Right- and Left-Handed Helices, What is in between? Interconversion of Helical Structures of Alternating Pyridinedicarboxamide/<i>m</i>‑(phenylazo)azobenzene Oligomers

Some unnatural polymers/oligomers have been designed to adopt a well-defined, compact, three-dimensional folding capability. Azobenzene units are common linkages in these oligomer designs. Two alternating pyridinedicarboxamide/<i>m</i>-(phenylazo)­azobenzene oligomers that can fold into both right- and left-handed helices were studied computationally in order to understand their dynamical properties. Helical structures were shown to be the global minima among the many different conformations generated from the Monte Carlo simulations, and extended conformations have higher potential energies than compact ones. To understand the interconversion process between right- and left-handed helices, replica-exchange molecular dynamic (REMD) simulations were performed on both oligomers, and with this method, both right- and left-handed helices were successfully sampled during the simulations. REMD trajectories revealed twisted conformations as intermediate structures in the interconversion pathway between the two helical forms of these azobenzene oligomers. This mechanism was observed in both oligomers in current study and occurred locally in the larger oligomer. This discovery indicates that the interconversion between helical structures with different handedness goes through a compact and partially folded structure instead of globally unfold and extended structure. This is also verified by the nudged elastic band (NEB) calculations. The temperature weighted histogram analysis method (T-WHAM) was applied on the REMD results to generate contour maps of the potential of mean force (PMF). Analysis showed that right- and left-handed helices are equally sampled in these REMD simulations. In large oligomers, both right- and left-handed helices can be adopted by different parts of the molecule simultaneously. The interconversion between two helical forms can occur in the middle of the helical structure and not necessarily at the termini of the oligomer

Hypercoordinate Iodine Catalysts in Enantioselective Transformation: The Role of Catalyst Folding in Stereoselectivity

The need for metal-free environmentally benign catalysts has provided a strong impetus toward the emergence of hypercoordinate iodine reagents. At this stage of development, molecular insights on the mechanism and origin of stereoselectivity are quite timely. In this study, the origin of stereoinduction in a class of iodoresorcinol-based chiral hypercoordinate iodine-catalyzed synthesis of biologically important spirocyclic bisoxindoles from aryl dianilides has been established by using density functional computations. Formation of an interesting helical fold by the 2,6-chiral amide arms on the resorcinol framework is found to be facilitated by a network of noncovalent interactions. In the chiral environment provided by the helical fold, enantioselectivity is surprisingly controlled in a mechanistic event prior to the ring closure to the final spirocyclic product, unlike that commonly found in spirocyclic ring formation. A vital 1,3-migration of the chiral aryl iodonium (Ar*-I­(CF₃COO)) in an O-iodonium enolate to the corresponding C-iodonium enolate, which retains the chiral memory, holds the key to the enantiocontrol in this reaction and thus renders ring closure to be stereospecific

Cooperative Asymmetric Dual Catalysis Involving a Chiral N‑Heterocyclic Carbene Organocatalyst and Palladium in an Annulation Reaction: Mechanism and Origin of Stereoselectivity

The increasing number of examples on cooperative dual catalysis involving organocatalysts and transition metal catalysts indicate their wider acceptance and utility in synthetic applications. In such reactions, the concurrent activation of substrates is likely to present mechanistic complexities. In one of the studies, designed for intermolecular annulation aimed at making a biologically important class of benzazepines, chiral N-heterocyclic carbenes engage an enal in the form of a Breslow intermediate (nucleophilic partner) and Pd(0) activates rac-vinyl benzoxazinanone as a Pd-π-allyl intermediate (electrophile). Given the current importance and the lack of molecular insights on the origin of high enantio-/diastereoselectivities and cooperativity in such dual catalytic reactions, we have undertaken a detailed computational investigation using density functional theory. The kinetically most accessible Pd-π-allyl intermediate from the (S)- and (R)-vinyl benzoxazinanone is found to be Cre and Csi (where re and si denote the open prochiral faces through which the nucleophile can add), respectively. An energetically favorable change in configuration from Csi to Cre, via a PPh3-induced π–σ–π isomerization, suggests that an enantioconvergent mechanism was responsible for the enrichment of the desired Cre Pd-π-allyl species. Ready availability of Cre and the higher energy transition state (TS) for the alternative nucleophilic addition to the Csi is responsible for the high ee (computed >99%, experimental 99%). Improved shape complementarity between the chiral electrophile and nucleophile in the most preferred C–C bond formation TS as well as the noncovalent interactions (C–H··· π, π···π, and H-bonding) therein dictates the diastereoselectivity. An intramolecular C–N bond formation to the final annulated product is the turnover-determining TS. Molecular insights and energetic features, as obtained through our computations, are found to be in concert with several experimental observations, even beyond the sense and extent of stereoselectivities

Aminoacyl-tRNA Substrate and Enzyme Backbone Atoms Contribute to Translational Quality Control by YbaK

