Calixarene

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IUPAC definition

calixarenes: Originally macrocyclic compounds capable of assuming a basket (or 'calix') shaped conformation. They are formed from p-hydrocarbyl phenols and formaldehyde. The term now applies to a variety of derivatives by substitution of the hydrocarbon cyclo{oligo(1,3-phenylene)methylene}. [1]

Contents

A calixarene is a macrocycle or cyclic oligomer based on a methylene-linked phenols. With hydrophobic cavities that can hold smaller molecules or ions, calixarenes belong to the class of cavitands known in host–guest chemistry. [2]

Nomenclature

Calixarene nomenclature is straightforward and involves counting the number of repeating units in the ring and including it in the name. A calix[4]arene has 4 units in the ring and a calix[6]arene has 6. A substituent in the meso position Rb is added to the name with a prefix C- as in C-methylcalix[6]arene [3] The word calixarene is derived from the Greek calix or chalice because this type of molecule resembles a vase (or cup) and from the word arene that refers to the aromatic building block.

Synthesis

Calixarenes are generally produced by condensation of two components: an electron-rich aromatic compound, classically a 4-substituted phenol, and an aldehyde, classically formaldehyde. [4] [5]

Calixarenes can be challenging to synthesize, producing instead complex mixtures of linear and cyclic oligomers. With finely tuned starting materials and reaction conditions, synthesis can also be surprisingly efficient. Calixarenes are sparingly soluble as parent compounds and have high melting points. [8]

from left to right with n = 4 calix[4]arene, resorcinol[4]arene, pyrogallol[4]arene. Ra is an alkyl substituent, Rb is hydrogen with formaldehyde or phenyl with benzaldehyde, Rc is hydrogen in the parent compounds Calixarene-schema.png
from left to right with n = 4 calix[4]arene, resorcinol[4]arene, pyrogallol[4]arene. Ra is an alkyl substituent, Rb is hydrogen with formaldehyde or phenyl with benzaldehyde, Rc is hydrogen in the parent compounds

Structure

Calixarenes are characterised by a three-dimensional basket, cup or bucket shape. In calix[4]arenes the internal volume is around 10 cubic angstroms. Calixarenes are characterised by a wide upper rim and a narrow lower rim and a central annulus. With phenol as a starting material the 4 hydroxyl groups are intrannular on the lower rim. In a resorcin[4]arene 8 hydroxyl groups are placed extraannular on the upper ring. Calixarenes exist in different chemical conformations because rotation around the methylene bridge is not difficult. In calix[4]arene 4 up–down conformations exist: cone (point group C2v,C4v), partial cone Cs, 1,2 alternate C2h and 1,3 alternate D2d. The 4 hydroxyl groups interact by hydrogen bonding and stabilize the cone conformation. This conformation is in dynamic equilibrium with the other conformations. Conformations can be locked in place with proper substituents replacing the hydroxyl groups which increase the rotational barrier. Alternatively placing a bulky substituent on the upper rim also locks a conformation. The calixarene based on p-tert-butyl phenol is also a cone. [9] Calixarenes are structurally related to the pillararenes.

P-tert-butylcalix-4-arene.svg Calixarene.png
Calix[4]arene with para-tert-butyl substituents3D representation of a cone conformation

History

In 1872 Adolf von Baeyer mixed various aldehydes, including formaldehyde, with phenols in a strongly acidic solution. The resultant tars defied characterization; but represented the typical products of a phenol/formaldehyde polymerization. Leo Baekeland discovered that these tars could be cured into a brittle substance which he marketed as "Bakelite". This polymer was the first commercial synthetic plastic.

The success of Bakelite spurred scientific investigations into the chemistry of the phenol/formaldehyde reaction. One result was the discovery made in 1942 by Alois Zinke, that p-alkyl phenols and formaldehyde in a strongly basic solution yield mixtures containing cyclic tetramers. Concomitantly, Joseph Niederl and H. J. Vogel obtained similar cyclic tetramers from the acid-catalyzed reaction of resorcinol and aldehydes such as benzaldehyde. A number of years later, John Cornforth showed that the product from p-tert-butylphenol and formaldehyde is a mixture of the cyclic tetramer and another ambiguous cyclomer. His interest in these compounds was in the tuberculostatic properties of their oxyethylated derivatives.

