Comprehensive Benchmark of Association (Free) Energies of Realistic Host–Guest Complexes

The S12L test set for supramolecular Gibbs free energies of association Δ<i>G</i>_<i>a</i> (Grimme, S. Chem. Eur. J. 2012, 18, 9955−9964) is extended to 30 complexes (S30L), featuring more diverse interaction motifs, anions, and higher charges (−1 up to +4) as well as larger systems with up to 200 atoms. Various typical noncovalent interactions like hydrogen and halogen bonding, π–π stacking, nonpolar dispersion, and CH−π and cation–dipolar interactions are represented by “real” complexes. The experimental Gibbs free energies of association (Δ<i>G</i>_<i>a</i>^<i>exp</i>) cover a wide range from −0.7 to −24.7 kcal mol^–1. In order to obtain a theoretical best estimate for Δ<i>G</i>_<i>a</i>, we test various dispersion corrected density functionals in combination with quadruple-ζ basis sets for calculating the association energies in the gas phase. Further, modern semiempirical methods are employed to obtain the thermostatistical corrections from energy to Gibbs free energy, and the COSMO-RS model with several parametrizations as well as the SMD model are used to include solvation contributions. We investigate the effect of including counterions for the charged systems (S30L-CI), which is found to overall improve the results. Our best method combination consists of PW6B95-D3 (for neutral and charged systems) or ωB97X-D3 (for systems with counterions) energies, HF-3c thermostatistical corrections, and Gibbs free energies of solvation obtained with the COSMO-RS 2012 parameters for nonpolar solvents and 2013-fine for water. This combination gives a mean absolute deviation for Δ<i>G</i>_<i>a</i> of only 2.4 kcal mol^–1 (S30L) and 2.1 kcal mol^–1 (S30L-CI), with a mean deviation of almost zero compared to experiment. Regarding the relative Gibbs free energies of association for the 13 pairs of complexes which share the same host, the correct trend in binding affinities could be reproduced except for two cases. The MAD compared to experiment amounts to 1.2 kcal mol^–1, and the MD is almost zero. The best-estimate theoretical corrections are used to back-correct the experimental Δ<i>G</i>_<i>a</i> values in order to get an empirical estimate for the “experimental”, zero-point vibrational energy exclusive, gas phase binding energies. These are then utilized to benchmark the performance of various “low-cost” quantum chemical methods for noncovalent interactions in large systems. The performance of other common DFT methods as well as the use of semiempirical methods for structure optimizations is discussed

Comprehensive Benchmark of Association (Free) Energies of Realistic Host–Guest Complexes

The S12L test set for supramolecular Gibbs free energies of association Δ<i>G</i>_<i>a</i> (Grimme, S. Chem. Eur. J. 2012, 18, 9955−9964) is extended to 30 complexes (S30L), featuring more diverse interaction motifs, anions, and higher charges (−1 up to +4) as well as larger systems with up to 200 atoms. Various typical noncovalent interactions like hydrogen and halogen bonding, π–π stacking, nonpolar dispersion, and CH−π and cation–dipolar interactions are represented by “real” complexes. The experimental Gibbs free energies of association (Δ<i>G</i>_<i>a</i>^<i>exp</i>) cover a wide range from −0.7 to −24.7 kcal mol^–1. In order to obtain a theoretical best estimate for Δ<i>G</i>_<i>a</i>, we test various dispersion corrected density functionals in combination with quadruple-ζ basis sets for calculating the association energies in the gas phase. Further, modern semiempirical methods are employed to obtain the thermostatistical corrections from energy to Gibbs free energy, and the COSMO-RS model with several parametrizations as well as the SMD model are used to include solvation contributions. We investigate the effect of including counterions for the charged systems (S30L-CI), which is found to overall improve the results. Our best method combination consists of PW6B95-D3 (for neutral and charged systems) or ωB97X-D3 (for systems with counterions) energies, HF-3c thermostatistical corrections, and Gibbs free energies of solvation obtained with the COSMO-RS 2012 parameters for nonpolar solvents and 2013-fine for water. This combination gives a mean absolute deviation for Δ<i>G</i>_<i>a</i> of only 2.4 kcal mol^–1 (S30L) and 2.1 kcal mol^–1 (S30L-CI), with a mean deviation of almost zero compared to experiment. Regarding the relative Gibbs free energies of association for the 13 pairs of complexes which share the same host, the correct trend in binding affinities could be reproduced except for two cases. The MAD compared to experiment amounts to 1.2 kcal mol^–1, and the MD is almost zero. The best-estimate theoretical corrections are used to back-correct the experimental Δ<i>G</i>_<i>a</i> values in order to get an empirical estimate for the “experimental”, zero-point vibrational energy exclusive, gas phase binding energies. These are then utilized to benchmark the performance of various “low-cost” quantum chemical methods for noncovalent interactions in large systems. The performance of other common DFT methods as well as the use of semiempirical methods for structure optimizations is discussed

