F. Matthias Bickelhaupt

Vrije Universiteit Amsterdam | VU · Department of Chemistry and Pharmaceutical Sciences

The hydrogen-bond donor strength of ureas, widely used in hydrogen-bond donor catalysis, molecular recognition, and self-assembly, can be enhanced by increasing the size of the chalcogen X in the C=X bond from O to S to Se and by introducing more electron-withdrawing substituents because both modifications increase the positive charge on the NH gro...

Herein, we dismiss a recent proposal by Civiš, Hobza, andco-workers to modify the IUPAC definition of hydrogen bonds in orderto expand the scope from protonic Y−Hδ+ to hydridic Y−Hδ− hydrogen-bond donor fragments [J. Am. Chem. Soc. 2023, 145, 8550]. Based onaccurate Kohn−Sham molecular orbital (KS-MO) analyses, we falsify theconclusion that interac...

The retro-Cope elimination reaction between dimethylhydroxylamine (DMHA) and various cyclic alkynes has been quantum chemically explored using DFT at ZORA-BP86/TZ2P. The purpose of this study is to understand the role of the following three unique activation modes on the overall reactivity, that is (i) additional cycloalkyne predistortion via fused...

We have quantum chemically analyzed the closed-shell d8–d8 metallophilic interaction in dimers of square planar [M(CO)2X2] complexes (M = Ni, Pd, Pt; X = Cl, Br, I) using dispersion-corrected density...

Quantum chemical calculations were carried out to quantitatively understand the origin of the Felkin–Anh(–Eisenstein) model, widely used to rationalize the π-facial stereoselectivity in the nucleophilic addition reaction to carbonyl groups directly attached to a stereogenic center. To this end, the possible approaches of cyanide to both (S)-2-pheny...

We have quantum chemically investigated how microsolvation affects the various E2 and S N 2 pathways, their mutual competition, as well as the a-effect of the model reaction system HOO ⁻ (H 2 O) n + CH 3 CH 2 Cl, at the...

Correction for ‘Pericyclic reaction benchmarks: hierarchical computations targeting CCSDT(Q)/CBS and analysis of DFT performance’ by Pascal Vermeeren et al. , Phys. Chem. Chem. Phys. , 2022, 24 , 18028–18042, https://doi.org/10.1039/D2CP02234F.

An enantioselective cobalt‐catalyzed C(sp³)−H alkenylation of thioamides with but‐2‐ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 %) and high ena...

The origin of the electrophilicity of a series of cyclohexanones and benzaldehydes is investigated using the activation strain model and quantitative Kohn–Sham molecular orbital (MO) theory. We find that this electrophilicity is mainly determined by the electrostatic attractions between the carbonyl compound and the nucleophile (cyanide) along the...

We have quantum chemically investigated the nature and stability of C–C and Si–Si bonds in R3A–AR3 (A = C, Si; R3 = H3, Me3, Me2Ph, MePh2, Ph3, t-Bu3) using density functional theory (DFT). Systematic increase of steric bulk of the substituents R has opposite effects on C–C and Si–Si bonds: the former becomes weaker whereas the latter becomes stron...

Opposite to what one might expect, we find that the C=X group can become effectively more, not less, electronegative when the Pauling electronegativity of atom X decreases down Groups 16, 15, and 14 of the Periodic Table. Our quantum‐chemical analyses, show that, and why, this phenomenon is a direct consequence of the increasing size of atom X down...

“The TheoCheM group develops sophisticated quantum mechanical models and techniques to uncover the physical principles behind the many incompletely (or supposedly) understood phenomena in chemistry. In the present work, we explain the physical mechanism behind the blueshift in the trifurcated hydrogen‐bonded X–•••H3C–Y complexes…” This and more abo...

An enantioselective cobalt‐catalyzed C(sp3)–H alkenylation of thioamides with but‐2‐ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85%) and high enan...

We have quantum chemically investigated the boron‐boron bonds in B2, diborynes B2L2, and diborenes B2H2L2 (L=none, OH2, NH3) using dispersion‐corrected relativistic density functional theory at ZORA‐BLYP‐D3(BJ)/TZ2P. B2 has effectively a single B−B bond provided by two half π bonds, whereas B2H2 has effectively a double B=B bond provided by two hal...

