| dc.description.abstract | The thesis entitled “Theoretical Studies of Structural and Electronic Effects in Organic Reactions” involves computational investigations of various factors influencing organic reactivity. Several classes of reactions of considerable experimental interest have been studied with a variety of computational methodologies to obtain detailed insights into the relative importance of various stereoelectronic factors. For each reaction studied, the characteristic structural and electronic features of the reactants have been analysed. This is followed by a direct examination of the structural, energetic, and electronic effects in the transition state. While simplified models have been used for some complex systems, transition-state structures have been computed rigorously in most cases.
Chapter 1 provides a brief review of the various experimental and theoretical approaches used in the study of organic reaction mechanisms. The advantages and limitations of computational procedures are highlighted. Several strategies appropriate for modelling chemical reactivity problems of differing complexity are described. The computational procedures used in the present work are also briefly discussed.
In Chapter 2, factors contributing to the experimentally observed ??facial selectivities in the Diels–Alder reaction in two types of substrates have been critically evaluated. The facially perturbed dienophiles, norbornenyl?fused p?benzoquinone (NPBQ), 1, and norbornyl?fused p?benzoquinone (DNPBQ), 2, exhibit a range of stereoselectivities in their reactions with various dienes. Molecular mechanics and semiempirical MO calculations, as well as a hybrid Force Field/MO model, have been employed to determine the importance of ground?state geometric distortions, orbital interactions, and steric effects in the transition states. Model calculations that exclusively account for non?bonded forces between the diene and dienophile at the transition state explain the observed product distributions.
In the next section, the observed selectivities in the cycloaddition reactions of a set of facially non?equivalent hexacyclic dienes 3 and 4 have been rationalized. After summarizing previous interpretations, a comprehensive explanation is provided based on computational studies of transition?state energetics with various model dienophiles at the AM1 level. The calculations reveal that the face selectivities of alkynes reflect the intrinsic facial bias dictated by the electronic structure of the diene substrate. In the case of alkene?type dienophiles, steric effects imposed by the cyclobutane ring hydrogen atoms also contribute to facial bias. For heteroatomic dienophiles, such as azo derivatives and singlet oxygen, the preferred direction of approach is strongly affected by dipolar repulsions from the carbonyl oxygen atoms. These interpretations are confirmed through additional calculations performed with model diene 5.
The [2+2+2] cycloaddition of a 1,4?diene with a dienophile—known as the Homo?Diels–Alder reaction—represents a relatively less understood and underexplored synthetic transformation. Molecular mechanics calculations have been performed on several experimentally studied non?conjugated dienes to gain general insights into the geometric and strain?energy constraints required for efficient Homo?Diels–Alder reactivity. More detailed insights have been obtained from MO calculations of energy profiles for representative systems. The relative preferences for synchronous and asynchronous transition states have been computed. These calculations reveal a previously unsuspected electronic symmetry factor in the Homo?Diels–Alder reaction. Through?bond interactions are shown to be critical in determining the HOMO of the biradicaloid transition state and may, in turn, control the feasibility of the reaction.
The surprising importance of orbital?symmetry effects in reactions proceeding via biradicaloid pathways is demonstrated for another system in Chapter 4. AM1 calculations with CI have been carried out on a number of substrates potentially capable of undergoing Bergman cyclization. This reaction is of current interest because of its role in the DNA?cleaving activity of enediyne antitumor antibiotics such as Esperamicin, Dynemicin, Calicheamicin, and Neocarzinostatin. Simpler models have generally focused on geometric and strain criteria. The present semiquantitative MO calculations demonstrate the importance of orbital symmetry and through?bond effects in determining the energy profiles of the Bergman cyclization. Using suitable models, the critical role of these factors is established. In the same chapter, the dependence of activation energies for Myers’ cyclization in allene–yne systems on the distance between the terminal reacting sites has been computationally evaluated. These results are compared with the known sensitivity of cyclization rates in ene?diyne systems to distance requirements.
In the final chapter, AM1 calculations are used to rationalize the observed stereocontrol of Claisen rearrangement rates in unsaturated sugar systems. The relative activation barriers for ?? and ??anomeric pairs of vinyl and aryl ethers at different positions of an unsaturated pyranose ring have been precisely computed. The role of the anomeric effect in determining the ground?state conformation and transition?state stability, along with steric interactions between the migrating unit and the underlying sugar ring, has been analysed using appropriate model systems. The conformational preferences of the rearranging fragment and the sugar ring have been studied in detail. The computed results are consistent with available experimental data and are of considerable significance for the use of Claisen rearrangements in carbohydrate synthesis. | |
