Stefano Santoro

Green chemistry with selenium reagents: development of efficient catalytic reactions.

Selenium goes green! Recent advances in organoselenium chemistry clearly demonstrate that selenium-based catalysts can be used conveniently in a series of functional group transformations. Organoselenium compounds are promising “green catalysts” as they can transfer oxygen from environmentally friendly oxidants such as H2O2.

Arylation with Unsymmetrical Diaryliodonium Salts : A Chemoselectivity Study

Phenols, anilines, and malonates have been arylated under metal-free conditions with twelve aryl(phenyl)iodonium salts in a systematic chemoselectivity study. A new “anti-ortho effect” has been identified in the arylation of malonates. Several “dummy groups” have been found that give complete chemoselectivity in the transfer of the phenyl moiety, irrespective of the nucleophile. An aryl exchange in the diaryliodonium salts has been observed under certain arylation conditions. DFT calculations have been performed to investigate the reaction mechanism and to elucidate the origins of the observed selectivities. These results are expected to facilitate the design of chiral diaryliodonium salts and the development of catalytic arylation reactions that are based on these sustainable and metal-free reagents.

“The green side of the moon: ecofriendly aspects of organoselenium chemistry”

Organoselenium chemistry has proven to be a powerful tool for organic synthesis over several decades. Nevertheless, the use of selenating reagents has often been limited by a generally bad reputation surrounding selenium toxicity and its potential impact on the environment. In this review we would like to stress some aspects that will encourage the reader to discover an unexpected “green side” to this element and the chemistry connected with its organic derivatives.

Heterogeneous catalytic approaches in C–H activation reactions

Despite the undisputed advances and progress in metal-catalyzed C–H functionalizations, this atom-economical approach had thus far largely been developed with the aid of various metal catalysts that were operative in a homogeneous fashion. While thereby major progress was accomplished, these catalytic systems featured notable disadvantages, such as low catalyst recyclability. This review summarizes the development of user-friendly, recyclable and easily separable heterogeneous catalysts for C–H activation. This strategy was characterized by a remarkably broad substrate scope, considerable levels of chemo- and site-selectivities and proved applicable to C–C as well as C–heteroatom formation processes. Thus, recyclable catalysts were established for arylations, hydroarylations, alkenylations, acylations, nitrogenations, oxygenations, or halogenations, among others. The rapid recent progress in selective heterogeneous C–H functionalizations during the last decade until December 2015 is reviewed.

Theoretical Study of Mechanism and Selectivity of Copper-Catalyzed C–H Bond Amidation of Indoles

Density functional theory calculations are used to study the reaction mechanism and origins of C2 selectivity in a copper(I)-catalyzed amidation of indoles. It is shown that concerted metalation-deprotonation is not able to reproduce the observed regioselectivity. Instead, an unprecedented mechanism based on a four-center reductive elimination is proposed to be responsible for the reaction outcome. This mechanism has a lower reaction barrier and is able to reproduce the experimentally observed selectivity. A possible alternative mechanism involving a Cu(II) species instead of Cu(III) is presented, but it is shown that higher energy barriers are associated with this mechanism. An important technical detail is that addition of dispersion effects to the B3LYP results is necessary to reproduce the observed selectivity, although not important for the overall mechanistic proposal.

Biomass-derived solvents as effective media for cross-coupling reactions and C–H functionalization processes

Palladium-catalyzed cross-coupling reactions are indispensable tools in molecular syntheses with numerous applications in academia and for the practitioners in the chemical and pharmaceutical industries. Recent years have witnessed the increasing use of biomass-derived solvents as green reaction media in the palladium-, copper- and nickel-catalyzed cross-coupling technology, the key advances until January 2017 being summarized in this review. In addition, very recent first examples of transition metal-catalyzed C–H activations in biomass-originated solvents, such as γ-valerolactone and 2-MeTHF, are discussed as well.

Heterogeneous palladium-catalysed Catellani reaction in biomass-derived γ-valerolactone

Herein, we report the unprecedented use of a heterogeneous palladium catalyst for the step-economical Catellani reaction. The substrate scope with encapsulated Pd(OAc)2 (Pd EnCat™ 30) or Pd/Al2O3 proved to be broad, while the renewable biomass-derived γ-valerolactone (GVL) was identified as an effective reaction medium. Mechanistic studies highlighted the possible heterogeneous nature of the Pd/Al2O3 catalyst, while showing that the reaction performed in the presence of Pd EnCat™ 30 is most likely catalysed by leached homogeneous palladium species. The heterogeneous Pd/Al2O3 catalyst can be easily recovered at the end of the reaction and efficiently reused in consecutive reaction runs.

