Predicting and Understanding Binding Affinities of Synthetic Anion Receptors

Anion receptors are molecules that can recognise and bind anions. They have applications in organocatalysis, anion sensing and the removal of anions from wastewater. Some anion receptors are also able to transport anions across cell membranes and show promise for the treatment of diseases such as cystic fibrosis and cancer. As such, it is of interest to develop computational methods that can reliably predict the physicochemical properties and anion binding affinities of these molecules. However, efforts to computationally model these molecules are hampered by the sheer size of typical receptors, making them too expensive to treat using accurate quantum chemical methods. Whilst efficient approximations such as local-correlation methods have been developed, the broader accuracy of these methods, particularly in their application to ionic non-covalent systems remains unclear. To address this gap, this thesis has carried out an extensive validation of local-correlation methods, and economical density functional theory (DFT) methods for receptors with different binding motifs. Additionally, multiscale models have also been examined with the view to extending the scope of these methods to model very large anion receptors. DFT methods giving good agreement with highly accurate calculations at a fraction of the cost were identified. The use of semiempirical methods combined with DFT in a multiscale model for calculating anion binding affinities lead to unexpectedly large errors with modest savings of computational time, while some "three-fold corrected" methods show promise in reducing the cost of geometry optimisations of large receptors. These validated protocols were subsequently applied to investigate the structure-binding relationships of a wide range of dual-hydrogen bonding receptors. Notably, different receptor motifs were found to have different conformational preferences, which could explain why experimentally, thioureas, thiosquaramides and croconamides show weaker chloride binding affinities than would be expected based on their acidity. The results suggest that pre-organising anion receptors in the conformer that facilitates hydrogen bond formation could be a promising strategy for the development of anion receptors. It is envisaged that these findings will aid in the design and screening of novel anion receptors with increased binding affinity and selectivity

Visible-Light Photoswitching by Azobenzazoles

Three visible-light responsive photoswitches are reported, azobis(1-methyl-benzimidazole) (1), azobis(benzoxazole) (2) and azobis(benzothiazole) (3). Photostationary distributions are obtained upon irradiation with visible light comprising approximately 80 % of the thermally unstable isomer, with thermal half-lives up to 8 min and are mostly invariant to solvent. On protonation, compound 1H+ has absorption extending beyond 600 nm, allowing switching with yellow light, and a thermal half-life just under 5 minutes. The two isomers have significantly different pKa values, offering potential as a pH switch. The absorption spectra of 2 and 3 are insensitive to acid, although changes in the thermal half-life of 3 indicate more basic intermediates that significantly influence the thermal barrier to isomerization. These findings are supported by high-level ab initio calculations, which validate that protonation occurs on the ring nitrogen and that the Z isomer is more basic in all cases

Theoretical investigation of the photodissociation of solvated phenol

Im Rahmen dieser Arbeit wurden zwei Mechanismen der Photodissoziation von Phenol untersucht: 1) Elongation der O-H Bindung; 2) Reorganisation der Lösungsmittelmoleküle und die dadurch begünstigte Entstehung von solvatisierten Elektronen. Zur Untersuchung des Mechanismus der O-H-Elongation wurden Scans der O-H-Bindungslänge mit CASPT2/CASSCF und ADC(2)/CASSCF durchgeführt um die Höhe der Energiebarriere zwischen dem Minimum des hellen ππ*-Zustands und dem dunklen, dissoziativen πσ*-Zustand zu ermitteln. Die mit ADC(2) berechnete Barriere stimmt besser mit der experimentellen Zeitkonstante für die Entstehung von solvatisierten Elektronen überein, während mit CASPT2 die Höhe der Barriere überschätzt wird. Aus energetischer Sicht erscheint der Mechanismus der O-H-Elongation plausibel. Um den Mechanismus der Reorganisierung der Lösungsmittelmoleküle zu untersuchen, der die Entstehung von solvatisierten Elektronen begünstigt, wurden, basierend auf Momentaufnahmen einer klassischen Molekulardynamiksimulation, das Absorptionsspektrum und die Zustandsdichte mittels ADC(2) berechnet. Für die Beschreibung der Umgebung wurde ein Clustermodell bestehend aus 15 Wassermolekülen verwendet. Während die πσ*-Zustände weitestgehend dunkel sind, zeigt eine Analyse der Zustandsdichte, dass für mehrere Geometrien der πσ*-Zustand eine geringere Anregungsenergie als das Maximum der ππ*-Bande hat. Durch Reorganisierung der Lösungsmittelmoleküle können diese energetisch niedrigen Zustände nach elektronischer Anregung in die ππ*-Bande ohne Elongation der O-H-Bindung populiert werden. Die Energie des πσ*-Zustandes wird verringert, wenn das σ*-Orbital durch eine große Anzahl an Wassermolekülen in einer relativ großen Distanz von Phenol solvatisiert wird. Unsere Arbeit zeigt die Möglichkeit der Photodissoziation von Phenol durch Reorganisation der Lösungsmittelmoleküle und legt eine Untersuchung dieses Mechanismus in Derivaten von Phenol nahe.In this work, two possible mechanisms for the photodissociation of phenol are investigated: 1) elongation of the O-H bond; 2) reorganization of solvent molecules, facilitating the formation of solvated electrons. In order to investigate the mechanism of O-H elongation, scans of the O-H distance were carried out with CASPT2/CASSCF and ADC(2)/CASSCF to determine the height of the energy barrier between the bright ππ* state and the dark, dissociative πσ* state. While CASPT2 overestimates the barrier, ADC(2) provides better agreement with the experimental time scale for the formation of solvated electrons. From an energetic point of view, the mechanism of O-H elongation is plausible. To investigate the mechanism of reorganization of the solvent molecules, facilitating the formation of a solvated electron, the absorption spectrum and the density of states were calculated with ADC(2) based on snapshots from a classical molecular dynamics simulation. For the description of the environment, a cluster model comprised of 15 water molecules was chosen. While the πσ* states are mainly dark, the density of states shows that for several geometries the πσ* state has a lower excitation energy than the maximum of the ππ* band. These low-lying states can be populated after excitation to the ππ* band by reorganization of the solvent molecules without elongation of the O--H bond. A geometrical analysis reveals that the energy of the πσ* state is lowered if the σ*-orbital is well solvated by a large number of water molecules at a rather large distance from phenol. Our work demonstrates that the reorganization of solvent molecules may drive photodissociation of phenol and suggests that the investigation of this mechanism in derivatives of phenol might be worthwhile