Amino acids are covalently attached to their corresponding transfer RNAs (tRNAs) by aminoacyl-tRNA synthetases. Proofreading mechanisms exist to ensure that high fidelity is maintained in this key step in protein synthesis. Prolyl-tRNA synthetase (ProRS) can misacylate cognate tRNA^Pro with Ala and Cys. The <i>cis</i>-editing domain of ProRS (INS) hydrolyzes Ala-tRNA^Pro, whereas Cys-tRNA^Pro is hydrolyzed by a single domain editing protein, YbaK, <i>in trans</i>. Previous studies have proposed a model of substrate-binding by bacterial YbaK and elucidated a substrate-assisted mechanism of catalysis. However, the microscopic steps in this mechanism have not been investigated. In this work, we carried out biochemical experiments together with a detailed hybrid quantum mechanics/molecular mechanics study to investigate the mechanism of catalysis by Escherichia coli YbaK. The results support a mechanism wherein cyclization of the substrate Cys results in cleavage of the Cys-tRNA ester bond. Protein side chains do not play a significant role in YbaK catalysis. Instead, protein backbone atoms play crucial roles in stabilizing the transition state, while the product is stabilized by the 2′-OH of the tRNA

Substrate and Enzyme Functional Groups Contribute to Translational Quality Control by Bacterial Prolyl-tRNA Synthetase

Aminoacyl-tRNA synthetases activate specific amino acid substrates and attach them via an ester linkage to cognate tRNA molecules. In addition to cognate proline, prolyl-tRNA synthetase (ProRS) can activate cysteine and alanine and misacylate tRNA^Pro. Editing of the misacylated aminoacyl-tRNA is required for error-free protein synthesis. An editing domain (INS) appended to bacterial ProRS selectively hydrolyzes Ala-tRNA^Pro, whereas Cys-tRNA^Pro is cleared by a freestanding editing domain, YbaK, through a unique mechanism involving substrate sulfhydryl chemistry. The detailed mechanism of catalysis by INS is currently unknown. To understand the alanine specificity and mechanism of catalysis by INS, we have explored several possible mechanisms of Ala-tRNA^Pro deacylation via hybrid QM/MM calculations. Experimental studies were also performed to test the role of several residues in the INS active site as well as various substrate functional groups in catalysis. Our results support a critical role for the tRNA 2′-OH group in substrate binding and catalytic water activation. A role is also proposed for the protein’s conserved GXXXP loop in transition state stabilization and for the main chain atoms of Gly261 in a proton relay that contributes substantially to catalysis

[3 + 2]-Cycloadditions with Porphyrin β,β′-Bonds: Theoretical Basis of the Counterintuitive <i>meso</i>-Aryl Group Influence on the Rates of Reaction

Removal of a β,β′-bond from meso-tetraarylporphyrin using [3 + 2]-cycloadditions generates meso-tetraarylhydroporphyrins. Literature evidence indicates that meso-tetraphenylporphyrins react more sluggishly with 1,3-dipoles such as ylides and OsO4 (in the presence of pyridine) than meso-tetrakis(pentafluorophenyl)porphyrin. The trend is counterintuitive for the reaction with OsO4, as this formal oxidation reaction is expected to proceed more readily with more electron-rich substrates. This work presents a density functional theory–based computational study of the frontier molecular orbital (FMO) interactions and reaction profile thermodynamics involved in the reaction of archetypical cycloaddition reactions (a simple ylide, OsO4, OsO4·py, OsO4·(py)2, and ozone) with the β,β′-double bonds of variously fluorinated meso-arylporphyrins. The trend observed for the Type I cycloaddition of an ylide is straightforward, as lowering the LUMO of the porphyrin with increasing meso-phenyl-fluorination also lowers the reaction barrier. The corresponding simple FMO analyses of Type III cycloadditions do not correctly model the reaction energetics. This is because increasing fluorination leads to lowering of the porphyrin HOMO–2, thus increasing the reaction barrier. However, coordination of pyridine to OsO4 preorganizes the transition state complex; lowering of the energy barrier by the preorganization exceeds the increase in repulsive orbital interactions, overall accelerating the cycloaddition and rationalizing the counterintuitive experimental findings

C2 Hydroxyl Group Governs the Difference in Hydrolysis Rates of Methyl-α-d-glycero-d-guloseptanoside and Methyl-β-d-glycero-d-guloseptanoside

