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Substituent effects in cation/π interactions have been examined using the M05-2X DFT functional and CCSD(T) paired with triple-ζ quality basis sets. In contrast to popular, intuitive models, trends in substituent effects are accounted for primarily by direct, through-space interactions with the substituents. While there is some scatter in the data, which is attributed to π-polarization, the trend in substituents effects in cation/π interactions is captured by an additive model in which the substituent is isolated from the aryl ring. Similarly, changes in the electrostatic potential at a point above the center of substituted benzenes arise largely from through-space effects of the substituents. π-polarization is not the dominant underlying cause.Cation/π interactions are ubiquitous in molecular biology, drug design, and host-guest chemistry. 1,2 These strong non-covalent interactions, which often involve an alkali metal or tetraalkylammonium cation interacting with the face of an aromatic ring, were thrust into the limelight by Dougherty and co-workers. 1,3-6 Substituent effects in cation/π interactions have been exploited to characterize binding sites of nicotinic acetylcholine receptors and have provided insight into these systems in the absence of detailed structural information. 5 While numerous factors contribute to binding, 7 substituent effects in cation/π interactions are usually explained using simple electrostatic models. 1 Mecozzi, West, and Dougherty 6 demonstrated that the electrostatic potential (ESP) evaluated at a single point above the center of a substituted aryl ring predicts the strength of the cation/π interaction; more negative ESPs indicate stronger interactions. In this context, Dougherty et al. 1,6 stressed the importance of inductive effects over π-resonance, based on correlations with σ m rather than σ p . However, Hunter and co-workers and others 8 have attributed substituent effects to the polarization of the aryl π-system. Below, we show that π-polarization models of the cation/π interaction are flawed; substituent effects arise primarily from direct, through-space interactions with the substituents.swheele2@chem.ucla.edu; houk@chem.ucla.edu. Interaction energies [E int (C 6 H 5 X), kcal mol −1 ] for Na + above the center of 25 substituted benzenes were computed using M05-2X/6-311+G(2df,2p). 9 The equilibrium distance (R e ) of Na + above the ring centroid was found by scanning normal to the benzene plane at 0.05 Å intervals with the substituted benzene fixed at the M05-2X/6-31+G(d) optimized geometry. The mean R e value for the 25 systems studied is 2.37 Å. CCSD(T) energies were evaluated for five substituents (H, CN, F, CH 3 , and NH 2 ) at M05-2X geometries using the cc-pCVTZ basis set for Na and aug-cc-pVTZ otherwise. These correlated computations, denoted CCSD(T)/ AVTZ henceforth, employed the standard frozen-core approximation for all atoms except Na, for which only the 1s orbital was frozen. M05-2X slightly overestimates the C 6 H 5 X ⋯ Na + binding energy relative to ...

Substituent effects in Cl − ••• C 6 H 6−n X n complexes, models for anion/π interactions, have been examined using density functional theory and robust ab initio methods paired with large basis sets. Predicted interaction energies for 83 model Cl − ••• C 6 H 6−n X n complexes span almost 40 kcal mol −1 and show an excellent correlation (r = 0.99) with computed electrostatic potentials. In contrast to prevailing models of anion/π interactions, which rely on substituent-induced changes in the aryl π-system, it is shown that substituent effects in these systems are due mostly to direct interactions between the anion and the substituents. Specifically, interaction energies for Cl − ••• C 6 H 6−n X n complexes are recovered using a model system in which the substituents are isolated from the aromatic ring and π-resonance effects are impossible. Additionally, accurate potential energy curves for Cl − interacting with prototypical anion-binding arenes can be qualitatively reproduced by adding a classical charge-dipole interaction to the Cl − ••• C 6 H 6 interaction potential. In substituted benzenes, binding of anions arises primarily from interactions of the anion with the local dipoles induced by the substituents, not changes in the interaction with the aromatic ring itself. When designing anion-binding motifs, phenyl rings should be viewed as a scaffold upon which appropriate substituents can be placed, because there are no attractive interactions between anions and the aryl π-system of substituted benzenes.

Computational chemistry and biochemistry began with Isaac Newton's classical mechanics in the 17th century and the establishment of quantum mechanics in the 1920s. Enabled by extraordinary advances in computers, in the last half century, this field has become a robust partner with experiment. The challenges facing computational chemists and biochemists, the Holy Grails of the field, are described. These include the development of a highly accurate density functional, ideally one that has universal chemical accuracy, and accurate polarizable force fields, as well as methods to handle efficiently the massive number of computations that must be performed for molecular dynamics and for the computation of flexible systems such as proteins. We estimate when the breakthroughs that will make computation a powerful engine for chemical discovery and design will be achieved. The Holy Grails of this field involve methods to enable the accurate and efficient prediction of structures and properties of complex biological systems and materials. The principal Holy Grail is a routine computational method for the prediction and design of multicomponent, often heterogeneous, functional systems and devices.

