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We have quantum chemically studied the influence of ring strain on the competition between the two mechanistically different S N 2 and E2 pathways using a series of archetypal ethers as substrate in combination with a diverse set of Lewis bases (F - , Cl - , Br - , HO - , H 3 CO - , HS - , H 3 CS - ), using relativistic density functional theory at ZORA-OLYP/QZ4P. The ring strain in the substrate is systematically increased on going from a model acyclic ether to a 6- to 5- to 4- to 3-membered ether ring. We have found that the activation energy of the S N 2 pathway sharply decreases when the ring strain of the system is increased, thus on going from large to small cyclic ethers, the S N 2 reactivity increases. In contrast, the activation energy of the E2 pathway generally rises along this same series, that is, from large to small cyclic ethers. The opposing reactivity trends induce a mechanistic switch in the preferred reaction pathway for strong Lewis bases from E2, for large cyclic substrates, to S N 2, for small cyclic substrates. Weak Lewis bases are unable to overcome the higher intrinsic distortivity of the E2 pathway and, therefore, always favor the less distortive S N 2 reaction., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

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 CO 2 via a retro-DA reaction. Base catalysis, for example, by triethylamine, lowers the reaction barrier up to 10 kcal mol -1 , causing the reaction to proceed smoothly at low temperature, which quenches the expulsion of CO 2 , yielding efficient access to polyoxygenated natural compounds. Our activation strain analyses reveal that the base accelerates the DA reaction via two distinct electronic mechanisms: i) by the HOMO-raising effect, which enhances the normal electron demand orbital interaction; and ii) by donating charge into 3-hydroxy-2-pyrone which accumulates in its reactive region and promotes strongly stabilizing secondary electrostatic interactions with N-methylmaleimide., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

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°) = H 3 C- (methyl, 0°), CH 3 H 2 C- (primary, 1°), (CH 3 ) 2 HC- (secondary, 2°), (CH 3 ) 3 C- (tertiary, 3°) by palladium were investigated using relativistic dispersion-corrected density functional theory at ZORA-BLYP-D3(BJ)/TZ2P. The effect of the stepwise introduction of substituents was pinpointed at the C-X bond on the bond activation process. The C(n°)-X bonds become substantially weaker going from C(0°)-X, to C(1°)-X, to C(2°)-X, to C(3°)-X because of the increasing steric repulsion between the C(n°)- and X-group. Interestingly, this often does not lead to a lower barrier for the C(n°)-X bond activation. The C-H activation barrier, for example, decreases from C(0°)-X, to C(1°)-X, to C(2°)-X and then increases again for the very crowded C(3°)-X bond. For the more congested C-C bond, in contrast, the activation barrier always increases as the degree of substitution is increased. Our activation strain and matching energy decomposition analyses reveal that these differences in C-H and C-C bond activation can be traced back to the opposing interplay between steric repulsion across the C-X bond versus that between the catalyst and substrate., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

We have studied the palladium-mediated activation of C(sp n )-X bonds (n = 1-3 and X = H, CH 3 , Cl) in archetypal model substrates H 3 C-CH 2 -X, H 2 C=CH-X and HC≡C-X by catalysts PdL n with L n = no ligand, Cl - , and (PH 3 ) 2 , using relativistic density functional theory at ZORA-BLYP/TZ2P. The oxidative addition barrier decreases along this series, even though the strength of the bonds increases going from C(sp 3 )-X, to C(sp 2 )-X, to C(sp)-X. Activation strain and matching energy decomposition analyses reveal that the decreased oxidative addition barrier going from sp 3 , to sp 2 , to sp, originates from a reduction in the destabilizing steric (Pauli) repulsion between catalyst and substrate. This is the direct consequence of the decreasing coordination number of the carbon atom in C(sp n )-X, which goes from four, to three, to two along this series. The associated net stabilization of the catalyst-substrate interaction dominates the trend in strain energy which indeed becomes more destabilizing along this same series as the bond becomes stronger from C(sp 3 )-X to C(sp)-X., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