Reaction of OH with Aliphatic and Aromatic Isocyanates

Isocyanates are highly relevant industrial intermediates for polyurethane production. In this work, we used quantum chemistry and transition state theory (TST) to investigate the gas-phase reaction of isocyanates with the OH radical, which is likely one of the most significant chemical sinks for these compounds in the troposphere. para-Tolyl-isocyanate (p-tolyl-NCO) was chosen as a proxy substance for the large-volume aromatic diisocyanate species toluene diisocyanate and methylene diphenyl diisocyanate. Besides p-tolyl-NCO + OH, the model reactions CH3NCO + OH, H2CCHNCO + OH, C6H5-NCO + OH, C6H5-CH3 + OH, and C6H6 + OH have been studied as well to analyze various substituent effects and to allow for comparison with literature. Quantum chemical computations at the CCSD(T)/cc-pV(T,Q → ∞)Z//M06-2X/def2-TZVP level were used as the basis for tunneling-corrected canonical TST calculations. For CH3NCO + OH, H abstraction by OH at the methyl group is the main reaction channel according to our calculations and predicted to be four orders of magnitude faster than OH addition at the NCO group. The calculated rate coefficient (8.8 × 10–14 cm3 molecule–1 s–1) at 298 K is in good agreement with experimental data from the literature. Likewise, for aromatic isocyanates, OH attack at the isocyanate group was found to be only a minor pathway compared to addition to the aromatic ring. In the OH + p-tolyl-NCO reaction, OH addition at the ortho-position relative to the NCO group has been identified as the main initial reaction channel (branching fraction: 53.2%), with smaller but significant branching fractions for the H abstraction at the methyl group (9.6%) as well as the other ring addition reactions (ipso: 2.3%, meta: 24.5%, para: 10.5%, all relative to the NCO group). By comparing OH addition to the aromatic ring in p-tolyl-NCO with the respective ring addition reactions of phenyl isocyanate and toluene, the site-selective reactivity trends observed for ring addition in the OH + p-tolyl-NCO could be rationalized by a dominating positive mesomeric effect of the NCO group and a positive electron-donating (inductive) effect of the CH3 group. Except for the OH ring adduct formed from OH addition in ipso-position to the NCO group, we estimate the first-generation radical intermediates in the OH + p-tolyl-NCO reaction to have sufficiently long lifetimes to react with O2 under atmospheric conditions and undergo typical oxidative reaction cascades like those known for benzene or toluene

Synthesis, Chiral Resolution, and Absolute Configuration of Dissymmetric 4,15-Difunctionalized [2.2]Paracyclophanes

