Partial Cone Conformation Research Articles

Coordination Chemistry of Calix[3]Pyrrole-Related Macrocycles

Calix[3]pyrrole is a ring-contracted porphyrinogen-like macrocycle in which three pyrrole units are linked by three sp3-carbon atoms at the a-positions. While synthetic routes to calix[3]pyrrole and its furan and thiophene derivatives have been established using oligoketone precursors,[1–3] their coordination chemistry remains fully unexplored. Here, the author reports the direct macrocyclization synthesis and metal complexation properties of novel thiazole-containing calix[3]pyrrole analogues that exhibit better metal chelation than that of calix[3]pyrrole.Treatment of calix[3]pyrrole (1) with n-butyl lithium (4 eq.) resulted in the deprotonation of all the NH protons to generate a tridentate trianionic ligand. Successive reaction with BBr3 furnished a boron(III)-complex 2 in 25% isolated yield. However, attempts to synthesize stable complexes with other metal ions were unsuccessful. The obtained boron complex 2 were unusually stable towards acids; even in pure trifluoroacetic acid (TFA) or methanesulfonic acid, no deboronation was observed, instead, protonation at a pyrrole carbon atom was detected by NMR spectroscopy.In order to generate isolable metal complexes with calix[3]pyrrole-related macrocycles, we have designed calix[1]pyrrole[2]thiazole (4). Calix[1]furan[2]thiazole (3), a precursor of 4, was synthesized by direct macrocyclization between bis(a-bromoketone) and 2,2-dimethylpropanebis(thioamide) in 60% yield. While calix[3]pyrrole (1)undergoes a strain-induced ring expansion reaction to give calix[6]pyrrole under acidic conditions, less strained 3 was stable in TFA, thus its furan moiety was hydrolyzed to a diketone moiety. Further Paal–Knorr pyrrole formation reaction led to the formation of 4 in 78% yield.When macrocycle 4 was mixed with Et2Zn, monoethyl zinc complex 5 was formed in 72% yield. Single crystal X-ray analysis revealed that 4 adopted a C s-symmetric cone conformation to behave as a monoanionic tridentate ligand. Due to the steric protection of the ethyl zinc center by meso-methyl groups, organozinc complex 5 was stable in the presence of excess water or alcohol at room temperature.Complexation of 4 with Pd(MeCN)4(BF4)2 afforded cationic palladium complex 6 in which macrocycle 4 adopted a partial cone conformation to chelate a Pd2+ ion as a neutral bidentate ligand. Similar complexation behavior was also observed with AgBF4, demonstrating conformational flexibility of macrocycle 4 upon metal complexation. Furthermore, coordination-driven self-assembly was confirmed for Ag+ complex of 4.In this presentation, the detailed synthesis and electronic properties of the metal complexes of calix[3]pyrrole-related macrocycles will be discussed.

Towards Antibacterial Agents: Synthesis and Biological Activity of Multivalent Amide Derivatives of Thiacalix[4]arene with Hydroxyl and Amine Groups.

Antimicrobial resistance to modern antibiotics stimulates the search for new ways to synthesize and modify antimicrobial drugs. The development of synthetic approaches that can easily change different fragments of the molecule is a promising solution to this problem. In this work, a synthetic approach was developed to obtain multivalent thiacalix[4]arene derivatives containing different number of amine and hydroxyl groups. A series of macrocyclic compounds in cone, partial cone, and 1,3-alternate stereoisomeric forms containing -NHCH2CH2R (R = NH2, N(CH3)2, and OH) and -N(CH2CH2OH)2 terminal fragments, and their model non-macrocyclic analogues were obtained. The antibacterial activity against Gram-positive (Staphylococcus aureus, Bacillus cereus, and Enterococcus faecalis) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains and cytotoxicity of the obtained compounds were studied. Structure-activity relationships were established: (1) the macrocyclic compounds had high antibacterial activity, while the monomeric compounds had low activity; (2) the compounds in cone and partial cone conformations had better antibacterial activity compared to the compounds in 1,3-alternate stereoisomeric form; (3) the macrocyclic compounds containing -NHCH2CH2N(CH3)2 terminal fragments had the highest antibacterial activity; (4) introduction of additional terminal hydroxyl groups led to a significant decrease in antibacterial activity; (5) the compounds in partial cone conformation had significant bactericidal activity against all studied cell strains; the best selectivity was observed for the compounds in cone conformation. The mechanism of antibacterial activity of lead compounds with terminal fragments -NHCH2CH2N(CH3)2 was proved using model negatively charged POPG vesicles, i.e., the addition of these compounds led to an increase in the size and zeta potential of the vesicles. The obtained results open up the possibility of using the synthesized macrocyclic compounds as promising antibacterial agents.

