Experimental and Computational Studies for the Synthesis of Functionalized Cyclopropanes from 2-Substituted Allylic Derivatives with Ethyl Diazoacetate.

The catalytic asymmetric synthesis of highly functionalized cyclopropanes from 2-substituted allylic derivatives is reported. Using ethyl diazo acetate, the reaction, catalyzed by a chiral ruthenium complex (Ru(II)-Pheox), furnished the corresponding easily separable cis and trans cyclopropanes in moderate to high yields (32-97 %) and excellent ee (86-99 %). This approach significantly extends the portfolio of accessible enantioenriched cyclopropanes from an underexplored class of olefins. DFT calculations suggest that an outer-sphere mechanism is operative in this system.

Oxidative hydrolysis of aliphatic bromoalkenes: scope study and reactivity insights.

We have developed an operationally simple method for the synthesis of dialkyl α-bromoketones from bromoalkenes by utilizing a hypervalent iodine-catalyzed oxidative hydrolysis reaction. This catalytic process provides both symmetrical and unsymmetrical dialkyl bromoketones with moderate yields across a broad range of bromoalkene substrates. Our studies also reveal the formation of Ritter-type side products by an alternative reaction pathway.

Gold(I)-Mediated Isomerization of Spring-loaded 1,7-Enynes seen through the Lens of Density Functional Theory.

We propose a mechanism for the previously reported formation of benzobicyclo[3.2.0]heptane derivatives from 1,7-enyne derivatives bearing a terminal cyclopropane. -> A mechanism for the previously reported formation of benzobicyclo[3.2.0]heptane derivatives from 1,7-enyne derivatives bearing a terminal cyclopropane is proposed.

N-Oxides as Control Element for the Direction of a Sigmatropic Rearrangement: Application as a Switch for Fluorescence.

An exceptional level of control over the direction of the (2,3)-sigmatropic rearrangement between N-oxides and alkoxylamine is achieved by simply changing the solvent in which they are dissolved. Protic solvents like water, methanol and hexafluoroisopropanol favour the N-oxide form, while other solvents like acetone, acetonitrile and benzene favour the alkoxylamine. The reaction temperature and nature of the substituents on the alkene affect the rate of rearrangement. A N-oxide fragment was attached to two fluorescent molecules and acted as an on/off switch for their fluorescence. The conversion of alkoxylamines into the corresponding N-oxides has not previously been described and is here termed the 'Reverse Meisenheimer Rearrangement'.

Tracking SF5 I in the Iodopentafluorosulfanylation of Alkynes.

In the vibrant field of SF5 chemistry, SF5 X reagents (X=F, Cl, Br) are at the heart of current investigations in radical pentafluorosulfanylation reactions. SF5 I is the missing link whose existence has not been reported despite its potential as SF5 donor. This study reports the formal addition of the hitherto unknown SF5 I reagent to alkynes by means of a combination of SF5 Cl/KI/18-crown-6 ether. The exclusive regio- and stereoselective synthesis of unprecedented (E)-1-iodo-2-(pentafluoro-λ6 -sulfanyl) alkenes was achieved. A consensus was reached through computational and mechanistic studies for the realistic formation of SF5 - anion but not SF5 I in solution and the rational involvement of SF5 ⋅ and iodine radicals in the iodo pentafluorosulfanylation reaction.

A Quantum-chemical Analysis on the Lewis Acidity of Diarylhalonium Ions.

Cyclic diaryliodonium compounds like iodolium derivatives have increasingly found use as noncovalent Lewis acids in the last years. They are more stable toward nucleophilic substitution than acyclic systems and are markedly more Lewis acidic. Herein, this higher Lewis acidity is analyzed and explained via quantum-chemical calculations and energy decomposition analyses. Its key origin is the change in energy levels and hybridization of iodine's orbitals, leading to both more favorable electrostatic interaction and better charge transfer. Both of the latter seem to contribute in similar fashion, while hydrogen bonding as well as steric repulsion with the phenyl rings play at best a minor role. In comparison to iodolium, bromolium and chlorolium are less Lewis acidic the lighter the halogen, which is predominantly based on less favorable charge-transfer interactions.

Synthesis of Indoles Using the Electrophilic Potential of Diazirines.

The electrophilic potential of diazirines has been utilized to obtain N-substituted diaziridines that are directly hydrolyzed to produce monosubstituted hydrazines. The hydrazines can undergo the Fisher process with enolizable carbonyls to yield multiple indole derivatives in moderate to high yields. The N-metalated diaziridine intermediates can undergo isomerization prior to electrophilic substitution, to form N,N-disubstituted hydrazones. The latter react with enolizable carbonyls to produce N-protected indole derivatives in a single step. This protocol was used to efficiently synthesize indomethacin, an anti-inflammatory drug.

Direct π-Activation vs. O-Activation in Halogen-Bonding Catalysis.