A fundamental and ubiquitous phenomenon in chemistry is the contraction of both C-H and C-C bonds as the carbon atoms involved vary, in s-p hybridization, along sp 3 to sp 2 to sp. Our quantum chemical bonding analyses based on Kohn-Sham molecular orbital theory show that the generally accepted rationale behind this trend is incorrect. Inspection of the molecular orbitals and their corresponding orbital overlaps reveals that the above-mentioned shortening in C-H and C-C bonds is not determined by an increasing amount of s-character at the carbon atom in these bonds. Instead, we establish that this structural trend is caused by a diminishing steric (Pauli) repulsion between substituents around the pertinent carbon atom, as the coordination number decreases along sp 3 to sp 2 to sp., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

A judiciously oriented external electric field (OEEF) can catalyze a wide range of reactions and can even induce endo/exo stereoselectivity of cycloaddition reactions. The Diels-Alder reaction between cyclopentadiene and maleic anhydride is studied by using quantitative activation strain and Kohn-Sham molecular orbital theory to pinpoint the origin of these catalytic and stereoselective effects. Our quantitative model reveals that an OEEF along the reaction axis induces an enhanced electrostatic and orbital interaction between the reactants, which in turn lowers the reaction barrier. The stronger electrostatic interaction originates from an increased electron density difference between the reactants at the reactive center, and the enhanced orbital interaction arises from the promoted normal electron demand donor-acceptor interaction driven by the OEEF. An OEEF perpendicular to the plane of the reaction axis solely stabilizes the exo pathway of this reaction, whereas the endo pathway remains unaltered and efficiently steers the endo/exo stereoselectivity. The influence of the OEEF on the inverse electron demand Diels-Alder reaction is also investigated; unexpectedly, it inhibits the reaction, as the electric field now suppresses the critical inverse electron demand donor-acceptor interaction., (© 2020 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The selectivity and rate enhancement of bifunctional hydrogen bond donor-catalyzed Diels-Alder reactions between cyclopentadiene and acrolein were quantum chemically studied using density functional theory in combination with coupled-cluster theory. (Thio)ureas render the studied Diels-Alder cycloaddition reactions exo selective and induce a significant acceleration of this process by lowering the reaction barrier by up to 7 kcal mol -1 . Our activation strain and Kohn-Sham molecular orbital analyses uncover that these organocatalysts enhance the Diels-Alder reactivity by reducing the Pauli repulsion between the closed-shell filled π-orbitals of the diene and dienophile, by polarizing the π-orbitals away from the reactive center and not by making the orbital interactions between the reactants stronger. In addition, we establish that the unprecedented exo selectivity of the hydrogen bond donor-catalyzed Diels-Alder reactions is directly related to the larger degree of asynchronicity along this reaction pathway, which is manifested in a relief of destabilizing activation strain and Pauli repulsion., (© 2020 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

We have quantum chemically studied the reactivity, site-, and regioselectivity of the 1,3-dipolar cycloaddition between methyl azide and various allenes, including the archetypal allene propadiene, heteroallenes, and cyclic allenes, by using density functional theory (DFT). The 1,3-dipolar cycloaddition reactivity of linear (hetero)allenes decreases as the number of heteroatoms in the allene increases, and formation of the 1,5-adduct is, in all cases, favored over the 1,4-adduct. Both effects find their origin in the strength of the primary orbital interactions. The cycloaddition reactivity of cyclic allenes was also investigated, and the increased predistortion of allenes, that results upon cyclization, leads to systematically lower activation barriers not due to the expected variations in the strain energy, but instead from the differences in the interaction energy. The geometric predistortion of cyclic allenes enhances the reactivity compared to linear allenes through a unique mechanism that involves a smaller HOMO-LUMO gap, which manifests as more stabilizing orbital interactions., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

