Kink-Controlled Gold Nanoparticles for Electrochemical Glucose Oxidation.

Enzymes in nature efficiently catalyze chiral organic molecules by elaborately tuning the geometrical arrangement of atoms in the active site. However, enantioselective oxidation of organic molecules by heterogeneous electrocatalysts is challenging because of the difficulty in controlling the asymmetric structures of the active sites on the electrodes. Here, we show that the distribution of chiral kink atoms on high-index facets can be precisely manipulated even on single gold nanoparticles; and this enabled stereoselective oxidation of hydroxyl groups on various sugar molecules. We characterized the crystallographic orientation and the density of kink atoms and investigated their specific interactions with the glucose molecule due to the geometrical structure and surface electrostatic potential.

Interrupted SNAr-Alkylation Dearomatization.

Dearomatizations provide powerful synthetic routes to rapidly assemble substituted carbocycles and heterocycles found in a plethora of bioactive molecules. Harnessing the advantages of dearomatization typically requires vigorous reagents because of the difficulty in disrupting the stable aromatic core. A relatively mild dearomatization strategy is described that employs lithiated nitriles or isocyanides in a simple SNAr-type addition to form σ-complexes that are trapped by alkylation. The dearomatizations are diastereoselective and efficient and rapidly install two new carbon-carbon bonds, one of which is a quaternary center, as well as nitrile, isocyanide, and cyclohexadiene functionalities.

Anomalous π-backbonding in complexes between B(SiR3)3 and N2: catalytic activation and breaking of scaling relations.

Chemical transformations of molecular nitrogen (N2), including the nitrogen reduction reaction (NRR), are difficult to catalyze because of the weak Lewis basicity of N2. In this study, it is shown that Lewis acids of the types B(SiR3)3 and B(GeR3)3 bind N2 and CO with anomalously short and strong B-N or B-C bonds. B(SiH3)3·N2 has a B-N bond length of 1.48 Å and a complexation enthalpy of -15.9 kcal mol-1 at the M06-2X/jun-cc-pVTZ level. The selective binding enhancement of N2 and CO is due to π-backbonding from Lewis acid to Lewis base, as demonstrated by orbital analysis and density difference plots. The π-backbonding is found to be a consequence of constructive orbital interactions between the diffuse and highly polarizable B-Si and B-Ge bond regions and the π and π* orbitals of N2. This interaction is strengthened by electron donating substituents on Si or Ge. The π-backbonding interaction is predicted to activate N2 for chemical transformation and reduction, as it decreases the electron density and increases the length of the N-N bond. The binding of N2 and CO by the B(SiR3)3 and B(GeR3)3 types of Lewis acids also has a strong σ-bonding contribution. The relatively high σ-bond strength is connected to the highly positive surface electrostatic potential [VS(r)] above the B atom in the tetragonal binding conformation, but the σ-bonding also has a significant coordinate covalent (dative) contribution. Electron withdrawing substituents increase the potential and the σ-bond strength, but favor the binding of regular Lewis acids, such as NH3 and F-, more strongly than binding of N2 and CO. Molecules of the types B(SiR3)3 and B(GeR3)3 are chemically labile and difficult to synthesize. Heterogenous catalysts with the wanted B(Si-)3 or B(Ge-)3 bonding motif may be prepared by boron doping of nanostructured silicon or germanium compounds. B-doped and hydrogenated silicene is found to have promising properties as catalyst for the electrochemical NRR.

The Importance of Electrostatics and Polarization for Noncovalent Interactions: Ionic Hydrogen Bonds vs Ionic Halogen Bonds.

A series of 26 hydrogen-bonded complexes between Br- and halogen, oxygen and sulfur hydrogen-bond (HB) donors is investigated at the M06-2X/6-311 + G(2df,2p) level of theory. Analysis using a model in which Br- is replaced by a point charge shows that the interaction energy ([Formula: see text]) of the complexes is accurately reproduced by the scaled interaction energy with the point charge ([Formula: see text]).This is demonstrated by [Formula: see text] with a correlation coefficient, R2 =0.999. The only outlier is (Br-H-Br)-, which generally is classified as a strong charge-transfer complex with covalent character rather than a HB complex. [Formula: see text] can be divided rigorously into an electrostatic contribution ([Formula: see text]) and a polarization contribution ([Formula: see text]).Within the set of HB complexes investigated, the former varies between -7.2 and -32.7 kcal mol-1, whereas the latter varies between -1.6 and -11.5 kcal mol-1. Compared to our previous study of halogen-bonded (XB) complexes between Br- and C-Br XB donors, the electrostatic contribution is generally stronger and the polarization contribution is generally weaker in the HB complexes. However, for both types of bonding, the variation in interaction strength can be reproduced accurately without invoking a charge-transfer term. For the Br-···HF complex, the importance of charge penetration on the variation of the interaction energy with intermolecular distance is investigated. It is shown that the repulsive character of [Formula: see text] at short distances in this complex to a large extent can be attributed to charge penetration.

