Noncovalent interactions are ubiquitous in organic systems, and can play decisive roles in the outcome of asymmetric organocatalytic reactions. Their prevalence, combined with the often subtle line separating favorable dispersion interactions from unfavorable steric interactions, often complicates the identification of the particular noncovalent interactions responsible for stereoselectivity. Ultimately, the stereoselectivity of most organocatalytic reactions hinges on the balance of both favorable and unfavorable noncovalent interactions in the stereocontrolling transition state (TS).In this Account, we provide an overview of our attempts to understand the role of noncovalent interactions in organocatalyzed reactions and to develop new computational tools for organocatalyst design. Following a brief discussion of noncovalent interactions involving aromatic rings and the associated challenges capturing these effects computationally, we summarize two examples of chiral phosphoric acid catalyzed reactions in which noncovalent interactions play pivotal, although somewhat unexpected, roles. In the first, List’s catalytic asymmetric Fischer indole reaction, we show that both π-stacking and CH/π interactions of the substrate with the 3,3′-aryl groups of the catalyst impact the stability of the stereocontrolling TS. However, these noncovalent interactions oppose each other, with π-stacking interactions stabilizing the TS leading to one enantiomer and CH/π interactions preferentially stabilizing the competing TS. Ultimately, the CH/π interactions dominate and, when combined with hydrogen bonding interactions, lead to preferential formation of the observed product. In the second example, a series of phosphoric acid catalyzed asymmetric ring openings of meso-epoxides, we show that noncovalent interactions of the substrates with the 3,3′-aryl groups of the catalyst play only an indirect role in stereoselectivity. Instead, the stereoselectivity of these reactions are driven by the electrostatic stabilization of a fleeting partial positive charge in the SN2-like transition state by the chiral electrostatic environment of the phosphoric acid catalyst.Next, we describe our studies of bipyridine N-oxide and N,N′-dioxide catalyzed alkylation reactions. Based on several examples, we demonstrate that there are many potential arrangements of ligands around a hexacoordinate silicon in the stereocontrolling TS, and one must consider all of these in order to identify the lowest-lying TS structures. We also present a model in which electrostatic interactions between a formyl CH group and a chlorine in these TSs underlie the enantioselectivity of these reactions.Finally, we discuss our efforts to develop computational tools for the screening of potential organocatalyst designs, starting in the context of bipyridine N,N′-dioxide catalyzed alkylation reactions. Our new computational tool kit (AARON) has been used to design highly effective catalysts for the asymmetric propargylation of benzaldehyde, and is currently being used to screen catalysts for other reactions. We conclude with our views on the potential roles of computational chemistry in the future of organocatalyst design.

The development of asymmetric catalysts is typically driven by the experimental screening of potential catalyst designs. Herein, we demonstrate the design of asymmetric propargylation catalysts through computational screening. This was done using our computational toolkit AARON (automated alkylation reaction optimizer for N-oxides), which automates the prediction of enantioselectivities for bidentate Lewis base catalyzed alkylation reactions. A systematic screening of 59 potential catalysts built on 6 bipyridine N,N′-dioxide-derived scaffolds results in predicted ee values for the propargylation of benzaldehyde ranging from 45% (S) to 99% (R), with 12 ee values exceeding 95%. These data provide a broad set of experimentally testable predictions. Moreover, the associated data revealed key details regarding the role of stabilizing electrostatic interactions in asymmetric propargylations, which were harnessed in the design of a propargylation catalyst for which the predicted ee exceeds 99%.Keywords: computational design; density functional theory; electrostatics; noncovalent interactions; stereoinduction; steric interactions

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.Keywords: desymmetrizations; enantioselectivity; stereochemical models; steric interactions; π-stacking interactions

Computational studies of three chiral phosphoric-acid-catalyzed asymmetric ring-openings of meso-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. J. Am. Chem. Soc. 2014, 136, 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.Keywords: density functional theory; electrostatics; noncovalent interactions; organocatalysis; stereoselectivity

