Magneto-Structural Correlations in a Mixed Porphyrin(Cu2+ )/Trityl Spin System: Magnitude, Sign, and Distribution of the Exchange Coupling Constant.

Tetrathiatriarylmethyl radicals (TAM or trityl) are receiving increasing attention in various fields of magnetic resonance such as imaging, dynamic nuclear polarization, spin labeling, and, more recently, molecular magnetism and quantum information technology. Here, a trityl radical attached via a phenyl bridge to a copper(II)tetraphenylporphyrin was synthesized, and its magnetic properties studied by multi-frequency continuous-wave electron paramagnetic resonance (EPR) spectroscopy and magnetic measurements. EPR revealed that the electron spin-spin coupling constant J between the trityl and Cu2+ spin centers is ferromagnetic with a magnitude of -2.3 GHz (-0.077 cm-1 , + J S → 1 S → 2 ${+J{\vec{S}}_{1}{\vec{S}}_{2}}$ convention) and a distribution width of 1.2 GHz (0.040 cm-1 ). With the help of density functional theory (DFT) calculations, the obtained ferromagnetic exchange coupling, which is unusual for para-substituted phenyl-bridged biradicals, could be related to the almost perpendicular orientation of the phenyl linker with respect to the porphyrin and trityl ring planes in the energy minimum, while the J distribution was rationalized by the temperature weighted rotation of the phenyl bridge about the molecular axis connecting both spin centers. This study exemplifies the importance of molecular dynamics for the homogeneity (or heterogeneity) of the magnetic properties of trityl-based systems.

Ox-SLIM: Synthesis of and Site-Specific Labelling with a Highly Hydrophilic Trityl Spin Label.

The combination of pulsed dipolar electron paramagnetic resonance spectroscopy (PDS) with site-directed spin labelling is a powerful tool in structural biology. Rational design of trityl-based spin labels has enabled studying biomolecular structures at room temperature and within cells. However, most current trityl spin labels suffer either from aggregation with proteins due to their hydrophobicity, or from bioconjugation groups not suitable for in-cell measurements. Therefore, we introduce here the highly hydrophilic trityl spin label Ox-SLIM. Engineered as a short-linked maleimide, it combines the most recent developments in one single molecule, as it does not aggregate with proteins, exhibits high resistance under in-cell conditions, provides a short linker, and allows for selective and efficient spin labelling via cysteines. Beyond establishing synthetic access to Ox-SLIM, its suitability as a spin label is illustrated and ultimately, highly sensitive PDS measurements are presented down to protein concentrations as low as 45 nm resolving interspin distances of up to 5.5 nm.

Excitation Energy Transfer and Exchange-Mediated Quartet State Formation in Porphyrin-Trityl Systems.

Photogenerated multi-spin systems hold great promise for a range of technological applications in various fields, including molecular spintronics and artificial photosynthesis. However, the further development of these applications, via targeted design of materials with specific magnetic properties, currently still suffers from a lack of understanding of the factors influencing the underlying excited state dynamics and mechanisms on a molecular level. In particular, systematic studies, making use of different techniques to obtain complementary information, are largely missing. This work investigates the photophysics and magnetic properties of a series of three covalently-linked porphyrin-trityl compounds, bridged by a phenyl spacer. By combining the results from femtosecond transient absorption and electron paramagnetic resonance spectroscopies, we determine the efficiencies of the competing excited state reaction pathways and characterise the magnetic properties of the individual spin states, formed by the interaction between the chromophore triplet and the stable radical. The differences observed for the three investigated compounds are rationalised in the context of available theoretical models and the implications of the results of this study for the design of a molecular system with an improved intersystem crossing efficiency are discussed.

Intramolecular O-H⋯S hydrogen bonding in threefold symmetry: Line broadening dynamics from ultrafast 2DIR-spectroscopy and ab initio calculations.

The dynamics of intramolecular hydrogen-bonding involving sulfur atoms as acceptors is studied using two-dimensional infrared (2DIR) spectroscopy. The molecular system is a tertiary alcohol whose donating hydroxy group is embedded in a hydrogen-bond potential with torsional C3-symmetry about the carbon-oxygen bond. The linear and 2DIR-spectra recorded in the OH-stretching region of the alcohol can be simulated very well using Kubo's line shape theory based on the cumulant expansion for evaluating the linear and nonlinear optical response functions. The correlation function for OH-stretching frequency fluctuations reveals an ultrafast component decaying with a time constant of 700 fs, which is in line with the apparent decay of the center line slopes averaged over absorption and bleach/emission signals. In addition, a quasi-static inhomogeneity is detected, which prevents the 2DIR line shape to fully homogenize within the observation window of 4 ps. The experimental data were then analyzed in more detail using a full ab initio approach that merges time-dependent structural information from classical molecular dynamics (MD) simulations with an OH-stretching frequency map derived from density functional theory (DFT). The latter method was also used to obtain a complementary transition dipole map to account for non-Condon effects. The 2DIR-spectra obtained from the MD/DFT method are in good agreement with the experimental data at early waiting delays, thereby corroborating an assignment of the fast decay of the correlation function to the dynamics of hydrogen-bond breakage and formation.