The bioorthogonal retro‐Cope elimination reaction of linear alkynes R3C−C≡C−X (R3 = combinations of H, MeO, F; X = H, F, Cl, Br, I) with N,N‐dimethylhydroxylamine was quantum chemically investigated using relativistic density functional theory at ZORA‐BP86/TZ2P. This novel reaction can be tuned through judicious substitution of the alkyne at both t...

We have quantum chemically investigated the origin of the atypical blueshift of the H−C bond stretching frequency in the hydrogen‐bonded complex X⁻•••H3C−Y (X, Y=F, Cl, Br, I), as compared to the corresponding redshift occurring in Cl⁻•••H3N and Cl⁻•••H3C−H, using relativistic density functional theory (DFT) at ZORA‐BLYP‐D3(BJ)/QZ4P. Previously, th...

Understanding the geometrical preferences in chemical reactions is crucial for advancing the field of organic chemistry and improving synthetic strategies. One such preference, the Bürgi-Dunitz angle, is central to nucleophilic addition reactions involving carbonyl groups. This study successfully employs a novel two-dimensional Distortion-Interacti...

Understanding the geometrical preferences in chemical reactions is crucial for advancing the field of organic chemistry and improving synthetic strategies. One such preference, the Bürgi-Dunitz angle, is central to nucleophilic addition reactions involving carbonyl groups. This study successfully employs a novel two-dimensional Distortion-Interacti...

We have quantum chemically studied the influence of ring strain on the competition between the two mechanistically different SN2 and E2 pathways using a series of archetypal ethers as substrate in combination with a diverse set of Lewis bases (F⁻, Cl⁻, Br⁻, HO⁻, H3CO⁻, HS⁻, H3CS⁻), using relativistic density functional theory at ZORA‐OLYP/QZ4P. The...

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 contributio...

The Bürgi‐Dunitz (BD) angle plays a pivotal role in organic chemistry to rationalize the nucleophilic addition to carbonyl groups. Yet, the origin of the obtuse trajectory of the nucleophile remains incompletely understood. Herein, we quantify the importance of the underlying physical factors quantum chemically. The obtuse BD angle appears to origi...

We have quantum chemically analyzed the origin of the captodative effect in the dimerization of para‐substituted phenyl dicyanomethyl radicals RPh(CN)2C⋅ in the gas phase and in solution. Captodative radicals are characterized by the presence of both, electron‐donating and electron‐withdrawing groups, and a weakening of the associated C−C bond in t...

The uptake and release of small molecules continue to be challenging tasks of utmost importance in synthetic chemistry. The combination of such small molecule activation with subsequent transformations to generate unusual reactivity patterns opens up new prospects for this field of research. Here, we report the reaction of CO2 and CS2 with cationic...

The heterocyclic tetrazole, a well‐established bioisosteric replacement of carboxylic acid, plays an important role in medicinal chemistry. To deepen the functional understanding of tetrazoles in chemical sciences, it is essential to investigate the noncovalent interactions between the tetrazole ring and aromatic rings. Here, we report synthetic, s...

We have quantum chemically studied activation of H n A–AH n bonds (AH n = CH 3 , NH 2 , OH, F) by PdL n catalysts with L n = no ligand, PH 3 , (PH 3 ) 2 , using relativistic density functional theory at ZORA-BLYP/TZ2P. The activation energy associated with the oxidative addition step decreases from H 3 C–CH 3 to H 2 N–NH 2 to HO–OH to F–F, where th...

Quantum chemical methods were employed to analyze the nature and the origin of the directionality of pnictogen (PnB), chalcogen (ChB), and halogen bonds (XB) in archetypal FmZ⋅⋅⋅F⁻ complexes (Z=Pn, Ch, X), using relativistic density functional theory (DFT) at ZORA‐M06/QZ4P. Quantitative Kohn‐Sham MO and energy decomposition analyses (EDA) show that...

Boron‐boron multiple bonds, such as those found in diborenes and diborynes, are typically stabilized by σ‐donor ligands that furnish electron density to these otherwise electron‐deficient species. These compounds are not only of fundamental importance in the study of chemical bonding, but can also activate small molecules in a chemistry reminiscent...

We have quantum chemically studied the base‐catalyzed Diels‐Alder (DA) reaction between 3‐hydroxy‐2‐pyrone and N‐methylmaleimide using dispersion‐corrected density functional theory. The uncatalyzed reaction is slow and is preceded by the extrusion of CO2 via a retro‐DA reaction. Base catalysis, for example, by triethylamine, lowers the reaction ba...