Complexes of 9-methyladenine with 46 heterocycles commonly found in drugs were located using dispersion-corrected density functional theory, providing a representative set of 408 unique stacked dimers. The predicted binding enthalpies for each heterocycle span a broad range, highlighting the strong dependence of heterocycle stacking interactions on the relative orientation of the interacting rings. Overall, the presence of NH and carbonyl groups lead to the strongest stacking interactions with 9-methyadenine, and the strength of π-stacking interactions is sensitive to the distribution of heteroatoms within the ring as well as the specific tautomer considered. Although molecular dipole moments provide a sound predictor of the strengths and orientations of the 28 monocyclic heterocycles considered, dipole moments for the larger fused heterocycles show very little correlation with the predicted binding enthalpies.

Stereoselectivities were predicted for the allylation of benzaldehyde using allyltrichlorosilanes catalyzed by 18 axially chiral bipyridine N,N′-dioxides. This was facilitated by the computational toolkit AARON (Automated Alkylation Reaction Optimizer for N-oxides), which automates the optimization of all of the required transition-state structures for such reactions. Overall, we were able to predict the sense of stereoinduction for all 18 of the catalysts, with predicted ee’s in reasonable agreement with experiment for 15 of the 18 catalysts. Curiously, we find that ee’s predicted from relative energy barriers are more reliable than those based on either relative enthalpy or free energy barriers. The ability to correctly predict the stereoselectivities for these allylation catalysts in an automated fashion portends the computational screening of potential organocatalysts for this and related reactions. By studying a large number of allylation catalysts, we were also able to gain new insight into the origin of stereoselectivity in these reactions, extending our previous model for bipyridine N-oxide-catalyzed alkylation reactions (Organic Letters 2012, 14, 5310). Finally, we assessed the potential performance of these bipyridine N,N′-dioxide catalysts for the propargylation of benzaldehyde using allenyltrichlorosilanes, finding that two of these catalysts should provide reasonable stereoselectivities for this transformation. Most importantly, we show that bipyridine N,N′-dioxides constitute an ideal scaffold for the development of asymmetric propargylation catalysts and, along with AARON, should enable the rational design of such catalysts purely through computation.Keywords: computational design; density functional theory; high-throughput screening; organocatalysis; stereoselectivity

Computational analyses of the first catalytic asymmetric Fischer indolization (J. Am. Chem. Soc. 2011, 133, 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.

Stacking interactions in nitroarene binding sites of proteins were studied through analyses of structures in the protein data bank (PDB), as well as DFT and ab initio computations applied to model systems. Stacked dimers of mono-, di-, and trinitrobenzene with the amino acid side chains histidine (His), phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp) were optimized at the B97-D/TZV(2d,2p) level of theory. Binding energies for the global minimum dimer geometries were further refined at the estimated CCSD(T)/aug-cc-pVTZ level of theory. The results show that the interactions between aromatic amino acids and nitroarenes are very strong (up to −14.6 kcal mol–1), and the regiochemistry of the nitro substituents plays a significant role in the relative monomer orientations and strength of the interaction. In contrast to model stacked benzene dimers, effects of nitro substituents in stacking complexes with aromatic amino acid side chains are not perfectly additive. This is attributed to direct interactions of the nitro substituents with functional groups in the amino acid side chain. Overall, the strength of stacking interactions with these nitrobenzenes follows the order Trp > Tyr > Phe ≈ His. We also analyzed nitroarene binding sites in the PDB. Out of 216 selected crystal structures containing nitroarene ligands, 191 have nearby aromatic residues, providing 65 examples of π-stacking interactions involving a nitroarene. Of these, the representations of the different aromatic amino acids (Trp > Tyr > Phe > His) are correlated with the strength of model complexes of nitroarenes, with the exception of His. B97-D computations applied to complexes extracted from these crystal structures reveal that π-stacking interactions between the nitroarene and aromatic amino acid side chains exhibit a broad range of strengths, with many contributing significantly to binding.

Matile et al. introduced the concept of anion−π catalysis [Angew. Chem., Int. Ed. 2013, 52, 9940; J. Am. Chem. Soc. 2014, 136, 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.

