrocarbons. The performance of the different rungs of the hierarchy was initially evaluated using density functional theory. In this study, we have carried out a wave function-based analysis of the CBH method to analyze the influence of electron correlation effects on the reaction energies and enthalpies of formation. For a test set containing unstrained molecules, all levels of theory (HF, MP2, and CCSD(T)) yield small reaction energies and accurate enthalpies of formation even with modest-sized polarized double-ζ or triple-ζ basis sets. For an initial test set of five strained molecules, however, the computed reaction energies are not small, though correlated schemes still yield accurate enthalpies of formation. Thus, small reaction energies cannot be used as the principal criterion to calibrate the success of thermochemical reaction schemes for molecules possessing special features (such as ring strain or aromaticity). Overall, for the relatively large nonaromatic molecules considered in this study, the mean absolute deviation with the MP2 method at the isoatomic CBH-2 rung is comparable to that with the more expensive CCSD(T) method at the higher CBH-3 rung.

Fluxionality in the chemical reactions of transition metal oxide clusters: the role of metal, spin state, and the reactant molecule.

The phenomenon of fluxionality in the reactions of transition metal oxide clusters provides many opportunities in various catalytic and industrial processes. To gain a better understanding into the various factors influencing this phenomenon, we have carried out an electronic structure investigation of the fluxionality pathways when W(3)O(6)(-) and Mo(3)O(6)(-) clusters react with hydrogen sulfide and ammonia. The study illustrates how the metal (W vs Mo), different spin states of the anionic metal oxide cluster (doublet vs quartet), and the nature of the nonmetal in the small molecule (O vs S vs N), all affect the fluxionality pathway. The thermodynamically facile fluxionality pathway with H(2)S detaches both the hydrogens from hydrogen sulfide and can thus be very useful in the petrochemical and desulfurization industries. The fluxionality pathway with NH(3) results in interesting metal-bound imines and bridged amines. However, the overall fluxionality process with NH(3) is found to be thermodynamically unfavorable.

Aza-PNA: Engineering E-Rotamer Selectivity Directed by Intramolecular H-bonding.

The replacement of α(CH2) by NH in monomers of standard aeg PNA and its homologue ß-ala PNA leads to respective aza-PNA monomers (1 and 2) in which the NαH can form either an 8-membered H-bonded ring with folding of the backbone (DMSO and water) or a 5-membered NαH─αCO (water) to stabilize E-type rotamers. Such aza-PNA oligomers with exclusive E rotamers and intraresidue backbone H-bonding can modulate its DNA/RNA binding and assembling properties.