A study on the reactivity of the N-heterocyclic silylene Dipp 2 NHSi (1,3-bis(diisopropylphenyl)-1,3-diaza-2-silacyclopent-4-en-2-yliden) with the transition metal complexes [Ni(CO) 4 ], [M(CO) 6 ] (M=Cr, Mo, W), [Mn(CO) 5 (Br)] and [(η 5 -C 5 H 5 )Fe(CO) 2 (I)] is reported. We demonstrate that N-heterocyclic silylenes, the higher homologues of the now ubiquitous NHC ligands, show a remarkably different behavior in coordination chemistry compared to NHC ligands. Calculations on the electronic features of these ligands revealed significant differences in the frontier orbital region which lead to some peculiarities of the coordination chemistry of silylenes, as demonstrated by the synthesis of the dinuclear, NHSi-bridged complex [{Ni(CO) 2 (μ-Dipp 2 NHSi)} 2 ] (2), complexes [M(CO) 5 (Dipp 2 NHSi)] (M=Cr 3, Mo 4, W 5), [Mn(CO) 3 (Dipp 2 NHSi) 2 (Br)] (9) and [(η 5 -C 5 H 5 )Fe(CO) 2 (Dipp 2 NHSi-I)] (10). DFT calculations on several model systems [Ni(L)], [Ni(CO) 3 (L)], and [W(CO) 5 (L)] (L=NHC, NHSi) reveal that carbenes are typically the much better donor ligands with a larger intrinsic strength of the metal-ligand bond. The decrease going from the carbene to the silylene ligand is mainly caused by favorable electrostatic contributions for the NHC ligand to the total bond strength, whereas the orbital interactions were often found to be higher for the silylene complexes. Furthermore, we have demonstrated that the contribution of σ- and π-interaction depends significantly on the system under investigation. The σ-interaction is often much weaker for the NHSi ligand compared to NHC but, interestingly, the π-interaction prevails for many NHSi complexes. For the carbonyl complexes, the NHSi ligand is the better σ-donor ligand, and contributions of π-symmetry play only a minor role for the NHC and NHSi co-ligands., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The ability to understand and predict ambident reactivity is key to the rational design of organic syntheses. An approach to understand trends in ambident reactivity is the hard and soft acids and bases (HSAB) principle. The recent controversy over the general validity of this principle prompted us to investigate the competing gas-phase S N 2 reaction channels of archetypal ambident nucleophiles CN - , OCN - , and SCN - with CH 3 Cl (S N 2@C) and SiH 3 Cl (S N 2@Si), using DFT calculations. Our combined analyses highlight the inability of the HSAB principle to correctly predict the reactivity trends of these simple, model reactions. Instead, we have successfully traced reactivity trends to the canonical orbital-interaction mechanism and the resulting nucleophile-substrate interaction energy. The HOMO-LUMO orbital interactions set the trend in both S N 2@C and S N 2@Si reactions. We provide simple rules for predicting the ambident reactivity of nucleophiles based on our Kohn-Sham molecular orbital analysis., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The ligand-controlled rhodium-catalyzed regioselective coupling of 1,2,3-benzotriazoles and allenes was investigated by DFT calculations. Because allylation can occur at either the N1 or N2 position of the 1,2,3-benzotriazole, the complete Gibbs free energy profiles for both pathways were computed. A kinetic preference emerged for the experimentally observed N1 allylation with the JoSPOphos ligand, whereas N2 allylation was favored with DPEphos. Analysis of the regiodetermining oxidative addition step by using the activation strain model in conjunction with a matching energy decomposition analysis has revealed that the unprecedented N2 reaction regioselectivity is dictated by the strength of the electrostatic interactions between the 1,2,3-benzotriazole and the rhodium catalyst. The nature of the electrostatic interaction was rationalized by analysis of the electrostatic potential maps and Hirshfeld charges: a stabilizing electrostatic interaction was found between the key atoms involved in the oxidative addition for the N2 pathway, analogous interactions are weaker in the N1 case., (© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The reactivity of a diruthenium tetrahydride complex towards three selected dihydroboranes was investigated. The use of [DurBH 2 ] (Dur=2,3,5,6-Me 4 C 6 H) and [(Me 3 Si) 2 NBH 2 ] led to the formation of bridging borylene complexes of the form [(Cp*RuH) 2 BR] (Cp*=C 5 Me 5 ; 1 a: R=Dur; 1 b: R=N(SiMe 3 ) 2 ) through oxidative addition of the B-H bonds with concomitant hydrogen liberation. Employing the more electron-deficient dihydroborane [3,5-(CF 3 ) 2 -C 6 H 3 BH 2 ] led to the formation of an anionic complex bearing a tetraarylated chain of four boron atoms, namely Li(THF) 4 [(Cp*Ru) 2 B 4 H 5 (3,5-(CF 3 ) 2 C 6 H 3 ) 4 ] (4), through an unusual, incomplete threefold dehydrocoupling process. A comparative theoretical investigation of the bonding in a simplified