Machine learning meets mechanistic modelling for accurate prediction of experimental activation energies.

Accurate prediction of chemical reactions in solution is challenging for current state-of-the-art approaches based on transition state modelling with density functional theory. Models based on machine learning have emerged as a promising alternative to address these problems, but these models currently lack the precision to give crucial information on the magnitude of barrier heights, influence of solvents and catalysts and extent of regio- and chemoselectivity. Here, we construct hybrid models which combine the traditional transition state modelling and machine learning to accurately predict reaction barriers. We train a Gaussian Process Regression model to reproduce high-quality experimental kinetic data for the nucleophilic aromatic substitution reaction and use it to predict barriers with a mean absolute error of 0.77 kcal mol-1 for an external test set. The model was further validated on regio- and chemoselectivity prediction on patent reaction data and achieved a competitive top-1 accuracy of 86%, despite not being trained explicitly for this task. Importantly, the model gives error bars for its predictions that can be used for risk assessment by the end user. Hybrid models emerge as the preferred alternative for accurate reaction prediction in the very common low-data situation where only 100-150 rate constants are available for a reaction class. With recent advances in deep learning for quickly predicting barriers and transition state geometries from density functional theory, we envision that hybrid models will soon become a standard alternative to complement current machine learning approaches based on ground-state physical organic descriptors or structural information such as molecular graphs or fingerprints.

Asymmetric Synthesis of Adjacent Tri- and Tetrasubstituted Carbon Stereocenters: Organocatalytic Aldol Reaction of an Hydantoin Surrogate with Azaarene 2-Carbaldehydes.

A bifunctional amine/squaramide catalyst promoted direct aldol addition of an hydantoin surrogate to pyridine 2-carbaldehyde N-oxides to afford adducts bearing two vicinal tertiary/quaternary carbons in high diastereo- and enantioselectivity (d.r. up to >20:1; ee up to 98 %) is reported. Acid hydrolysis of adducts followed by reduction of the N-oxide group yields enantiopure carbinol-tethered quaternary hydantoin-azaarene conjugates with densely functionalized skeletons. DFT studies of the potential energy surface (B3LYP/6-31+G(d)+CPCM (dichloromethane)) of the reaction correlate the activity of different catalysts and support an intramolecular hydrogen-bond-assisted activation of the squaramide moiety in the transition state of the catalytic reaction.

The local electron attachment energy and the electrostatic potential as descriptors of surface-adsorbate interactions.

Two local reactivity descriptors computed by Kohn-Sham density functional theory (DFT) are used to predict and rationalize interactions of nucleophilic molecules (exemplified by CO and H2O) with transition metal (TM) and oxide surfaces. The descriptors are the electrostatic potential, VS(r), and the local electron attachment energy, ES(r), evaluated on surfaces defined by the 0.001 e Bohr-3 isodensity contour. These descriptors have previously shown excellent abilities to predict regioselectivity and rank molecular as well as nanoparticle reactivities and interaction affinities. In this study, we generalize the descriptors to fit into the framework of periodic DFT computations. We also demonstrate their capabilities to predict local surface propensity for interaction with Lewis bases. It is shown that ES(r) and VS(r) can rationalize the interaction behavior of TM oxides and of fcc TM surfaces, including low-index, stepped and kinked surfaces spanning a wide range of interaction sites with varied coordination environments. Broad future applicability in surface science is envisaged for the descriptors, including heterogeneous catalysis and electrochemistry.

Electrostatics and polarization determine the strength of the halogen bond: a red card for charge transfer.

