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The proton-induced electron-transfer reaction of a CuII µ-thiolate complex to a CuI-containing species has been investigated, both experimentally and computationally. The CuII µ-thiolate complex [CuII 2(LMeS)2]2+ is isolated with the new pyridyl-containing ligand LMeSSLMe, which can form both CuII thiolate and CuI disulfide complexes, depending on the solvent. Both the CuII and the CuI complexes show reactivity upon addition of protons. The multivalent tetranuclear complex [CuI 2CuII 2(LS)2(CH3CN)6]4+ crystallizes after addition of two equivalents of strong acid to a solution containing the µ-thiolate complex [CuII 2(LS)2]2+ and is further analyzed in solution. This study shows that, upon addition of protons to the CuII thiolate compound, the ligand dissociates from the copper centers, in contrast to an earlier report describing redox isomerization to a CuI disulfide species that is protonated at the pyridyl moieties. Computational studies of the protonated CuII µ-thiolate and CuI disulfide species with LSSL show that already upon addition of two equivalents of protons, ligand dissociation forming [CuI(CH3CN)4]+ and protonated ligand is energetically favored over conversion to a protonated CuI disulfide complex. [ABSTRACT FROM AUTHOR]

Reaction of the donor-stabilized silylene 1 (which is three-coordinate in the solid state and four-coordinate in solution) with [HMCp(CO)3] (M=Mo, W; Cp=cyclopentadienyl) leads to the cationic five-coordinate silicon(IV) complexes 2 and 3, respectively, and reaction of 1 with CH3COOH yields the neutral six-coordinate silicon(IV) complex 4. Compounds 2- 4 were structurally characterized by crystal structure analyses and multinuclear NMR spectroscopic studies in the solid state and in solution. The formation of 2- 4 can be formally described in terms of a Brønsted acid/base reaction, coupled with a redox process (SiII→SiIV, H+→H−). [ABSTRACT FROM AUTHOR]

Reaction of the donor-stabilized silylene 1 (which is three-coordinate in the solid state and four-coordinate in solution) with BEt3 and BPh3 leads to the formation of the Lewis acid/base complexes 2 and 3, respectively, which are the first five-coordinate silicon compounds with an SiB bond. These compounds were structurally characterized by crystal structure analyses and by multinuclear NMR spectroscopic studies in the solid state and in solution. Additionally, the bonding situation in 2 and 3 was analyzed by quantum chemical studies. [ABSTRACT FROM AUTHOR]

A convenient and robust synthesis of bis[ N, N′-diisopropylbenzamidinato(−)]silicon( II) ( 1), a donor-stabilized silylene, has been developed (35 g scale). To get further information about the reactivity profile of 1, a series of oxidative addition reactions were studied. Treatment of 1 with PhSeSePh (SeSe bond activation), C6F6 (CF activation), and CO2 (CO activation/cycloaddition) yielded the neutral six-coordinate silicon( IV) complexes 10, 11, and 13, respectively. Treatment of 1 with N2O resulted in the formation of the dinuclear five-coordinate silicon( IV) complex 12 (oxidative addition/dimerization), which contains a four-membered Si2O2 ring. Compounds 10- 13 were characterized by NMR spectroscopic studies in the solid state and in solution and by crystal structure analyses. Silylene 1 is three-coordinate in the solid state (from crystal structure analysis) and exists as the four-coordinate isomer 1′ in benzene solution (from computational studies). Based on state-of-the-art relativistic DFT analyses, the four-coordinate species 1′ was demonstrated to be the thermodynamically favored isomer in benzene solution (favored by Δ G=6.6 kcal mol−1 over the three-coordinate species 1). The reason for this was studied by bonding analyses of 1 and 1′. Furthermore, the 29Si NMR chemical shifts of 1 and 1′ were computed, and in the case of 1′ it was analyzed how this NMR spectroscopic parameter is affected by solvation. These studies further supported the assumption that the silylene is four-coordinate in solution. [ABSTRACT FROM AUTHOR]

