Thesis

Synthesis and conformational properties of Hexamethyl Triazacalix[6]arene

A variety of calixarene analogues involving heteroatoms as the bridging units have been reported because the substitution of the carbon bridges with heteroatoms can impart novel properties and influence the conformer of the macrocycle. However, the chemistry of replacing the bridging methylene units of calixarenes derived from p-tert-butylphenol with free amino groups to prepare azacalixarene macrocycles is still in its infancy. Nitrogen bridges can alter the conformational properties of the macrocyclic array through changes in bond lengths and angles associated with the nitrogen heteroatom, which results in a cone conformation. Additionally, the nitrogen heteroatom also provides additional binding sites to the macrocycle and can participate in hydrogen bonding along the endo rim which may also influence conformational properties. Furthermore, the nitrogen heteroatom opens up new avenues to further functionalize the bridge position through amine alkylation or acylation chemistry. The synthetic methodology was developed for hexamethyl triazacalix[6]arene by preparing a functionalized linear oligomer followed by cyclization over seven reactions steps in 32.1% overall yield. Of the eight conformers possible for the hexamethyl triazacalix[6]arene, in solution the cone conformer is preferred due to the bifurcated hydrogen bonding by the amine-methoxy functional groups along the endo rim. Additionally, the cone-to-cone ring inversion can be observed by temperature-dependent 1H-NMR spectroscopy since the temperature dependent signal is the result of the conformational flexibility of calixarenes and indicates that the protons are exchanging environments rapidly on the NMR time scale at high temperature but are frozen at lower temperatures. 1H NMR spectra was collected at various temperatures beginning at room temperature (298 K) and stopping at -57 ⁰C (216 K). The rate of exchange for a given temperature was determined by the iterative parameter refinement of the line shape (1000 cycles and with a 92+ % overlap) and used in an Erying plot to determine the thermodynamic parameters. The enthalpy of activation (∆H‡) was determined to be 8.95 kcal/mol and the entropy of activation (∆S‡) was determined to be -4.3 cal/mol*K for the cone-to-cone inversion barrier. The Gibbs free energy of activation (∆G‡) for hexamethyl triazacalix[6]arene was calculated to 9.9 kcal/mol at coalescence. In comparison, the activation barrier for cone-to-cone inversion for the full carbon-bridged calix[6]arene is estimated to be below 9.3 kcal/mol.

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