Quantum Chemical Calculation of p<i>K</i>_as of Environmentally Relevant Functional Groups: Carboxylic Acids, Amines, and Thiols in Aqueous Solution

Developing accurate quantum chemical approaches for calculating p<i>K</i>_as is of broad interest. Useful accuracy can be obtained by using density functional theory (DFT) in combination with a polarizable continuum solvent model. However, some classes of molecules present problems for this approach, yielding errors greater than 5 p<i>K</i> units. Various methods have been developed to improve the accuracy of the combined strategy. These methods perform well but either do not generalize or introduce additional degrees of freedom, increasing the computational cost. The Solvation Model based on Density (SMD) has emerged as one of the most commonly used continuum solvent models. Nevertheless, for some classes of organic compounds, e.g., thiols, the p<i>K</i>_as calculated with the original SMD model show errors of 6–10 p<i>K</i> units, and we traced these errors to inaccuracies in the solvation free energies of the anions. To improve the accuracy of p<i>K</i>_as calculated with DFT and the SMD model, we developed a scaled solvent-accessible surface approach for constructing the solute–solvent boundary. By using a “direct” approach, in which all quantities are computed in the presence of the continuum solvent, the use of thermodynamic cycles is avoided. Furthermore, no explicit water molecules are required. Three benchmark data sets of experimentally measured p<i>K</i>_a values, including 28 carboxylic acids, 10 aliphatic amines, and 45 thiols, were used to assess the optimized SMD model, which we call SMD with a scaled solvent-accessible surface (SMD_sSAS). Of the methods tested, the M06-2X density functional approximation, 6-31+G­(d,p) basis set, and SMD_sSAS solvent model provided the most accurate p<i>K</i>_as for each set, yielding mean unsigned errors of 0.9, 0.4, and 0.5 p<i>K</i> units, respectively, for carboxylic acids, aliphatic amines, and thiols. This approach is therefore useful for efficiently calculating the p<i>K</i>_as of environmentally relevant functional groups

Toward Quantitatively Accurate Calculation of the Redox-Associated Acid–Base and Ligand Binding Equilibria of Aquacobalamin

Redox processes in complex transition metal-containing species are often intimately associated with changes in ligand protonation states and metal coordination number. A major challenge is therefore to develop consistent computational approaches for computing pH-dependent redox and ligand dissociation properties of organometallic species. Reduction of the Co center in the vitamin B12 derivative aquacobalamin can be accompanied by ligand dissociation, protonation, or both, making these properties difficult to compute accurately. We examine this challenge here by using density functional theory and continuum solvation to compute Co–ligand binding equilibrium constants (<i>K</i>_on/off), p<i>K</i>_as, and reduction potentials for models of aquacobalamin in aqueous solution. We consider two models for cobalamin ligand coordination: the first follows the hexa, penta, tetra coordination scheme for Co^III, Co^II, and Co^I species, respectively, and the second model features saturation of each vacant axial coordination site on Co^II and Co^I species with a single, explicit water molecule to maintain six directly interacting ligands or water molecules in each oxidation state. Comparing these two coordination schemes in combination with five dispersion-corrected density functionals, we find that the accuracy of the computed properties is largely independent of the scheme used, but including only a continuum representation of the solvent yields marginally better results than saturating the first solvation shell around Co throughout. PBE performs best, displaying balanced accuracy and superior performance overall, with RMS errors of 80 mV for seven reduction potentials, 2.0 log units for five p<i>K</i>_as and 2.3 log units for two log <i>K</i>_on/off values for the aquacobalamin system. Furthermore, we find that the BP86 functional commonly used in corrinoid studies suffers from erratic behavior and inaccurate descriptions of Co–axial ligand binding, leading to substantial errors in predicted p<i>K</i>_as and <i>K</i>_on/off values. These findings demonstrate the effectiveness of the present approach for computing electrochemical and thermodynamic properties of a complex transition metal-containing cofactor

Torquoselective Ring Opening of Fused Cyclobutenamides: Evidence for a <i>Cis,Trans</i>-Cyclooctadienone Intermediate

Electrocyclic ring opening of 4,6-fused cyclobutenamides <b>1</b> under thermal conditions leads to <i>cis,trans</i>-cyclooctadienones <b>2</b>-<i>E</i>,<i>E</i> as transient intermediates, en route to 5,5-bicyclic products <b>3</b>. Theoretical calculations predict that 4,5-fused cyclobutenamides should likewise undergo thermal ring opening, giving <i>cis,trans</i>-cycloheptadienones, but in this case conversion to 5,4-bicyclic products is thermodynamically disfavored, and these cyclobutenamides instead rearrange to vinyl cyclopentenones

Torquoselective Ring Opening of Fused Cyclobutenamides: Evidence for a <i>Cis,Trans</i>-Cyclooctadienone Intermediate

Electrocyclic ring opening of 4,6-fused cyclobutenamides <b>1</b> under thermal conditions leads to <i>cis,trans</i>-cyclooctadienones <b>2</b>-<i>E</i>,<i>E</i> as transient intermediates, en route to 5,5-bicyclic products <b>3</b>. Theoretical calculations predict that 4,5-fused cyclobutenamides should likewise undergo thermal ring opening, giving <i>cis,trans</i>-cycloheptadienones, but in this case conversion to 5,4-bicyclic products is thermodynamically disfavored, and these cyclobutenamides instead rearrange to vinyl cyclopentenones