We show that the positive electrostatic potentials and molecular quadrupole moments characteristic of π-acidic azines, which underlie the ability of these rings to bind anions above their centres, arise from the position of nuclear charges, not changes in the π-electron density distribution.

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 ab initio 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.

Enantioselectivities for the allylation and propargylation of benzaldehyde catalyzed by bipyridine N,N′-dioxides were predicted using popular DFT methods. The results reveal deficiencies of several DFT methods while also providing a new explanation for the stereoselectivity of these reactions. In particular, even though many DFT methods provide accurate predictions of experimental ee's for these reactions, these predictions sometimes stem from qualitatively incorrect transition states. Overall, B97-D/TZV(2d,2p) provides the best compromise between accurate predictions of low-lying transition states and stereoselectivities for these reactions. The origin of stereoselectivity in these reactions was also examined, and arises from electrostatic interactions within the chiral electrostatic environment of a hexacoordinate silicon intermediate; the previously published transition state model for these reactions is flawed. Ultimately, these results suggest two strategies for the design of highly stereoselective catalysts for the propargylation of aromatic aldehydes, and pave the way for the computational design of novel catalysts for these reactions.

We present detailed computational analyses of the binding of four dinucleotides to a highly sequence-selective single-stranded DNA (ssDNA) binding antibody (ED-10) and selected point mutants. Anti-DNA antibodies are central to the pathogenesis of systemic lupus erythematosus (SLE), and a more complete understanding of the mode of binding of DNA and other ligands will be necessary to elucidate the role of anti-DNA antibodies in the kidney inflammation associated with SLE. Classical molecular mechanics based molecular dynamics simulations and density functional theory (DFT) computations were applied to pinpoint the origin of selectivity for the 5′-nucleotide. In particular, the strength of interactions between each nucleotide and the surrounding residues were computed using MMGBSA as well as DFT applied to a cluster model of the binding site. The results agree qualitatively with experimental binding free energies, and indicate that π-stacking, CH/π, NH/π, and hydrogen-bonding interactions all contribute to 5′-base selectivity in ED-10. Most importantly, the selectivity for dTdC over dAdC arises primarily from differences in the strength of π-stacking and XH/π interactions with the surrounding aromatic residues; hydrogen bonds play little role. These data suggest that a key Tyr residue, which is not present in other anti-DNA antibodies, plays a key role in the 5′-base selectivity, while we predict that the mutation of a single Trp residue can tune the selectivity for dTdC over dAdC.

Substituent effects in model stacked homodimers and heterodimers of benzene, borazine, and 1,3,5-triazine have been examined computationally. We show that substituent effects in these dimers are strongly dependent on the identity of the unsubstituted ring, yet are independent of the ring bearing the substituent. This supports the local, direct interaction model [J. Am. Chem. Soc. 2011, 133, 10262], which maintains that substituent effects in π-stacking interactions are dominated by through-space interactions of the substituents with the proximal vertex of the unsubstituted ring. In addition to dimers in which the unsubstituted ring is held constant, substituent effects are correlated in many other stacked dimers, including those in which neither the substituted nor unsubstituted rings are conserved. Whether substituent effects in a pair of dimers will be correlated is shown to hinge on the electrostatic components of the interaction energies, and the correlations are explained in terms of the interaction of the local dipole moments associated with the substituents and the electric fields of the unsubstituted rings. Overall, substituent effects are similar in two stacked dimers as long as the electric fields above the unsubstituted rings are similar, providing a more sound physical justification for the local, direct interaction model.

Nickel(II) complexes with varying reactive ligands, which were designed to selectively accelerate the initiation rate without influencing the propagation rate in the chain-growth polymerization of π-conjugated monomers, were investigated. Precatalysts with electronically varied reacting groups led to faster initiation rates and narrower molecular weight distributions. Computational studies revealed that the reductive elimination rates are largely modulated by the ability of the two reacting arenes to stabilize the increasing electron density on the catalyst during reductive elimination. Overall, these studies provide insight into a key mechanistic step of cross-coupling reactions (reductive elimination) and highlight the importance of initiation in controlled chain-growth polymerizations.