Improved, Odorless Access to Benzo[1,2-d;4,5-d']- bis[1,3]dithioles and Tert-butyl Arylsulfides via C-S Cross Coupling.

Benzo[1,2-d;4,5-d']bis[1,3]dithioles are important building blocks within a range of functional materials such as fluorescent dyes, conjugated polymers, and stable trityl radicals. Access to these is usually gained via tert-butyl aryl sulfides, the synthesis of which requires the use of highly malodorous tert-butyl thiol and relies on SNAr-chemistry requiring harsh reaction conditions, while giving low yields. In the present work, S-tert-butyl isothiouronium bromide is successfully applied as an odorless surrogate for tert-butyl thiol. The C-S bond formation is carried out under palladium catalysis with the thiolate formed in situ resulting in high yields of tert-butyl aryl sulfides. The subsequent formation of benzo[1,2-d;4,5-d']bis[1,3]dithioles is here achieved with scandium(III)triflate, a less harmful reagent than the usually used Lewis acids, e.g., boron trifluoride or tetrafluoroboric acid. This enables a convenient and environmentally more compliant access to high yields of benzo[1,2-d;4,5-d']bis[1,3]dithioles.

SLIM: A Short-Linked, Highly Redox-Stable Trityl Label for High-Sensitivity In-Cell EPR Distance Measurements.

The understanding of biomolecular function is coupled to knowledge about the structure and dynamics of these biomolecules, preferably acquired under native conditions. In this regard, pulsed dipolar EPR spectroscopy (PDS) in conjunction with site-directed spin labeling (SDSL) is an important method in the toolbox of biophysical chemistry. However, the currently available spin labels have diverse deficiencies for in-cell applications, for example, low radical stability or long bioconjugation linkers. In this work, a synthesis strategy is introduced for the derivatization of trityl radicals with a maleimide-functionalized methylene group. The resulting trityl spin label, called SLIM, yields narrow distance distributions, enables highly sensitive distance measurements down to concentrations of 90 nm, and shows high stability against reduction. Using this label, the guanine-nucleotide dissociation inhibitor (GDI) domain of Yersinia outer protein O (YopO) is shown to change its conformation within eukaryotic cells.

Pulsed EPR Dipolar Spectroscopy on Spin Pairs with one Highly Anisotropic Spin Center: The Low-Spin FeIII Case.

Pulsed electron paramagnetic resonance (EPR) dipolar spectroscopy (PDS) offers several methods for measuring dipolar coupling constants and thus the distance between electron spin centers. Up to now, PDS measurements have been mostly applied to spin centers whose g-anisotropies are moderate and therefore have a negligible effect on the dipolar coupling constants. In contrast, spin centers with large g-anisotropy yield dipolar coupling constants that depend on the g-values. In this case, the usual methods of extracting distances from the raw PDS data cannot be applied. Here, the effect of the g-anisotropy on PDS data is studied in detail on the example of the low-spin Fe3+ ion. First, this effect is described theoretically, using the work of Bedilo and Maryasov (Appl. Magn. Reson. 2006, 30, 683-702) as a basis. Then, two known Fe3+ /nitroxide compounds and one new Fe3+ /trityl compound were synthesized and PDS measurements were carried out on them using a method called relaxation induced dipolar modulation enhancement (RIDME). Based on the theoretical results, a RIDME data analysis procedure was developed, which facilitated the extraction of the inter-spin distance and the orientation of the inter-spin vector relative to the Fe3+ g-tensor frame from the RIDME data. The accuracy of the determined distances and orientations was confirmed by comparison with MD simulations. This method can thus be applied to the highly relevant class of metalloproteins with, for example, low-spin Fe3+ ions.

Pulsed EPR Dipolar Spectroscopy under the Breakdown of the High-Field Approximation: The High-Spin Iron(III) Case.

Pulsed EPR dipolar spectroscopy (PDS) offers several methods for measuring dipolar coupling and thus the distance between electron-spin centers. To date, PDS measurements to metal centers were limited to ions that adhere to the high-field approximation. Here, the PDS methodology is extended to cases where the high-field approximation breaks down on the example of the high-spin Fe3+ /nitroxide spin-pair. First, the theory developed by Maryasov et al. (Appl. Magn. Reson. 2006, 30, 683-702) was adapted to derive equations for the dipolar coupling constant, which revealed that the dipolar spectrum does not only depend on the length and orientation of the interspin distance vector with respect to the applied magnetic field but also on its orientation to the effective g-tensor of the Fe3+ ion. Then, it is shown on a model system and a heme protein that a PDS method called relaxation-induced dipolar modulation enhancement (RIDME) is well-suited to measuring such spectra and that the experimentally obtained dipolar spectra are in full agreement with the derived equations. Finally, a RIDME data analysis procedure was developed, which facilitates the determination of distance and angular distributions from the RIDME data. Thus, this study enables the application of PDS to for example, the highly relevant class of high-spin Fe3+ heme proteins.

