Substituent-controlled, mild oxidative fluorination of iodoarenes: synthesis and structural study of aryl I(iii)- and I(v)-fluorides.

We report a mild approach to the synthesis of difluoro(aryl)-λ3-iodanes (aryl-IF2 compounds) and tetrafluoro(aryl)-λ5-iodanes (aryl-IF4 compounds) using trichloroisocyanuric acid (TCICA) and potassium fluoride (KF). Under these reaction conditions, selective access to either the I(iii)- or I(v)-derivatives is predictable based solely on the substitution pattern of the iodoarene starting material. Moreover, the discovery of this TCICA/KF approach prompted detailed dynamic NMR, kinetic, computational, and crystallographic studies on the relationship between the IF2 group and the ortho-substituents on carefully designed probe molecules. It was during these experiments that the role of the ortho-substituent in inhibiting further oxidative fluorination of I(iii)-compounds to I(v)-compounds during the reaction with TCICA and KF was revealed. Additionally, a notable exception to this empirical trend is discussed herein.

Importance of Nonclassical σ-Hole Interactions for the Reactivity of λ3-Iodane Complexes.

Key for the observed reactivity of λ3-iodanes, powerful reagents for the selective transfer of functional groups to nucleophiles, are the properties of the 3-center-4-electron bond involving the iodine atom and the two linearly arranged ligands. This bond is also involved in the formation of the initial complex between the λ3-iodane and a nucleophile, which can be a solvent molecule or a reactant. The bonding in such complexes can be described by means of σ-hole interactions. In halogen compounds, σ-hole interaction was identified as a force in crystal packing or in the formation of supramolecular chains. More recently, σ-hole interactions were also shown to affect the reactivity of the iodine-based hypervalent reagents. Relative to their monovalent counterparts, where the σ-hole is located on the extension of the sigma-bond, in the hypervalent species our DFT calculations reveal the formation of a nonclassical σ-hole region with one or even two maxima. This observation is also made in fully relativistic calculations. The SAPT analysis shows that the σ-hole bond between the λ3-iodane and the nucleophile is not necessarily of purely electrostatic nature but may also contain a significant covalent component. This covalent component may facilitate chemical transformation of the compound by means of reductive elimination or other mechanisms and is therefore an indicator for its reactivity. Here, we also show that the shape, location, and strength of the σ-holes can be tuned by the choice of ligands and measures such as Brønsted activation of the iodane reagent. At the limit, the tuning transforms the nonclassical σ-hole regions into coordination sites, which allows us to control how a nucleophile will bind and react with the iodane.

S-Trifluoromethylation of Thiols by Hypervalent Iodine Reagents: A Joint Experimental and Computational Study.

The radical trifluoromethylation of thiophenol in condensed phase applying reagent 1 (3,3-dimethyl-1-(trifluoromethyl)-1λ(3),2-benziodoxol) has been examined by both theoretical and experimental methodologies. On the basis of ab initio molecular dynamics and metadynamics we show that radical reaction mechanisms favourably compete with polar ones involving the S-centred nucleophile thiophenol, their free energies of activation, ΔF(≠), lying between 9 and 15 kcal mol(-1). We further show that the origin of the proton activating the reagent is important. Hammett plot analysis reveals intramolecular protonation of 1, thus generating negative charge on the sulfur atom in the rate-determining step. The formation of a CF3 radical can be thermally induced by internal dissociative electron transfer, its activation energy, ΔF(≠), amounting to as little as 10.8 and 2.8 kcal mol(-1) for reagent 1 and its protonated form 2, respectively. The reduction of the iodine atom by thiophenol occurs either subsequently or in a concerted fashion.

Exploring the role of the 3-center-4-electron bond in hypervalent λ(3)-iodanes using the methodology of domain averaged Fermi holes.

