Evasive Neutral 2‐Aza‐Cope Rearrangements. Kinetic and Computational Studies with Cyclic Nitrones

Abstract

A full experimental study of the activation energy required for the hitherto unknown neutral 2‐aza‐Cope rearrangement is presented. A kinetic study of the process showed activation energies in the range of 22.91–24.06 kcal/mol, in agreement with a process operating at moderate temperature (70 °C). Calculations at B3LYP/6‐311+G(d,p) and M06‐2X/6‐311+G(d,p) levels of theory considering solvent (dimethyl sulfoxide (DMSO) and toluene) effects (PCM model) predict reaction energy barriers that are in agreement with the values obtained from 1H NMR‐based kinetic experiments. Results obtained by using enantiomerically pure substrates demonstrate that the rearrangement takes place with complete transfer of chirality, in contrast to previously described cationic processes. The effects of solvent and acid catalysis, which converts the process into the more common cationic rearrangement, have also been studied. DFT calculations also predict correctly the acceleration of the process under acid catalysis, estimating energy barriers in the range of 16.80–18.57 kcal/mol.

Deacetylation of per-acetatylated glycopyranosides: An overall pattern for acidic catalyzis

“…The obtained scheme is in good agreement with experimental data. Thus, the deacetylation reaction of fully-protected glucoside 1 yield mixed products if stopped at reaction times which correspond to steps "a", "b" or "c" while at higher reaction time which correspond to "d" step, experimental work was capable of yielding a single product 2-O-acetyl glucoside 2. previous studies [36,37]. The presence of ethanol in xylene and in DMSO can influence the experimentally estimated activation energies.…”

BET & ELF Quantum Topological Analysis of Neutral 2-Aza-Cope Rearrangement of γ-Alkenyl Nitrones

“…This is in agreement with the fact that the process is catalyzed by Brønsted acids. Protonation of the nitrone oxygen renders the nitrone moiety more electrophilic, moving the rearrangement from neutral to cationic 2-aza-Cope and increasing the reaction rate [ 37 ]. Consequently, a transfer of electron density from the allylic fragment towards the nitrone function is expected.…”

“…The resulting asynchronicity of the process can be evidenced by an ELF analysis [ 32 , 33 , 34 ]. An exception to the loss of degeneration upon inclusion of a heteroatom is the neutral 2-aza-Cope rearrangement of nitrones ( Scheme 1 ), suggested by Hoffmann in 1986 [ 35 ], and confirmed by us more than twenty years later [ 36 , 37 ].…”

“…However, although the two fragments involved in the process, i.e., the allylic moiety and the nitrone function, are isoelectronic (four electrons for three atoms), the presence of nitrogen and oxygen atoms in the latter should induce different electronic properties that might be affected by the presence of substituents. The transition structure (TS) analysis of the 2-aza-Cope reaction was reported in our previous paper with special focus on cyclic nitrones to explain the experimentally observed results on the competitive intramolecular dipolar cycloaddition [ 37 ]. Herein, we applied the ELF analysis to study in detail the neutral 2-aza-Cope rearrangement of nitrones by comparing up to 17 differently substituted substrates.…”

Metal-Free Solvent Promoted Oxidation of Benzylic Secondary Amines to Nitrones with H2O2

“…Nitrones 2a , 23 2b , 34 2c , 35 2d , 36 2e , 37 2f , 38 2g , 23 2h , 39 2i , 40 2j , 41 2l , 42 2m , 43 and 2n ( 42 ) and cycloadducts 6 and 7 ( 33 ) have been previously described. Spectroscopic data match those previously reported.…”