Theoretical Investigation Of The Construction Of Nitrogen-Containing Heterocyclic Compounds By Intra-Molecular Cyclization Of Iminyl Radicals

Radical reaction is an important branch of chemical reactions.Intramolecular radical cyclization as a kind of radical reaction has become one of the effective ways to access to carbon-and heterocyclic compounds in organic synthesis.Generally,the formation of the new ? bond and the high activity of radical reactants and intermediates make this type of reaction thermodynamically and kinetically favorable,respectively.An intramolecular radical cyclization often provides kinetic products controlled by relative Gibbs free energies of the rate-determining transition states on the competitive exo and endo cyclization-oxidation/reduction pathways.The final preferred product should be determined by relative Gibbs free energies of the rate-determining transition states on the competitive pathways.Furthermore,in intramolecular radical cyclizations,neophyl-like rearrangement was often considered as an important isomerization channel of radical intermediates cyclized in different modes.Relative to the concentration distribution of cyclic radicals coming from competitive cyclizations,the neophyl-like rearrangement may lead to the change of branching ratio of different regioselective products.Although the neophyl-like rearrangement was deemed to exist in lots of experiments,almost all of evidences resulting from theoretical investigations do not support this rearrangement as dominant channel.The intramolecular cyclization of nitrogen-centered iminyl radicals as an effective method for the construction of nitrogen-containing heterocyclic molecules is more complex in reaction mechanism than their carbon-centered analogues.Furthermore,it is difficult to directly predict its preferred cyclization mode and dominant product using the Baldwin rules and classical reaction trajectory theory often used in the investigations of cyclizations of the carbon-centered analogues.Such a complexity is neatly illustrated by the observed varied regioselective products.To give an deep insight into the complexity in products and mechanism of the intramolecular cyclization of nitrogen-centered iminyl radicals,we herein selected the representative and experimentally available 1-(3-phenylallyl)-6-oxo-1,6-dihydropyridine-2-carbonitrile-2-yl,1-(3-(2-methoxyphenyl)-allyl)-6-oxo-1,6-dihydropyridine-2-carbonitrile-2-yl,and 2-Allyl-2-methyl-2,3-dihydro-1H-inden-1-iminyl radicals and several model compounds as target molecules to perform this investigation.We used quantum-mechanics computation to locate the geometries of stationary points and the corresponding energies,which were further used to construct reaction potential energy profiles.Furthermore,we employed the numerical simulation technology to obtain the numerical solution of the multivariable dynamical differential equation set established based on the constructed potential energy profiles.Using the numerical solution,we can directly obtain the available time-dependent concentrations of all species,dominant reaction pathway,and product branching ratio.Further,we also employed several theoretical methods based on electron level to investigate the effect of kinetics,thermodynamics,and temperature on the preferred reaction channel and product branching ratio and conducted the comparative analysis of the present theoretical results with availably experimental suggestions.The investigated results indicate that when the radical reactants cyclize to construct five-and six-membered rings,the orbital orientation of radical center and attack trajectory lead to less steric hindrance(intrinsic barrier)of exo cyclization than endo one.Although the geometry of radical reactants has only minor effect on the ordering of intrinsic barriers of the radical cyclizations with different modes,for the substrates with different molecular structures the contribution of temperature and reaction energy to barrier often leads to different preferred cyclization mode and product.For several of the investigated radical reactants with polycyclic structure,the strong dependence of barriers to the reduction of cyclized intermediates on temperature results in a significant effect of temperature on the preferred regioselective product;for instance,in high-temperature region close to the boiling point of solvent the preferred product is endo-cyclized molecule,but with the decreasing temperature the exo-product is gradually close to and finally higher in concentration than the endo-product.Thereby,for those polycyclic substrates,the reaction regioselectivity can be controlled by adjusting reaction temperature.Furthermore,the neophyl-like rearrangement is a minor channel for all of examples.This investigation of intramolecular cyclizations of iminyl radicals give a considerable insight into not only the reaction mechanism but also the effect of geometric structure,electron,and temperature on the regioselective product.The revealed reaction mechanism is extremely useful for the selection of substrates,predicting reaction products,and determining reaction conditions.Further,it also provide direct information of data and theoretical support for understanding the nature of intramolecular cyclization and experimental design of constructing nitrogen-containing heterocyclic compounds using intramolecular cyclization of iminyl radicals.