Calix[4]arene–pyrazole conjugates as potential cancer therapeutics

Tumor selectivity is yet a challenge in chemotherapy-based cancer treatment. A series of calixarenes derivatized at the lower rim with 3-phenyl-1H-pyrazole units with variable upper-rim substituent and conformations of macrocyclic core, alkyl chain length between heterocycle and core, as well as phenolic monomer (5-(4-tert-butylphenyloxy)methoxy-3-phenyl-1H-pyrazole) have been synthesized and characterized in a range of therapeutically relevant cellular models (M-HeLa, MCF7, A-549, PC3, Chang liver, and Wi38) from different target organs/systems. Specific cytotoxicity for M-HeLa cells has been observed in tert-butylcalix[4]arene pyrazoles in 1,3-alternate (compound 7b) and partial cone (compound 7c) conformations with low mutagenicity and haemotoxicity and in vivo toxicity in mice. Compounds 7b,c have induced mitochondrial pathway of apoptosis of M-HeLa cells through caspase-9 activation preceded by the cell cycle arrest at G0/G1 phase. A concomitant overexpression of DNA damage markers in pyrazole-treated M-HeLa cells suggests that calixarene pyrazoles target DNA, which was supported by the presence of interactions between calixarenes and ctDNA at the air–water interface.

A Series of New Manganese(II) Polynuclear Complexes Based on Nitrothiacalix[4]arenes: The Study of Interplay between Macrocycle Platform Flexibility and Structural Diversity of Coordination Compounds

Four new manganese(II) complexes, based on dinitro and tetranitrothiacalix[4]arenes, were synthesized and characterized from structural points of view in the crystalline phase. It was revealed that thiacalix[4]arenes decorated with two and four electron withdrawing groups, when combined with MnCl2, afforded the formation of similar tetranuclear complexes 1 and 2a with two non-equivalent metal ions and a rhombic geometry of the metallic cluster core. The distortion of the coordination sphere of metal cations within the obtained complexes was found to be dependent on the number of nitro groups located at the upper rim of the macrocyclic backbone, adopted in cone conformation. The tetranuclear complex 2b of a different type, displaying the formation of a dinuclear cluster core, crystallized in a non-centrosymmetric space group was obtained, when tetranitrothiacalix[4]arene, adopted in a partial cone conformation, was involved in coordination with manganese(II) cations. The switching of coordination behavior for the macrocyclic ligand in 2b was achieved due to the presence of upper-rim-disposed electron-withdrawing nitro groups, increasing the flexibility of the macrocyclic backbone by breaking the H-bonding between the OH phenolate moieties within the ligand structure. Finally, the use of 2,2′-bipyridine as an auxiliary ligand in coordination with tetranitrothiacalix[4]arene and manganese(II) cations led to the third type complex formation 3, where the macrocycle platform adopted in a 1.2-alternate conformation.

Chiral Calix[3]pyrrole Derivatives: Synthesis, Racemization Kinetics, and Ring Expansion to Calix[9]- and Calix[12]pyrrole Analogues.

Chiral pyrrolic macrocycles continue to attract interest. However, their molecular design remains challenging. Here, we report a calixpyrrole-based chiral macrocyclic system, calix[1]furan[1]pyrrole[1]thiophene (1), synthesized from an oligoketone. Macrocycle 1 adopts a partial cone conformation in the solid state, and undergoes racemization via ring inversion. Molecular dynamics simulations revealed that inversion of the thiophene is the rate determining step. Pyrrole N-methylation suppressed racemization and permitted chiral resolution. Enantioselective N-methylation also occurred in the presence of a chiral ammonium salt, although the stereoselectivity is modest. A unique feature of 1 is that it acts as a useful synthetic precursor to yield several calix[n]furan[n]pyrrole[n]thiophene products (n=2-4), including a calix[12]pyrrole analogue that to our knowledge constitutes the largest calix[n]pyrrole-like species to be structurally characterized.