Hypervalent iodine compounds, in particular λ(3)-iodanes, have become important reagents in organic synthesis for the electrophilic transfer of substituents to arenes and other nucleophiles. The structure and reactivity of these compounds are usually described based on a 3-center-4-electron bond model, involving the iodine central atom and its two trans substituents. The goal of this computational study is to explore Fermi correlation in view of a more advanced description of bonding in these compounds. For that matter, we apply the analysis of Domain Averaged Fermi Holes (DAFH). The DAFH analysis reveals a relationship between the occurrence of multicenter bonding and structural parameters which cannot be easily observed based on simple MO theory. Whereas for λ(3)-iodanes carrying electron-rich ligands pairing of electrons over three centers is indeed observed, compounds with electron-withdrawing substituents fall into a different category: the pairing of electrons is restricted to extend over two centers only, thus challenging the multicenter bonding picture in this case. Accordingly, a drastic reduction of the DAFH three center bond index is observed. The establishment of the multicenter bond in λ(3)-iodanes is driven by a pseudo Jahn-Teller (PJT) effect, whose extent is tightly coupled to the reactivity of the corresponding compound. The PJT stabilization scales with the degree of s-p hybridization of the central atom, which, in return, depends on the electron-withdrawing power of the ligands in the trans position. The response of the multicenter bond to the iodine "ligand field" can be expressed quantitatively in terms of DAFH bond indices. These show, for example, that the activation of the reacting hypervalent species by means of protonation results in a weaker 3-center-4-electron bond, thus making the reagent more reactive. In this work we explain a number of experimentally known facts concerning the reactivity of these compounds. We also show that the DAFH analysis offers a more complete understanding of hypervalency in λ(3)-iodanes, and that it is a tool to assist the search for novel reagents.

Dividing a complex reaction involving a hypervalent iodine reagent into three limiting mechanisms by ab initio molecular dynamics.

The electrophilic N-trifluoromethylation of MeCN with a hypervalent iodine reagent to form a nitrilium ion, that is rapidly trapped by an azole nucleophile, is thought to occur via reductive elimination (RE). A recent study showed that, depending on the solvent representation, the S(N)2 is favoured to a different extent over the RE. However, there is a discriminative solvent effect present, which calls for a statistical mechanics approach to fully account for the entropic contributions. In this study, we perform metadynamic simulations for two trifluoromethylation reactions (with N- and S-nucleophiles), showing that the RE mechanism is always favoured in MeCN solution. These computations also indicate that a radical mechanism (single electron transfer) may play an important role. The computational protocol based on accelerated molecular dynamics for the exploration of the free energy surface is transferable and will be applied to similar reactions to investigate other electrophiles on the reagent. Based on the activation parameters determined, this approach also gives insight into the mechanistic details of the trifluoromethylation and shows that these commonly known mechanisms mark the limits within which the reaction proceeds.

"Why and How it Works": The Development of Hypervalent Iodine Reagents as an Illustration for the Collaboration of Chemical Synthesis with Modeling and Simulation.

Much of the focus of quantum chemical modeling and simulation is on understanding chemical phenomena and in assisting experiment to further improve and develop the respective chemistry. Given the computational tools available today, rather than assisting the development of new chemicals, modeling and simulation are in the process of making the step towards guiding experiment towards novel targets. In this article we show how an intense collaboration between chemical synthesis and computation leads to a better understanding of hypervalent iodine reagents and how modeling and simulation may direct the search of novel reagents.

The solvent effect on two competing reaction mechanisms involving hypervalent iodine reagents (λ(3)-iodanes): facing the limit of the stationary quantum chemical approach.

Trifluoromethylation of acetonitrile with 3,3-dimethyl-1-(trifluoromethyl)-1λ(3),2- benziodoxol is assumed to occur via reductive elimination (RE) of the electrophilic CF3-ligand and MeCN bound to the hypervalent iodine. Computations in gas phase showed that the reaction might also occur via an SN2 mechanism. There is a substantial solvent effect present for both reaction mechanisms, and their energies of activation are very sensitive toward the solvent model used (implicit, microsolvation, and cluster-continuum). With polarizable continuum model-based methods, the SN2 mechanism becomes less favorable. Applying the cluster-continuum model, using a shell of solvent molecules derived from ab initio molecular dynamics (AIMD) simulations, the gap between the two activation barriers ( ΔΔG‡) is lowered to a few kcal mol(-1) and also shows that the activation entropies (ΔS‡) and volumes (ΔV‡) for the two mechanisms differ substantially. A quantitative assessment of ΔΔG‡ will therefore only be possible using AIMD. A natural bond orbital-analysis gives further insight into the activation of the CF3-reagent by protonation.