Interactions between an inhibitor and amino acids from a binding pocket could help not only to understand the nature of these interactions, but also to support the design of new inhibitors. In this paper, we explore the key interaction between a second generation non-nucleoside reverse transcriptase inhibitor (NNRTI), GW420867X, and HIV-1 RT amino acid Lys101 (K101), by quantum mechanical methods. The neutral, protonated, and zwitterionic complexes of GW420867X-K101 were studied. The interaction energies were determined by SCS-MP2/def2-cc-pVQZ, and the electron density was analyzed by natural bond orbital (NBO), atoms in molecules (AIM) and reduced gradient analysis. A large increase in the interaction was observed with the tautomerization of neutral or neutral protonated species. The monomers interact by two medium-strength hydrogen bonds, one partially covalent and another noncovalent. There are some van der Waals intramolecular interactions that are topologically unstable. The nature of the intermolecular interactions was also analyzed using quantitative molecular orbital (MO) theory in combination with an energy decomposition analysis (EDA) based on dispersion-corrected density functional theory (DFT) at BLYP-D/TZ2P. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Front Cover: How the Chalcogen Atom Size Dictates the Hydrogen-Bond Donor Capability of Carboxamides, Thioamides, and Selenoamides (Chem. Eur. J. 31/2022) Keywords: amides; chalcogens; density functional calculations; hydrogen bonding; organocatalysis EN amides chalcogens density functional calculations hydrogen bonding organocatalysis 1 1 1 06/06/22 20220601 NES 220601 B Thioamides and selenoamides b are better hydrogen-bond donors than carboxamides because their amino groups are more positively charged. Amides, chalcogens, density functional calculations, hydrogen bonding, organocatalysis. [Extracted from the article]

We have computationally studied para-X-substituted phenols and phenolates (X = NO, NO2, CHO, COMe, COOH, CONH2, Cl, F, H, Me, OMe, and OH) and their hydrogen-bonded complexes with B− and HB (B = F and CN), respectively, at B3LYP/6-311++G** and BLYP-D/QZ4P levels of theory. Our purpose is to explore the structures and stabilities of these complexes. Moreover, to understand the emerging trends, we have analyzed the bonding mechanisms using the natural bond orbital scheme as well as Kohn-Sham molecular orbital (MO) theory in combination with quantitative energy decomposition analyses [energy decomposition analysis (EDA), extended transition state-natural orbitals for chemical valence (ETS-NOCV)]. These quantitative analyses allow for the construction of a simple physical model that explains all computational observations. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Metal-mediated Hoogsteen-type base pairs are useful for the construction of DNA duplexes containing contiguous stretches of metal ions along the helical axis. To fine-tune the stability of such base pairs and the selectivity toward different metal ions, the availability of a selection of artificial nucleobases is highly desirable. In this study, we follow a theoretical approach utilizing dispersion-corrected density functional methods to evaluate a variety of artificial nucleobases as candidates for metal-mediated Hoogsteen-type base pairs. We focus on silver(I)-mediated Hoogsteen- and reverse Hoogsteen-type base pairs formed between 1-deaza- and 1,3-dideazapurine-derived nucleobases, respectively, and cytosine. Apart from two coordinative bonds, these base pairs are stabilized by a hydrogen bond. We elucidate the impact of different substituents at the C6 position and the presence or absence of an endocyclic N3 nitrogen atom on the overall stability of a base pair and concomitantly on the strength of the hydrogen and coordinative bonds. All artificial base pairs investigated in this study are less stable than the experimentally established benchmark base pair C–Ag+–G. The base pair formed from 1,3-dideaza-6-methoxypurine is isoenergetic to the experimentally observed C–Ag+–C base pair. This makes 1,3-dideaza-6-methoxypurine a promising candidate for the use as an artificial nucleobase in DNA. [Copyright &y& Elsevier]

Keywords: cooperative effects; density functional calculations; energy decomposition analysis; hydrogen bonds; supramolecular chemistry EN cooperative effects density functional calculations energy decomposition analysis hydrogen bonds supramolecular chemistry 1 1 1 02/28/22 20220201 NES 220201 B The cover picture shows -electrons b , which by traveling through the chain, strengthen the hydrogen bonds in squaramide linear chains. Cooperative effects, density functional calculations, energy decomposition analysis, hydrogen bonds, supramolecular chemistry As the charge flows from one end of the chain towards the other, it amplifies the charge separation across the chain, resulting in a stronger hydrogen bond with the new incoming monomer. [Extracted from the article]