A series of 20 halogen bonded complexes of the types R-Br•••Br- (R is a substituted methyl group) and R´-C≡C-Br•••Br- are investigated at the M06-2X/6-311+G(d,p) level of theory. Computations using a point-charge (PC) model, in which Br- is represented by a point charge in the electronic Hamiltonian, show that the halogen bond energy within this set of complexes is completely described by the interaction energy (ΔEPC) of the point charge. This is demonstrated by an excellent linear correlation between the quantum chemical interaction energy and ΔEPC with a slope of 0.88, a zero intercept, and a correlation coefficient of R2 = 0.9995. Rigorous separation of ΔEPC into electrostatics and polarization shows the high importance of polarization for the strength of the halogen bond. Within the data set, the electrostatic interaction energy varies between 4 and -18 kcal mol-1, whereas the polarization energy varies between -4 and -10 kcal mol-1. The electrostatic interaction energy is correlated to the sum of the electron-withdrawing capacities of the substituents. The polarization energy generally decreases with increasing polarizability of the substituents, and polarization is mediated by the covalent bonds. The lower (more favorable) ΔEPC of CBr4---Br- compared to CF3Br•••Br- is found to be determined by polarization as the electrostatic contribution is more favorable for CF3Br•••Br-. The results of this study demonstrate that the halogen bond can be described accurately by electrostatics and polarization without any need to consider charge transfer.

Theoretical Investigation into Rate-Determining Factors in Electrophilic Aromatic Halogenation.

The halogenation of monosubstituted benzenes in aqueous solvent was studied using density functional theory at the PCM-M06-2 X/6-311G(d,p) level. The reaction with Cl2 begins with the formation of C atom coordinated π-complex and is followed by the formation of the σ-complex, which is rate-determining. The final part proceeds via the abstraction of the proton by a water molecule or a weak base. We evaluated the use of the σ-complex as a model for the rate-determining transition state (TS) and found that this model is more accurate the later the TS comes along the reaction coordinate. This explains the higher accuracy of the model for halogenations (late TS) compared to nitrations (early TS); that is, the more deactivated the substrate the later the TS. The halogenation with Br2 proceeds with a similar mechanism as the corresponding chlorination, but the bromination has a very late rate-determining TS that is similar to the σ-complex in energy. The iodination with ICl follows a different mechanism than chlorination and bromination. After the formation of the π-complex, the reaction proceeds in a concerted manner without a σ-complex. This reaction has a large primary hydrogen kinetic isotope effect in agreement with experimental observations.

σ-Holes and σ-lumps direct the Lewis basic and acidic interactions of noble metal nanoparticles: introducing regium bonds.

Using local DFT-based probes for electrostatic as well as charge transfer/polarization interactions, we are able to characterize Lewis basic and acidic sites on copper, silver and gold nanoparticles. The predictions obtained using the DFT-probes are compared to the interaction energies of the electron donating (CO, H2O, NH3 and H2S) and the electron accepting (BH3, BF3, HCl [H-down] and Na+) compounds. The probes include the local electron attachment energy [E(r)], the average local ionization energy [I(r)], and the electrostatic potential [V(r)] and are evaluated on isodensity surfaces located at distances corresponding to typical interaction distances. These probes have previously been successful in characterizing molecular interactions. Good correlations are found between Lewis acidity and maxima in V(r), appearing as a consequence of σ-holes, as well as minima in E(r), of the noble metal nanoparticles. Similarly are Lewis basic sites successfully described by surface minima in V(r) and I(r); the former are indicative of σ-lumps, i.e. regions of enhanced σ-density. The investigated probes are anticipated to function as reliable tools in nanoparticle reactivity and interaction characterization, and may act as suitable descriptors in large-scale screenings for materials of specific properties, e.g. in heterogeneous catalysis. Because of the similarity between the noble metal nanoparticle's interactions with Lewis bases and the concepts of halogen and hydrogen bonding, a new class of bonds is introduced - regium bonds - taking place between a σ-hole of a Cu, Ag or Au compound and an electron donor.

Mechanism and regioselectivity of electrophilic aromatic nitration in solution: the validity of the transition state approach.

The potential energy surfaces in gas phase and in aqueous solution for the nitration of benzene, chlorobenzene, and phenol have been elucidated with density functional theory at the M06-2X/6-311G(d,p) level combined with the polarizable continuum solvent model (PCM). Three reaction intermediates have been identified along both surfaces: the unoriented π-complex (I), the oriented reaction complex (II), and the σ-complex (III). In order to obtain quantitatively reliable results for positional selectivity and for modeling the expulsion of the proton, it is crucial to take solvent effects into consideration. The results are in agreement with Olah's conclusion from over 40 years ago that the transition state leading to (II) is the rate-determining step in activated cases, while it is the one leading to (III) for deactivated cases. The simplified reactivity approach of using the free energy for the formation of (III) as a model of the rate-determining transition state has previously been shown to be very successful for halogenations, but problematic for nitrations. These observations are rationalized with the geometric and energetic resemblance, and lack of resemblance respectively, between (III) and the corresponding rate determining transition state. At this level of theory, neither the σ-complex (III) nor the reaction complex (II) can be used to accurately model the rate-determining transition state for nitrations.