Chiral Calix[3]pyrrole Derivatives: Synthesis, Racemization Kinetics, and Ring Expansion to Calix[9]‐ and Calix[12]pyrrole Analogues

AbstractChiral pyrrolic macrocycles continue to attract interest. However, their molecular design remains challenging. Here, we report a calixpyrrole‐based chiral macrocyclic system, calix[1]furan[1]pyrrole[1]thiophene (1), synthesized from an oligoketone. Macrocycle 1 adopts a partial cone conformation in the solid state, and undergoes racemization via ring inversion. Molecular dynamics simulations revealed that inversion of the thiophene is the rate determining step. Pyrrole N‐methylation suppressed racemization and permitted chiral resolution. Enantioselective N‐methylation also occurred in the presence of a chiral ammonium salt, although the stereoselectivity is modest. A unique feature of 1 is that it acts as a useful synthetic precursor to yield several calix[n]furan[n]pyrrole[n]thiophene products (n=2–4), including a calix[12]pyrrole analogue that to our knowledge constitutes the largest calix[n]pyrrole‐like species to be structurally characterized.

Synthesis, structural studies and computational evaluation of cyclophanes incorporating imidazole-2-selones.

We report new cyclophanes containing imidazole-2-selone groups linked by xylylene rings. A set of imidazole-2-selone cyclophanes is synthesized by reaction corresponding to imidazolium cyclophanes with selenium in the presence of K2CO3. The structural behavior of the new imidazole-2-selone cyclophanes was determined by 1H and 13C NMR spectra and X-ray diffraction studies. Cyclophanes incorporating o-xylylene or mesitylene-m-cyclophane linked by selone groups were mutually syn in both the solid state and solution, and the cyclophanes showed a conformation similar to the cone conformation of calix[4]arenes. Cyclophanes incorporating p-xylylene or m-xylylene linked by selone groups showed two conformations in the solution: one mutually syn and the other mutually anti. There was no interconversion for both conformations observed on the NMR timescale. In the solid state, three conformations were detected for the p-xylylene-linked cyclophane: one is mutually syn and the other two are mutually anti and partial cone conformations. In the m-xylylene-linked case, only anti-conformation was characterized in the solid state. A density functional analysis was conducted to interpret the stability of the studied compounds and shed light on their origin. The energy preference analysis is in consistent agreement with the observed geometries and their co-existence.

Macrocyclic Ionic Liquids with Amino Acid Residues: Synthesis and Influence of Thiacalix[4]arene Conformation on Thermal Stability.

Novel thiacalix[4]arene based ammonium ionic liquids (ILs) containing amino acid residues (glycine and L-phenylalanine) in cone, partial cone, and 1,3-alternate conformations were synthesized by alkylation of macrocyclic tertiary amines with N-bromoacetyl-amino acids ethyl ester followed by replacing bromide anions with bis(trifluoromethylsulfonyl)imide ions. The melting temperature of the obtained ILs was found in the range of 50-75 °C. The effect of macrocyclic core conformation on the synthesized ILs' melting points was shown, i.e., the ILs in partial cone conformation have the lowest melting points. Thermal stability of the obtained macrocyclic ILs was determined via thermogravimetry and differential scanning calorimetry. The onset of decomposition of the synthesized compounds was established at 305-327 °C. The compounds with L-phenylalanine residues are less thermally stable by 3-19 °C than the same glycine-containing derivatives.

A highly selective fluorescence probe for Co2+ or Cu2+ detection based on a new tetraquinoline-substituted calix[4]arene derivative

A new calixarene derivative (AlQuin-Calix) bearing two quinoline groups at its lower rim was synthesized at cone conformation. Then, upon functionalization of AlQuin-Calix with two more quinoline groups resulted with a novel calixarene-based fluorescent chemosensor (TetQuin-Calix) at partial cone conformation. The structures of all calixarene derivatives were duly characterized by spectroscopic methods such as FTIR, 1H NMR, 13C NMR, ESI-MS and elemental analysis. Moreover, ion sensing properties of AlQuin-Calix and TetQuin-Calix against different cations such as Co2+, Cu2+, Ni2+, Zn2+ and Ba2+ were evaluated. It was found that the calixarene-based chemosensor (TetQuin-Calix) exhibits remarkable affinity and high selectivity for Cu2+ and Co2+ in 50% water-CH3CN, while AlQuin-Calix provides an efficient chemosensor property towards only Co2+ ion among others. The fluorescence of TetQuin-Calix, with excitation/emission peaks at 268/397 nm, is quenched by Cu2+ or Co2+ ions. The limits of detection of TetQuin-Calix for Cu2+ and Co2+ ions were estimated to be 0.75 and 0.72 μM, respectively. Besides, stoichiometry, and binding constant in terms of the quenching mechanism were also determined using fluorescence data.