Halogen bond donors had an increasing impact on catalysis in recent years, and their development is highly active. In particular, numerous iodine-based halogen bond donors have been developed and used to promote various reactions through coordinating carbonyl groups, a ubiquitous mode of activation in catalysis. We now report computational data which strongly suggests that an alternative activation mode, through direct π-complexation, is operative for unsaturated carbonyl substrates. Calculations also suggest that solvent polarity could have a clear impact on the preference of the mode of activation, raising the possibility of a mechanistic manifold switch through solvent variation. These findings could profoundly impact the development of the next generation of halogen-bond donor catalysts.

CalcUS: An Open-Source Quantum Chemistry Web Platform.

Computational chemistry is an increasingly active field due to the improvement of computing resources and theoretical tools. However, its use remains usually limited to technically inclined users due to the technical challenges of preparing, launching, and analyzing calculations. In this context, we have developed CalcUS, an open-source platform to streamline quantum chemistry studies. Its objective is to democratize access to computational chemistry by providing a user-friendly web interface to simplify running and analyzing quantum mechanical calculations. It is freely available, expandable, and customizable. It promotes connectivity to multiple software packages and algorithms, thus providing state-of-the-art techniques to all practitioners. We propose CalcUS as a standalone tool and infrastructure to support other open-source packages.

Iodine(III)-Based Halogen Bond Donors: Properties and Applications.

Halogen bonding, the non-covalent interaction of Lewis bases with an electron-deficient region of halogen substituents, received increased attention recently. Consequently, the design and evaluation of numerous halogen-containing species as halogen bond donors have been subject to intense research. More recently, organoiodine compounds at the iodine(III) state have been receiving growing attention in the field. Due to their electronic and structural properties, they provide access to unique binding modes. For this reason, our groups have been involved in the development of such compounds, in the quantification of their halogen bonding strength (through the evaluation of their Lewis acidities), as well as in the evaluation of their activities as catalysts in several model reactions. This account will describe these contributions.

Iodine-Catalyzed Synthesis of Substituted Furans and Pyrans: Reaction Scope and Mechanistic Insights.

Substituted pyrans and furans are core structures found in a wide variety of natural products and biologically active compounds. Herein, we report a practical and mild catalytic method for the synthesis of substituted pyrans and furans using molecular iodine, a simple and inexpensive catalyst. The method described is performed under solvent-free conditions at an ambient temperature and atmosphere, thus offering a facile and practical alternative to currently available reaction protocols. A combination of experimental studies and density functional theory calculations revealed interesting mechanistic insights into this seemingly simple reaction.

A low cost, high accuracy method for halogen bonding complexes.

The ONIOM scheme M052X/[Def2TZVP+Def2TZVPD.ECP(I)]:AM1 is shown to represent halogen bond (XB) geometries nearly as well as DFT while being more than two orders of magnitude faster in systems containing >40 atoms. This finding is shown to hold for 40 XB donors, which cover most known backbones, and for a range of neutral and anionic Lewis bases. Complexation free energies can be accurately computed using these geometries and a single-point energy calculation at the DFT level. This approach circumvents the unfavorable scaling of computing time associated with modeling large systems involving halogen bonding.

Lewis Acidity Scale of Diaryliodonium Ions toward Oxygen, Nitrogen, and Halogen Lewis Bases.

Equilibrium constants for the associations of 17 diaryliodonium salts Ar2I+X- with 11 different Lewis bases (halide ions, carboxylates, p-nitrophenolate, amines, and tris(p-anisyl)phosphine) have been investigated by titrations followed by photometric or conductometric methods as well as by isothermal titration calorimetry (ITC) in acetonitrile at 20 °C. The resulting set of equilibrium constants KI covers 6 orders of magnitude and can be expressed by the linear free-energy relationship lg KI = sI LAI + LBI, which characterizes iodonium ions by the Lewis acidity parameter LAI, as well as the iodonium-specific affinities of Lewis bases by the Lewis basicity parameter LBI and the susceptibility sI. Least squares minimization with the definition LAI = 0 for Ph2I+ and sI = 1.00 for the benzoate ion provides Lewis acidities LAI for 17 iodonium ions and Lewis basicities LBI and sI for 10 Lewis bases. The lack of a general correlation between the Lewis basicities LBI (with respect to Ar2I+) and LB (with respect to Ar2CH+) indicates that different factors control the thermodynamics of Lewis adduct formation for iodonium ions and carbenium ions. Analysis of temperature-dependent equilibrium measurements as well as ITC experiments reveal a large entropic contribution to the observed Gibbs reaction energies for the Lewis adduct formations from iodonium ions and Lewis bases originating from solvation effects. The kinetics of the benzoate transfer from the bis(4-dimethylamino)-substituted benzhydryl benzoate Ar2CH-OBz to the phenyl(perfluorophenyl)iodonium ion was found to follow a first-order rate law. The first-order rate constant kobs was not affected by the concentration of Ph(C6F5)I+ indicating that the benzoate release from Ar2CH-OBz proceeds via an unassisted SN1-type mechanism followed by interception of the released benzoate ions by Ph(C6F5)I+ ions.

Activation of a Metal-Halogen Bond by Halogen Bonding.

