Stereoelectronic and dynamical effects dictate nitrogen inversion during valence isomerism in benzene imine.

Benzene imine (1) ⇌ 1H-azepine (2) isomerization occurs through sequential valence and endo-exo isomerism. Quantum chemical and quasiclassical trajectory (QCT) simulations reveal the coupled reaction pathway - ring-expansion followed by N-inversion to the most stable isomer, exo-1H-azepine (Exo-2). Direct-dynamics produce a mixture of endo- and exo-1H-azepine stereoisomers and govern the endo-1H-azepine (Endo-2) ⇌ exo-1H-azepine (Exo-2) ratio. Exo-2 is computationally identified as the most stable product while Endo-2 is fleetingly stable with a survival time (S T) ∼50 fs. N-Methyl substitution exclusively results in an exo-1-methyl-1H-azepine isomer. F-substitution at the N-site increases the barrier for N-inversion and alters the preference by stabilizing Endo-2. Interestingly, the exo-1-fluoro-1H-azepine (minor product) is formed through bifurcation via non-statistical dynamics. A highly concaved Arrhenius plot for 1a → 2a highlights the influence of heavy-atom tunneling on valence isomerism, particularly at low temperatures. Heavy-atom tunneling also results in a normal N-H(D) secondary KIE above 100 K even though the increase in hybridization from sp2 to sp3 at nitrogen should cause an inverse KIE classically.

Harnessing Noncovalent Interactions for a Directed Evolution of a Six-Component Molecular Crystal.

Building up on weak orthogonal interactions in supramolecular chemistry, a six-component crystal is designed. Using five distinctly different noncovalent forces, namely, hydrogen bonding, halogen bonding, cation-π, anion-π, and ion-pair interactions, three six-component crystals were designed with crown-ether (I), thiourea (II), 2,3,5,6-tetrafluoro-1,4-dibromobenzene (III), lone-pair donating anion (IV), ammonium cation (V), and electron-rich aromatic ring (VI). The M06-2X functional which is highly suitable in describing other weak interactions fails for ion-pairs. Tuned range-separated (RS)-DFT calculations are found to be capable in describing the ionic interactions in molecular solids. Molecular dynamics simulations show that the predicted multicomponent crystals are stable at room temperature and reducing the ionic charges for the ion-pairs destabilizes them. The strong electrostatic interactions between the three ion-pairs, NH4+···ClO4-, NH4+···HSO4-, and NH4+···HCO3- is the primary driving force for the stabilization of the six-component crystal. Using a hybrid of strong and weak intermolecular interactions, one may generate exotic molecular complexity like n-component crystals.

Molecular designs for expanding the limits of ultralong C-C bonds and ultrashort HH non-bonded contacts.

Recent experiments have reported the formation of very long C-C bonds (dC-C > 1.80 Å) and very short HH non-bonded contacts (dHH < 1.5 Å) in several sets of molecules. Both these rare phenomena arise due to specific donor-acceptor interactions and London dispersion interactions respectively. Favorable negative hyperconjugation, namely H2N(lone-pair) →σ*(C-C), creates an ultralong C-C bond in diamino-o-carborane with dC-C > 1.829 Å and a planar amine reminiscent of a transition-state like structure for ammonia inversion. The small and narrow barrier favours rapid inversion through quantum mechanical tunnelling (QMT) and produces a translationally averaged planar amine as observed in the experiments. On the other hand, designing specific confined molecular cavities or chambers like in,in-bis(hydrosilane) or its germanane analogs furnishes an ultrashort HH distance = 1.47 Å and 1.38 Å respectively. The predisposition of such closely placed HH contacts arises from the rather effective attractive dispersion interactions between them. Controlling the strength of the dispersion interactions provides a rich landscape for realizing such close HH distances. Molecular design ably assisted by computational modeling to further tune these interactions provides new avenues to break the glass-ceilings of ultralong C-C bonds or ultrashort HH contacts. Dispersion-corrected DFT calculations and ab initio molecular dynamics simulations generate a large library of such unique features in a diverse class of molecules. This feature article highlights the design principles to realize hitherto longest C-C bonds/shortest HH contacts.

Harnessing the Efficacy of 2-Pyridone Ligands for Pd-Catalyzed (ß/γ)-C(sp3)-H Activations.

Mechanisms of palladium-aminooxyacetic acid and 2-pyridone-enabled cooperative catalysis for the ß- and γ-C(sp3)-H functionalizations of ketones are investigated with density functional theory. 2-Pyridone-assisted dissociation of the trimeric palladium acetate [Pd3(OAc)6] is found to be crucial for these catalytic pathways. The evolution of the [6,6]-membered palladacycles (Int-4) are elucidated and are active complexes in Pd(II/IV) catalytic cycles. Nevertheless, 2-pyridone acts as an external ligand, which accelerates ß-C(sp3)-H activation. Computational investigations suggest that the C(sp3)-H bond activation is the rate-limiting step for both the catalytic processes. To overcome the kinetic inertness, an unsubstituted aminooxyacetic acid auxiliary is used for the ß-C(sp3)-H activation pathway to favor the formation of the [5,6]-membered palladacycle intermediate, Int-IV. Among the several modeled ligands, 3-nitro-5-((trifluoromethyl)sulfonyl)pyridine-2(1H)-one (L8) is found to be highly valuable for both the (ß/γ)-C(sp3)-H functionalization catalytic cycles. A favorable free energy pathway of late-stage functionalization of (R)-muscone paves the path to design other bioactive molecules.

Transition-State-like Planar Structures for Amine Inversion with Ultralong C-C Bonds in Diamino-o-carborane and Diamino-o-dodecahedron.

