DFT mechanistic study on tandem sequential [4+2]/[3+2] addition reaction of cyclooctatetraene with functionalized acetylenes and nitrile imines

The mechanistic pathways for the tandem sequential [4+2] / [3+2] and [3+2]/[4+2] cycloaddition reaction of functionalized-acetylenes with cyclooctatetraene (COTE) and nitrile imines for the formation of the biologically-active tricyclic cyclobutane-condensed pyrazoline systems, and the subsequent cycloreversion/thermolysis of these adducts, have been studied using density functional theory (DFT) at the M06-2X/6-31G(d) and 6-311G(d,p) levels with the aim of providing mechanistic rationale for the regioselectivities and stereoselectivities. Along the [4+2] / [3+2] addition sequence, it has been found that the initial 6 pi -electrocyclic ring-closure of the COTE is the rate-determining step irrespective of the type of substituent on the parent acetylene or the nitrile imine. The mechanistic channels along the [4+2] / [3+2] addition sequence show that the addition of the dipole across the unsubstituted olefinic bond in the cyclohexadiene moiety in the endo fashion is the most favored, which is in agreement with experimentally observed selectivity. The results show that the thermolysis proceeds with relatively high activation barriers toward formation of the monocyclic pyrazolines among other products. The decomposition of the tandem adducts has been found to be controlled solely by kinetic factors. An exploration of a [3+2] / [4+2] addition sequence as a mechanistic possibility reveals that in contrast to the [4+2] / [3+2] addition sequence, the Diels-Alder addition step is the rate-determining. The [3+2] / [4+2] addition order is found as an approach with better selectivity as it leads to formation of only tandem adducts where the nitrile imines are attached to the substituted olefinic bond in the cyclohexadiene subunit. The results show that the monocyclic pyrazolines obtained from the thermolysis of the [4+2] / [3+2] tandem adducts could easily be obtained from a direct 1,3-dipolar addition of the alkynes with the dipoles which has been found to proceed rapidly with low activation barriers. The results are rationalized with perturbation molecular orbital theory.