Versatile Trityl Radicals: Improving Applications via Tailored Synthesis

Abstract

Generally, organic radicals are considered as rather unstable and highly reactive species that are just intermediates of chemical reactions. <br /> However, this paradigm was disproved already in 1900 my Moses Gomberg, who coincidently discovered the triphenylmethyl radical. Subsequently, many derivatives of the Gomberg-radical, bearing an increased stability, have been developed. Nowadays, especially the sulfur-rich tetrathiotriarylmethyl (TAM)-radicals found widespread application ranging from functional imaging techniques towards spin labelling in terms of structural biology. . <br /> Despite the tremendous interest into these truly stable radicals from the application perspective, the synthetic chemistry of these has been less developed. Therefore, this thesis aims to overcome limitations arising from that issue by tailored synthetic approaches. . <br /> Initially, a Migita-type C-S cross-coupling process employing odorless isothiouronium salts as the thiolate source was developed to yield tetrakis(tert-butylthio)benzene as an important precursor. Then, the functionalization of the trityl skeleton was approached insofar, as an iodinated trityl alcohol was obtained. This allowed to construct π-conjugated trityl arrays, interesting for material development, via straightforward Suzuki-coupling. Additionally, Sonogashira-coupling was examined and a competitive carbothiolation was encountered. However, this side-reaction could be restrained by a rational choice of conditions to yield the first ethynyl-substituted TAM-radical. . <br /> Another focus of this thesis lied on the development of trityl spin labels. In that course, a novel spin label given the acronym SLIM (short-linked maleimide) was developed and obtained via a tailored Mitsunobu/Retro-Diels-Alder sequence. Its chemical architecture does not only allow to obtain narrow distance distribution, but also enhances its reduction stability in a thermodynamic fashion. In view of these enticing properties, EPR-based distance measurements within intact oocytes of Xenopus Laevis were conducted and revealed a conformational change of the Yersinia protein YopO upon entering the cells. . <br /> As the hydrophobicity of trityl-based spin labels is an intrinsic drawback, a hydroxylated trityl spin label, Ox-SLIM, was developed. It shares all beneficial properties with SLIM, but is highly hydrophilic and does, thus, not aggregate with proteins. Moreover, it exhibits a longer transversal relaxation time, which allowed so set a new sensitivity record for EPR-based distance measurements at 45 nM protein concentration.