Torquoselective Ring Opening of Fused Cyclobutenamides: Evidence for a <i>Cis,Trans</i>-Cyclooctadienone Intermediate

Electrocyclic ring opening of 4,6-fused cyclobutenamides <b>1</b> under thermal conditions leads to <i>cis,trans</i>-cyclooctadienones <b>2</b>-<i>E</i>,<i>E</i> as transient intermediates, en route to 5,5-bicyclic products <b>3</b>. Theoretical calculations predict that 4,5-fused cyclobutenamides should likewise undergo thermal ring opening, giving <i>cis,trans</i>-cycloheptadienones, but in this case conversion to 5,4-bicyclic products is thermodynamically disfavored, and these cyclobutenamides instead rearrange to vinyl cyclopentenones

Torquoselective Ring Opening of Fused Cyclobutenamides: Evidence for a <i>Cis,Trans</i>-Cyclooctadienone Intermediate

Electrocyclic ring opening of 4,6-fused cyclobutenamides <b>1</b> under thermal conditions leads to <i>cis,trans</i>-cyclooctadienones <b>2</b>-<i>E</i>,<i>E</i> as transient intermediates, en route to 5,5-bicyclic products <b>3</b>. Theoretical calculations predict that 4,5-fused cyclobutenamides should likewise undergo thermal ring opening, giving <i>cis,trans</i>-cycloheptadienones, but in this case conversion to 5,4-bicyclic products is thermodynamically disfavored, and these cyclobutenamides instead rearrange to vinyl cyclopentenones

Construction of Stereogenic α,α-Disubstituted Cycloalkanones via 1° Amine Thiourea Dual Catalysis: Experimental Scope and Computational Analyses

The mechanistic exploration and an expanded experimental discussion of the organocatalyzed, asymmetric Pfau–d’Angelo reaction by exploiting a bifunctional 1° amine thiourea catalyst system is disclosed. Notable breadth in substrate scope has been demonstrated on both the cyclic ketone moiety and the α,β-unsaturated electrophile. Exploration into the matched and mismatched selectivity of this process with a ketone containing pre-existing stereocenters has been demonstrated. Computational analyses of the reaction mechanism are reported. In concert with kinetic isotope effect (KIE) experiments, these computational results provide a detailed understanding of the likely mechanism, including the aspects of the organocatalyst scaffold that are critical for stereoselectivity

Torquoselective Ring Opening of Fused Cyclobutenamides: Evidence for a <i>Cis,Trans</i>-Cyclooctadienone Intermediate

Electrocyclic ring opening of 4,6-fused cyclobutenamides <b>1</b> under thermal conditions leads to <i>cis,trans</i>-cyclooctadienones <b>2</b>-<i>E</i>,<i>E</i> as transient intermediates, en route to 5,5-bicyclic products <b>3</b>. Theoretical calculations predict that 4,5-fused cyclobutenamides should likewise undergo thermal ring opening, giving <i>cis,trans</i>-cycloheptadienones, but in this case conversion to 5,4-bicyclic products is thermodynamically disfavored, and these cyclobutenamides instead rearrange to vinyl cyclopentenones

AlCl₃‑Catalyzed Ring Expansion Cascades of Bicyclic Cyclobutenamides Involving Highly Strained <i>Cis</i>,<i>Trans</i>-Cycloheptadienone Intermediates

We report the first experimental evidence for the generation of highly strained <i>cis</i>,<i>trans</i>-cycloheptadienones by electrocyclic ring opening of 4,5-fused cyclobutenamides. In the presence of AlCl₃, the cyclobutenamides rearrange to [2.2.1]-bicyclic ketones; DFT calculations provide evidence for a mechanism involving torquoselective 4π-electrocyclic ring opening to a <i>cis</i>,<i>trans</i>-cycloheptadienone followed by a Nazarov-like recyclization and a 1,2-alkyl shift. Similarly, 4,6-fused cyclobutenamides undergo AlCl₃-catalyzed rearrangements to [3.2.1]-bicyclic ketones through <i>cis</i>,<i>trans</i>-cyclooctadienone intermediates. The products can be further elaborated via facile cascade reactions to give complex tri- and tetracyclic molecules

Hyperconjugation Promotes Catalysis in a Pyridoxal 5′-Phosphate-Dependent Enzyme

Pyridoxal 5′-phosphate (PLP)-dependent enzymes facilitate reaction specificity by aligning the scissile σ-bond of the PLP-substrate covalent complex perpendicular to the ring of the cofactor. Current models propose that this alignment causes a destabilization of the ground state. To test this hypothesis, quantum chemical calculations, utilizing our recent neutron diffraction models of aspartate aminotransferase, were performed. The calculations reveal that the scissile σ-bond orbital overlaps significantly with the π* orbital of the Schiff base. This σ → π* hyperconjugation interaction stabilizes the ground state of the external aldimine and substantially contributes to transition-state stabilization by withdrawing electron density from the Cα-H σ bond into the π system of PLP, enhancing the rate of catalysis