The 1,3-dipolar cycloaddition and Diels-Alder reaction have been applied countless times in synthetic organic chemistry, materials chemistry, and now chemical biology. The stereoselectivity and rapid kinetics have been harnessed to develop the field of bioorthogonal chemistry. In this thesis, the origins of the rapid kinetics and exo-facial selectivity of norbornene was explained and extended to a series of pyramidalized norbornenes and sesquinorbornenes. These were studied using DFT (Density Functional Theory) at the M06-2X/6-311G(d,p) level along with other computational models. The transition structures and activation barriers for these reactions were calculated. An analysis of the calculations revealed that distortion energy is greatly responsible for the observed stereoselectivity, and a simple relationship was derived between pyramidalization and activation barriers. We propose the term, distortion-accelerated, to describe why the reactions are fast, rather than strain-promoted, because the alkenes release most of their strain energy before the transition state.

In a second portion of the thesis I applied the concept of distortion-acceleration to a recently discovered mutually orthogonal 1,3-dipolar cycloaddition and an inverse-demand Diels-Alder reaction. Mutually orthogonal reactions were used in the literature to selectively label two different cancer cells simultaneously. We explained this selectivity difference using modern computational methodology. DFT was used for this computational investigation at the M06-2X/6-311+G(d,p) level and the Polarizable Continuum Model (PCM) was used to correct for solvation effects. It was found that distortion energy, LUMO energies, and steric effects are responsible for the observed selectivity. General rules were developed to easily predict new mutually orthogonal pairs once their bioorthogonality is known.

The first part of this thesis describes how quantum mechanical calculations using density functional theory (DFT) have been used to understand mechanisms, reactivities, and stereoselectivities of cycloadditions for applications in organic synthesis. Cycloadditions are among the most important tools to synthetic organic chemists, because complex natural products can be constructed efficiently and with high atom economy. These reactions have emerged as tools by which chemical biologists can label biomolecules (i.e. lipids, sugars, nucleic acids) with fluorophores rapidly and selectively. The second part of the thesis describes my contributions to morphology (molecular dynamics) and hole mobility simulations of organic semiconducting materials.

Chapter 1 describes the origin of the exo-stereoselectivities of a series of norbornenes towards phenyl azide. The exo-stereoselectivities arise from alkene pyramidalization, which causes the alkene to more closely resembles the exo transition state than the endo transition state. Chapter 2 builds upon the previous studies of predistorted alkenes to include concave-stereoselective cycloadditions to an oxabicyclo[3.3.0]octene in collaboration with Gais et al. The alkene moiety of the oxabicyclo[3.3.0]octene is pre-distorted in the convex direction, resulting in a preference for concave addition. Calculations on a Pd-catalyzed (3+2) cycloaddition mechanism reveal that the rate- and stereodetermining step is the addition of the π-complex to the oxabicyclo[3.3.0]octene. Chapter 3 illustrates the concept of mutually orthogonal bioorthogonal reactions; the origin of this extraordinary selectivity is determined with DFT calculations. The azide–dibenzocyclooctyne and trans-cyclooctene–tetrazine cycloadditions are both inert to biological media and mutually orthogonal: trans-cyclooctene derivatives greatly prefer to react with tetrazines rather than azides, while dibenzocyclooctyne derivatives react with azides but not with tetrazines. Dibenzocyclooctyne chemoselectivity is controlled by distortion energy, and trans-cyclooctene chemoselectivity is controlled by interaction energy. Chapter 4 describes a mutually orthogonal bioorthogonal pair of isomeric 1,3-disubstituted and 3,3-disubstituted cyclopropenes that are chemoselective for reactions with tetrazines (Diels-Alder cycloaddition) and nitrile imines (1,3-dipolar cycloaddition), respectively. Prescher et al. discovered that 3,3-disubstituted cyclopropenes react exclusively with nitrile imines over tetrazines because of unfavorable steric clashes in the alkene-tetrazine transition state (distortion energy control), whereas and 1,3-disubstituted cyclopropenes react exclusively with tetrazines because of more favorable orbital interactions in the transition state (interaction energy control). Chapter 5 describes calculations on enamine-azide cycloadditions. The reactions are concerted, and the high regioselectivities are controlled by interaction energy. Chapter 6 extends our understanding of enamine-azide cycloadditions for a wide scope of perfluoroarylazides (PFAAs) towards acetophenone- and phenylacetaldehyde-derived enamines in collaboration with Yan et al. Enamines undergo cycloadditions several orders of magnitude faster with perfluoroarylazides than with phenyl azide, because PFAAs have relatively low-lying LUMOs. The 1,3-dipolar cycloadditions of norbornene and DIBAC also show increased reactivity towards PFAAs over phenyl azide, but are slower than enamine-azide cycloaddition. Chapter 7 is a theoretical study of 4π-electrocyclic ring-opening reactions of N-substituted-2-azetines, for a wide range of substituents from π acceptors (e.g., CHO, CN) to π donors (NMe2, OMe). Reactivity is controlled by a reactant state effect; acceptor substituents delocalize the nitrogen lone pair and stabilize the reactant state of 2-azetines. Torquoselectivities are controlled by a favorable nN–π*CC orbital interaction upon inward rotation of the N¬–substituent. The torquoselectivities and reactivities of 4-fluoroalkyl-oxetenes are considered in Chapter 8 in collaboration with Mikami et al. The torquoselectivities are controlled by the interplay of closed-shell repulsions and a favorable through-space orbital interaction between the breaking σCO orbital and the σ*CF orbital of the fluoroalkyl substitutent. The electronic character of the substituent of 4-substituted oxetenes controls oxetene electrocyclic ring opening rates.

The last two chapters of the thesis focus on studies of the factors that control the performance of extended π-conjugated materials in organic field-effect transistors (OFETs). Chapter 9 outlines how a multiscale method is used to extract hole mobilities for 2,5-bis(3-tetradecylthiophen-2-yl)thieno[3,2-b]-thiophene (BTTT) semiconducting materials. Briseño et al. report that BTTT monomers and dimers bearing alkyl side chains have hole mobilities of ~10–3 cm2/Vs, while the unsubstituted BTTT monomer has undetectable hole mobilities. Molecular dynamics simulations suggest that alkyl side chains improve crystal packing because of inter alkyl chain dispersive interactions. Chapter 10 explores the photooxidation rubrene to the corresponding endo-peroxide. DFT calculations of the cycloaddition and subsequent acid-catalyzed rearrangement mechanism are included.