The racemization of axially chiral biaryls is a fundamental step toward transforming kinetic resolutions into dynamic kinetic resolutions (DKRs). The high enantiomerization barriers of many biaryl compounds of synthetic relevance, however, may render DKR strategies challenging. Here, we computationally explore the potential of a paraxylene bridged perylene bisimide cyclophane to serve as a conceptually transferrable biaryl enantiomerization catalyst for fundamental biphenyl and binaphthyl scaffolds, as well as the versatile reagent 1,1′-binaphthyl2,2′-diol and a precursor to the heterobiaryl ligand QUINAP. The calculated enantiomerization barriers of the different biaryls decrease by 19.8−73.2% upon complexation, suggesting that the cyclophane may form an effective biaryl racemization catalyst. We find that these observed barrier reductions predominantly originate from a combination of transition structure stabilization through π−π stacking interactions between the shape-complementary transition structures and catalyst, as well as ground-state destabilization of the less complementary reactants, indicating a generalizable strategy toward biaryl racemization catalysis. In exploring all enantiomerization pathways of the biaryls under consideration, we further find a systematic enantiomer- and conformer-dependent chirality transfer from biaryl to cyclophane in host−guest complexes.

The enthalpies of formation and isomerization energies of P₄S_n molecular cages are not experimentally (or theoretically) well known. We obtain accurate enthalpies of formation and isomerization energies for P₄S_n cages (n = 3, 4, 5, 6, and 10) by means of explicitly correlated high-level thermochemical procedures approximating the CCSD(T) and CCSDT(Q) energies at the complete basis set (CBS) limit. The atomization reactions have very significant contribution from post-CCSD(T) correlation effects and, due to the presence of many second-row atoms, the CCSD and (T) correlation energies converge exceedingly slowly with the size of the one-particle basis set. As a result, these cage structures are challenging targets for thermochemical procedures approximating the CCSD(T) energy (e.g., W1-F12 and G4). Our best enthalpies of formation at 298 K (∆_fH°₂₉₈) are obtained from thermochemical cycles in which the P₄S_n cages are broken down into P₂S₂ and S₂ fragments for which highly accurate ∆_fH°₂₉₈ values are available from W4 theory. For the smaller P₄S₃ and P₄S₄ cages, the reaction energies are calculated at the CCSDT(Q)/CBS level and for the larger P₄S₅, P₄S₆, and P₄S₁₀ cages, they are obtained at the CCSD(T)/CBS level. Our best ∆_fH°₂₉₈ values are - 94.5 (P₄S₃), - 108.4 (α-P₄S₄), - 98.7 (β-P₄S₄), - 126.2 (α-P₄S₅), - 126.1 (β-P₄S₅), - 112.7 (γ-P₄S₅), - 144.7 (α-P₄S₆), - 153.9 (β-P₄S₆), - 134.4 (γ-P₄S₆), - 136.3 (δ-P₄S₆), - 118.7 (ε-P₄S₆), and - 215.4 (P₄S₁₀) kJ mol^-1. Interestingly, we find a linear correlation (R2 = 0.992) between the enthalpies of formation of the most stable isomers of each molecular formula and the number of atoms in the P₄S_n cages. We use our best ∆_fH°₂₉₈ values to assess the performance of a number of lower-cost composite ab initio methods. For absolute enthalpies of formation, G4(MP2) and G3(MP2)B3 result in the best overall performance with root-mean-square deviations (RMSDs) of 10.6 and 12.9 kJ mol^-1, respectively, whereas G3, G3B3, and CBS-QB3 result in the worst performance with RMSDs of 27.0-38.8 kJ mol^-1. In contrast to absolute enthalpies of formation, all of the considered composite procedures give a good-to-excellent performance for the isomerization energies with RMSDs below the 5 kJ mol^-1 mark.

Despite versatile applications of functionalized graphene in catalysis, applications of pure, unfunctionalized graphene in catalysis are in their infancy. This work uses both computational and experimental approaches to show that single-layer graphene can efficiently catalyze the racemization of axially chiral BINOL in solution. Using double-hybrid density functional theory (DHDFT) we calculate the uncatalyzed and catalyzed Gibbs free reaction barrier heights in a number of representative solvents of varying polarity: benzene, diphenyl ether, dimethylformamide (DMF), and water. These calculations show that (i) graphene can achieve significant catalytic efficiencies (ΔΔG^≠_cat) varying between 47.2 (in diphenyl ether) and 60.7 (in DMF) kJ mol⁻¹. An energy decomposition analysis reveals that this catalytic activity is driven by electrostatic and dispersion interactions. Based on these computational results, we explore the graphene-catalyzed racemization of axially chiral BINOL experimentally and show that single-layer graphene can efficiently catalyze this process. Whilst the uncatalyzed racemization requires high temperatures of over 200 °C, a pristine single-layer graphene catalyst makes it accessible at 60 °C.

