“…The amide functional group can be accessed through a broad range of synthetic methods. These include the coupling of amines and carboxylic acids (typically requiring the use of a coupling reagent), nucleophilic acyl substitutions, rearrangements (e.g., Beckmann, Favorskii), and transamidations . All of these approaches involve either a retrosynthetic disconnection at the N–carbonyl bond or a rearrangement of the core structure of the substrate, thereby limiting the synthetic routes available to accessing highly functionalized amides.…”
This paper describes a mild strategy to promote amide arylations. Photoinduced oxidation of a Ni(II) aryl amido intermediate is proposed to facilitate the challenging C−N reductive elimination step at moderate temperatures. Notably, the mildly basic conditions employed facilitate access to a broad scope including protected amino acids, heterocycles, phenols, and sterically hindered substituents. Hence, this work presents an attractive strategy to enable late-stage functionalization of preexisting amide moieties in commercial drugs and natural products.
“…The amide functional group can be accessed through a broad range of synthetic methods. These include the coupling of amines and carboxylic acids (typically requiring the use of a coupling reagent), nucleophilic acyl substitutions, rearrangements (e.g., Beckmann, Favorskii), and transamidations . All of these approaches involve either a retrosynthetic disconnection at the N–carbonyl bond or a rearrangement of the core structure of the substrate, thereby limiting the synthetic routes available to accessing highly functionalized amides.…”
This paper describes a mild strategy to promote amide arylations. Photoinduced oxidation of a Ni(II) aryl amido intermediate is proposed to facilitate the challenging C−N reductive elimination step at moderate temperatures. Notably, the mildly basic conditions employed facilitate access to a broad scope including protected amino acids, heterocycles, phenols, and sterically hindered substituents. Hence, this work presents an attractive strategy to enable late-stage functionalization of preexisting amide moieties in commercial drugs and natural products.
“…The Favorskii rearrangement, originally described in 1894, corresponds to the nucleophilic attack of bases, e.g., hydroxide, alkoxide ions, or amines, on α-halo ketones to yield the salts, esters, or amides of the corresponding carboxylic acids, respectively, with a skeleton of the same number of carbon atoms. − Due to its versatility, it has become an increasingly reliable and specialized instrument of organic synthesis and an appreciable number of experimental works on the Favorskii rearrangement can be found in recent literature. − In particular, this reaction has found application for the preparation of highly branched acyclic carboxylic acids and its derivatives, providing a direct method for ring contraction in simple alicyclic systems and steroids. − However, some controversy over the nature of the molecular mechanism of this reaction persists, and at least five mechanisms have been proposed.…”
The molecular mechanism of the α-chlorocyclobutanone
transposition to yield cyclopropanecarboxylic
acid, as a model of the Favorskii rearrangement, has been theoretically
characterized in vacuo by means of ab
initio
molecular orbital procedures at the Hartree−Fock (HF) level of theory
with the 6-31G* and 6-31+G* basis sets.
The electron correlation has been estimated at the MP2/6-31G*
level and calculations based on density functional
theory, BLYP/6-31G*. The solvent effects are included at HF/6-31G*
level by means of a polarizable continuum
model. The questions related to the two accepted molecular
mechanisms, the semibenzilic acid and the cyclopropanone
transpositions, as well as the competition between both reaction
pathways are addressed in this investigation. The
dependence of the geometries of the stationary structures along the
corresponding reaction pathways and the transition
vectors associated with the transition structures upon theoretical
methods is discussed. The analysis of the results
shows that the electrostatic solute−solvent interactions modify
appreciably the topology of the potential energy
surface. The cyclopropanone mechanism is stabilized with respect
to the semibenzilic acid mechanism, but this
latter remains the energetically favorable reactive channel both
in vacuo and in solution. The semibenzilic
acid
mechanism is a two-step process and the rate-limiting step corresponds
to the nucleophilic attack of the hydroxyl ion
on the carbon atom of the carbonyl group belonging to the
α-chlorocyclobutanone ring. In the cyclopropanone
mechanism three transition structures appear along the energy profile
and the rate-limiting step is the dehydration
process of the bicyclo[1.1.0]2-butanone intermediate with
concomitant ring contraction and formation of the
cyclopropanecarboxylic acid product.
“…Originally described in 1894, Favorskii reaction corresponds to the nucleophilic attack of bases, e.g., hydroxide, alkoxide ions, or amines, on α-halo ketones to yield the salts, esters, or amides of the corresponding carboxylic acids, respectively, with a skeleton of the same number of carbon atoms. − Due to its versatility, it has become an increasingly reliable and specialized instrument of organic synthesis, and an appreciable number of experimental works on this rearrangement and its applications can be found in the recent literature. − Nevertheless, some controversy over the nature of the molecular mechanism of this reaction persists and at least five mechanisms have been proposed. − According to the current bibliography, only two of the proposed mechanisms have been supported by most of the evidence and remain as the accepted mechanisms: the Loftfield cyclopropanone mechanism 72,73 and the semibenzilic acid one, depicted in Scheme . 1 …”
Section: Introductionmentioning
confidence: 99%
“…[49][50][51][52][53][54][55] Due to its versatility, it has become an increasingly reliable and specialized instrument of organic synthesis, and an appreciable number of experimental works on this rearrangement and its applications can be found in the recent literature. [56][57][58][59][60][61][62][63][64][65] Nevertheless, some controversy over the nature of the molecular mechanism of this reaction persists and at least five mechanisms have been proposed. [66][67][68][69][70][71][72][73] According to the current bibliography, only two of the proposed mechanisms have been supported by most of the evidence and remain as the accepted mechanisms: the Loftfield cyclopropanone mechanism 72,73 and the semibenzilic acid one, 70 depicted in Scheme 1.…”
In this paper, hybrid quantum mechanical/molecular mechanical (QM/MM) calculations including 500 water molecules mold solvent effects on the molecular mechanisms of the R-chlorocyclobutanone and R-chlorocyclohexanone transpositions to yield cyclopropane and cyclopentane carboxylic acids, respectively, as a model of the Favorskii rearrangement. The two accepted molecular mechanisms, the semibenzilic acid and the cyclopropanone transpositions, as well as the competition between both reaction pathways and the ring size effects are addressed in this investigation. Stationary pointssreactants, products, transition structures, and intermediary species along both reaction pathwaysshave been located and characterized, involving a fully flexible active-site region, by means of GRACE and CHARMM software. The transition structures have been connected with their respective reactants and products by the intrinsic reaction coordinate procedure carried out in the presence of water media, thus obtaining for the first time a realistic reaction pathway for this chemical transposition. The analysis of the results obtained by QM/MM methods shows that the semibenzilic acid mechanism is favored over the cyclopropanone mechanism for the R-chlorocyclobutanone system. However, the study of the ring size effects reveals that the cyclopropanone mechanism is the energetically preferred reactive channel for the R-chlorocyclohexanone ring, probably due to the straining effects on bicycle cyclopropanone, an intermediate that appears on the semibenzilic acid pathway. This later mechanism is described as a two-step one, while the cyclopropanone or Loftfield mechanism is for the first time described as a four-step reaction. These results provide new information on an important chemical reaction and the key factors responsible for the behavior of reactant systems embedded in aqueous media. This methodology allows evaluation of specific solute-solvent interactions as well as weighing up of the different energy contribution terms.
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