Computational mechanistic study of thionation of carbonyl compounds with Lawesson's reagent

The thionation reaction of carbonyl compounds with Lawesson's reagent (LR) has been studied using density functional theory methods and topological analyses. After dissociation of LR, the reaction takes place through a two-step mechanism involving (i) a concerted cycloaddition between one monomer and the carbonyl compound to form a four-membered intermediate and (ii) a cycloreversion leading to the thiocarbonyl derivative and phenyl(thioxo)phosphine oxide. Topological analyses confirmed the concertedness and asynchronicity of the process. The second step is the rate-limiting one, and the whole process resembles the currently accepted mechanism for the lithium salt-free Wittig reaction. No zwitterionic intermediates are formed during the reaction, although stabilizing electrostatic interactions are present in initial stages. Phenyl(thioxo)phosphine oxide formed in the thionation reaction is capable of performing a second thionation, although with energy barriers higher than the first one. The driving force of the thionation reactions is the formation of trimers from the resulting monomers. In agreement with experimental observations, the amides are the most reactive when compared with esters, aldehydes, and ketones and the reaction is slightly influenced by the polarity of the solvent. Whereas for amides and esters substituents have little effect, aldehydes and ketones are influenced by both steric and electronic effects.This work was supported by the Spanish Ministerio de Economia y Competitividad (MINECO) (Project CTQ2013-44367-C2-1-P), by the Fondos Europeos para el Desarrollo Regional (FEDER), and by the Gobierno de Aragon (Zaragoza, Spain, Bioorganic Chemistry Group, E-10). M.A.C. thanks the University of Catania for partial financial support.Peer Reviewe

[2n2π + 2n2π] Cycloadditions: an alternative to forbidden [4π + 4π] processes. The case of nitrone dimerization

A theoretical study based on (U)M06-2X/cc-pVTZ calculations has been used to investigate the [3 + 3] thermal dimerization of nitrones to 1,4,2,5-dioxadiazinanes in both the gas phase and in dichloromethane solution. Calculations suggest that dimerization of nitrones takes place through a concerted mechanism involving a formal disallowed [4π + 4π] cycloaddition with a free energy barrier of 30.8 kcal mol−1. The corresponding diradical and zwitterionic stepwise mechanisms have also been studied, but the located transition structures are kinetically disfavoured. An alternative mechanism through a five-membered ring intermediate formed by a classical [3 + 2] dipolar cycloaddition can also be discarded. The five-membered ring intermediate is unstable to cycloreversion and its isomerization to the final dioxadiazinane involves a high free energy barrier (68.6 kcal mol−1). Calculations also show that the dimerization process is slower in dichloromethane than in the gas phase owing to the larger polarity of nitrones and that inclusion of diffuse functions at the studied level does not modify the observed results. The apparently disfavoured [3 + 3] dimerization of nitrones can actually be explained as a bispseudopericyclic [2n2π + 2n2π] process in which the favourable FO interactions between the nitrone oxygen and the CN π* bypass the WH-forbidden process.The authors acknowledge the Spanish Ministry of Science and Innovation (MICINN) and FEDER (EU) for financial support (Madrid, project CTQ2010-19606). One of us (D.R.-L.) thanks the Spanish Ministry of Education (MEC) for a pre-doctoral grant (FPU program).Peer reviewe

Synthesis and Synthetic Applications of 1,2,4-Oxadiazole-4-Oxides

The first 1,2,4-oxadiazole-4-oxide was prepared by Wieland a century ago, but-this compound remained largely a chemical curiosity until very recently. 1,2,4-Oxadiazole-4-oxides are a family of heterocycles closely related to the chemistry of nitrile oxides which were actively studied in the past half century and provided the basic knowledge on 1,2,4-oxadiazole-4 -oxides. The dimerizations of nitrile oxides under acidic or basic conditions were thoroughly studied by different research groups, and offer the more common entries to the symmetrical substituted 1,2,4-oxadiazole-4-oxides. A more general route to symmetrical and unsymmetrical substituted 1,2,4-oxadiazole-4 -oxides is based on the nitrile oxide cycloadditions to amidoximes. A variety of other 1,2,4-oxadiazole-4-oxides forming reactions are also known in the literature. Many of these reactions were neither fully exploited nor mechanistically understood since they require unusual starting reagents, often difficult to prepare, or take place affording complex mixtures of products. Some of these methods still await for improved procedures and proper mechanistic attention to be of general use and will be reviewed shortly. The chemistry of 1,2,4-oxadiazole-4-oxides is related to the fragility of the heterocyclic ring, which undergoes thermal or photochemical cycloreversion to nitriles and nitrosocarbonyl intermediates. Trapping of the nitrosocarbonyls takes place easily with dienes and enes, affording a variety of hetero Diels-Alder and ene adducts, which attract great interest because of their useful synthetic elaboration toward many natural products of potential pharmaceutical applications. The high efficiency of the photochemical cleavage of 1,2,4-oxadiazole-4-oxides at room temperature or well below affords the softest entry to the nitrosocarbonyls and allows for the study of their chemistry under convenient and simple experimental conditions. The photochemical cleavage have been applied successfully to Solid Phase chemistry, allowing for a safe and environmental friendly methodology for the synthesis of important intermediates. This report is comprehensive of the synthesis and synthetic applications of the 1,2,4-oxadiazole4-oxides

