The Antiaromatic Nucleophilic Substitution Reaction (SNAAr) in Cycloheptatrienyl-Anion Containing Zwitterions with a Möbius-Aromatic Intermediate.

Antiaromatic nucleophilic substitution reactions in cycloheptatrienide pyridinium and phosphonium zwitterions with initial formation of a cycloheptatetraene intermediate are explored. The mechanism was supported by quantum chemical calculations, first-order reaction kinetics, and high-resolution mass spectrometry. The pyridinium zwitterion exhibited weak antiaromaticity, whereas the intermediate displayed Möbius aromaticity, as evidenced by nuclear independent chemical shift values and the shape of its HOMO. This study represents the eighth confirmed instance of a Möbius-aromatic organic species in its ground state.

Antiaromaticity of Cycloheptatrienyl Anions: Structure, Acidity, and Magnetic Properties.

Investigations of the nature and degree of antiaromaticity of cycloheptatrienyl anion derivatives using both experimental and computational tools are presented. The ground state of cycloheptatrienyl anion in the gas phase is triplet, planar and Baird-aromatic. In DMSO, it assumes a singlet distorted allylic form with a paratropic ring current. The other derivatives in both phases assume either allylic or diallylic conformations depending on the substituent pattern. A combination of experimental and computational methods was used to determine the pKa values of 16 derivatives in DMSO, which ranged from 36 to -10.7. We revealed that the stronger stabilization of the anionic system, which correlates with acidity, does not necessarily imply a lower degree of antiaromaticity in terms of magnetic properties. Conversely, the substitution pattern first affects the geometry of the ring through the bulkiness of the substituents and their better conjugation with a more distorted system. Consequently, the distortion reduces the cyclic conjugation in the π-system and thereby decreases the paratropic current in a magnetic field, which manifests itself as a decrease in the NICS. The triplet-state geometries and magnetic properties are nearly independent on the substitution pattern, which is typical for simple aromatic systems.

Cascade Vinylation/8π-Electrocyclization and Cu(II)-Catalyzed Dehydrogenation toward Highly Stable Formally Antiaromatic Cycloheptatrienyl Anions.

An approach to the synthesis of seven-membered systems via the chain elongation of nucleophilic propenes and subsequent 8π-electrocyclization is proposed. The cascade reaction yields either cycloheptadienes or bicycloheptenes, and the latter are formed via a 6π-electrocyclization of intermediate cycloheptadienyl anion which was proved to be reversible in a basic medium. The electrocyclic nature of the ring-closing reactions was supported by density functional theory and DLPNO/CCSD(T) calculations. Highly electron-deficient cycloheptatrienes can be obtained from cycloheptadienes or bicycloheptenes via oxidation either introduced into the cascade reaction or performed as a separate reaction, with the overall yield of up to 81%. The oxidation step was performed by means of a rarely encountered Cu(II)-catalyzed dehydrogenation of cycloheptadienes or bicycloheptenes, and so the reaction mechanism was proposed. Stable formally 8π-antiaromatic cycloheptatrienyl-anion containing compounds were obtained, and some correlations between their UV-vis spectra and the structure of the distorted cycloheptatrienyl-anion moiety were clarified. Additionally, a base-induced retro-[2 + 2]-cycloaddition in a bicycloheptene derivative gave cyanotetra(methoxycarbonyl)cyclopentadienyl cesium.

Branching tryptamines as a tool to tune their antiproliferative activity.

The influence of a series of tryptamine derivatives on the viability of normal (HEK293) and tumor (HepG2, Jurkat and SH-SY5Y) cells has been evaluated. All tryptamines tested were three different substitution types: C- and N-branching, and indole benzylation. All the derivations enhance the activity of compounds separately, although the effects of different substitutions were not additive. Thus, combinations of C- and N-branchings as well as C-branching and indole benzylation gave little or no increase in activity.

Synthesis of Branched Tryptamines via the Domino Cloke-Stevens/Grandberg Rearrangement.

The rearrangement of cyclopropylketone arylhydrazones generated in situ from arylhydrazine hydrochlorides and ketones leads to formation of tryptamine derivatives. The use of (2-arylcyclopropyl)ethanones in the reactions with model 4-bromophenylhydrazine hydrochloride gives branched tryptamines with aryl groups in the α-position to the amino group, while (2-methylcyclopropyl)ethanone gives a mixture of α- and ß-substituted products in a ratio of 1:3. The method was found effective in the synthesis of enantiomerically pure tryptamine. Thus, (R,R)-(2-phenylcyclopropyl)ethanone gives the (S)-α-phenyltryptamine derivative with an enantiomeric excess over 99%.

Synthesis and cytotoxic properties of tryptamine derivatives.

The cyclopropyliminium and subsequent Grandberg rearrangements of cyclopropylketone hydrozones lead to the formation of tryptamines, which were additionally substituted at either the aromatic ring atoms or the amino group. The products were tested for their cytotoxic properties against HepG2, Jurkat and HEK293 cell lines using MTT assay. The highest activity as well as the highest selectivity was found amongst the compounds derived with one benzyl substituent at the amino group. The flow cytometry technique revealed cell-type specificity in terms of the mechanism of viability inhibition. Thus, the compounds were found to induce mainly apoptosis in HEK293 and HepG2 cells, while Jurkat cells displayed late apoptotic and necrotic responses. The apoptosis pathway is most likely to include mitochondrial damage.