Despite the fact that functionalized planar chiral [2.2]­paracyclophanes have received a lot of attention, the chemistry of pseudo-<i>meta</i> 4,15-distubstituted [2.2]­paracyclophanes is largely unexplored. This is mainly due to the fact that the 4,5-dibromo-functionalized [2.2]­paracyclophane is much less prone to halogen-metal exchange reactions than its constitutional pseudo-<i>ortho</i> or pseudo-<i>para</i> isomers. Here, we give an account of an efficient protocol to achieve this, which allows the synthesis of a broad variety of 4,15-disubstituted [2.2]­paracyclophanes. Furthermore, we were able to resolve several of the racemic compounds via chiral HPLC and assign the absolute configurations of the isolated enantiomers by X-ray diffraction and/or by the comparison of calculated and measured CD-spectra

Synthesis, Chiral Resolution, and Absolute Configuration of Dissymmetric 4,15-Difunctionalized [2.2]Paracyclophanes

Despite the fact that functionalized planar chiral [2.2]­paracyclophanes have received a lot of attention, the chemistry of pseudo-<i>meta</i> 4,15-distubstituted [2.2]­paracyclophanes is largely unexplored. This is mainly due to the fact that the 4,5-dibromo-functionalized [2.2]­paracyclophane is much less prone to halogen-metal exchange reactions than its constitutional pseudo-<i>ortho</i> or pseudo-<i>para</i> isomers. Here, we give an account of an efficient protocol to achieve this, which allows the synthesis of a broad variety of 4,15-disubstituted [2.2]­paracyclophanes. Furthermore, we were able to resolve several of the racemic compounds via chiral HPLC and assign the absolute configurations of the isolated enantiomers by X-ray diffraction and/or by the comparison of calculated and measured CD-spectra

Substituent Effects and Supramolecular Interactions of Titanocene(III) Chloride: Implications for Catalysis in Single Electron Steps

The electrochemical properties of titanocene­(III) complexes and their stability in THF in the presence and absence of chloride additives were studied by cyclic voltammetry (CV) and computational methods. The anodic peak potentials of the titanocenes can be decreased by as much as 0.47 V through the addition of an electron-withdrawing substituent (CO₂Me or CN) to the cyclopentadienyl ring when compared with Cp₂TiCl. For the first time, it is demonstrated that under the conditions of catalytic applications low-valent titanocenes can decompose by loss of the substituted ligand. The recently discovered effect of stabilizing titanocene­(III) catalysts by chloride additives was analyzed by CV, kinetic, and computational studies. An unprecedented supramolecular interaction between [(C₅H₄R)₂TiCl₂]⁻ and hydrochloride cations through reversible hydrogen bonding is proposed as a mechanism for the action of the additives. This study provides the critical information required for the rational design of titanocene-catalyzed reactions in single electron steps

HYDROPHOBE Challenge: A Joint Experimental and Computational Study on the Host–Guest Binding of Hydrocarbons to Cucurbiturils, Allowing Explicit Evaluation of Guest Hydration Free-Energy Contributions

The host–guest complexation of hydrocarbons (22 guest molecules) with cucurbit[7]­uril was investigated in aqueous solution using the indicator displacement strategy. The binding constants (10³–10⁹ M^–1) increased with guest size, pointing to the hydrophobic effect and dispersion interactions as driving forces. The measured affinities provide unique benchmark data for the binding of neutral guest molecules. Consequently, a computational blind challenge, the HYDROPHOBE challenge, was conducted to allow a comparison with state-of-the-art computational methods for predicting host–guest affinity constants. In total, three quantum-chemical (QM) data sets and two explicit-solvent molecular dynamics (MD) submissions were received. When searching for sources of uncertainty in predicting the host–guest affinities, the experimentally known hydration energies of the investigated hydrocarbons were used to test the employed solvation models (explicit solvent for MD and COSMO-RS for QM). Good correlations were obtained for both solvation models, but a rather constant offset was observed for the COSMO data, by ca. +2 kcal mol^–1, which was traced back to a required reference-state correction in the QM submissions (2.38 kcal mol^–1). Introduction of the reference-state correction improved the predictive power of the QM methods, particularly for small hydrocarbons up to C5