The affinities of hosts—ranging from small synthetic cavitands to large proteins—for organic molecules are well documented. The average association constants for the binding of organic molecules by cyclodextrins, synthetic hosts, and albumins in water, as well as of catalytic antibodies or enzymes for substrates are 103.5±2.5 M−1. Binding affinities are elevated to 108±2 M−1 for the complexation of transition states and biological antigens by antibodies or inhibitors by enzymes, and to 1016±4 M−1 for transition states with enzymes. The origins of the distributions of association constants observed for the broad range of host–guest systems are explored in this Review, and typical approaches to compute and analyze host–guest binding in solution are discussed. In many classes of complexes a rough correlation is found between the binding affinity and the surface area that is buried upon complexation. Enzymes transcend this effect and achieve transition‐state binding much greater than is expected from the surface areas.

Experimental and theoretical data are provided for a set of 11 pericyclic reactions of unsaturated hydrocarbons. Literature experimental data are evaluated and standardized to ∆H q 0K for comparison to theory. Hartree-Fock, MP2, CASSCF, CASPT2, density functional theory (B3LYP, BPW91, MPW1K, and KMLYP functionals), and CBS-QB3 transition-structure geometries, activation enthalpies and entropies, and reaction enthalpies and entropies for these reactions are reported and are compared to experimental results. For activation enthalpies, several density functionals rival CASPT2 and CBS-QB3 for closest agreement with experiment, while CASPT2 and CBS-QB3 provide the most accurate heats of reaction. Transition-structure geometries are reproduced well by all methods with the exception of the Cope rearrangement and cyclopentadiene dimerization transition structures.

pH−rate profiles for aqueous−organic protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, and varied substantially between the boronic acids, with rate maxima that varied over 6 orders of magnitude. A mechanistic model containing five general pathways (k 1 −k 5 ) has been developed, and together with input of [B] tot , K W , K a , and K aH , the protodeboronation kinetics can be correlated as a function of pH (1−13) for all 18 species. Cyclopropyl and vinyl boronic acids undergo very slow protodeboronation, as do 3-and 4-pyridyl boronic acids (t 0.5 > 1 week, pH 12, 70 °C). In contrast, 2-pyridyl and 5-thiazolyl boronic acids undergo rapid protodeboronation (t 0.5 ≈ 25−50 s, pH 7, 70 °C), via fragmentation of zwitterionic intermediates. Lewis acid additives (e.g., Cu, Zn salts) can attenuate (2-pyridyl) or accelerate (5-thiazolyl and 5-pyrazolyl) fragmentation. Two additional processes compete when the boronic acid and the boronate are present in sufficient proportions (pH = pK a ± 1.6): (i) self-/autocatalysis and (ii) sequential disproportionations of boronic acid to borinic acid and borane.

Cover picture: Microscope image of unfunctionalised polystyrene resin taken using a FTIR microscope.

The mechanism of the ene reaction of singlet ((1)delta(g)) oxygen with simple alkenes is investigated by a combination of experimental isotope effects and several levels of theoretical calculations. For the reaction of 2,4-dimethyl-3-isopropyl-2-pentene, the olefinic carbons exhibit small and nearly equal (13)C isotope effects of 1.005-1.007, while the reacting methyl groups exhibit (13)C isotope effects near unity. In a novel experiment, the (13)C composition of the product is analyzed to determine the intramolecular (13)C isotope effects in the ene reaction of tetramethylethylene. The new (13)C and literature (2)H isotope effects are then used to evaluate the accuracy of theoretical calculations. RHF, CASSCF(10e, 8o), and restricted and unrestricted B3LYP calculations are each applied to the ene reaction with tetramethylethylene. Each predicts a different mechanism, but none leads to reasonable predictions of the experimental isotope effects. It is concluded that none of these calculations accurately describe the reaction. A more successful approach was to use high-level, up to CCSD(T), single-point energy calculations on a grid of B3LYP geometries. The resulting energy surface is supported by its accurate predictions of the intermolecular (13)C and (2)H isotope effects and a very good prediction of the reaction barrier. This CCSD(T)//B3LYP surface features two adjacent transition states without an intervening intermediate. This is the first experimentally supported example of such a surface and the first example of a valley-ridge inflection with significant chemical consequences.

By identifying every pair of molecules that differ only by a particular, well-defined, structural transformation in a database of measured properties and computing the corresponding change in property, we obtain an overview of the effect that structural change has upon the property and set an expectation for what will happen when that transformation is applied elsewhere. The mean change indicates the expected magnitude of the change in the property and the number of cases in which the property increases give the probability that the structural transformation will cause the property to increase. Outliers indicate potential ways of avoiding the general trend. Comparing to changes in lipophilicity highlights structural transformations that have unusual effects, some of which can be explained by conformational changes. In this paper, we focus upon the effects on aqueous solubility, plasma protein binding and oral exposure of adding substituents to aromatic rings and methylating heteroatoms.

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Pioneering studies by Kuivila, published more than 50 years ago, suggested ipso protonation of the boronate as the mechanism for base-catalyzed protodeboronation of arylboronic acids. However, the study was limited to UV spectrophotometric analysis under acidic conditions, and the aqueous association constants (K) were estimated. By means of NMR, stopped-flow IR, and quenched-flow techniques, the kinetics of base-catalyzed protodeboronation of 30 different arylboronic acids has now been determined at pH > 13 in aqueous dioxane at 70 °C. Included in the study are all 20 isomers of CHFB(OH) with half-lives spanning 9 orders of magnitude: <3 ms to 6.5 months. In combination with pH-rate profiles, pK and ΔS values, kinetic isotope effects (H, B,C), linear free-energy relationships, and density functional theory calculations, we have identified a mechanistic regime involving unimolecular heterolysis of the boronate competing with concerted ipso protonation/C-B cleavage. The relative Lewis acidities of arylboronic acids do not correlate with their protodeboronation rates, especially when ortho substituents are present. Notably, 3,5-dinitrophenylboronic acid is orders of magnitude more stable than tetra- and pentafluorophenylboronic acids but has a similar pK.