Extending the σ-Hole Concept to Metals: An Electrostatic Interpretation of the Effects of Nanostructure in Gold and Platinum Catalysis.

Crystalline surfaces of gold are chemically inert, whereas nanoparticles of gold are excellent catalysts for many reactions. The catalytic properties of nanostructured gold have been connected to increased binding affinities of reactant molecules for low-coordinated Au atoms. Here we show that the high reactivity at these sites is a consequence of the formation of σ-holes, i.e., maxima in the surface electrostatic potential (VS,max), due to the overlap of mainly the valence s-orbitals when forming the bonding σ-orbitals. The σ-holes are binding sites for Lewis bases, and binding energies correlate with the magnitudes of the VS,max. For symmetrical Au clusters, of varying sizes, the most positive VS,max values are found at the corners, edges, and surfaces (facets), decreasing in that order. This is in agreement with the experimentally and theoretically observed dependence of catalytic activity on local structure. The density of σ-holes can explain the increasing catalytic activity with decreasing particle size for other transition metal catalysts also, such as platinum.

Dehydrogenation of methanol on Cu2O(100) and (111).

Adsorption and desorption of methanol on the (111) and (100) surfaces of Cu2O have been studied using high-resolution photoelectron spectroscopy in the temperature range 120-620 K, in combination with density functional theory calculations and sum frequency generation spectroscopy. The bare (100) surface exhibits a (3,0; 1,1) reconstruction but restructures during the adsorption process into a Cu-dimer geometry stabilized by methoxy and hydrogen binding in Cu-bridge sites. During the restructuring process, oxygen atoms from the bulk that can host hydrogen appear on the surface. Heating transforms methoxy to formaldehyde, but further dehydrogenation is limited by the stability of the surface and the limited access to surface oxygen. The (√3 × âˆš3)R30°-reconstructed (111) surface is based on ordered surface oxygen and copper ions and vacancies, which offers a palette of adsorption and reaction sites. Already at 140 K, a mixed layer of methoxy, formaldehyde, and CHxOy is formed. Heating to room temperature leaves OCH and CHx. Thus both CH-bond breaking and CO-scission are active on this surface at low temperature. The higher ability to dehydrogenate methanol on (111) compared to (100) is explained by the multitude of adsorption sites and, in particular, the availability of surface oxygen.

Nucleophilic Aromatic Substitution Reactions Described by the Local Electron Attachment Energy.

A local multiorbital electrophilicity descriptor, the local electron attachment energy [E(r)], is used to study the nucleophilic aromatic substitution reactions of SNAr and VNS (vicarious nucleophilic substitution). E(r) considers all virtual orbitals below the free electron limit and is determined on the molecular isodensity contour of 0.004 atomic units. Good (R2 = 0.83) to excellent (R2 = 0.98) correlations are found between descriptor values and experimental reactivity data for six series of electron deficient arenes. These include homo- and heteroarenes, rings of five to six atoms, and a variety of fluorine, bromine, and hydride leaving groups. The solvent, temperature, and nucleophile are in addition varied across the series. The surface E(r) [ES(r)] is shown to provide reactivity predictions better than those of transition-state calculations for a concerted SNAr reaction with a bromine nucleofug, gives correlations substantially stronger than those of LUMO energies, and is overall more reliable than the molecular electrostatic potential. With the use of ES(r), one can identify the various electrophilic sites within a molecule and correctly predict isomeric distributions. Since the calculations of ES(r) are computationally inexpensive, the descriptor offers fast but accurate reactivity predictions for the important nucleophilic aromatic substitution class of reactions. Applications in, e.g., drug discovery, synthesis, and toxicology studies are envisaged.

MD Simulations Reveal Complex Water Paths in Squalene-Hopene Cyclase: Tunnel-Obstructing Mutations Increase the Flow of Water in the Active Site.

Squalene-hopene cyclase catalyzes the cyclization of squalene to hopanoids. A previous study has identified a network of tunnels in the protein, where water molecules have been indicated to move. Blocking these tunnels by site-directed mutagenesis was found to change the activation entropy of the catalytic reaction from positive to negative with a concomitant lowering of the activation enthalpy. As a consequence, some variants are faster and others are slower than the wild type (wt) in vitro under optimal reaction conditions for the wt. In this study, molecular dynamics (MD) simulations have been performed for the wt and the variants to investigate how the mutations affect the protein structure and the water flow in the enzyme, hypothetically influencing the activation parameters. Interestingly, the tunnel-obstructing variants are associated with an increased flow of water in the active site, particularly close to the catalytic residue Asp376. MD simulations with the substrate present in the active site indicate that the distance for the rate-determining proton transfer between Asp376 and the substrate is longer in the tunnel-obstructing protein variants than in the wt. On the basis of the previous experimental results and the current MD results, we propose that the tunnel-obstructing variants, at least partly, could operate by a different catalytic mechanism, where the proton transfer may have contributions from a Grotthuss-like mechanism.

