Vladimir V. Kovalev

Efficient approaches have been developed for the synthesis of heteromultifunctional cone calix[4]arenes containing four amino groups at the wide rim and one, two or four propargyl or 2-azidoethyl groups at the narrow rim of the macrocycle, which can be used for expanding functionalization of the calixarene core in the well-known amine acylation (or similar reactions) and CuAAC ‘click’ reactions. Two different strategies were implemented to obtain propargylated and 2-azidoethylated p -aminocalixarenes. In the case of propargylated calixarenes, sterically crowding silyl protection was introduced into the alkyne groups of p-tert -butylcalix[4]arene (multiple) propargyl ethers, and the resulting compounds were ipso -nitrated followed by reduction of the nitro groups. To prepare 2-azidoethylated macrocycles, the ipso -nitration/reduction sequence was applied to p-tert -butylcalix[4]arenes containing 2-tosyloxyethyl groups at the narrow rims followed by replacement of the tosyloxy groups with azide ones. In all cases, p -aminocalix[4]arenes were obtained as the readily cleavable tert -butoxycarbonyl (Boc) derivatives, which was crucial for certain transformation and purification steps. To confirm the functionalization capabilities of the five obtained multifunctional calixarenes, they were reacted with excess benzyl azide or phenylacetylene, taken as representatives, under copper(I) catalysis, resulting in the narrow-rim triazolated macrocycles. By removing the Boc protecting groups and involving the free amino groups in reactions with p -tolyl isocyanate, a series of narrow-rim triazolated tetraureacalix[4]arenes was obtained. Examination of the ¹ H NMR spectra of the tetraureas in CDCl ₃ showed that in most cases triazole heterocycles do not intervene the formation of homo- and heterodimeric capsules by these compounds. Thus, considering the synthetic value of CuAAC and amine transformations, p -aminocalix[4]arenes enriched with alkyne or azide functionalities can be readily used as multifunctional platforms to obtain even higher functionalized macrocycles. As an example, they can be used for the preparation of sophisticated supramolecular assemblies with homo- or heterodimeric calixarene cores and virtually any functional units attached to them via triazole groups.

The title compound crystallizes as a dichloromethane monosolvate, C ₆₃ H ₇₃ N ₃ O ₄ ·CH ₂ Cl ₂ . The main molecule represents a calix[4]arene and possesses a pinched cone shape, with the two distal para -amino groups at the wide rim of the macrocycle being brought into close proximity due to steric repulsion between the bulky trityl-amino and tert -butyl groups attached to the other two distal positions of the wide rim. In the crystal, the calixarene molecules are assembled by numerous C—H...π and van der Waals interactions, while the solvent molecules reside in the cavities forming C—H...π and Cl...π contacts with the phenyl rings of the trityl group.

A cone calix[4]arene having one tert-butyl group and three amino groups at the wide rim was bis-N-protected stepwise using sulfonylation with 4-nitrobenzylsulfonyl chloride, followed by acylation with di-tert-butyl dicarbonate. The selective sulfonylation was shown to prefer the amino group located in the proximal calixarene aromatic unit relative to the tert-butylated moiety, resulting in the formation of an inherently chiral calix[4]arene with a wide-rim substitution pattern of AABC type. Further acylation of one of the two remaining amino groups also proceeded selectively. It involved the calixarene aromatic unit adjacent to the sulfonylated moiety, as clearly demonstrated by 2D NMR data for the ABCD-substituted reaction product, which was obtained as a mixture of enantiomers. The mixture was acylated with (R)-mandelic acid succinimide ester, and the resulting diastereomers were separated by conventional column chromatography, thus demonstrating the applicability of the stepwise protection strategy for the further preparation of enantiopure calix[4]arene cores possessing inherent chirality due to four different substituents at their wide rims.

Inherently chiral calix[4]arenes, which have triazole and amine-based functional/receptor groups asymmetrically arranged at the wide rim of a cone macrocycle, can be readily prepared through desymmetrization of a calix[4]arene triamine.

It is found that CF ₃ SO ₃ H/(CF ₃ CO) ₂ O‐mediated cross‐acylation acetic acid with bulky substituted acetic acids RCH ₂ COOH (R = i Pr, t Bu, 1‐adamantyl) proved to be the simple and convenient method for the synthesis of lipophilic dehydroacetic acid homologues. The conditions of deacylation of symmetrical α‐pyrones with subsequent acylation with adamantyl acetic acids have been developed, leading to an expansion of available derivatives of dehydroacetic acid. It has also been shown that adamantylacetone is readily formed by cross‐acylation of malonic acid and adamantyl acetic acid. Enamines derived from obtained α‐pyrones show strong cytotoxic activity against HeLa human cell lines.

The review describes the history of the development of adamantane chemistry and shows moments that stimulated rise in the studies, as well as the main lines of research in this field and prospects thereof, on the basis of published data (up to 2024) with an emphasis on the last two decades.