The potent antioxidant α-tocopherol is known to trap two hydroxyl radicals leading to the formation of the experimentally observed α-tocopherylquinone product. Based on double-hybrid density functional theory calculations, we propose for the first time, a reaction mechanism for the conversion of α-tocopherol to α-tocopherylquinone. We find that a water-catalysed ring-opening reaction plays a key role in this conversion. The water catalysts act as proton shuttles facilitating the proton transfers and reducing the ring strain in the cyclic transition structures. On the basis of the proposed reaction mechanism, we proceed to design an antioxidant with potentially enhanced antioxidant properties.

Crotonaldehyde, a common environmental pollutant and product of endogenous lipid peroxidation, reacts with guanine to form DNA adducts with pronounced genotoxicity and mutagenicity. Here, we explore the molecular mechanism of this adduct formation using double-hybrid density functional theory methods. The reaction can be envisaged to occur in a two-step fashion via an aza-Michael addition leading to an intermediate ring-open adduct followed by a cyclization reaction giving the mutagenic ring-closed adduct. We find that (i) a 1,2-type addition is favored over a 1,4-type addition for the aza-Michael addition, and (ii) an initial tautomerization of the guanine moiety in the resulting ring-open adduct significantly reduces the barrier toward cyclization compared to the direct cyclization of the ring-open adduct in its keto-form. Overall, the aza-Michael addition is found to be rate-determining. We further find that participation of a catalytic water molecule significantly reduces the energy barriers of both the addition and cyclization reaction. © 2018 Wiley Periodicals, Inc.

Ingenol esters have been identified as potent anticancer and HIV latency reversing agents. Ingenol-3-angelate was recently approved as a topical treatment for precancerous actinic keratosis skin lesions. It was found, however, that ingenol esters can undergo a series of acyl rearrangements, which may affect their biological potency and the shelf-life of drug formulations. We use double-hybrid density functional theory to explore the mechanisms for the uncatalysed and water-catalysed acyl migrations in a model ingenol ester. The uncatalysed reaction may proceed either via a concerted mechanism or via a stepwise mechanism that involves a chiral orthoester intermediate. We find that the stepwise pathway is kinetically preferred by a significant amount of ΔΔH^‡₂₉₈ = 44.5 kJ mol⁻¹. The uncatalysed 3-O-acyl to 5-O-acyl and 5-O-acyl to 20-O-acyl stepwise rearrangements involve cyclisation and ring-opening steps, both concomitant with a proton transfer. We find that the ring-opening step is the rate-determining step for both rearrangements, with reaction barrier heights of ΔH^‡₂₉₈ = 251.6 and 177.1 kJ mol⁻¹ respectively. The proton transfers in the cyclisation and ring-opening steps may be catalysed by a water molecule. The water catalyst reduces the reaction barrier heights of these steps by over 90 kJ mol⁻¹.

We use Gaussian-4 theory to investigate the reaction mechanism for the conversion of a 2-methylstyrene-based Criegee intermediate into o-toluic acid and 2-methylphenylformate. o-Toluic acid can be formed via an α-hydroxyalkyl-hydroperoxide intermediate with an activation energy of ΔG^‡₂₉₈ = 82.9 kJ mol⁻¹ for the rate-determining-step (RDS). The RDS for the formation of 2-methylphenylformate has an activation energy of ΔG^‡₂₉₈ = 61.9 kJ mol⁻¹. Formation of the o-toluic acid product is more exergonic by 67.4 kJ mol⁻¹. Consistent with recent experimental results, our high-level calculations show that Zo-toluic acid is the thermodynamic product and 2-methylphenylformate is the kinetic product.

Stable equilibrium compounds containing a planar antiaromatic cyclooctatetraene (COT) ring are promising candidates for organic electronic devices such as organic semiconductor transistors. The planarization of COT by incorporation into rigid planar π-systems, as well as by oxidation or reduction has attracted considerable attention in recent years. Using dispersion-corrected density functional theory calculations, we explore an alternative approach of planarizing COT derivatives by adsorption onto graphene. We show that strong π–π stacking interactions between graphene and COT derivatives induce a planar structure with an antiaromatic central COT ring. In addition to being reversible, this strategy provides a novel approach for planarizing COT without the need for incorporation into a rigid structure, atomic substitution, oxidation, or reduction.

Enzymes actuate catalysis through a combination of transition state stabilization and ground state destabilization, inducing enantioselectivity through chiral binding sites. Here, we present a supramolecular model system that employs these basic principles to catalyze the enantiomerization of [5]helicene. Catalysis is hereby mediated not through a network of functional groups but through π-π catalysis exerted from the curved aromatic framework of a chiral perylene bisimide (PBI) cyclophane offering a binding pocket that is intricately complementary with the enantiomerization transition structure. Although transition state stabilization originates simply from dispersion and electrostatic interactions, enantiomerization kinetics are accelerated by a factor of ca. 700 at 295 K. Comparison with the mesocongener of the catalytically active cyclophane shows that upon configurational inversion in only one PBI moiety the catalytic effect is lost, highlighting the importance of precise transition structure recognition in supramolecular enzyme mimics.

In most catalytic applications, graphene is either functionalized or acts as the catalyst support. DFT calculations show on the example of the racemizations of binaphthyl compounds that pure unmodified graphene can directly catalyze chemical processes through stabilizing noncovalent π-π interactions resulting from shape complementarity between transition structures and catalyst.