Calix[4]arene Bridge Mononitration with tert-Butyl Nitrite: Synthesis of Bridging Chiral p-tert-Butylcalix[4]arene with a Mononitro Bridge Substituent.

To explore the reaction universality of bridge nitration, the mononitration of different p-tert-butylcalix[4]arene derivatives was executed with tert-butyl nitrite as a nitration reagent. The effects of calix[4]arene conformations, substituents on the lower rim, and reaction conditions on bridge mononitration are systematically studied. The bridge nitration of p-tert-butylcalix[4]arene derivatives in 1,3-alternate, 1,2-alternate, and partial cone conformations can be smoothly executed while that of p-tert-butylcalix[4]arene derivatives strictly regulated in a cone conformation cannot. The nitration product complexity shows a positive correlation with the bridge-hydrogen types, and the optimal bridge-mononitrated substrate is calix[4]arene with only one bridge-hydrogen type. The electron-withdrawing substituent on the lower rim is apparently beneficial for the bridge mononitration. As a result, a variety of bridging chiral p-tert-butylcalix[4]arenes with a mononitro bridge substituent have been successfully synthesized. The highest bridge-mononitrated yield can reach 27% from 1,3-alternate p-tert-butylcalix[4]arene biscrown-5 under optimal reaction conditions.

Anion Binding by Fluorescent Ureido-Hexahomotrioxacalix[3]arene Receptors: An NMR, Absorption and Emission Spectroscopic Study.

Fluorescent receptors (4a–4c) based on (thio)ureido-functionalized hexahomotrioxacalix[3]arenes were synthesised and obtained in the partial cone conformation in solution. Naphthyl or pyrenyl fluorogenic units were introduced at the lower rim of the calixarene skeleton via a butyl spacer. The binding of biologically and environmentally relevant anions was studied with NMR, UV–vis absorption, and fluorescence titrations. Fluorescence of the pyrenyl receptor 4c displays both monomer and excimer fluorescence. The thermodynamics of complexation was determined in acetonitrile and was entropy-driven. Computational studies were also performed to bring further insight into the binding process. The data showed that association constants increase with the anion basicity, and AcO−, BzO− and F− were the best bound anions for all receptors. Pyrenylurea 4c is a slightly better receptor than naphthylurea 4a, and both are more efficient than naphthyl thiourea 4b. In addition, ureas 4a and 4c were also tested as ditopic receptors in the recognition of alkylammonium salts.

Structure-Activity Relationship of the Thiacalix[4]arenes Family with Sulfobetaine Fragments: Self-Assembly and Cytotoxic Effect against Cancer Cell Lines.

Regulating the structure of macrocyclic host molecules and supramolecular assemblies is crucial because the structure–activity relationship often plays a role in governing the properties of these systems. Herein, we propose and develop an approach to the synthesis of the family of sulfobetaine functionalized thiacalix[4]arenes with regulation of the self-assembly and cytotoxic effect against cancer cell lines. The dynamic light scattering method showed that the synthesized macrocycles in cone, partial cone and 1,3-alternate conformations form submicron-sized particles with Ag+ in water, but the particle size and polydispersity of the systems studied depend on the macrocycle conformation. Based on the results obtained by 1H and 1H-1H NOESY NMR spectroscopy and transmission electron microscopy for the macrocycles and their aggregates with Ag+, a coordination scheme for the Ag+ and different conformations of p-tert-butylthiacalix[4]arene functionalized with sulfobetaine fragments was proposed. The type of coordination determines the different shapes of the associates. Cytotoxic properties are shown to be controlled by the shape of associates, with the highest activity demonstrated by thiacalix[4]arenes in partial cone conformation. This complex partial cone/Ag+ is two times higher than the reference drug imatinib mesylate. High selectivity against cervical carcinoma cell line indicates the prospect of their using as components of new anticancer system.

1,2-Phenylene-Incorporated Smallest Expanded Calix[4]pyrrole via One-Step Synthesis of Tetrapyrrane: A Fluorescent Host for Fluoride Ion.