The heterocyclic structure of pyrones has a variety of biological activities and plays an important role in the creation of new drugs. Therefore, the study of the structure and spectra of pyrones is of considerable interest. In this work, the IR and Raman spectra of 3-(3,3-Dimethylbutanoyl)-4-hydroxy-6-neopentyl-2H-pyran-2-one (1) in its crystalline state was studied. The tautomerization of 1 was followed by a quantum-chemical method at the DFT/B3LYP/6-311G** level. The calculation for the 4-hydroxy enol tautomer (A) reproduces the experimental IR and Raman spectra of compound 1. The classification of the bands in the experimental vibrational spectra of 1 has been carried out. The intramolecular H-bond was characterized by IR spectroscopy. The free energies of the tautomers and their populations were calculated for two different solvents. It appears from our data that type A dominates. The content of tautomer B increases in the nonpolar solvent but does not exceed 13%. As evident from the calculations and experimental X-ray data, the pyran ring of the molecule is flat. HOMO and LUMO of molecule 1 are located on the pyran ring. During tautomeric transformations, there is a significant delocalization of charge and a change in the reactivity of the molecule. The reactivity of pyrone 1 was characterized using descriptors. The form B was found to have higher ionization energy, electron affinity, chemical potential, and electrophilic index than the A form. The dipole moment is higher for form A, and the softness of the two molecules is the same.

Distally substituted bis-1,3-diketone derivatives of calix[4]arene were synthesized, in which chelate groups are attached via a carbonyl carbon atom to the p -positions of phenolic fragments of a macrocycle fixed in 1,3-alternate isomeric form. 1,3-Diketone derivatives were obtained by acylation of magnesium enolate of a calix[4]arene ketone with 1-benzoylbenzotriazoles. In the synthesized compounds, 1,3-diketone groups are conjugated with the π-aromatic system of calix[4]arene. It was found by means of UV spectroscopy and NMR diffusion methods in combination with quantum chemical (DFT) calculations that a mononuclear complex with bis-chelate coordination of the lanthanide ion is predominantly formed in the solution. The formation of the complex leads to a decrease in the conjugation degree in the ligand. The most effective sensitization of Eu ³⁺ luminescence, compared to the p -F- or p -CF ₃ -phenyl-substituted complexes is observed for calix[4]arene complexes with H-phenyl-substituted 1,3-diketone groups.

1,3-Alternate calix[4]arenes were prepared, having bulky adamantyl groups in the p-positions of all four aromatic units of the macrocycles and pairs of propargyl or 2-azidoethyl groups alternating with n-propyl groups at the phenol oxygen atoms. The step-wise syntheses were carried out through a selective distal alkylation of the parent p-adamantylcalix[4]arene with propargyl bromide or 1,2-dibromoethane, resulting in calix[4]arenes bearing pairs of propargyl or 2-bromoethyl groups at their narrow rims. The bromine atoms were replaced by azide groups, and then both calix[4]arene diethers were exhaustively alkylated at the remaining OH-groups with 1-iodopropane under stereoselective conditions to fix the macrocycles in an 1,3-alternate shape. The structures of the prepared p-adamantylcalix[4]arenes were confirmed by NMR and HRMS data, and, for the 1,3-alternate dipropargyl ether, the X-ray diffraction data were also collected. Preliminary data on the reactivity of the prepared calixarenes under the CuAAC conditions suggested a strong steric hampering created by the adamantane units nearby the reacting alkyne or azide groups that affected the outcome of the two-fold cycloaddition involving the calixarene bis(azides) or bis(alkynes) as complementary partners.

The calixarenes, 5,17-dibromo-26,28-dihydroxy-25,27-dipropynyloxycalix[4]arene (C₃₄H₂₆Br₂O₄, 1), 5,17-dibromo-26,28-dipropoxy-25,27-dipropynyloxycalix[4]arene (C₄₀H₃₈Br₂O₄, 2) and 25,27-bis(2-azidoethoxy)-5,17-dibromo-26,28-dihydroxycalix[4]arene (C₃₂H₂₈Br₂N₆O₄, 3) possess a pinched cone molecular shape for 1 and 3, and a 1,3-alternate shape for compound 2. In calixarenes 1 and 3, the cone conformations are additionally stabilized by intramolecular O—H...O hydrogen bonds, while in calixarene 2 intramolecular Br...Br interactions consolidate the 1,3-alternate molecular conformation. The dense crystal packing of the cone dialkyne 1 is a consequence of π–π, C—H...π and C—H...O interactions. In the crystal of the diazide 3, there are large channels extending parallel to the c axis, which are filled by highly disordered CH₂Cl₂ solvent molecules. Their contribution to the intensity data was removed by the SQUEEZE procedure that showed an accessible void volume of 585 ų where there is room for 4.5 CH₂Cl₂ solvent molecules per unit cell. Rigid molecules of the 1,3-alternate calixarene 2 form a columnar head-to-tail packing parallel to [010] via van der Waals interactions, and the resulting columns are held together by weak C—H...π contacts.