The iron‐catalyzed oxidative addition of C(spⁿ)−X bonds (n=1–3 and X=H, CH3, Cl) in archetypal model substrates H3C−CH2−X, H2C=CH−X and HC≡C−X to Fe(CO)4 was investigated using relativistic density functional theory at ZORA‐OPBE/TZ2P. The C(spⁿ)−X bonds become substantially stronger going from C(sp³)−X to C(sp²)−X to C(sp)−X, whereas the oxidative...

Recently, Sowlati-Hashjin et al.1 have used the exchange-correlation interaction collectivity index (ICIXC; ICIXC  [0,1]) to conclude that the nature of the Li–C chemical bond in LiCF3 differs significantly from that in LiCPh3 (Ph = phenyl). Whereas the Li–C bond of LiCF3 is classified as a conventional two-center two-electron bond (ICIXC = 0.910,...

The traditional and widespread rationale behind the stability trend of alkyl-substituted carbocations is incomplete.

The C–H bond of the methylidyne radical, CH•, is abnormally long and weak, even longer and weaker than that of methane, CH4. This is remarkable given the fact that the C–H bond has been shown to contract as the number of substituents around the pertinent carbon atom decreases (e.g., from ethane to ethene to ethyne) because of the accompanying reduc...

The traditional and widespread rationale behind the stability trend of alkyl-substituted carbocations is incomplete. Through state-of-the-art quantum chemical analyses, we quantitatively established a generally overlooked driving force behind the stability...

Simple mathematical models can serve to reveal the essence of experimental phenomena and scientific concepts. The particle in a box (PIB), for example, is widely used in undergraduate programs to teach the quantum mechanical principles behind the UV-vis spectra of conjugated polyenes and polyynes. In this work, the particle on a ring (POR) and the...

The gauche conformer in 1-X,2-Y-disubstituted ethanes, that is, the staggered orientation in which X and Y are in closer contact, is only favored for relatively small substituents that do not give rise to large X···Y steric repulsion. For more diffuse substituents, weakly attractive orbital interactions between antiperiplanar bonds (i.e., hyperconj...

We have quantum chemically investigated how methyl substituents affect the stability of alkyl radicals MemH3−mC⋅ and the corresponding MemH3−mC−X bonds (X = H, CH3, OH; m = 0 – 3) using density functional theory at M06‐2X/TZ2P. The state‐of‐the‐art in physical organic chemistry is that alkyl radicals are stabilized upon an increase in their degree...

Hierarchical, convergent ab initio benchmark computations were performed followed by a systematic analysis of DFT performance for five pericyclic reactions comprising Diels-Alder, 1,3-dipolar cycloaddition, electrocyclic rearrangement, sigmatropic rearrangement, and double group transfer prototypes. Focal point analyses (FPA) extrapolating to the a...

We have quantum chemically studied the palladium‐mediated activation of C(spⁿ)−X bonds (n=1–3; X=F, Cl, Br, I) in the archetypal model substrates H3C−CH2−X, H2C=CH−X, and HC≡C−X by a model bare palladium catalyst, using relativistic density functional theory at ZORA‐BLYP/TZ2P. The bond activation reaction barrier decreases, for all sp‐hybridized ca...

We have quantum chemically investigated how methyl substituents affect the stability of alkyl radicals Me m H 3‐m C • and the corresponding Me m H 3‐m C–X bonds (X = H, CH 3 , OH; m = 0 ‐ 3) using density functional theory at M06‐2X/TZ2P. The state‐of‐the‐art in physical organic chemistry is that alkyl radicals are stabilized upon an increase in th...

We have quantum chemically explored the competition between the SN2 and SN2' pathways for X− + H2C=CHCH2Y (X, Y = F, Cl, Br, I) using a combined relativistic density functional theory and coupled-cluster theory approach. Bimolecular nucleophilic substitution reactions at allylic systems, i.e., Cy=Cb–Ca–Y, bearing a leaving-group at the a-position,...