Umbrella-like inversion of pyramidalized amines proceed through a planar transition state (TS). Stabilization of the TS through N(lone-pair) → σ*(C-C) "negative hyperconjugation" in diamino-o-carborane (1) causes rapid inversion in the amine, which results in the observation of a planarized -NH2 from the X-ray crystal structure. This proceeds through quantum mechanical tunneling across the small and narrow barrier (low pyramidalization). Tuning this secondary orbital (donor-acceptor) interaction for various derivatives of 1 and diamino-o-dodecahedron (2) provides a rational approach toward increasing dC-C to as large as 2.001, 2.011, and 1.807 Å for 1b (amino oxide-o-carborane), 1i (di-N,N-dimethylamino-o-carborane), and 2g (di-N,N-diisopropylamino-o-dodecahedron), respectively.

Gold(I)-Catalyzed Intramolecular Diels-Alder Reaction: Evolution of Trappable Intermediates via Asynchronous Transition States.

In recent years allenes have been shown to be capable of exhibiting several modes of cycloadditions in the presence of transition metal catalysts that are otherwise unattainable for ethylene and acetylene. Herein, we predict that the [1 + 2]-cycloaddition pathway is accessible in a Au(I)-catalyzed reaction of allene with cis-1,3-butadiene. The electrophilicity of the central carbon of allene can be harnessed using a Au(I)-catalyst and -COOMe mediated stereoelectronics. A potential energy modification approach is applied to stabilize the diradicaloid intermediates. Our simulations establish that the product selectivity of the [4 + 2]- and [2 + 2]-pathways are steered by dynamical effects. Furthermore, a bioinspired version of this reaction is shown to afford an alternative synthetic pathway for proline and azepine analogs indicating rich prospects for thermal allene-butadiene reactions in drug discovery.

Dynamical Effects along the Bifurcation Pathway Control Semibullvalene Formation in Deazetization Reactions.

Post-transition-state dynamics during the deazetization of 3 resulting in two degenerate semibullvalenes (4 and 5) have been investigated with density functional theory (DFT) and quasi-classical trajectory (QCT) calculations. Removal of N2 from 3 occurs through a synchronous and concerted pathway through an ambimodal transition-state (TS1). In addition to TS2, the exclusively anticipated product from minimum energy pathway (MEP) calculations, trajectories initiated from TS1 produce 4, TS2, and 5 in 1:1:1 ratio. Isotopic substitutions (12C(13C/14C)-H(D) at 1-2 positions) result in purely Newtonian kinetic isotope effects (4:5 ≈ 1.4 for 13C1-13C2), an unequivocal evidence for dynamics controlled product formation.

Structure and Electronic Properties of Unnatural Base Pairs: The Role of Dispersion Interactions.

Recent reports of the successful incorporation of unnatural base pairs (UBPs), such as d5SICS-dNaM, in the gene sequence and replication with DNA is an important milestone in synthetic biology. Followed by this, several other UBPs, such as dTPT3-dNaM, dTPT3-dFIMO, dTPT3-IMO, dTPT3-FEMO, FTPT3-NaM, FTPT3-FIMO, FTPT3-IMO, and FTPT3-FEMO, have demonstrated similar or better retention and fidelity inside cells. Of these base pairs, dNaM-dTPT3 has been optimized to be a better fit inside a pAIO plasmid. Based on both implicit and explicit dispersion-corrected density functional theory (DFT) calculations, we show that although this set of UBPs is significantly diverse in elemental and structural configuration, the members do share a common trait of favoring a slipped parallel stacked dimer arrangement. Unlike the natural bases (A, T, G, C, and U), this set of UBPs has a negligible affinity for a Watson-Crick (WC)-type planar structure because they are invariably more stable within slipped parallel stacked orientations. We also observed that all the UBPs have either similar or higher binding energies with the natural bases in similar stacked orientations. When arranged between two natural base pairs, the UBPs exhibited a binding energy similar to that of three-base sequences of natural bases. Our computational data show that the most promising base pairs are 5SICS-NaM, TPT3-NaM, and TPT3-FEMO. These results are consistent with recent progress on experimental research into UBPs along with our previous calculations on the d5SICS-dNaM pair and, therefore, strengthen the hypothesis that hydrogen bonding might not be absolutely essential and that interbase stacking dispersion interactions play a key role in the stabilization of genetic materials.

Exploring Ultrashort Hydrogen-Hydrogen Nonbonded Contacts in Constrained Molecular Cavities.

Confined molecular chambers such as macrocycle bridged E1-H···H-E2 (E1(E2) = Si(Si), 1) exhibit rare ultrashort H···H nonbonded contacts (d(H···H) = 1.56 Å). In this article, on the basis of density functional theory and ab initio molecular dynamics simulations, we propose new molecular motifs where d(H···H) can be reduced to 1.44 Å (E1(E2) = Si(Ge), 3). Further tuning the structure of the macrocycle by replacing the bulky phenyl groups by ethylenic spacers and substitution of the H-atoms by -CN groups makes the cavity more compact and furnishes even shorter d(H···H) = 1.38 Å (E1(E2) = Ge(Ge), 8). These unusually close H···H nonbonded contacts originate from the strong attractive noncovalent interactions between them, which are evident from various computational indicators, namely, NCI, Wiberg bond index, relaxed force constant, quantum theory of atoms in molecules, and natural orbitals for chemical valence combined with the extended transition state method analyses. Substantial stabilization of the in,in-configuration (exhibiting short H···H contacts) compared with the out,out-configuration (by ∼5.7 kcal/mol) and statistically insignificant fluctuations in ⟨d(H···H)⟩ and ⟨θav⟩(θ(E1(E2)-H···H = 152°) at room temperature confirm that the ultrashort H···H distances in these molecules are thermodynamically stable and would be persistent under ambient experimental conditions.