In the early 1970s C. David Gutsche recognized the calix shape of the cyclic tetramer and thought that it might furnish the structure for building an enzyme xenologue. He initiated a study that lasted for three decades. His attention to these compounds came from acquaintance with the Petrolite company's commercial demulsifiers, made by ethoxylation of the still ambiguous products from p-alkylphenols and formaldehyde. He introduced the name "calixarene": from "calix", the Greek name for a chalice, and "arene" for the presence of aryl groups in the cyclic array. He also determined the structures for the cyclic tetramer, hexamer, and octamer, along with procedures for obtaining these materials in good to excellent yields. He then established procedures for attaching functional groups to both the upper and lower rims and mapped the conformational states of these flexible molecules. Additionally, he proved that the cyclic tetramer can be frozen into a cone conformation, by the addition of measurably large substituents to the lower "rim" of the calix shape.

Concomitant with Gutsche's work was that of the Hermann Kämmerer and Volker Böhmer. They developed methods for the stepwise synthesis of calixarenes. Chemists of University of Parma, Giovanni Andreetti, Rocco Ungaro and Andrea Pochini were the first to resolve X-ray crystallographic images of calixarenes. In the mid 1980s, other investigators joined the field of calixarene chemistry. It has become an important aspect of supramolecular chemistry and attracts the attention of hundreds of scientists around the world. The Niederl cyclic tetramers from resorcinol and aldehydes were studied in detail by Donald J. Cram, who called the derived compounds "cavitands" and "carcerands". An accurate and detailed history of the calixarenes along with extensive discussion of calixarene chemistry can be found in Gutsche's monograph.

Medical uses

Water soluble calixarenes, such as para-sulfontocalix[4]arene, have not only been examined for drug delivery., [10] but also for their potential as pharmaceutical drugs themselves, directly combating disease. [11] Calix[6]arene, for instance, has been shown to inhibit extracellular vesicle biogenesis of extracellular vesicles in pancreatic cancer. In turn, this impairs release of matrix metalloprotease enzymes in the tumor microenvironment, in turn slowing down metastasis of disease. [12] Thus in conjunction with their low toxicity they are considered promising agents for combating oncological disease disease. [13]

Host guest interactions

Calixarenes are used in commercial applications as sodium selective electrodes for the measurement of sodium levels in blood. Calixarenes also form complexes with cadmium, lead, lanthanides and actinides. Calix[5]arene and the C70 fullerene in p-xylene form a ball-and-socket supramolecular complex. [14] Calixarenes also form exo-calix ammonium salts with aliphatic amines such as piperidine. [15] Derivatives or homologues of calix[4]arene exhibit highly selective binding behavior towards anions (especially halogen anions) with changes in optical properties such as fluorescence. [16]

Calixarenes in general, and more specifically calix[4]arenes have been extensively investigated as platforms for catalysts. Some complexes compounds are active for hydrolytic reactions. [17] [18]

Calixarenes are of interest as enzyme mimetics, components of ion sensitive electrodes or sensors, selective membranes, non-linear optics [19] and in HPLC stationary phases. In addition, in nanotechnology calixarenes are used as negative resist for high-resolution electron beam lithography. [20]

A tetrathia[4]arene is found to mimic some properties of the aquaporin proteins. [21] This calixarene adopts a 1,3-alternate conformation (methoxy groups populate the lower ring) and water is not contained in the basket but grabbed by two opposing tert-butyl groups on the outer rim in a pincer. The nonporous and hydrophobic crystals are soaked in water for 8 hours in which time the calixarene:water ratio nevertheless acquires the value of one.

Calixarenes accelerate reactions taking place inside the concavity by a combination of local concentration effect and polar stabilization of the transition state. An extended resorcin[4]arene cavitand is found to accelerate the reaction rate of a Menshutkin reaction between quinuclidine and butylbromide by a factor of 1600. [22]

In heterocalixarenes the phenolic units are replaced by heterocycles, [23] for instance by furans in calix[n]furanes and by pyridines in calix[n]pyridines. Calixarenes have been used as the macrocycle portion of a rotaxane and two calixarene molecules covalently joined together by the lower rims form carcerands.