Elucidation of mechanisms and selectivities of metal- catalyzed reactions using quantum chemical methodology

Quantum chemical techniques today are indispensable for the detailed mechanistic understanding of catalytic reactions. The development of modern density functional theory approaches combined with the enormous growth in computer power have made it possible to treat quite large systems at a reasonable level of accuracy. Accordingly, quantum chemistry has been applied extensively to a wide variety of catalytic systems. A huge number of problems have been solved successfully, and vast amounts of chemical insights have been gained. In this Account, we summarize some of our recent work in this field. A number of examples concerned with transition metal-catalyzed reactions are selected, with emphasis on reactions with various kinds of selectivities. The discussed cases are (1) copper-catalyzed C-H bond amidation of indoles, (2) iridium-catalyzed C(sp(3))-H borylation of chlorosilanes, (3) vanadium-catalyzed Meyer-Schuster rearrangement and its combination with aldol- and Mannich-type additions, (4) palladium-catalyzed propargylic substitution with phosphorus nucleophiles, (5) rhodium-catalyzed 1:2 coupling of aldehydes and allenes, and finally (6) copper-catalyzed coupling of nitrones and alkynes to produce β-lactams (Kinugasa reaction). First, the methodology adopted in these studies is presented briefly. The electronic structure method in the great majority of these kinds of mechanistic investigations has for the last two decades been based on density functional theory. In the cases discussed here, mainly the B3LYP functional has been employed in conjunction with Grimmes empirical dispersion correction, which has been shown to improve the calculated energies significantly. The effect of the surrounding solvent is described by implicit solvation techniques, and the thermochemical corrections are included using the rigid-rotor harmonic oscillator approximation. The reviewed examples are chosen to illustrate the usefulness and versatility of the adopted methodology in solving complex problems and proposing new detailed reaction mechanisms that rationalize the experimental findings. For each of the considered reactions, a consistent mechanism is presented, the experimentally observed selectivities are reproduced, and their sources are identified. Reproducing selectivities requires high accuracy in computing relative transition state energies. As demonstrated by the results summarized in this Account, this accuracy is possible with the use of the presented methodology, benefiting of course from a large extent of cancellation of systematic errors. It is argued that as the employed models become larger, the number of rotamers and isomers that have to be considered for every stationary point increases and a careful assessment of their energies is therefore necessary in order to ensure that the lowest energy conformation is located. This issue constitutes a bottleneck of the investigation in some cases and is particularly important when analyzing selectivities, since small energy differences need to be reproduced.

A general phosphoric acid-catalyzed desymmetrization of meso-aziridines with silylated selenium nucleophiles

The first example of meso-aziridine desymmetrization with selenium nucleophiles is reported. The reaction, promoted by VAPOL-hydrogen phosphate using (phenylseleno)trimethylsilane as the nucleophile, proves to be very general and highly enantioselective (84-99% ee).

Theoretical Study of Mechanism and Stereoselectivity of Catalytic Kinugasa Reaction

The mechanism of the catalytic Kinugasa reaction is investigated by means of density functional theory calculations. Different possible mechanistic scenarios are presented using phenanthroline as a ligand, and it is shown that the most reasonable one in terms of energy barriers involves two copper ions. The reaction starts with the formation of a dicopper-acetylide that undergoes a stepwise cycloaddition with the nitrone, generating a five-membered ring intermediate. Protonation of the nitrogen of the metalated isoxazoline intermediate results in ring opening and the formation of a ketene intermediate. This then undergoes a copper-catalyzed cyclization by an intramolecular nucleophilic attack of the nitrogen on the ketene, affording a cyclic copper enolate. Catalyst release and tautomerization gives the final β-lactamic product. A comprehensive study of the enantioselective reaction was also performed with a chiral bis(azaferrocene) ligand. In this case, two different reaction mechanisms, involving either the scenario with the two copper ions or a direct cycloaddition of the parent alkyne using one copper ion, were found to have quite similar barriers. Both mechanisms reproduced the experimental enantioselectivity, and the current calculations can therefore not distinguish between the two possibilities.