In recent years, the non-covalent interaction of halogen bonding (XB) has found increasing application in organocatalysis. However, reports of the activation of metal-ligand bonds by XB have so far been limited to a few reactions with elemental iodine or bromine. Herein, we present the activation of metal-halogen bonds by two classes of inert halogen bond donors and the use of the resulting activated complexes in homogenous gold catalysis. The only recently explored class of iodolium derivatives were shown to be effective activators in two test reactions and their activity could be modulated by blocking of the Lewis acidic sites. Bis(benzimidazolium)-based halogen bonding activators provided even more rapid conversion, while the non-iodinated reference compound showed little activity. The role of halogen bonding in the activation of metal-halogen bonds was further investigated by NMR experiments and DFT calculations, which support the mode of activation occurring via halogen bonding.

Denitrogenative Hydrotrifluoromethylation of Benzaldehyde Hydrazones: Synthesis of (2,2,2-Trifluoroethyl)arenes.

Reacting hydrazones of arylaldehydes with Togni's CF3 -benziodoxolone reagent, in the presence of potassium hydroxide and cesium fluoride, induces a denitrogenative hydrotrifluoromethylation event to produce (2,2,2-trifluoroethyl)arenes. This novel reaction was tolerant to many electronically-diverse functional groups and substitution patterns, as well as naphthyl- and heteroaryl-derived substrates. Advantages of this process include the easy access to hydrazone precursors on a large scale, speed and operational simplicity, and being transition metal-free.

Experimental and Theoretical Quantification of the Lewis Acidity of Iodine(III) Species.

The role of hypervalent iodine reagents as oxidants has been widely recognized for more than 20 years. As electrophilic species, they could also play the role of Lewis acids. While not surprising, this aspect of these reagents has not been fully considered and exploited in the literature. The experimental quantification of the Lewis acidity of a small series of diaryliodonium salts was performed using the Gutmann-Beckett method. Validation of a theoretical model using the experimental data was done in order to predict the Lewis acidity of other cationic iodine(III) species. Comparison with known common Lewis acids is presented.

Tunable Approach for the Stereoselective Synthesis of 1-C-Diethylphosphono(difluoromethyl) Iminosugars as Glycosyl Phosphate Mimics.

An efficient methodology for the stereoselective and tunable addition of LiCF2P(O)(OEt)2 and BrMgCF2P(O)(OEt)2 reagents to N-t-butanesulfinyl glycosylamines is described with details on the stereochemical effects at play in this process. It provides a practical route to various 1-C-diethylphosphono(difluoromethyl) iminosugars as glycosyl phosphate and sugar nucleotide mimics.

Mechanistic insights on the iodine(III)-mediated α-oxidation of ketones.

The synthesis of α-substituted carbonyl compounds is of great importance due to their ubiquity in both natural and man-made biologically active compounds. The field of hypervalent iodine chemistry has been a great contributor to access these molecules. For example, the α-oxidation of carbonyl compounds has been one of the most investigated iodine(III)-mediated stereoselective transformations. Yet, it is also the transformation that has met the most challenge in terms of achieving high stereoselectivities. The different mechanistic pathways of the iodine(III)-mediated α-tosyloxylation of ketones have been investigated. The calculations suggest an unprecedented iodine(III)-promoted enolization process. Indications that iodonium intermediates could serve as proficient Lewis acids are reported. This concept could have broad impact and foster new developments in the field of hypervalent iodine chemistry.

Study of the Reactivity of [Hydroxy(tosyloxy)iodo]benzene Toward Enol Esters to Access α-Tosyloxy Ketones.

The reactivity of enol esters toward [hydroxy(tosyloxy)iodo]benzene (HTIB) was assessed. These substrates were found to be rapidly converted in high yields to their corresponding α-tosyloxy ketones. This transformation demonstrates that these substrates can act as ketone surrogates. The scope of the method was investigated and aromatic, aliphatic, and cyclic enol esters were found to be suitable substrates for the reaction. The relative reactivity of a model substrate toward HTIB and m-CPBA was investigated, and it was found that the reaction could be performed under catalytic conditions.

Origin of chemoselectivity in N-heterocyclic carbene catalyzed cross-benzoin reactions: DFT and experimental insights.

An exploration into the origin of chemoselectivity in the NHC-catalyzed cross-benzoin reaction reveals several key factors governing the preferred pathway. In the first computational study to explore the cross-benzoin reaction, a piperidinone-derived triazolium catalyst produces kinetically controlled chemoselectivity. This is supported by (1)H NMR studies as well as a series of crossover experiments. Major contributors include the rapid and preferential formation of an NHC adduct with alkyl aldehydes, a rate-limiting carbon-carbon bond formation step benefiting from a stabilizing π-stacking/π-cation interaction, and steric penalties paid by competing pathways. The energy profile for the analogous pyrrolidinone-derived catalyst was found to be remarkably similar, despite experimental data showing that it is less chemoselective. The chemoselectivity could not be improved through kinetic control; however, equilibrating conditions show substantial preference for the same cross-benzoin product kinetically favored by the piperidinone-derived catalyst.