Keywords: activation strain model; density functional calculations; diagonal interactions; DNA structures; nucleotide composition EN activation strain model density functional calculations diagonal interactions DNA structures nucleotide composition 1 1 1 02/28/22 20220201 NES 220201 B The front cover b provided by the TheoCheM group from Vrije Universiteit Amsterdam shows the four primary interaction components (hydrogen bonding, cross-terms, base stacking, and solvation) that determine the stability of B-DNA duplexes. Front Cover: B-DNA Structure and Stability: The Role of Nucleotide Composition and Order (ChemistryOpen 2/2022) Activation strain model, density functional calculations, diagonal interactions, DNA structures, nucleotide composition. [Extracted from the article]

[Display omitted] • The central helix domain (CH) of the spike (S) proteins shows a funnel-like polar structure, fully conserved in human and bat SARS-CoVs. • Peculiar glutamine sidechain patterns have been found within the cryo-EM structure CHs of both SARS-CoV-1 and SARS-CoV-2 S-proteins, potentially conducive to ion-binding. • Ion-binding motifs are superimposable to the post-fusion state of SARS-CoV-1 S-protein, bound to chlorides in its experimental X-ray crystal structure. • DFT calculations and subsequent comparison with the post-fusion X-ray crystal structure predict a positive interaction between physiological electrolytes (Na+, K+ and Cl−) and the S-protein funnel. The trimeric spike (S) glycoprotein is the trojan horse and the stronghold of the severe acute respiratory syndrome coronaviruses. Although several structures of the S-protein have been solved, a complete understanding of all its functions is still lacking. Our multi-approach study, based on the combination of structural experimental data and quantum-chemical DFT calculations, led to identify a sequestration site for sodium, potassium and chloride ions within the central cavity of both the SARS-CoV-1 and SARS-CoV-2 spike proteins. The same region was found as strictly conserved, even among the sequences of the bat-respective coronaviruses. Due to the prominent role of the main three electrolytes at many levels, and their possible implication in the molecular mechanisms of COVID-19 disease, our study can take the lead in important discoveries related to the SARS-CoV-2 biology, as well as in the design of novel effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

The Cover Feature shows how understanding the growth of linear molecular chains is key for the rational design and synthesis of novel supramolecular materials. Using state‐of‐the‐art quantum chemical computations, this work demonstrates that the cooperative properties of halogen bonds in linear chains can be rationalized by the increased charge separation within the σ‐electronic system, resulting from a stronger charge transfer from the lone‐pair orbital of the nitrogen atom on one unit to the C–halogen acceptor orbital on the adjacent unit. More information can be found in the Full Paper by G. Paragi, C. Fonseca Guerra, and co‐workers. [ABSTRACT FROM AUTHOR]

Activation strain model, bonding analysis, density functional calculations, hybridization theory, Pauli repulsion Keywords: activation strain model; bonding analysis; density functional calculations; hybridization theory; Pauli repulsion EN activation strain model bonding analysis density functional calculations hybridization theory Pauli repulsion 6997 6997 1 04/30/21 20210426 NES 210426 B In s-p hybridization b , the contraction of C-H and C-C bonds as the carbon atom involved varies from sp3 to sp2 to sp is a fundamental and ubiquitous phenomenon in chemistry. Cover Feature: Not Carbon s-p Hybridization, but Coordination Number Determines C-H and C-C Bond Length (Chem. Eur. J. 24/2021). [Extracted from the article]

Keywords: Activation strain analysis; Bond energy; Density functional calculations; Energy decomposition analysis; Lewis acid-base pairs EN Activation strain analysis Bond energy Density functional calculations Energy decomposition analysis Lewis acid-base pairs 3913 3913 1 12/03/20 20201201 NES 201201 B The Lewis acid/base interaction b is a cornerstone of chemistry and is teaching material for every undergraduate chemistry student. The bond dissociation energy of X SB 3 sb B-NY SB 3 sb Lewis pairs increases along X,Y=F, Cl, Br, I, H because the Lewis acids become easier to pyramidalize, while the Lewis bases engage in stronger orbital interactions. Activation strain analysis, Bond energy, Density functional calculations, Energy decomposition analysis, Lewis acid-base pairs. [Extracted from the article]