model of 4 and the analogous complex nido-[1,2(Cp*Ru) 2 (μ-H)B 4 H 9 ] (I) indicates that there appear to be no classical σ-bonds between the boron atoms in complex I, whereas in the case of 4 the B 4 chain better resembles a network of three B-B σ bonds, the central bond being significantly weaker than the other two., (© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The steric and electronic properties of aryl substituents in monoaryl borohydrides (Li[ArBH 3 ]) and dihydroboranes were systematically varied and their reactions with [Ru(PCy 3 ) 2 HCl(H 2 )] (Cy: cyclohexyl) were studied, resulting in bis(σ)-borane or terminal borylene complexes of ruthenium. These variations allowed for the investigation of the factors involved in the activation of dihydroboranes in the synthesis of terminal borylene complexes. The complexes were studied by multinuclear NMR spectroscopy, mass spectrometry, X-ray diffraction analysis, and density functional theory (DFT) calculations. The experimental and computational results suggest that the ortho-substitution of the aryl groups is necessary for the formation of terminal borylene complexes., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The unusually fast Diels-Alder reactions of [5]cyclophanes were analyzed by DFT at the BLYP-D3(BJ)/TZ2P level of theory. The computations were guided by an integrated activation-strain and Kohn-Sham molecular orbital analysis. It is revealed why both [5]metacyclophane and [5]paracyclophane exhibit a significant rate enhancement compared to their planar benzene analogue. The activation strain analyses revealed that the enhanced reactivity originates from 1) predistortion of the aromatic core resulting in a reduced activation strain of the aromatic diene, and/or 2) enhanced interaction with the dienophile through a distortion-controlled lowering of the HOMO-LUMO gap within the diene. Both of these physical mechanisms and thus the rate of Diels-Alder cycloaddition can be tuned through different modes of geometrical distortion (meta versus para bridging) and by heteroatom substitution in the aromatic ring. Judicious choice of the bridge and heteroatom in the aromatic core enables effective tuning of the aromatic Diels-Alder reactivity to achieve activation barriers as low as 2 kcal mol -1 , which is an impressive 35 kcal mol -1 lower than that of benzene., (© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The reactivities of 2-butyne, cycloheptyne, cyclooctyne, and cyclononyne in the 1,3-dipolar cycloaddition reaction with methyl azide were evaluated through DFT calculations at the M06-2X/6-311++G(d)//M06-2X/6-31+G(d) level of theory. Computed activation free energies for the cycloadditions of cycloalkynes are 16.5-22.0 kcal mol -1 lower in energy than that of the acyclic 2-butyne. The strained or predistorted nature of cycloalkynes is often solely used to rationalize this significant rate enhancement. Our distortion/interaction-activation strain analysis has been revealed that the degree of geometrical predistortion of the cycloalkyne ground-state geometries acts to enhance reactivity compared with that of acyclic alkynes through three distinct mechanisms, not only due to (i) a reduced strain or distortion energy, but also to (ii) a smaller HOMO-LUMO gap, and (iii) an enhanced orbital overlap, which both contribute to more stabilizing orbital interactions., (© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The strain-promoted alkyne-azide cycloaddition (SPAAC) is the most commonly employed bioorthogonal reaction with applications in a broad range of fields. Over the years, several different cyclooctyne derivatives have been developed and investigated in regard to their reactivity in SPAAC reactions with azides. However, only a few studies examined the influence of structurally diverse azides on reaction kinetics. Herein, we report our investigations of the reactivity of primary, secondary, and tertiary azides with the cyclooctynes BCN and ADIBO applying experimental and computational methods. All azides show similar reaction rates with the sterically non-demanding cyclooctyne BCN. However, due to the increased steric demand of the dibenzocyclooctyne ADIBO, the reactivity of tertiary azides drops by several orders of magnitude in comparison to primary and secondary azides. We show that this chemoselective behavior of tertiary azides can be exploited to achieve semiorthogonal dual-labeling without the need for any catalyst using SPAAC exclusively., (© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The control of stereoselectivity in a glycosylation reaction remains one of the most challenging