Local Nature of Substituent Effects in Stacking Interactions

Popular explanations of substituent effects in π-stacking interactions hinge upon substituent-induced changes in the aryl π-system. This entrenched view has been used to explain substituent effects in countless stacking interactions over the past 2 decades. However, for a broad range of stacked dimers, it is shown that substituent effects are better described as arising from local, direct interactions of the substituent with the proximal vertex of the other ring. Consequently, substituent effects in stacking interactions are additive, regardless of whether the substituents are on the same or opposite rings. Substituent effects are also insensitive to the introduction of heteroatoms on distant parts of either stacked ring. This local, direct interaction viewpoint provides clear, unambiguous explanations of substituent effects for myriad stacking interactions that are in accord with robust computational data, including DFT-D and new benchmark CCSD(T) results. Many of these computational results cannot be readily explained using traditional π-polarization-based models. Analyses of stacking interactions based solely on the sign of the electrostatic potential above the face of an aromatic ring or the molecular quadrupole moment face a similar fate. The local, direct interaction model provides a simple means of analyzing substituent effects in complex aromatic systems and also offers simple explanations of the crystal packing of fluorinated benzenes and the recently published dependence of the stability of protein–RNA complexes on the regiochemistry of fluorinated base analogues [<i>J. Am. Chem. Soc.</i> <b>2011</b>, <i>133</i>, 3687–3689]

Quantifying the Role of Anion−π Interactions in Anion−π Catalysis

Matile et al. introduced the concept of anion−π catalysis [<i>Angew. Chem., Int. Ed.</i> <b>2013</b>, <i>52</i>, 9940; <i>J. Am. Chem. Soc.</i> <b>2014</b>, <i>136</i>, 2101], reporting naphthalene diimide (NDI)-based organocatalysts for the Kemp elimination reaction. We report computational analyses of the operative noncovalent interactions, revealing that anion−π interactions actually increase the activation barriers for some of these catalyzed reactions. We propose new catalysts that are predicted to achieve significant lowering of the activation energy through anion−π interactions

Importance of Electrostatic Effects in the Stereoselectivity of NHC-Catalyzed Kinetic Resolutions

Three <i>N</i>-heterocyclic carbene (NHC) catalyzed kinetic resolutions (KR) and one dynamic kinetic resolution (DKR) were examined using modern density functional theory methods to identify the origin of catalytic activity and selectivity and the role of cocatalysts in these reactions. The results reveal electrostatic interactions as the common driver of selectivity. Furthermore, in the case of a recently described KR of BINOL-derivatives, a computational examination of the full catalytic cycle reveals that a benzoic acid byproduct changes the turnover limiting transition step, obviating the need for an added cocatalyst. Together, these data provide key insights into the activity and selectivity of NHC-catalyzed kinetic resolutions, and underscore the importance of electrostatic interactions as a driver of selectivity

Electrostatic Basis for Enantioselective Brønsted-Acid-Catalyzed Asymmetric Ring Openings of <i>meso</i>-Epoxides

Computational studies of three chiral phosphoric-acid-catalyzed asymmetric ring-openings of <i>meso</i>-epoxides show that the enantioselectivity of these reactions stems from favorable electrostatic interactions of the preferred transition state with the phosphoryl oxygen of the catalyst. The 3,3′-aryl substituents of the catalysts, which are vital for enantioselectivity, serve primarily to create a narrow binding groove that restricts the substrate orientations within the chiral electrostatic environment of the phosphoric acid. This electrostatic, enzyme-like mode of stereoinduction appears to be general for these reactions and suggests a complementary means of achieving stereoinduction in chiral phosphoric acid catalysis. Finally, examination of the mechanism for subsequent reactions in List’s organocatalytic cascade for the synthesis of β-hydroxythiols (Monaco, M. R.; Prévost, S.; List, B. <i>J. Am. Chem. Soc</i>. <b>2014</b>, <i>136</i>, 16982) explains the requirement for elevated temperatures for the latter steps in the cascade sequence, as well as the lack of reactivity of five-membered cyclic epoxides in this transformation

Intercolumnar Interactions Control the Local Orientations within Columnar Stacks of Sumanene and Sumanene Derivatives

Density functional theory, symmetry-adapted perturbation theory, and classical molecular dynamics simulations were used to understand the local orientations within columnar stacks of sumanene, sumaneneone, sumanenedione, and sumanenetrione, which can impact the electronic properties of the resulting materials. Unlike sumanene and sumaneneone, which pack in staggered columnar arrangements, sumanenetrione adopts an eclipsed configuration in the solid state. Reliable quantum chemical computations on stacked dimers and trimers of these molecules reveal that all four systems prefer staggered configurations. The tendency of sumanenetrione to pack in an eclipsed configuration was explained based on repulsive intercolumnar O···O interactions that override the inherent tendency of stacked columns to be staggered. Sumanenedione, for which crystal structure data are not available, was predicted to exhibit columnar packing with mixed staggered and eclipsed orientations