An unexpected bispericyclic transition structure leading to 4+2 and 2+4 cycloadducts in the endo dimerization of cyclopentadiene

The stereospecific endo dimerization of cyclopentadiene takes place through an asynchronous and symmetrical bispericyclic transition structure, which shows a merging of the 4+2 and 2+4 cycloaddition paths. The shape of the transition structure testifies to the presence of attractive Salem/Houk secondary orbital interactions assisting the endo approach

A photochemical generation of nitrosocarbonyl intermediates

Nitrosocarbonyl intermediates are photochemically generated from 1,2,4-oxadiazole-4-oxides and efficiently trapped with enes and dienes

Crystal structure and DFT calculations of 3,8–Diphenyl–3a,4,5,5a,8a,8b–hexahydro–benzo[1,2–d: 3,4–d’]diisoxazole, C20H18N2O2 J. Mol. Struct., 2005, 741, 135.

The molecular and crystal structures of 3,8-diphenyl-3a,4,5,5a,8a,8b-hexahydro-benzo[1,2-d: 3,4-d']diisoxazole have been XRD determined. The compound crystallizes in the monoclinic system (space group P2(1)/c) with cell dimensions a=15.278(1), b = 9.839(1), c = 10.912(2) &ANGS;, β = 92.15(1)°. The structure was solved from 2193 reflections with I ≥ 2σ(I). The final R was 0.039 for 289 variables

Nitrosocarbonyl Intermediates as Super-Enophiles: a Mild Method for Carbon-Nitrogen Bond Formation

Nitrosocarbonyl intermediates, generated at r.t. by the mild oxidation of nitrile oxides, undergo clean ene reactions with tetramethyl- and trimethyl-ethylene and with cyclohexene. With less substituted ethylenes the ene pathway is still active but the oxidation step of the nitrile oxides competes with the cycloadditions to the olefins

Nonbonded Interactions Tune Selectivities in Cycloadditions to2,3-Dioxabicyclo[2.2.2]oct-5-ene

The facial selectivity of 2,3-dioxabicyclo[2.2.2]oct-5-ene in cycloaddition reactions is distressingly variable and akin to that of 2-oxa-3-azabicyclo[2.2.2]oct-5-ene derivatives. Osmilation takes place on the face anti to the dihetero bridge, while cycloaddition of butadiene affords exclusively the syn cycloadduct. Nitrile oxides add unselectively. B3LYP/LANL2DZ calculations of cycloadditions to 2,3-dioxabicyclo[2.2.2]oct-5-ene reproduce well the experimental selectivities and give insights into the origin of the changes. The double bonds of the olefins are moderately pyramidalized toward the anti space, implying a preferred anti addition. This natural predisposition to anti addition is tuned by the mutual interaction between the addends. On going from osmilation to nitrile oxide and butadiene cycloadditions, the steric effects between the addend and the dimethylene bridge of the olefin increase remarkably and affect the attacking angle T and the tilting angle a of the anti addition, enforcing enhanced deformations of the olefin, which almost offset its natural anti predisposition. In the case of butadiene, the residual part of the steric effect increases further the anti barrier leading to a neat reversal of selectivity. 2,3-Dioxabicyclo[2.2.1]hept-5-ene shows a larger anti pyramidalization, which is akin to that of norbornene itself and to 2-oxa-3-azabicyclo[2.2.1]hept-5-ene derivatives, and mutual steric interactions have only a subordinate influence on selectivity

Classical and non-classical secondary orbital interactions and Coulombic attraction in regiospecific dimerization of acrolein

Non-classical (bridging) and classical (Woodward-Hoffmann) secondary orbital interactions as well as a favourable electrostatic interaction are involved in the stabilization of the two lowest transition passes of the acrolein dimerization. The heteroatoms provide anchimeric assistance to the hetero Diels-Alder reaction through a neighbouring-group mechanism