We have quantum chemically analyzed the influence of nucleotide composition and sequence (that is, order) on the stability of double‐stranded B‐DNA triplets in aqueous solution. To this end, we have investigated the structure and bonding of all 32 possible DNA duplexes with Watson–Crick base pairing, using dispersion‐corrected DFT at the BLYP‐D3(BJ)/TZ2P level and COSMO for simulating aqueous solvation. We find enhanced stabilities for duplexes possessing a higher GC base pair content. Our activation strain analyses unexpectedly identify the loss of stacking interactions within individual strands as a destabilizing factor in the duplex formation, in addition to the better‐known effects of partial desolvation. Furthermore, we show that the sequence‐dependent differences in the interaction energy for duplexes of the same overall base pair composition result from the so‐called "diagonal interactions" or "cross terms". Whether cross terms are stabilizing or destabilizing depends on the nature of the electrostatic interaction between polar functional groups in the pertinent nucleobases. [ABSTRACT FROM AUTHOR]

Highlights from the article: Front Cover: The Nature of Hydrogen Bonds: A Delineation of the Role of Different Energy Components on Hydrogen Bond Strengths and Lengths (Chem. This is done by discussing the following individual energy components: 1) electrostatic interactions, 2) charge-transfer interactions, 3) -resonance assistance, 4) steric repulsion, 5) cooperative effects, 6) dispersion interactions, and 7) secondary electrostatic interactions. Supramolecular chemistry, molecular interactions, hydrogen bonds, cooperative effects, noncovalent interactions.

Invited for this month's cover picture are Professor Célia Fonseca Guerra from Vrije Universiteit Amsterdam and Leiden University (The Netherlands) and André Nicolai Petelski from UTN‐FRRe University of Argentine (Argentina). The cover picture shows a colored pallet of melamine and ammeline tautomers that form hydrogen‐bonded hexameric rosettes. When it comes to self‐assembling capabilities, one of the ammeline structures (red) is shown to be distinctly superior to melamine, both in the gas phase and in water. Quantum chemical computations explain that this is due to the presence of stronger pair interactions and the manifestation of a large cooperativity effect. Read the full text of their Full Paper at 10.1002/open.201800210. "Hydrogen‐bonded rosettes of melamine are widely used in supramolecular chemistry. However, computational experiments suggest that ammeline is a more robust building block for fabricating these cyclic complexes..." Find out more about the story behind the front cover research at 10.1002/open.201800210. [ABSTRACT FROM AUTHOR]

The Front Cover shows a colored pallet of melamine and ammeline tautomers that form hydrogen‐bonded hexameric rosettes. When it comes to self‐assembling capabilities, one of the ammeline structures (red) is shown to be distinctly superior to melamine, both in the gas phase and in water. Quantum chemical computations explain that this is caused by the presence of stronger pair interactions and the manifestation of a large cooperativity effect. More information can be found in the Full Paper by A. N. Petelski and C. Fonseca Guerra on page 135 in Issue 2, 2019 (DOI: 10.1002/open.201800210). [ABSTRACT FROM AUTHOR]

A self‐sorting network comprising six different hydrogen bonding‐motifs is presented. Detailed analysis of the pairwise molecular recognition behavior of each hydrogen‐bonding motif by NMR spectroscopy, single‐crystal studies, and DFT allowed the construction of cascades exploiting integrative and non‐integrative narcissistic and social self‐sorted product distributions. Multiple distinct pathways within the network could be created depending on the presence or absence of different components. More information can be found in the Full Paper by C. Fonseca Guerra, A. J. Wilson, et al. on page 785. [ABSTRACT FROM AUTHOR]

G‐Quadrupex‐RNA is structurally similar to its DNA counterpart but shows higher stability. Quantum chemical (DFT‐D) calculations pinpoint the role of noncovalent interactions and better electrostatics in determining RNA‐GQs higher stabilities, focussing on the contribution of the extra ribonucleosidic 2'‐OH groups. New insight on the necessity of cations for the assembly of these structures has been given, emphasizing how they are required to overcome entropic penalty and not, like previously assumed, to minimize internal repulsion forces. More information can be found in the Full Paper by C. Fonseca Guerra and F. Zaccaria on page 16315. [ABSTRACT FROM AUTHOR]

We have quantum chemically studied the structure and nature of alkali‐ and coinage‐metal bonds (M‐bonds) versus that of hydrogen bonds between A−M and B− in archetypal [A−M⋅⋅⋅B]− model systems (A, B=F, Cl and M=H, Li, Na, Cu, Ag, Au), using relativistic density functional theory at ZORA‐BP86‐D3/TZ2P. We find that coinage‐metal bonds are stronger than alkali‐metal bonds which are stronger than the corresponding hydrogen bonds. Our main purpose is to understand how and why the structure, stability and nature of such bonds are affected if the monovalent central atom H of hydrogen bonds is replaced by an isoelectronic alkali‐ or coinage‐metal atom. To this end, we have analyzed the bonds between A−M and B− using the activation strain model, quantitative Kohn‐Sham molecular orbital (MO) theory, energy decomposition analysis (EDA), and Voronoi deformation density (VDD) analysis of the charge distribution. [ABSTRACT FROM AUTHOR]

