C–H···O Non-Classical Hydrogen Bonding in the Stereomechanics of Organic Transformations: Theory and Recognition

This manuscript describes the role of non-classical hydrogen bonds (NCHBs), specifically C–H···O interactions, in modern synthetic organic transformations. Our goal is to point out the seminal examples where C–H···O interactions have been invoked as a key stereocontrolling element and to provide predictive value in recognizing future and/or potential C–H···O interactions in modern transformations

Catalytic Kinetic Resolution of a Dynamic Racemate: Highly Stereoselective β-Lactone Formation by N-Heterocyclic Carbene Catalysis

This study describes the combined experimental and computational elucidation of the mechanism and origins of stereoselectivities in the NHC-catalyzed dynamic kinetic resolution (DKR) of α-substituted-β-ketoesters. Density functional theory computations reveal that the NHC-catalyzed DKR proceeds by two mechanisms, depending on the stereochemistry around the forming bond: 1) a concerted, asynchronous formal (2+2) aldol-lactonization process, or 2) a stepwise spiro-lactonization mechanism where the alkoxide is trapped by the NHC-catalyst. These mechanisms contrast significantly from mechanisms found and postulated in other related transformations. Conjugative stabilization of the electrophile and non-classical hydrogen bonds are key in controlling the stereoselectivity. This reaction constitutes an interesting class of DKRs in which the catalyst is responsible for the kinetic resolution to selectively and irreversibly capture an enantiomer of a substrate undergoing rapid racemization with the help of an exogenous base

Catalytic Kinetic Resolution of a Dynamic Racemate: Highly Stereoselective β-Lactone Formation by N-Heterocyclic Carbene Catalysis

This study describes the combined experimental and computational elucidation of the mechanism and origins of stereoselectivities in the NHC-catalyzed dynamic kinetic resolution (DKR) of α-substituted-β-ketoesters. Density functional theory computations reveal that the NHC-catalyzed DKR proceeds by two mechanisms, depending on the stereochemistry around the forming bond: 1) a concerted, asynchronous formal (2+2) aldol-lactonization process, or 2) a stepwise spiro-lactonization mechanism where the alkoxide is trapped by the NHC-catalyst. These mechanisms contrast significantly from mechanisms found and postulated in other related transformations. Conjugative stabilization of the electrophile and non-classical hydrogen bonds are key in controlling the stereoselectivity. This reaction constitutes an interesting class of DKRs in which the catalyst is responsible for the kinetic resolution to selectively and irreversibly capture an enantiomer of a substrate undergoing rapid racemization with the help of an exogenous base

Catalytic Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides: A Mechanistic and Computational Study

The research leading to these results (T. H. W., J. E. T., G. C. L.-J. and A.D.S) has received funding from the ERC under the European Union's Seventh Framework Programme (FP7/2007-2013) / E.R.C. grant agreements n° 279850 and n° 340163. A.D.S. thanks the Royal Society for a Wolfson Research Merit Award. P.H.-Y.C. is the Bert and Emelyn Christensen Professor and gratefully acknowledges financial support from the Stone Family of OSU. Financial support from the National Science Foundation (NSF) (CHE-1352663) is acknowledged. D.M.W. acknowledges the Bruce Graham and Johnson Fellowships of OSU. A.C.B. acknowledges the Johnson Fellowship of OSU. D.M.W., A.C.B., and R.C.J. and P.H.-Y.C. also acknowledge computing infrastructure in part provided by the NSF Phase2 CCI, Center for Sustainable Materials Chemistry (CHE1102637).A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically-relevant catalyst-substrate adduct has been observed, and its constitution elucidated unambiguously by 13C and 15N isotopic labeling. Isotopic entrainment has shown the observed catalyst-substrate adduct to be a genuine intermediate on the productive cycle towards catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state, and turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the proposed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S•••O interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity, while preference for cation-π interactions over C-H•••π is responsible for diastereoselectivity.Publisher PDFPeer reviewe

Catalyst selective and regiodivergent O- to C- or N-carboxyl transfer of pyrazolyl carbonates: synthetic and computational studies

The regiodivergent O- to C- or N-carboxyl transfer of pyrazolyl carbonates is described, with DMAP giving preferential N-carboxylation and triazolinylidenes promoting selective C-carboxylation (both with up to >99 : 1 regioselectivity). An enantioselective O- to C-carboxyl variant using NHC catalysis is demonstrated (up to 92% ee), while mechanistic and DFT studies outline the pathways operative in this system and provide insight into the reasons for the observed selectivity

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

We report the first experimental evidence for the generation of highly strained cis,trans-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 cis,trans-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 cis,trans-cyclooctadienone intermediates. The products can be further elaborated via facile cascade reactions to give complex tri- and tetracyclic molecules

Torquoselective ring opening of fused cyclobutenamides: evidence for a cis,trans-cyclooctadienone intermediate.

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

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