A computational investigation into the hydrolysis of two methyl septanosides, methyl-α-d-glycero-d-guloseptanoside and methyl-β-d-glycero-d-guloseptanoside was undertaken. These septanosides were chosen as model compounds for comparison to methyl pyranosides and allowed direct comparison of α versus β hydrolysis rates for a specific septanoside isomer. Results suggest that hydrolysis takes place without proceeding through a transition state, an observation that was suggested in previous computational studies on exocyclic bond cleavage of carbohydrates. A conformational analysis of α- and β-anomers <b>1</b> and <b>2</b> and their corresponding oxocarbenium <b>3</b>, coupled with relaxed potential energy surface (PES) scans (M06-2X/6-311+G**, implicit methanol), indicated that hydrolysis of the α-anomer is favored by 1–2 kcal/mol over the β-anomer, consistent with experiment. Model systems revealed that the lowest energy conformations of the septanoside ring system destabilize the β-anomer by 2–3 kcal/mol relative to the α-anomer, and the addition of a single hydroxyl group at the C2-position on a minimal oxepane acetal can reproduce the PES for the septanoside <b>1</b>. These results suggest that the C2 hydroxyl plays a unique role in the hydrolysis mechanism, destabilizing the septanoside via its proximity to the anomeric carbon and also through its interaction with the departing methanol from the α-anomer via hydrogen-bonding interactions

[MoO(S₂)₂L]^1– (L = picolinate or pyrimidine-2-carboxylate) Complexes as MoS_<i>x</i>‑Inspired Electrocatalysts for Hydrogen Production in Aqueous Solution

Crystalline and amorphous molybdenum sulfide (Mo–S) catalysts are leaders as earth-abundant materials for electrocatalytic hydrogen production. The development of a molecular motif inspired by the Mo–S catalytic materials and their active sites is of interest, as molecular species possess a great degree of tunable electronic properties. Furthermore, these molecular mimics may be important for providing mechanistic insights toward the hydrogen evolution reaction (HER) with Mo–S electrocatalysts. Herein is presented two water-soluble Mo–S complexes based around the [MoO­(S₂)₂L₂]^1– motif. We present ¹H NMR spectra that reveal (NEt₄)­[MoO­(S₂)₂picolinate] (Mo-pic) is stable in a <i>d</i>₆-DMSO solution after heating at 100 °C, in air, revealing unprecedented thermal and aerobic stability of the homogeneous electrocatalyst. Both Mo-pic and (NEt₄)­[MoO­(S₂)₂pyrimidine-2-carboxylate] (Mo-pym) are shown to be homogeneous electrocatalysts for the HER. The TOF of 27–34 s^–1 and 42–48 s^–1 for Mo-pic and Mo-pym and onset potentials of 240 mV and 175 mV for Mo-pic and Mo-pym, respectively, reveal these complexes as promising electrocatalysts for the HER

Anion-Redox Mechanism of MoO(S₂)₂(2,2′-bipyridine) for Electrocatalytic Hydrogen Production

Redox processes of molybdenum-sulfide (Mo-S) compounds are important in the function of materials for various applications from electrocatalysts for the hydrogen evolution reaction (HER) to cathode materials for batteries. Our group has recently described a series of Mo-S molecular HER catalysts based on a MoO­(S₂)₂L₂ structural motif. Herein, reductive pathways of MoO­(S₂)₂bpy (Mo-bpy) (bpy = 2,2′-bipyridine) are presented from both experimental and theoretical studies. We tracked chemical reduction of Mo-bpy with UV–vis spectroscopy using sodium napthalenide (NaNpth) as the reducing agent and found that Mo-bpy undergoes anionic persulfide reduction to form the tetragonal Mo­(VI) complex [MoOS₃]^2–. We also identified silver mercury amalgam as an inert working electrode (WE) for spectroectrochemical (SEC) studies. UV–vis spectra in the presence of trifluoroacetic acid with an applied potential confirmed that Mo-bpy maintains its structure during catalytic cycling. Finally, theoretical catalytic reaction pathways were explored, revealing that Mo=O may function as a proton relay. This finding together with the observed anion reduction as the redox center is of broad interest for amorphous Mo-S (a-MoS_<i>x</i>) electrocatalytic materials and anion-redox chalcogel battery materials

Russian Nesting Doll Complexes of Molecular Baskets and Zinc Containing TPA Ligands

In this study, we examined the structural and electronic complementarities of convex <b>1</b>–Zn­(II), comprising functionalized tris­(2-pyridylmethyl)­amine (TPA) ligand, and concave baskets <b>2</b> and <b>3</b>, having glycine and (<i>S</i>)-alanine amino acids at the rim. With the assistance of ¹H NMR spectroscopy and mass spectrometry, we found that basket <b>2</b> would entrap <b>1</b>–Zn­(II) in water to give equimolar <b>1</b>–Zn⊂<b>2</b>_in complex (<i>K</i> = (2.0 ± 0.2) × 10³ M^–1) resembling Russian nesting dolls. Moreover, <i>C</i>₃ symmetric and enantiopure basket <b>3</b>, containing (<i>S</i>)-alanine groups at the rim, was found to transfer its static chirality to entrapped <b>1</b>–Zn­(II) and, via intermolecular ionic contacts, twist the ligand’s pyridine rings into a left-handed (<i>M</i>) propeller (circular dichroism spectroscopy). With molecular baskets embodying the second coordination sphere about metal-containing TPAs, the here described findings should be useful for extending the catalytic function and chiral discrimination capability of TPAs