Computational study of the rate constants and free energies of intramolecular radical addition to substituted anilines

Abstract

SummaryThe intramolecular radical addition to aniline derivatives was investigated by DFT calculations. The computational methods were benchmarked by comparing the calculated values of the rate constant for the 5-exo cyclization of the hexenyl radical with the experimental values. The dispersion-corrected PW6B95-D3 functional provided very good results with deviations for the free activation barrier compared to the experimental values of only about 0.5 kcal mol−1 and was therefore employed in further calculations. Corrections for intramolecular London dispersion and solvation effects in the quantum chemical treatment are essential to obtain consistent and accurate theoretical data. For the investigated radical addition reaction it turned out that the polarity of the molecules is important and that a combination of electrophilic radicals with preferably nucleophilic arenes results in the highest rate constants. This is opposite to the Minisci reaction where the radical acts as nucleophile and the arene as electrophile. The substitution at the N-atom of the aniline is crucial. Methyl substitution leads to slower addition than phenyl substitution. Carbamates as substituents are suitable only when the radical center is not too electrophilic. No correlations between free reaction barriers and energies (ΔG ‡ and ΔG R) are found. Addition reactions leading to indanes or dihydrobenzofurans are too slow to be useful synthetically.

Synthesis of Dihydropyrrolizine and Tetrahydroindolizine Scaffolds from Pyrroles by Titanocene(III) Catalysis

“…To rule out the unlikely generation of a tertiary cation, the radical was trapped with t ‐butyl acrylate to give 4 at room temperature and at 66 °C. In agreement with a study on the radical arylation with anilines,, and comparison with slow cyclizations,, the results suggest an upper limit for the rate constant of radical addition of 10 3 at 298 K. Therefore, radical addition to pyrroles is relatively slow. The high yields of 3 highlight the fact that the alkyl radicals generated under our reaction conditions are fairly persistent.…”

Application of Cationic Poly(lactic‐co‐glycolic acid) Iron Oxide/Chitosan‐Based Nanocomposite for the Determination of Paraoxon

“…Again, the use of overstoichiometric amounts of Mn and 4 is of no consequence for the outcome of the arylation. Compared to the reactions of 1 , the calculations20 suggest that the radical arylation should be less competitive for 11 due to the methyl substituent on N.…”

“…The butyl radical adds to benzene with a rate constant of about 4×10 2 M −1 s −1 at 79 °C. The addition to substituted anilines was only studied computationally for relatively simple model systems 20. The rate constants (4×10 2 to 4×10 3 s −1 ) are lower than those of the 5‐exo cyclization21 but are still in the range of useful processes.…”

Theoretical and Experimental Insights into the Tandem Mannich—Electrophilic Amination Reaction: Synthesis of Safirinium Dyes

“…This theoretical approach predicted also relatively high energy barriers for the electrophilic amination processes by means of high Gibbs free energies of 28.4 and 22.7 kcal/mol for the transition states 1a,b in methanol. Since the correct determination of large molecular structures and their properties require inclusion of the van der Waals interactions between molecules, we have added to the B3LYP/6-31+G(d) functional Grimme's empirical dispersion corrections [15], which were found to reliable in describing large molecular systems [16]. Consequently, the results obtained show that formation Safirinum P dye (3a) is thermodynamically favorable with ∆G values of −4.0 and −3.1 kcal/mol for reactions carried in water and methanol, respectively.…”