Short, strong hydrogen bonds are common in charged systems in the gas phase, but the importance of such bonding in enzymatic catalysis has been the subject of considerable controversy. Confusion has arisen about the relationship among bond strength, the "low-barrier" or "no-barrier" nature of the hydrogen bonding, the role of pK a matching, the covalent or electrostatic nature of the bonding, and the role of solvation on the strengths of these types of hydrogen bonds. We have attempted to strip away the "Alice in Wonderland" quality of the definitions in this field by defining, through high-level calculations, when short-strong hydrogen bonds do and do not occur. The strengths and geometries of several types of hydrogen bonds involving anions have been investigated by ab initio quantum mechanical calculations. For a series of enols hydrogen-bonded to enolates, the strengths of the short, strong gas-phase hydrogen bonds are linearly related to the differences between the proton affinities (PA) of the two anions which share the proton. The bond strength is also related to the O‚‚‚O distance between them. There is no discontinuity at ∆PA ) 0, and hydrogen-bonding becomes even stronger in a computational experiment when the PA of the H-bond acceptor exceeds that of the donor. "Low-barrier" hydrogen bonds with single-well minima after inclusion of zero-point energies occur when ∆PA is near 0, but no special stability accrues when the double-well minimum becomes single-well. The maleic/fumaric and mesaconic/citraconic systems studied by Drueckhammer have been investigated computationally. The influence of solvation on hydrogen-bond strength was studied using solvent cavity models. Small increases in dielectric constant from the gas-phase value ( ) 1) rapidly reduce the strengths of charged hydrogen bonds. Short, strong hydrogen bonds occur only with charged systems, and only then in nonpolar ( < 10) environments. Alternative mechanisms are often available to account for enzymatic catalysis; the example of orotidine monophosphate decarboxylase is discussed.

Pericyclic reactions are among the most powerful synthetic transformations to make multiple regioselective and stereoselective carbon-carbon bonds1. These reactions have been widely applied for the synthesis of biologically active complex natural products containing contiguous stereogenic carbon centers2–6. Despite the prominence of pericyclic reactions in total synthesis, only three naturally existing enzymatic examples, intramolecular Diels-Alder (IMDA) reaction7, Cope8 and Claisen rearrangements9, have been characterized. Here, we report the discovery of a S-adenosyl-L-methionine (SAM) dependent enzyme LepI that can catalyse stereoselective dehydration, bifurcating IMDA/hetero-DA (HDA) reactions via an ambimodal transition state, and a [3,3]-sigmatropic retro-Claisen rearrangement leading to the formation of dihydopyran core in the fungal natural product leporin10. Combined in vitro enzymatic characterization and computational studies provide evidence and mechanistic insight about how the O-methyltransferase-like protein LepI regulates the bifurcating biosynthetic reaction pathways (“direct” HDA and “byproduct recycle” IMDA/retro-Claisen reaction pathways) by utilizing SAM as the cofactor in order to converge to the desired biosynthetic end product. This work highlights that LepI is the first example of an enzyme catalysing a (SAM-dependent) retro-Claisen rearrangement. We suggest that more pericyclic biosynthetic enzymatic transformations are yet to be discovered in the intriguing enzyme toolboxes in Nature11, and propose an ever expanding role of the versatile cofactor SAM in enzyme catalysis.

SpnF, an enzyme involved in the biosynthesis of spinosyn A, catalyzes a transannular Diels–Alder reaction. Quantum mechanical computations and dynamic simulations now show that this cycloaddition is not well described as either a concerted or stepwise process, and dynamical effects influence the identity and timing of bond formation. The transition state for the reaction is ambimodal and leads directly to both the observed Diels–Alder and an unobserved [6+4] cycloadduct. The potential energy surface bifurcates and the cycloadditions occur by dynamically stepwise modes featuring an “entropic intermediate”. A rapid Cope rearrangement converts the [6+4] adduct into the observed [4+2] adduct. Control of nonstatistical dynamical effects may serve as another way by which enzymes control reactions.

The OH radical is the key oxidizing agent in the troposphere, and ozone-alkene reactions appear to be a significant and sometimes dominant source of new HO x radicals in urban and rural air. In this work, we report the first study of the pressure dependence of the OH radical yield for the ozonolysis of ethene, propene, 1-butene, trans-2-butene, and 2,3-dimethyl-2-butene over the range 20-760 Torr and of trans-3-hexene and cyclopentene over the range 200-760 Torr. Low-pressure experiments were performed in a long-path evacuable FTIR cell or a steady-state flow-tube reactor in series with a gas chromatograph/flame ionization detector and FTIR cell. We have also investigated the effect of adding SF 6 at atmospheric pressure for ethene, 1-butene, and trans-2-butene, in a collapsible Teflon chamber. OH formation increased almost 3-fold for ethene at low pressures, from 0.22 ( 0.06 at 760 Torr to 0.61 ( 0.18 at 20 Torr, and increased somewhat for propene from 0.33 ( 0.07 at 760 Torr to 0.46 ( 0.11 at 20 Torr. A pressure dependence of the OH formation yield was not observed for 1-butene, trans-2-butene, 2,3-dimethyl-2-butene, trans-3-hexene, or cyclopentene over the ranges studied. Density functional theory calculations at the B3LYP/6-31G(d,p) level are presented to aid in understanding the trends observed. They lead to the proposal that the formation of a hydroperoxide via a diradical pathway can compete with the formation of the carbonyl oxide for the ethene primary ozonide.