Local Electron Attachment Energy and Its Use for Predicting Nucleophilic Reactions and Halogen Bonding.

A new local property, the local electron attachment energy [E(r)], is introduced and is demonstrated to be a useful guide to predict intermolecular interactions and chemical reactivity. The E(r) is analogous to the average local ionization energy but indicates susceptibility toward interactions with nucleophiles rather than electrophiles. The functional form E(r) is motivated based on Janak's theorem and the piecewise linear energy dependence of electron addition to atomic and molecular systems. Within the generalized Kohn-Sham method (GKS-DFT), only the virtual orbitals with negative eigenvalues contribute to E(r). In the present study, E(r) has been computed from orbitals obtained from GKS-DFT computations with a hybrid exchange-correlation functional. It is shown that E(r) computed on a molecular isodensity surface, ES(r), reflects the regioselectivity and relative reactivity for nucleophilic aromatic substitution, nucleophilic addition to activated double bonds, and formation of halogen bonds. Good to excellent correlations between experimental or theoretical measures of interaction strengths and minima in ES(r) (ES,min) are demonstrated.

Dual Lewis Acid/Lewis Base Catalyzed Acylcyanation of Aldehydes: A Mechanistic Study.

A mechanistic investigation, which included a Hammett correlation analysis, evaluation of the effect of variation of catalyst composition, and low-temperature NMR spectroscopy studies, of the Lewis acid-Lewis base catalyzed addition of acetyl cyanide to prochiral aldehydes provides support for a reaction route that involves Lewis base activation of the acyl cyanide with formation of a potent acylating agent and cyanide ion. The cyanide ion adds to the carbonyl group of the Lewis acid activated aldehyde. O-Acylation by the acylated Lewis base to form the final cyanohydrin ester occurs prior to decomplexation from titanium. For less reactive aldehydes, the addition of cyanide is the rate-determining step, whereas, for more reactive, electron-deficient aldehydes, cyanide addition is rapid and reversible and is followed by rate-limiting acylation. The resting state of the catalyst lies outside the catalytic cycle and is believed to be a monomeric titanium complex with two alcoholate ligands, which only slowly converts into the product.

Novel approach for identifying key residues in enzymatic reactions: proton abstraction in ketosteroid isomerase.

We propose a computationally efficient approach for evaluating the individual contributions of many different residues to the catalytic efficiency of an enzymatic reaction. This approach is based on the fragment molecular orbital (FMO) method, and it defines the energy of a deletion form, i.e., the energy of the system when a particular residue is deleted. Using this approach, we found that, among 10 investigated residues, three, Tyr14, Asp99, and Tyr55, in this order, significantly reduce the activation energy of the proton abstraction from a substrate, cyclopent-2-enone, catalyzed by ketosteroid isomerase (KSI). The relative activation energies estimated in this study are in good agreement with available previous experimental and theoretical data obtained for the similar proton abstraction with a native substrate and substitution mutants of KSI. It was thus indicated that the new approach is efficient for rationally evaluating the catalytic effects of multiple residues on an enzymatic reaction.

Searching for the thermodynamic limit--a DFT study of the step-wise water oxidation of the bipyramidal Cu7 cluster.

Oxidative degradation of copper in aqueous environments is a major concern in areas such as catalysis, electronics and construction engineering. A particular challenge is to systematically investigate the details of this process for non-ideal copper surfaces and particles under the conditions found in most real applications. To this end, we have used hybrid density functional theory to study the oxidation of a Cu7 cluster in water solution. Especially, the role of a large water coverage is explored. This has resulted in the conclusion that, under atmospheric H2 pressures, the thermodynamically most favored state of degradation is achieved upon the generation of four H2 molecules (i.e. Cu7 + 8H2O → Cu7(OH)8 + 4H2) in both condensed and gas phases. This state corresponds to an average oxidation state below Cu(I). The calculations suggest that the oxidation reaction is slow at ambient temperatures with the water dissociation as the rate-limiting step. Our findings are expected to have implication for, among other areas, the copper catalyzed water-gas shift reaction, and for the general understanding of copper corrosion in aqueous environments.