Synthesis of µ2 -Oxo-Bridged Iron(III) Tetraphenylporphyrin-Spacer-Nitroxide Dimers and their Structural and Dynamics Characterization by using EPR and MD Simulations.

Iron(III) porphyrins have the propensity to form µ2 -oxo-dimers, the structures of which resemble two wheels on an axle. Whereas their crystal structure is known, their solution structure and internal dynamics is not. In the present work, the structure and dynamics of such dimers were studied by means of electron paramagnetic resonance (EPR) spectroscopy and quantum chemistry based molecular dynamics (MD) simulations by using the semiempirical tight-binding method (GFN-xTB). To enable EPR investigation of the dimers, a nitroxide was attached to each of the tetraphenylporphyrin cores through a linear and a bent linker. The inter-nitroxide distance distributions within the dimers were determined by continuous-wave (cw)-EPR and pulsed electron-electron double resonance (PELDOR or DEER) experiments and, with the help of MD, interpreted in terms of the rotation of the porphyrin planes with respect to each other around the Fe-O-Fe axis. It was found that such rotation is restricted to the four registers defined by the phenyl substituents. Within the registers, the rotation angle swings between 30° and 60° in the proximal and between 125° and 145° in the distal register. With EPR, all four angles were found to be equally populated, whereas the 30° and 145° angles are strongly favored to the expense of the 60° and 125° angles in the MD simulation. In either case, the internal dynamics of these dimers thus resemble the motion of a step motor.

C-C Cross-Coupling Reactions of Trityl Radicals: Spin Density Delocalization, Exchange Coupling, and a Spin Label.

Organic radicals are usually highly reactive and short-lived species. In contrast, tetrathiatriarylmethyl radicals, the so-called trityl- or TAM-radicals, are stable and do survive over longer times even under in-cell conditions. In addition, they show strong EPR signals, have long phase memory times at room temperature, and are reporters on local oxygen and proton concentrations. These properties facilitated their use for magnetic resonance imaging, dynamic nuclear polarization, and spin-labeling EPR under in-cell conditions. Thus, synthetic approaches are required for functionalization of TAM radicals tailored to the desired application. However, most TAM derivatives reported in the literature are based on esterification of the Finland trityl, which is prone to hydrolysis. Here, we report on an approach in which TAM is site-selective iodinated and subsequently C-C cross-coupled to various building blocks in a modular approach. This yields conjugated trityl compounds such as a trityl attached to a porphyrin, an alkinyl functionalized trityl radical, and a strongly exchange-coupled trityl biradical. This synthesis approach thus has implications not only for magnetic resonance spectroscopy but also for the design of molecular magnets or quantum computing devices.

A sustainable synthesis of the SARS-CoV-2 Mpro inhibitor nirmatrelvir, the active ingredient in Paxlovid.

Pfizer's drug for the treatment of patients infected with COVID-19, Paxlovid, contains most notably nirmatrelvir, along with ritonavir. Worldwide demand is projected to be in the hundreds of metric tons per year, to be produced by several generic drug manufacturers. Here we show a 7-step, 3-pot synthesis of the antiviral nirmatrelvir, arriving at the targeted drug in 70% overall yield. Critical amide bond-forming steps utilize new green technology that completely avoids traditional peptide coupling reagents, as well as epimerization of stereocenters. Likewise, dehydration of a primary amide to the corresponding nitrile is performed and avoids use of the Burgess reagent and chlorinated solvents. DFT calculations for various conformers of nirmatrelvir predict that two rotamers about the tertiary amide would be present with an unusually high rotational barrier. Direct comparisons with the original literature procedures highlight both the anticipated decrease in cost and environmental footprint associated with this route, potentially expanding the availability of this important drug worldwide.

Tris[2,2,6,6-tetra-methyl-8-(tri-methyl-sil-yl)benzo[1,2-d;4,5-d']bis-(1,3-di-thiol)-4-yl]methanol diethyl ether monosolvate.

The title compound, a tri-aryl-methanol, C46H64OS12Si31, was synthesized via li-thia-tion of tris-2,2,6,6-tetra-methyl-benzo[1,2-d;4,5-d']bis-[1,3]di-thiol-4-yl-methanol, 2, and electrophilic quenching with tri-methyl-silyl chloride. The current crystal structure reveals information about the reactivity of this compound and compares well with the structure reported for the unsubstituted parent compound 2 [Driesschaert et al. (2012 ▸). Eur. J. Org. Chem.33, 6517-6525]. The title compound 1 forms mol-ecular propellers and crystallizes in P [Formula: see text], featuring an unusually long Si-Car bond of 1.910 (3) Å. Moreover, the geometry at the central quaternary carbon is rather trigonal-pyramidal than tetra-hedral due to vast intra-molecular stress. One tri-methyl-silyl group is disordered over two positions in a 0.504 (4):0.496 (4) ratio and one S atom is disordered over two positions in a 0.509 (7):0.491 (7) ratio. The contribution of disordered diethyl ether solvent mol-ecule(s) was removed using the PLATON SQUEEZE (Spek, 2015 ▸) solvent masking procedure. These solvent mol-ecules are not considered in the given chemical formula and other crystal data.