aspects of oligosaccharide synthesis. Especially the synthesis of 1,2-cis-glycosides is challenging and generally applicable methodology to prepare this linkage is needed to standardize oligosaccharide synthesis. This review highlights the recent development of an elegant strategy employing a C-2 auxiliary to control the anomeric stereoselectivity in glycosylations. The various auxiliaries developed to date, their compatibility with protecting groups and monosaccharide types as well as mechanistic aspects are summarized. Furthermore, the application, advantages and limitations of C-2 auxiliaries in oligosaccharide synthesis are discussed., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The influence of the encapsulation of an ion inside the C 60 fullerene cage on its exohedral reactivity was explored by means of DFT calculations. To this end, the Diels-Alder reaction between 1,3-cyclohexadiene and M@C 60 (M=Li + , Na + , K + , Be 2+ , Mg 2+ , Al 3+ , and Cl - ) was studied and compared to the analogous process involving the parent C 60 fullerene. A significant enhancement of the Diels-Alder reactivity is found for systems having an endohedral cation, whereas a clear decrease in reactivity is observed when an anion is encapsulated in the C 60 cage. The origins of this reactivity trend were quantitatively analyzed in detail by using the activation strain model of reactivity in combination with energy decomposition analysis., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We aim to understand the electronic factors determining the stability and coordination number of d 10 transition-metal complexes bearing N-heterocyclic carbene (NHC) ligands, with a particular emphasis on higher coordinated species. In this DFT study on the formation and bonding of Group 9-12 d 10 [M(NHC) n ] (n=1-4) complexes, we found that all metals form very stable [M(NHC) 2 ] complexes, but further coordination depends on the specific interplay of 1) the interaction energy (ΔE int ) between the [M(NHC) n-1 ] (n=2-4) fragment and the incoming NHC ligand, and 2) the strain energy (ΔE strain ) associated with bending of the linear NHC-M-NHC arrangement. The key observation is that ΔE strain , which is an antagonist for higher coordination numbers, can significantly be lowered by M→NHC π*-back-donation. This leads to favorable thermodynamics for n=3-4 for highly electrophilic metals in our study, and thus presents a general design motif to achieve coordination numbers beyond two. The scope of our findings extends beyond the NHC model systems and has wider implications for the synthesis of d 10 [ML n ] complexes and their catalytic activity., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The Diels-Alder reactivity of different bowl-shaped polycyclic aromatic hydrocarbons (namely, corannulene, cyclopentacorannulene, diindenochrysene, hemifullerene, and circumtrindene) has been explored computationally within the DFT framework. To this end, both the increase in reactivity with the size of the buckybowl and complete [6,6]-regioselectivity in the process have been analyzed in detail by using the activation strain model of reactivity in combination with the energy decomposition analysis method. These results have been compared with the parent C60 fullerene, which also produces the corresponding [6,6]-cycloadduct exclusively. The behavior of the buckybowls considered herein resembles, in general, that of C60 . Whereas the interaction energy between the deformed reactants along the reaction coordinate mainly controls the regioselectivity of the process, it is the interplay between the activation strain energy and the transition-state interaction that governs the reactivity of the system., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The physical factors behind the reduced Diels-Alder reactivity of the Sc3N@C78 metallofullerene as compared with free C78 have been investigated in detail by means of computational tools. To this end, the reactions between 1,3-butadiene and free C78 and endohedral Sc3N@C78 have been analysed in terms of regioselectivity and reactivity by using the activation strain model of reactivity in combination with the energy decomposition analysis method. Additional factors such as the molecular orbital overlap or the aromaticity of the corresponding transition states have been also explored. Our results indicate that the lower reactivity of the metallofullerene finds its origin mainly in the less stabilizing interaction between the deformed reactants along the reaction coordinate induced by the triscandium nitride moiety., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)