The enantioselective propargylation of aromatic aldehydes with allenyltrichlorosilanes catalyzed by bipyridine N-oxides was explored using density functional theory. Low-lying transition states for a highly enantioselective helical bipyridine N-oxide catalyst [Org. Lett. 2011, 13, 1654] were characterized at the B97-D/TZV(2d,2p) level of theory. Predicted free energy barrier height differences are in agreement with experimental ee’s for the propargylation of benzaldehyde and substituted analogues. The origin of enantioselectivity was pinpointed through distortion–interaction analyses. The stereoselectivity arises in part from through-space electrostatic interactions of the carbonyl carbon with the Cl ligands bound to Si, rather than noncovalent aryl–aryl interactions between the aromatic aldehyde and the helix as previously proposed. Moreover, aryl–aryl interactions between the aldehyde and helix are predicted to favor transition states leading to the R enantiomer, and ultimately reduce the enantioselectivity of this reaction. (S)-2,2′-bipyridine N-oxide was studied as a model catalyst in order to quantify the inherent enantioselectivity arising from different chiral arrangements of ligands around the hexacoordinate silicon in the stereocontrolling transition state for these reactions. The predicted selectivities arising from different chiral octahedral silicon complexes provide guidelines for the development of transition state models for N-oxide-based alkylation catalysts.

We address the recent debate surrounding the ability of 2,4-difluorotoluene (F), a low-polarity mimic of thymine (T), to form a hydrogen-bonded complex with adenine in DNA. The hydrogen bonding ability of F has been characterized as small to zero in various experimental studies, and moderate to small in computational studies. However, recent X-ray crystallographic studies of difluorotoluene in DNA/RNA have indicated, based on interatomic distances, possible hydrogen bonding interactions between F and natural bases in nucleic acid duplexes and in a DNA polymerase active site. Since F is widely used to measure electrostatic contributions to pairing and replication, it is important to quantify the impact of this isostere on DNA stability. Here, we studied the pairing stability and selectivity of this compound and a closely related variant, dichlorotoluene deoxyriboside (L), in DNA, using both experimental and computational approaches. We measured the thermodynamics of duplex formation in three sequence contexts and with all possible pairing partners by thermal melting studies using the van’t Hoff approach, and for selected cases by isothermal titration calorimetry (ITC). Experimental results showed that internal F-A pairing in DNA is destabilizing by 3.8 kcal/mol (van’t Hoff, 37 °C) as compared with T-A pairing. At the end of a duplex, base–base interactions are considerably smaller; however, the net F-A interaction remains repulsive while T-A pairing is attractive. As for selectivity, F is found to be slightly selective for adenine over C, G, T by 0.5 kcal mol, as compared with thymine’s selectivity of 2.4 kcal/mol. Interestingly, dichlorotoluene in DNA is slightly less destabilizing and slightly more selective than F, despite the lack of strongly electronegative fluorine atoms. Experimental data were complemented by computational results, evaluated at the M06-2X/6-31+G(d) and MP2/cc-pVTZ levels of theory. These computations suggest that the pairing energy of F to A is ∼28% of that of T-A, and most of this interaction does not arise from the F···HN interaction, but rather from the CH···N interaction. The nucleobase analogue shows no inherent selectivity for adenine over other bases, and L-A pairing energies are slightly weaker than for F-A. Overall, the results are consistent with a small favorable noncovalent interaction of F with A offset by a large desolvation cost for the polar partner. We discuss the findings in light of recent structural studies and of DNA replication experiments involving these analogues.

A simple electrostatic model explains the enhanced stereoselectivity of N-oxide catalyzed allylations compared to propargylations, which in turn explicates the dearth of stereoselective N-oxide propargylation catalysts. These results suggest that N-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.

