Overcoming barriers with non-covalent interactions: supramolecular recognition of adamantyl cucurbit[n]uril assemblies for medical applications.

Adamantane, a staple in medicinal chemistry, recently became a cornerstone of a supramolecular host-guest drug delivery system, ADA/CB[n]. Owing to a good fit between the adamantane cage and the host cavity of the cucurbit[n]uril macrocycle, formed strong inclusion complexes find applications in drug delivery and controlled drug release. Note that the cucurbit[n]uril host is not solely a delivery vehicle of the ADA/CB[n] system but rather influences the bioactivity and bioavailability of drug molecules and can tune drug properties. Namely, as host-guest interactions are capable of changing the intrinsic properties of the guest molecule, inclusion complexes can become more soluble, bioavailable and more resistant to metabolic conditions compared to individual non-complexed molecules. Such synergistic effects have implications for practical bioapplicability of this complex system and provide a new viewpoint to therapy, beyond the traditional single drug molecule approach. By achieving a balance between guest encapsulation and release, the ADA/CB[n] system has also found use beyond just drug delivery, in fields like bioanalytics, sensing assays, bioimaging, etc. Thus, chemosensing in physiological conditions, indicator displacement assays, in vivo diagnostics and hybrid nanostructures are just some recent examples of the ADA/CB[n] applicability, be it for displacements purposes or as cargo vehicles.

Nanostructured supramolecular networks from self-assembled diamondoid molecules under ultracold conditions.

Diamondoid molecules and their derivatives have attracted attention as fascinating building blocks for advanced functional materials. Depending on the balance between hydrogen bonds and London dispersion interactions, they can self-organize in different cluster structures with functional groups tailored for various applications. Here, we present a new approach to supramolecular aggregation where self-assembly of diamondoid acids and alcohols in the ultracold environment of superfluid helium nanodroplets (HNDs) was analyzed by a combination of time-of-flight mass spectrometry and computational tools. Experimentally observed magic numbers of the assembled cluster sizes were successfully identified and computed cluster structures gave valuable insights into a different conglomeration mode when compared to previously explored less-polar diamondoid derivatives. We have confirmed that functional groups acting as good hydrogen bond donors completely take over the self-organization process, resulting in fascinating pair-wise or cyclic supramolecular assemblies. Particularly noteworthy is that mono- and bis-substituted diamondoid derivatives of both series engage in completely different modes of action, which is reflected in differing non-covalent cluster geometries. Additionally, formed cyclic clusters with a polar cavity in the center and a non-polar diamondoid outer layer can be of high interest in porous material design and provide insights into the structural requirements needed to produce bulk materials with desired properties.

Diamondoid ether clusters in helium nanodroplets.

Diamondoid ethers were introduced into superfluid helium nanodroplets and the resulting clusters were analyzed by time-of-flight mass spectrometry. Clusters of higher abundances (magic number clusters) were identified and the corresponding potential cluster geometries were obtained from GFN2-xTB and DFT computations. We found that the studied diamondoid ethers readily self-assemble in helium nanodroplets and that London dispersion attraction between hydrocarbon subunits acts as a driving force for cluster formation. On the other hand, hydrogen bonding between ether oxygens and trace water molecules fosters the eventual breakdown of the initial supramolecular aggregate.

Ultrafast Photoelimination of Nitrogen from Upper Excited States of Diazoalkanes and the Fate of Carbenes Formed in the Reaction.

The photochemical reactivity of diphenyldiazomethane 1 and phenyl 1- and 2-adamantyl diazomethanes 2 and 3, respectively, was investigated by transient absorption spectroscopy (TA). Photoelimination of N2 upon UV excitation takes place in the anti-Kasha ultrafast photochemical reaction from the upper excited singlet states to deliver singlet carbenes, which were, in the case of 1 and 2, detected by fs-TA. The reactivity of the carbenes differs with respect to the substituent at the carbene center. The singlet car-1 in a nonpolar solvent delivers the triplet carbene by intersystem crossing (ISC). Singlet car-2 does not undergo ISC but reacts in the intermolecular insertion reactions into C-H bonds. Car-3 has an α-C-H bond next to the carbene center and reacts rapidly in the intramolecular C-H insertion reaction to deliver alkene, precluding its detection by fs-TA. However, the isolation of ketone photoproducts from 3 is highly indicative of triplet car-3's intermediate formation. The TA spectra from the S1-S3 states of 1-3 were computed using time-dependent density functional theory, while the multiconfigurational perturbation theory to the second order was used for the absorption spectra of the corresponding singlet and triplet carbenes. The modeled and measured spectra are in good agreement, and the computations corroborate the assignments of the key short-lived intermediates.