Donor- and/or acceptor-substituted expanded radialenes: theory, synthesis, and properties.

The synthesis of donor- (D) and/or acceptor (A)-expanded [4]radialenes has been developed on the basis of readily available dibromoolefin (7), tetraethynylethene (10 and 20), and vinyl triflate (12) building blocks. The successful formation of D/A radialenes relies especially on (1) effective use of a series alkynyl protecting groups, (2) Sonogashira cross-coupling reactions, and (3) the development of ring closing reactions to form the desired macrocyclic products. The expanded [4]radialene products have been investigated by spectroscopic (UV-vis absorption and emission) and quantum chemical computational methods (density functional theory and time dependent DFT). The combined use of theory and experiment provides a basis to evaluate the extent of D/A interactions via the cross-conjugated radialene framework as well as an interpretation of the origin of D/A interactions at an orbital level.

Breaking down the reactivity of λ(3)-iodanes: the impact of structure and bonding on competing reaction mechanisms.

The functionalization of arenes via diaryliodonium salts has gained considerable attention in synthesis, as these compounds react under mild conditions. Mechanistic studies have shown that the formation of corresponding λ(3)-iodane intermediates takes a key role, as they determine the course and selectivity of the reaction. Bridged diaryliodonium salts, featuring a heterocyclic moiety involving the iodine atom, were shown to exhibit a distinctly different reactivity, leading to different products. These products are not just the result of reductive elimination reactions but may also arise via radical mechanisms. Our quantum chemical calculations reveal that the λ(3)-iodane intermediate is also the "gateway" for reactions that are observed only for strained bridged systems. At the same time, we find a remarkable affinity of the hypervalent region to planarity for all reaction mechanisms. This also explains the correlation between the size of the bridge connecting the aryl groups and the reaction products observed. Furthermore, the energetics of these competing reactions are examined by analysis of the mechanisms. Finally, using model compounds, some of the basic features governing the reactivity of λ(3)-iodanes are discussed.

Significant substituent effect on the anomerization of pyranosides: mechanism of anomerization and synthesis of a 1,2-cis glucosamine oligomer from the 1,2-trans anomer.

Aminoglycosides containing a 2,3-trans carbamate group easily undergo anomerization from the 1,2-trans glycoside to the 1,2-cis isomer under mild acidic conditions. The N-substituent of the carbamate has a significant effect on the anomerization reaction; in particular, an N-acetyl group facilitated rapid and complete α-anomerization. The differences in reactivity due to the various N-substituents were supported by the results of DFT calculations; the orientation of the acetyl carbonyl group close to the anomeric position was found to contribute significantly to the directing of the anomerization reaction. By exploiting this reaction, oligoaminoglycosides with multiple 1,2-cis glycosidic bonds were generated from 1,2-trans glycosides in a one-step process.

Reductive eliminations from λ3-iodanes: understanding selectivity and the crucial role of the hypervalent bond.

This computational study investigates the factors governing the selectivity of the reductive eliminations from rapidly equilibrating isomeric λ(3)-iodanes derived from a diaryl iodonium salt and a nucleophile. The chemoselectivity is mainly determined by the partial charge at the ipso-carbon atom involved in the 3-center-4-electron bond.

Chemical information media in the chemistry lecture hall: a comparative assessment of two online encyclopedias.

The chemistry encyclopedia Römpp Online and the German universal encyclopedia Wikipedia were assessed by first-year university students on the basis of a set of 30 articles about chemical thermodynamics. Criteria with regard to both content and form were applied in the comparison; 619 ratings (48% participation rate) were returned. While both encyclopedias obtained very good marks and performed nearly equally with regard to their accuracy, the average overall mark for Wikipedia was better than for Römpp Online, which obtained lower marks with regard to completeness and length. Analysis of the results and participants' comments shows that students attach importance to completeness, length and comprehensibility rather than accuracy, and also attribute less value to the availability of sources which validate an encyclopedia article. Both encyclopedias can be promoted as a starting reference to access a topic in chemistry. However, it is recommended that instructors should insist that students do not rely solely on encyclopedia texts, but use and cite primary literature in their reports.