PAHs such as coronene and hexa-peri-hexabenzocoronene (HBC, a nanographene) are commonly used in discotic liquid crystals, for which achieving long-range columnular order is vital for the development of materials with maximized charge-transfer rates. We demonstrate that simple substituents can have a dramatic impact on the local orientation of π-stacked polycyclic aromatic hydrocarbons (PAHs), even in the absence of steric or other non-covalent interactions (e.g.: hydrogen bonds). The strong dependence of these π-stacking interactions on the relative position of substituents is a result of the direct, through-space interactions of aryl substituents. B97-D/TZV(2d,2p) interaction energies are presented for stacked dimers of substituted benzenes, coronenes, and HBC, which display diverse orientation potentials depending on the nature of the substituents. The results show that the position of the global energy minimum for stacked PAHs depends on the nature of the aryl substituents. The preferred arrangement of stacked coronenes, for example, can be shifted from a fully staggered arrangement to a fully eclipsed arrangement through the introduction of complementary pairs of substituents.

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 (J. Am. Chem. Soc., 2009, 131, 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 inclusive 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.

Conjugated organic oligomers are central to the development of efficient organic electronic devices and organic photovoltaics. However, the torsional flexibility of many of these organic materials, in particular oligothiophenes, can adversely affect charge transfer properties. Although previous studies have examined the torsional flexibility of oligothiophenes, there have been only limited studies of the effects of interchain interactions on their torsional potentials. B97-D/TZV(2d,2p) was first benchmarked against a CCSD(T)/aug-cc-pVTZ torsional potential for bithiophene as well as SCS-MP2/TZVPP interaction energies for noncovalent sexithiophene (6T) dimers. The effect of neighboring chains on three distinct torsional modes of sexithiophene was studied using B97-D. Complexation with one or more neighboring chains has a dramatic effect on each of these torsional potentials. For example, for two stacked chains, alternated twisting motions are competitive with torsion about a single terminal dihedral angle, and in both cases we predict nonplanar global energy minima and large amplitude torsional motions at room temperature. In other words, the presence of a single neighboring chain induces significant deviations from planarity in oligothiophenes. However, in the environment of crystalline 6T, the trend in predicted torsional potentials match those of isolated chains, but the force constants associated with torsional motions increase by an order of magnitude. Consequently, although individual oligothiophene chains are torsionally flexible and model stacked dimers exhibit extreme deviations from planarity, in crystalline 6T these oligomers are predicted to adopt planar configurations with a steep energetic cost associated with torsional defects.

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 [J. Am. Chem. Soc.2011, 133, 3687–3689].

We show that the positive electrostatic potentials and molecular quadrupole moments characteristic of π-acidic azines, which underlie the ability of these rings to bind anions above their centres, arise from the position of nuclear charges, not changes in the π-electron density distribution.

Nickel(II) complexes with varying reactive ligands, which were designed to selectively accelerate the initiation rate without influencing the propagation rate in the chain-growth polymerization of π-conjugated monomers, were investigated. Precatalysts with electronically varied reacting groups led to faster initiation rates and narrower molecular weight distributions. Computational studies revealed that the reductive elimination rates are largely modulated by the ability of the two reacting arenes to stabilize the increasing electron density on the catalyst during reductive elimination. Overall, these studies provide insight into a key mechanistic step of cross-coupling reactions (reductive elimination) and highlight the importance of initiation in controlled chain-growth polymerizations.

Enantioselectivities for the allylation and propargylation of benzaldehyde catalyzed by bipyridine N,N′-dioxides were predicted using popular DFT methods. The results reveal deficiencies of several DFT methods while also providing a new explanation for the stereoselectivity of these reactions. In particular, even though many DFT methods provide accurate predictions of experimental ee's for these reactions, these predictions sometimes stem from qualitatively incorrect transition states. Overall, B97-D/TZV(2d,2p) provides the best compromise between accurate predictions of low-lying transition states and stereoselectivities for these reactions. The origin of stereoselectivity in these reactions was also examined, and arises from electrostatic interactions within the chiral electrostatic environment of a hexacoordinate silicon intermediate; the previously published transition state model for these reactions is flawed. Ultimately, these results suggest two strategies for the design of highly stereoselective catalysts for the propargylation of aromatic aldehydes, and pave the way for the computational design of novel catalysts for these reactions.