Competing Noncovalent Interactions Control the Stereoselectivity of Chiral Phosphoric Acid Catalyzed Ring Openings of 3‑Substituted Oxetanes

The noncovalent interactions responsible for enantioselectivity in organocatalytic oxetane ring openings were quantified using density functional theory (DFT) computations. Data show that the mode of stereoinduction in these systems differs markedly for different substituted oxetanes, highlighting the challenge of developing general stereochemical models for such reactions. For oxetanes monosubstituted at the 3-position, the enantioselectivity is primarily due to differential CH···π interactions between the mercaptobenzothiazole nucleophile and the aromatic backbone of the catalyst. This can be contrasted with 3,3-disubstituted oxetanes, for which interactions between an oxetane substituent and the phosphoric acid functionality and/or the anthryl groups of the catalyst become more important. The former effects are particularly important in the case of 3-OH-substituted oxetanes. Overall, these reactions demonstrate the diversity of competing noncovalent interactions that control the stereoselectivity of many phosphoric acid catalyzed reactions

Benchmark Torsional Potentials of Building Blocks for Conjugated Materials: Bifuran, Bithiophene, and Biselenophene

The utility of π-conjugated oligomers and polymers continues to grow, and oligofurans, oligothiophenes, and oligoselenophenes have shown great promise in the context of organic electronic materials. Vital to the performance of these materials is the maintenance of planarity along the conjugated backbone. Consequently, there has been a great deal of work modeling the torsional behavior of these prototypical components of conjugated organic materials both in the gas and condensed phases. Such simulations generally rely on classical molecular mechanics force fields or density functional theory (DFT) potentials. Unfortunately, there is a lack of benchmark quality, converged <i>ab initio</i> torsional potentials for bifuran, bithiophene, and biselenophene against which these lower level theoretical methods can be calibrated. To remedy this absence, we present highly accurate torsional potentials for these three molecules based on focal point analyses. These potentials will enable the benchmarking and parametrization of DFT functionals and classical molecular mechanics force fields. Here, we provide an initial assessment of the performance of common DFT functional and basis set combinations, to identify methods that provide robust descriptions of the torsional behavior of these prototypical building blocks for conjugated systems

Explaining the Disparate Stereoselectivities of <i>N</i>‑Oxide Catalyzed Allylations and Propargylations of Aldehydes

A simple electrostatic model explains the enhanced stereoselectivity of <i>N</i>-oxide catalyzed allylations compared to propargylations, which in turn explicates the dearth of stereoselective <i>N</i>-oxide propargylation catalysts. These results suggest that <i>N</i>-oxide catalysts that are effective for both allylations and propargylations can be designed by targeting inherently stereoselective ligand configurations and through the manipulation of distortion effects in the operative transition states

Enantioselectivity in Catalytic Asymmetric Fischer Indolizations Hinges on the Competition of π‑Stacking and CH/π Interactions

Computational analyses of the first catalytic asymmetric Fischer indolization (<i>J. Am. Chem. Soc</i>. <b>2011</b>, <i>133</i>, 18534) reveal that enantioselectivity arises from differences in hydrogen bonding and CH/π interactions between the substrate and catalyst in the operative transition states. This selectivity occurs despite strong π-stacking interactions that reduce the enantioselectivity

Accurate Thermochemistry of Hydrocarbon Radicals via an Extended Generalized Bond Separation Reaction Scheme

Detailed knowledge of hydrocarbon radical thermochemistry is critical for understanding diverse chemical phenomena, ranging from combustion processes to organic reaction mechanisms. Unfortunately, experimental thermochemical data for many radical species tend to have large errors or are lacking entirely. Here we develop procedures for deriving high-quality thermochemical data for hydrocarbon radicals by extending Wheeler et al.’s “generalized bond separation reaction” (GBSR) scheme (<i>J. Am. Chem. Soc</i>., <b>2009</b>, <i>131</i>, 2547). Moreover, we show that the existing definition of hyperhomodesmotic reactions is flawed. This is because transformation reactions, in which one molecule each from the predefined sets of products and reactants can be converted to a different product and reactant molecule, are currently allowed. This problem is corrected via a refined definition of hyperhomodesmotic reactions in which there are equal numbers of carbon–carbon bond types <i>inclusive</i> of carbon hybridization and number of hydrogens attached. Ab initio and density functional theory (DFT) computations using the expanded GBSRs are applied to a newly derived test set of 27 hydrocarbon radicals (HCR27). Greatly reduced errors in computed reaction enthalpies are seen for hyperhomodesmotic and other highly balanced reactions classes, which benefit from increased matching of hybridization and bonding requirements. The best performing DFT methods for hyperhomodesmotic reactions, M06-2X and B97-dDsC, give average deviations from benchmark computations of only 0.31 and 0.44 (±0.90 and ±1.56 at the 95% confidence level) kcal/mol, respectively, over the test set. By exploiting the high degree of error cancellation provided by hyperhomodesmotic reactions, accurate thermochemical data for hydrocarbon radicals (e.g., enthalpies of formation) can be computed using relatively inexpensive computational methods