When carbonyl ligands coordinate to transition metals, their bond distance either increases (classical) or decreases (nonclassical) with respect to the bond length in the isolated CO molecule. C−O expansion can easily be understood by π‐back‐donation, which results in a population of the CO's π*‐antibonding orbital and hence a weakening of its bond. Nonclassical carbonyl ligands are less straightforward to explain, and their nature is still subject of an ongoing debate. In this work, we studied five isoelectronic octahedral complexes, namely Fe(CO)62+, Mn(CO)6+, Cr(CO)6, V(CO)6− and Ti(CO)62−, at the ZORA‐BLYP/TZ2P level of theory to explain this nonclassical behavior in the framework of Kohn–Sham molecular orbital theory. We show that there are two competing forces that affect the C−O bond length, namely electrostatic interactions (favoring C−O contraction) and π‐back‐donation (favoring C−O expansion). It is a balance between those two terms that determines whether the carbonyl is classical or nonclassical. By further decomposing the electrostatic interaction ΔVelstat into four fundamental terms, we are able to rationalize why ΔVelstat gives rise to the nonclassical behavior, leading to new insights into the driving forces behind C−O contraction. [ABSTRACT FROM AUTHOR]

Introducing a rigid linear π‐conjugated acetylene linker into a supramolecular building block consisting of a hydrogen‐bond donor side and a hydrogen‐bond acceptor side yields a decrease in cooperativity in the resulting formed quartet. This follows from our Kohn‐Sham molecular orbital and Voronoi deformation density analyses of hydrogen‐bonded macrocycles based on guanine and cytosine nucleobases. The acetylene linker abstracts electron density from the hydrogen‐bond acceptor and donor, making the hydrogen‐bond acceptor more negatively charged and the hydrogen‐bond donor more positively charged and hence suppressing the donor–acceptor charge transfer interaction between the interacting fragments. This, ultimately, hampers the cooperativity in the hydrogen‐bonded macrocycle. We envision that these findings could open the door to new design principles for the development of novel hydrogen‐bond supramolecular macrocycles. [ABSTRACT FROM AUTHOR]

It is shown, quantum chemically, how structural distortion of an aromatic dye molecule can be leveraged to rationally tune its optoelectronic properties. By using a quantitative Kohn–Sham molecular orbital (KS‐MO) approach, in combination with time‐dependent DFT (TD‐DFT), the influence of various structural and electronic tuning parameters on the HOMO–LUMO gap of a benzenoid model dye have been investigated. These parameters include 1) out‐of‐plane bending of the aromatic core, 2) bending of the bridge with respect to the core, 3) the nature of the bridge itself, and 4) π–π stacking. The study reveals the coupling of multiple structural distortions as a function of bridge length and number of bridges in benzene to be chiefly responsible for a decreased HOMO–LUMO gap, and consequently, red‐shifting of the absorption wavelength associated with the lowest singlet excitation (λ≈560 nm) in the model cyclophane systems. These physical insights together with a rational approach for tuning the oscillator strength were leveraged for the proof‐of‐concept design of an intense near‐infrared (NIR) absorbing cyclophane dye at λ=785 nm. This design may contribute to a new class of distortion‐controlled NIR absorbing organic dye molecules. [ABSTRACT FROM AUTHOR]