Synthesis of tetrapyrrane 8 from acetone and pyrrole via one-step condensation was achieved for the first time along with a much-improved yield of the tripyrrane 9. Diborylation of the tetrapyrrane and subsequent "1 + 1" cyclocoupling with 1,2-diiodobenzene following the Suzuki protocol generated novel o-phenylene incorporated macrocycle belonging to the smallest meso-expanded calix[4]pyrrole family. The latter macrocycle displays exclusive turn-on fluorescence sensing of fluoride ion upon complexation via a unique partial cone conformation supported by DFT analysis in acetonitrile solvent.

Synthesis of New Quinoline-Conjugated Calixarene as a Fluorescent Sensor for Selective Determination of Cu2+ Ion.

A novel quinoline-functionalized calix [4] arene derivative (Quin-Calix) has been successfully synthesized at partial cone conformation and duly characterized by using FTIR, 1H-NMR, 13C-NMR, ESI-MS and elemental analysis techniques. Moreover, the cation-binding property of the calix [4] arene derivative (Quin-Calix) has been investigated towards Cu2+, Ba2+, Cd2+, Co2+, Ni2+, Zn2+ and Fe3+ ions, and the recognition event monitored by UV-Vis absorption and fluorescence studies. The results indicated that Quin-Calix displays a remarkable affinity and selectivity only for Cu2+ ion. The binding constant and stoichiometry of the complex formed between Quin-Calix and Cu2+ ion have been also calculated from the fluorescence data. In addition, Stern-Vohmer equation has been used to elucidate the mechanism of quenching.

Alkane Shape- and Size-Recognized Selective Vapor Sorption in "Channel-Like" Crystals Based on Thiacalixarene Assemblies.

Alkanes composed of C-C and C-H show a low electric polarization, and therefore, there is only very weak interaction between alkanes and adsorbents. Thus, it is difficult to separate a specific alkane from a mixture of alkanes by adsorption. Here, two activated "channel-like" crystals generated from brominated thiacalix[4]arene propyl ethers, which adopt 1,3-alternate and partial cone conformations, recognize specific alkane vapors depending on alkane-shape and -size, sorting in three-type alkane guests such as linear, branched, and cyclic alkanes. Two activated crystals, which are prepared by removal of solvent upon heating under reduced pressure, incorporate branched and/or cyclic alkane vapors by a unique "gate-opening" mechanism via a crystal transformation in the process. Linear alkane vapors do not trigger gate opening and are not taken up by the activated crystals. The shape and size molecular-recognition properties of the activated crystals promises considerable usefulness for the separation of linear, branched, and cyclic alkanes.

Recognition of Anions, Monoamine Neurotransmitter and Trace Amine Hydrochlorides by Ureido‐Hexahomotrioxacalix[3]arene Ditopic Receptors

Hexahomotrioxacalix[3]arene‐based receptors (phenylurea 4a, phenylthiourea 4b and tert‐butylurea 4c) were synthesised and obtained in the partial cone conformation in solution. Phenylurea 4a was also obtained in the cone conformation and its X‐ray crystal structure is reported. Their binding properties towards several anions of different geometries were studied by 1H NMR titrations. The data showed that phenylurea cone 4a is the best anion receptor, displaying a very high affinity for the carboxylates AcO– and BzO– anions (log Kass = 4.12 and 4.00, respectively). Phenylurea partial cone 4a and phenylthiourea 4b, although weaker, are still reasonably good receptors, showing the same trend as cone 4a. tert‐Butylurea 4c exhibited very low affinity for all the anions, confirming that the association constants strongly depend on the nature of the substituent (aryl/alkyl) at the urea moiety. In addition, cone and partial cone 4a derivatives were also tested in the recognition of n‐alkylammonium salts and cone 4a also as a ditopic receptor for biogenic amine hydrochlorides by 1H NMR titrations. Cone 4a showed an outstanding affinity for the guest alkylammonium and amines, even at 298 K and in a more competitive solvent such as CDCl3/[D6]DMSO mixture. DFT calculations corroborated the NMR observations.

Mapping Out the Diversity of Lanthanide(III) Coordination Complexes Involving p-Sulfonatocalix[4,6]arenes

Structurally authenticated complexes of the cone-shaped p-sulfonatocalix[4]arene and conformationally flexible p-sulfonatocalix[6]arene devoid of co-ligands/ancillary molecules are limited. Early and late members of the lanthanide series as their trivalent ions, La3+, Er3+, and Yb3+, form complexes from aqueous media under these conditions. For La3+ and Er3+, distinct hydrophobic and hydrophilic bilayers are formed with p-sulfonatocalix[4]arene, whereas for Yb3+, two complexes form that deviate from the well-known bilayer arrangement of calixarenes. Replacing the calixarene with p-sulfonatocalix[6]arene results in a hydrogen-bonded network with alternating hydrophobic–hydrophilic layers associated with primary coordination of Yb3+, with the larger macrocyclic calixarene in a partial cone conformation.

