Chemistry of pseudopericyclic reactions and synthesis of new proton sponges




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The concept of a pseudopericyclic reaction has been deeply explored as an important mechanistic aspect of molecular orbital studies of organic chemistry. Indeed, various pseudopericyclic reactions have been studied experimentally and computationally in our group, including sigmatropic rearrangements, cheletropic fragmentations, cycloadditions, electrocyclizations, and transfer/elimination reactions. This dissertation describes some new reactions that are proposed to be pseudopericyclic. In the second chapter of this dissertation, we propose a pseudopericyclic mechanism for the [1,3]-sigmatropic rearrangement of the NO group in the synthesis of isoxazoles. Homopropargyl alcohols react with t-BuONO to form acyloximes which can be oxidatively cyclized to yield isoxazoles. The mechanism for the initial reaction of HONO with alkynes to form acyloximes as been explored at the B3LYP/6-31G(d,p) + ZPVE level of theory. The observed chemoselectivity and regioselectivity are explained via an acid-catalyzed mechanism. Furthermore, the potential energy surface revealed numerous surprising features. The addition of HONO to protonated 1-phenylpropyne is calculated to follow a reaction pathway involving sequential transition states, for which reaction dynamics likely play a role. This reaction pathway can bypass the expected addition product as well as a [1,3]-NO transition state, directly forming the rearranged product. Nevertheless, this transition state is key to understanding the potential energy surface; there is a low barrier to be pseudopericylic. Meanwhile, the valley-ridge inflection point (VRI or bifurcation) was used to describe two competitive reaction pathways. The final tautomerization step to the acyloxime can be considered to be a ix Texas Tech University, Ang Zuo, August 2017 [1,5]-proton shift. However, the tautomerization from one conformation is calculated to be barrierless, arguably because the pathway is pseudopericyclic and exothermic. In the third chapter of this dissertation, a new guanidine proton sponge, 1,8-bis(dimethylbenzimidazolguanidino)-naphthalene, DMBIGN was synthesized and characterized. Based on the literature, we propose that DMBIGN should be expected to be a stronger base than the previously known superbase, DMEGN. Crystal structures of DMBIGN and its monoprotonated form reveal an anti- and a syn-geometry, respectively. Furthermore, the crystal structure of monoprotonated form of DMBIGN was approximately planar, which is consistent with other proton sponges. The experimental pKBH+ of DMBIGN was determined to be 20.8 based on 13C NMR spectroscopy in acetonitrile. Unexpectedly, the basicity of DMBIGN is weaker than other GPSs, such as TMGN and DMEGN. The origin of low basicity of DMBIGN was explored by calculations at the B3LYP/6-31G(d,p) + ZPVE level of theory. The theoretical pKBH+ of DMBIGN was calculated to be 21.4, which is consistent with the experimental value. What is more, the calculated proton affinities of DMBIGN and the benzimidazolguanidine substituent were weaker than DMEGN and its substituent, respectively. The destabilization energy of DMBIGN and the energy of intramolecular hydrogen bonding (IMHB) in its conjugated acid were calculated, in which both values were smaller than DMEGN and the corresponding conjugate acid DMEGN + 1H. The electrostatic potential maps of benzimidazolguanidine and other guanidine substituents were studied, indicating that the aromatic ring system decreases the electron density in the guanidine moiety due to the electron-withdrawing nature of the aromatic ring. This arguably results in the lower basicity of DMBIGN. x Texas Tech University, Ang Zuo, August 2017 In the last chapter of this dissertation, a new understanding is explored for the chemistry of proton migration in the protonated macrocyclic guanidine proton sponge, 1,8-(Methyl-propylenethyleneguanidino)naphthalene, MPEGN. More specifically, a pseudopericyclic mechanism for this proton transfer was proposed by us. MPEGN was designed to be a stronger base than DMEGN due to the geometrical constraints of the macrocycle. Two guanidine substituents were connected by the propylene linker, suggesting a stronger electrostatic repulsion between the two basic nitrogen atoms would be expected. The similarities and differences between the crystal structures of MPEGN and other GPSs were studied. Based on 13C NMR spectroscopy, the experimental pKBH+ of MPEGN was determined to be 22.7 in acetonitrile. The pKBH+ value of MPEGN is lower than TMGN (25.1) by 2.4, but higher than DMBIGN (20.8) by 1.9. Dynamic NMR reveals an activation energy of 12.2 kcal/mol (ΔG⧧) for a conformation change of MPEGN + 1H. Theoretical calculations of proton affinities and pKBH+ values of GPSs are consistent with the experimental results with TMGN as the most basic GPS, whereas DMBIGN is the weakest GPS of the three. Electrostatic potential maps were studied to address the difference of basicity in terms of electronegativity and overall electron density. The similar electron density of MPEGN and DMEGN suggests a close basicity for those two GPSs, being consistent with the calculated proton affinities. Furthermore, the [1,5]-sigmatropic hydrogen rearrangement in the monoprotonated MPEGN could be a pseudopericyclic reaction due to an orbital disconnection at N where the N‒H bond is breaking. The calculated low barrier (only 1.3 kcal/mol) of a planar transition state meets the key characteristics of pseudopericyclic reactions. But including the calculated ZPVE correction suggests this barrier (-0.9 kcal/mol) vanishes.

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Pseudopericyclic, Proton Sponge, Superbase