The role of the alkaline-earth metal on the catalytic hydrogenation of imines is elucidated by means of conceptual quantum chemical techniques, revealing the main factors behind the striking reactivity differences between Mg and the heavier Ae metals. [Display omitted] Alkaline-earth metal (Ae) catalysts have been recently developed for challenging imine and alkene hydrogenation at moderate reaction conditions, providing a sustainable alternative to transition metal catalysis. The understanding of catalytic hydrogenations mediated by group 2 metals is underdeveloped and mechanistic studies are scarce from experimental and computational sides. Herein, we examine the role of the metal on the catalytic hydrogenation of imines by Ae[N(SiMe 3) 2 ] 2 (Ae = Mg, Ca, Sr, Ba) using state-of-the-art computational techniques. Trends in energy barriers and turnover frequencies agree remarkably well with the experimentally observed increase in catalytic activity upon descending group 2 (Mg ≪ Ca < Sr < Ba). Structural and chemical bonding differences in the key intermediates were found to be the main driving force behind the enhanced reactivity of heavier Ae catalysts. More specifically, the N - A e - H ^ bond angle is drastically reduced in the Ca, Sr, and Ba catalytic species driven by the participation of the d-orbitals in the chemical bonding. The activation strain model reveals that these catalytic reactions are strain controlled and the higher activation barriers for the Mg catalyst originates from unfavourable bond angles in the Mg hydride species featuring linear structures and a more covalent metal-hydride bond. Further decomposition of the interaction energy reveals that stronger repulsive interactions destabilize the Mg species, indicating that the steric congestion due to the small Mg centre impedes reaction kinetics. Overall, the different aspects to be considered in the Ae catalyst design for imine hydrogenations are the strength and flexibility of the Ae-H bond, the bond ionicity, the N - A e - H ^ angle and the strength of the noncovalent interactions in the TOF-determining intermediate. [ABSTRACT FROM AUTHOR]

Principles are presented for the design of functional near‐infrared (NIR) organic dye molecules composed of simple donor (D), spacer (π), and acceptor (A) building blocks in a D‐π‐A fashion. Quantitative Kohn–Sham molecular orbital analysis enables accurate fine‐tuning of the electronic properties of the π‐conjugated aromatic cores by effecting their size, including silaaromatics, adding donor and acceptor substituents, and manipulating the D‐π‐A torsional angle. The trends in HOMO–LUMO gaps of the model dyes correlate with the excitation energies computed with time‐dependent density functional theory at CAMY‐B3LYP. Design principles could be developed from these analyses, which led to a proof‐of‐concept linear D‐π‐A with a strong excited‐state intramolecular charge transfer and a NIR absorption at 879 nm. © 2018 The Authors. Journal of Computational Chemistry published by Wiley Periodicals, Inc. Capturing the Lost Photons: near‐infrared (NIR)‐absorbing D‐π‐A organic dyes are rare and often discovered via laborious exploration and serendipity. Herein, based on quantitative Kohn–Sham MO and time‐dependent density functional theory analyses, the authors develop a toolbox of generic design principles that support a more rational and efficient approach toward such dyes. The authors provide a proof of principle for their approach by in‐silico rational design of a NIR‐absorbing dye molecule. [ABSTRACT FROM AUTHOR]

The symmetry‐decomposed Voronoi deformation density (VDD) charge analysis is an insightful and robust computational tool to aid the understanding of chemical bonding throughout all fields of chemistry. This method quantifies the atomic charge flow associated with chemical‐bond formation and enables decomposition of this charge flow into contributions of (1) orbital interaction types, that is, Pauli repulsive or bonding orbital interactions; (2) per irreducible representation (irrep) of any point‐group symmetry of interacting closed‐shell molecular fragments; and now also (3) interacting open‐shell (i.e., radical) molecular fragments. The symmetry‐decomposed VDD charge analysis augments the symmetry‐decomposed energy decomposition analysis (EDA) so that the charge flow associated with Pauli repulsion and orbital interactions can be quantified both per atom and per irrep, for example, for σ, π, and δ electrons. This provides detailed insights into fundamental aspects of chemical bonding that are not accessible from EDA. [ABSTRACT FROM AUTHOR]

We have investigated the stereoselectivity and reactivity of the sodium borohydride reduction of 2‐X‐cyclohexanones (X=H, Cl, Br) using a combined approach of competitive experiments and density functional theory calculations. Our results show that the hydride addition proceeds via a late transition state in which the C–H bond is nearly formed, consistent with the mild reducing power of NaBH4. The reaction barrier decreases from the 2‐halocyclohexanones to the unsubstituted cyclohexanone, in line with relative reactivities observed in the competitive experiments. Furthermore, we provide a protocol to solve the longstanding issue of properly modelling the axial–equatorial facial selectivity of hydride addition to the carbonyl group substituted with a vicinal polar group. The inclusion of implicit solvation in combination with an explicit solvent molecule is crucial to reproduce the stereoselective formation of the cis product observed experimentally. [ABSTRACT FROM AUTHOR]