Anion Recognition by Partial Cone Dihomooxacalix[4]arene‐Based Receptors Bearing Urea Groups: Remarkable Affinity for Benzoate Ion

Tetraureido‐dihomooxacalix[4]arenes (tert‐butyl 4a and phenyl 4b) were synthesised and obtained in a partial cone conformation in solution and in the solid state, as confirmed by NMR and X‐ray diffraction studies. Their complexation ability towards halides, pseudo‐halides and oxoanions was assessed by 1H NMR and UV/Vis titrations. Structural and energetic insights of phenylurea 4b complexes were also obtained using molecular dynamics (MD) simulations. The binding data showed that the association constants are strongly dependent on the nature of the substituent (alkyl/aryl) at the urea unit. tert‐Butyl urea 4a is a much weaker receptor than phenylurea 4b, and showed association constants that decrease with decreasing of anion basicity. Phenylurea 4b is a highly efficient anion receptor, exhibiting a remarkable binding ability towards BzO– ion (log Kass = 4.81). In comparison to the phenylurea analogue bearing a butyl spacer and a cone conformation, receptor 4b containing a shorter spacer (three carbon atoms) and a partial cone conformation is more pre‐organized, displaying a strong enhancement of its binding efficiency. MD simulations have shown that the anions are preferentially bound to the urea moieties of the macrocycle lower rim, in agreement with the ROESY spectrum carried out with phenylurea 4b and BzO– anion.

Redox-Responsive Covalent Organic Nanosheets from Viologens and Calix[4]arene for Iodine and Toxic Dye Capture.

Owing to their chemical and thermal stabilities, high uptake capacities, and easy recyclability, covalent organic polymers (COPs) have shown promise as pollutant sponges. Herein, we describe the use of diazo coupling to synthesize two cationic COPs, COP1++ and COP2++ , that incorporate a viologen-based molecular switch and an organic macrocycle, calix[4]arene. The COPs form nanosheets that have height profiles of 6.00 nm and 8.00 nm, respectively, based on AFM measurements. The sheets remain morphologically intact upon one- or two-electron reductions of their viologen subunits. MD simulations of the COPs containing dicationic viologens indicate that the calix[4]arenes adopt a partial cone conformation and that, in height, the individual 2D polymer layers are 5.48 Å in COP1++ and 5.65 Å in COP2++ , which, together with the AFM measurements, suggests that the nanosheets are composed of 11 and 14 layers, respectively. Whether their viologens are in dicationic, radical cationic, or neutral form, the COPs exhibit high affinity for iodine, reaching up to 200 % mass increase when exposed to iodine vapor at 70 °C, which makes the materials among the best-performing nanosheets for iodine capture reported in the literature. In addition, the COPs effectively remove Congo red from solution in the pH range of 2-10, reaching nearly 100 % removal within 15 minutes at acidic pH.

Influence of polyether chain on the non-covalent interactions and stability of the conformers of calix[4]crown ethers

Conformational preferences of the calix[4]crown-(4,5,6,7)-ethers were studied utilizing HF/6-31G(d), B3LYP/6-31G(d), B3LYP/6-311G(d), MPWB95/6-31G(d), MPWIPW91/6-31G(d) and M062X/6-31G(d) methods. DFT-D3 (Becke–Johnson) dispersion correction method was also employed. The results acquired from the analysis of the computational data indicated that the stability of conformers of calix[4]crown-(4,5,6,7)-ethers follows the order; cone conformer > partial cone conformer > 1,3-alternate conformer. It was initially assessed, in general, that both hydrogen bond and OH⋯π interactions play a crucial role in determining the stability of the different conformers. It was further observed that the strength of both H-bond and OH⋯π interactions, are dependent on the length of the polyether bridge. Hence, in order to comprehend them better, the effect of these interactions was studied systematically on the conformational stability of different isomers. It is found that both intramolecular hydrogen bonds and O–H⋯π interactions are mainly responsible for relative stabilities of these conformers, which in turn is also dependent on the length of the polyether bridges. The computational study reported here demonstrate that the size of the polyether bridge along with non-covalent interactions such as hydrogen bond and OH⋯π interactions play an important role in determining the stability of the conformers of calix[4]crown ethers.