Solvent reorganization triggers photo-induced solvated electron generation in phenol

The analysis of the absorption spectrum and density of states of a cluster of phenol solvated with 15 water molecules indicates that the reorganization of the water molecules, facilitating the formation of solvated electrons, is a plausible mechanism in the photodissociation of phenol. Using quantitative wavefunction analysis, we demonstrate that while charge-transfer states involving electron transfer from phenol to water are mainly dark, a considerable number of them exists below the maximum of the ππ* absorption band and could be populated by internal conversion. These low-lying charge-transfer states do not show extended O–H distances, but are found for large electron–hole separations at which several water molecules can solvate and stabilize the transferred electron. Thus, charge-transfer states in solvated phenol can be stabilized by two factors: (i) elongation of the O–H bond, as was extensively discussed in the past, and (ii) reorganization of solvent molecules, as it is shown here

Anion binding affinity: acidity versus conformational effects

High-level quantum chemical calculations were used to elucidate the gas- and solution-phase conformational equilibria for a series of symmetrically substituted (thio)ureas, (thio)squaramides, and croconamides. Gas-phase calculations predict that the thermodynamic conformer of many of these anion receptors is not the dual-hydrogen-bond-facilitating anti-anti conformer as is commonly assumed. For ,'-diaryl thiosquaramides and croconamides, the syn-syn conformer is typically the predominant conformer. Solution-phase calculations show that the anti-anti conformer is increasingly stabilized as the polarity of the solvent increases. However, the syn-syn conformer remains the lowest energy conformation for croconamides. These predictions are used to explain the acidity versus chloride binding affinity correlations recently reported for some of these compounds. The chloride binding constants for thioureas and croconamides are significantly lower than expected on the basis of their p values, and this may be due in part to the need for these receptors to reorganize into the anti-anti conformer. Experimental NMR nuclear Overhauser effect (NOE) measurements of an asymmetrically substituted squaramide and its thio analogue are consistent with the syn-syn conformation being predominant at 298 K. The conformational equilibria should therefore be an important consideration for the design and development of future anion receptors and organocatalysts

Ruthenium Carbonyl Complexes with Azole Heterocycles - Synthesis, X-ray Diffraction Structures, DFT Calculations, Solution Behavior, and Antiproliferative Activity

International audienc

Rilpivirine in HIV-1-positive women initiating pregnancy: to switch or not to switch?

International audienceBackgroundSafety data about rilpivirine use during pregnancy remain scarce, and rilpivirine plasma concentrations are reduced during second/third trimesters, with a potential risk of viral breakthroughs. Thus, French guidelines recommend switching to rilpivirine-free combinations (RFCs) during pregnancy.ObjectivesTo describe the characteristics of women initiating pregnancy while on rilpivirine and to compare the outcomes for virologically suppressed subjects continuing rilpivirine until delivery versus switching to an RFC.MethodsIn the ANRS-EPF French Perinatal cohort, we included women on rilpivirine at conception in 2010–18. Pregnancy outcomes were compared between patients continuing versus interrupting rilpivirine. In women with documented viral suppression (<50 copies/mL) before 14 weeks of gestation (WG) while on rilpivirine, we compared the probability of viral rebound (≥50 copies/mL) during pregnancy between subjects continuing rilpivirine versus those switching to RFC.ResultsAmong 247 women included, 88.7% had viral suppression at the beginning of pregnancy. Overall, 184 women (74.5%) switched to an RFC (mostly PI/ritonavir-based regimens) at a median gestational age of 8.0 WG. Plasma HIV-1 RNA nearest delivery was <50 copies/mL in 95.6% of women. Among 69 women with documented viral suppression before 14 WG, the risk of viral rebound was higher when switching to RFCs than when continuing rilpivirine (20.0% versus 0.0%, P = 0.046). Delivery outcomes were similar between groups (overall birth defects, 3.8/100 live births; pregnancy losses, 2.0%; preterm deliveries, 10.6%). No HIV transmission occurred.ConclusionsIn virologically suppressed women initiating pregnancy, continuing rilpivirine was associated with better virological outcome than changing regimen. We did not observe a higher risk of adverse pregnancy outcomes