Invited for the cover of this issue are Pascal Vermeeren, Trevor A. Hamlin, and F. Matthias Bickelhaupt of the TheoCheM group at the Vrije Universiteit Amsterdam. The cover art depicts how ionizing the dienophile lowers the Diels–Alder reaction barrier between 1,3‐butadiene and acrylaldehyde by reducing the destabilizing steric Pauli repulsion and...

The C−X bond activation (X = H, C) of a series of substituted C(n°)−H and C(n°)−C(m°) bonds with C(n°) and C(m°) = H3C− (methyl, 0°), CH3H2C− (primary, 1°), (CH3)2HC− (secondary, 2°), (CH3)3C− (tertiary, 3°) by palladium were investigated using relativistic dispersion‐corrected density functional theory at ZORA‐BLYP‐D3(BJ)/TZ2P. The effect of the s...

Imidazole-based compounds are widely found in natural products, synthetic molecules, and biomolecules. Noncovalent interactions between the imidazole ring and other functional groups play an important role in determining the function of diverse molecules. However, there is a limited understanding of the underlying noncovalent interactions between i...

We discuss fundamental aspects of the EDA-NOCV method and we address some critical comments that have recently been made. The EDA-NOCV method unlike most other methods focuses on the process of the bond formation between the interacting species and not only on the analysis of the finally formed bond. This is demonstrated using LiF as example, which...

Ionization of the dienophile is an effective method to enhance the Diels–Alder reaction between buta‐1,3‐diene and acrylaldehyde. The origin of this ionization catalysis is both a reduction in steric Pauli repulsion and simultaneous enhancement of the orbital interactions between the reactants. Our work demonstrates the similarities and differences...

The catalytic effect of ionization on the Diels‐Alder reaction between 1,3‐butadiene and acrylaldehyde has been studied using relativistic density functional theory (DFT). Removal of an electron from the dienophile, acrylaldehyde, significantly accelerates the Diels‐Alder reaction and shifts the reaction mechanism from concerted asynchronous for th...

Nε-Methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription. The ‘highest’ methylation mark, Nε-trimethyllysine, is specifically recognised by Nε-trimethyllysine binding ‘reader’ domains, and undergoes demethylation, as catalysed by 2-oxoglutarate dependent JmjC oxygenases. We report studies o...

It has been experimentally observed that water–ice-embedded polycyclic aromatic hydrocarbons (PAHs) form radical cations when exposed to vacuum UV irradiation, whereas ammonia-embedded PAHs lead to the formation of radical anions. In this study, we explain this phenomenon by investigating the fundamental electronic differences between water and amm...

Invited for this month's cover are the groups of Célia Fonseca Guerra at the Vrije Universiteit Amsterdam and Leiden University, Giampaolo Barone from the Università degli Studi di Palermo, and F. Matthias Bickelhaupt at Vrije Universiteit Amsterdam and Radboud University Nijmegen. The cover picture shows the four primary interaction components (hy...

The front cover 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. Quantum chemical analyses identify an interplay between the stabilizing hydrogen bonds between nucleotides that d...

We have quantum chemically studied the iron‐mediated C–X bond activation (X = H, Cl, CH3) by d8‐FeL4 complexes using relativistic density functional theory at ZORA‐OPBE/TZ2P. We find that by either modulating the electronic effects of a generic iron‐catalyst by a set of ligands, that is, CO, BF, PH3, BN(CH3)2, or by manipulating structural effects...

We have studied the palladium‐mediated activation of C(spⁿ)−X bonds (n = 1–3 and X = H, CH3, Cl) in archetypal model substrates H3C−CH2−X, H2C=CH−X and HC≡C−X by catalysts PdLn with Ln = no ligand, Cl⁻, and (PH3)2, using relativistic density functional theory at ZORA‐BLYP/TZ2P. The oxidative addition barrier decreases along this series, even though...

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...

Boronic acids are Lewis acids that exist in equilibrium with boronate forms in aqueous solution. Here we experimentally and computationally investigated the Lewis acidity of 2,6‐diarylphenylboronic acids; specially designed phenylboronic acids that possess two flanking aromatic rings with tunable aromatic character. Hammett analysis of 2,6‐diarylph...

We have quantum chemically investigated how solvation influences the competition between the SN2 and E2 pathways of the model F– + C2H5Cl reaction. The system is solvated in a stepwise manner by going from the gas phase, then via microsolvation of one to three explicit solvent molecules, then last to bulk solvation using relativistic density functi...