Photoelimination of Nitrogen from Diazoalkanes: Involvement of Higher Excited Singlet States in the Carbene Formation.

Although diazoalkanes are important carbene precursors in organic synthesis, a comprehensive mechanism of photochemical formation of carbenes from diazoalkanes has not been proposed. Synergies of experiments and computations demonstrate the involvement of higher excited singlet states in the photochemistry of diazoalkanes. In all investigated diazoalkanes, excitation to S1 results in nonreactive internal conversion to S0. On the contrary, excitation to higher-lying singlet states (Sn, n > 1) drives the reaction toward a different segment of the S1/S0 conical intersection seam and results in nitrogen elimination and formation of carbenes.

Photoelimination of nitrogen from adamantane and pentacycloundecane (PCU) diazirines: a spectroscopic study and supramolecular control.

Photochemical reactivity of pentacycloundecane (PCU) and adamantane diazirines was investigated by preparative irradiation in different solvents, laser flash photolysis (LFP) and quantum chemical computations. In addition, formation of inclusion complexes for diazirines with cucurbit[7]uril, ß- and γ-cyclodextrin (ß- and γ-CD) was investigated by 1H NMR spectroscopy, isothermal microcalorimetry and circular dichroism spectroscopy, followed by the investigation of photochemical reactivity of the formed complexes. Diazirines undergo efficient photochemical elimination of nitrogen (ΦR > 0.5) and deliver the corresponding singlet carbenes. Singlet carbenes react in intra- and intermolecular reactions and we found a rare singlet carbene pathway in CH3OH involving protonation and formation of a carbocation, detected due to the specific rearrangement of the pentacycloundecane skeleton. Singlet diazirines undergo intersystem crossing and deliver triplet carbenes that react with oxygen to form ketones which were isolated after irradiation. Our main finding is that the formation of diazirine inclusion complexes with ß-CD and γ-CD changes the relative ratio of singlet vs. triplet pathways, with singlet carbene products being dominant from the chemistry of the irradiated complexes. Our combined theoretical and experimental studies provide new insights into the supramolecular control of carbene reactivity which has possible applications for the control of product distribution by solvent effects and the choice of constrained media.

Photochemical deuterium exchange in phenyl-substituted pyrroles and indoles in CD3CN-D2O.

A new mechanism of photochemical deuteration of some phenylpyrroles and indoles is reported. Irradiation of 2-phenylpyrrole (8), 2-phenylindole (9), and 7-phenylindole (12) in CH(3)CN-D(2)O gives rise to deuterium exchange at the C-atoms of the heterocycle and the adjacent phenyl ring. Photolysis of indole (7), 8, 9, 12 and N-methyl-2-phenylindole (10) in CD(3)CN-D(2)O also leads to deuteration at C-atoms with significantly higher yield. The mechanism most probably involves ejection of an electron on excitation and formation of radical cations that abstract D-atoms from CD(3)CN or undergo bimolecular D-abstraction (photolysis in CH(3)CN-D(2)O). The other possible mechanism of deuterium exchange for 7, 8, 9 and 12 may take place via a homolytic N-D cleavage and recombination of the radical pair. Radical cations of 8, 9 and 10 were detected by laser flash photolysis. Steady state and time-resolved fluorescence of 8, 9, 10 and 12 showed that photoinduced intramolecular electron transfer probably does not occur. The fluorescence was quenched by acid and base and the rate constants determined by Stern-Volmer analyses. The estimated pK(a) values for the protonation and deprotonation of the singlet excited states indicated that in neutral aqueous solutions ESPT probably does not take place, additionally corroborating the radical or radical cationic mechanism of deuteration.