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References

  1. ↑ "calixarenes". Gold Book. IUPAC. doi:10.1351/goldbook.C00783 . Retrieved 1 April 2024.
  2. ↑ Gutsche, C. David (1989). Calixarenes. Cambridge: Royal Society of Chemistry. ISBN   978-0-85186-385-6.
  3. ↑ IUPAC , Compendium of Chemical Terminology , 2nd ed. (the "Gold Book") (1997). Online corrected version: (1995) " Calixarenes ". doi : 10.1351/goldbook.C00783
  4. ↑ J. H. Munch, C. D. Gutsche (1990). "p-tert-Butylcalix[8]arene". Organic Syntheses. 68: 243. doi:10.15227/orgsyn.068.0243.
  5. ↑ C. D. Gutsche, M. Iqbal (1990). "p-tert-Butylcalix[4]arene". Organic Syntheses. 68: 234. doi:10.15227/orgsyn.068.0234.
  6. ↑ Timmerman, Peter; Verboom, Willem; Reinhoudt, David (1996). "Resorcinarenes". Tetrahedron. 52 (8): 2663–2704. doi:10.1016/0040-4020(95)00984-1.
  7. ↑ J.H. Jordan; B.C. Gibb (2017). "1.16 Water-Soluble Cavitands". In Atwood, Jerry (ed.). Comprehensive Supramolecular Chemistry II. Oxford: Elsevier. pp. 387–404. ISBN   978-0-12-803199-5.
  8. ↑ McMahon G; O'Malley S; Nolan K; Diamond D (2003). "Important Calixarene Derivatives – Their Synthesis and Applications". Arkivoc . Part (vii): 23–31. doi: 10.3998/ark.5550190.0004.704 . hdl: 2027/spo.5550190.0004.704 . ISSN   1551-7012 . Retrieved 2011-10-10.
  9. ↑ Van Dienst, E.; Bakker, W. I. Iwema; Engbersen, J. F. J.; Verboom, W.; Reinhoudt, D. N. (1993). "Calixarenes, chemical chameleons". Pure and Applied Chemistry. 65 (3): 387–392. doi: 10.1351/pac199365030387 . S2CID   97287177.
  10. ↑ Gu, Alice; Wheate, Nial (2021). "Macrocycles as drug-enhancing excipients in pharmaceutical formulations". Journal of Inclusion Phenomena and Macrocyclic Chemistry. 100 (1–2): 55–69. doi:10.1007/s10847-021-01055-9. S2CID   233139034.
  11. ↑ Cordeiro HG, Azevedo-Martins JM, Faria AV, Rocha-Brito KJ, Milani R, Peppelenbosch M, Fuhler G, de Fátima Â, Ferreira-Halder CV (April 2024). "Calix[6]arene dismantles extracellular vesicle biogenesis and metalloproteinases that support pancreatic cancer hallmarks". Cellular Signalling. 119: 111174. doi:10.1016/j.cellsig.2024.111174. PMID   38604340.
  12. ↑ Cordeiro HG, Azevedo-Martins JM, Faria AV, Rocha-Brito KJ, Milani R, Peppelenbosch M, Fuhler G, de Fátima Â, Ferreira-Halder CV (April 2024). "Calix[6]arene dismantles extracellular vesicle biogenesis and metalloproteinases that support pancreatic cancer hallmarks". Cellular Signalling. 119: 111174. doi:10.1016/j.cellsig.2024.111174. PMID   38604340.
  13. ↑ Paul S, Jeyaprakash RS, Pai A, Venkatachalam H, Jayashree BS (July 2023). "Calixarenes and their Relevance in Anticancer Drug Development". Med Chem. 19 (10): 939–945. doi:10.2174/1573406419666230703114605. PMID   37403386.
  14. ↑ Atwood, Jerry L.; Barbour, Leonard J.; Heaven, Michael W.; Raston, Colin L. (2003-09-01). "Association and orientation of C70 on complexation with calix[5]arene". Chemical Communications (18): 2270–2271. doi:10.1039/B306411P. PMID   14518869 . Retrieved 2011-10-10.
  15. ↑ Nachtigall FF, Lazzarotto M, Braz FN (2002). "Interaction of Calix[4]arene and Aliphatic Amines: A Combined NMR, Spectrophotometric and Conductimetric Investigation". Journal of the Brazilian Chemical Society. 13 (3): 295–299. doi: 10.1590/S0103-50532002000300002 .
  16. ↑ Jin, Jaehyeok; Park, Ji Young; Lee, Yoon Sup (2016-10-27). "Optical Nature and Binding Energetics of Fluorescent Fluoride Sensor Bis(bora)calix[4]arene and Design Strategies of Its Homologues". The Journal of Physical Chemistry C. 120 (42): 24324–24334. doi:10.1021/acs.jpcc.6b06729. ISSN   1932-7447.
  17. ↑ Cacciapaglia, Roberta (2013). "Reactivity of carbonyl and phosphoryl groups at calixarenes". Supramolecular Chemistry. 25 (9–11): 537–554. doi:10.1080/10610278.2013.824578. S2CID   96940268.
  18. ↑ Rebilly, Jean-Noël (2014). "Calixarenes and resorcinarenes as scaffolds for supramolecular metallo-enzyme mimicry". Supramolecular Chemistry. 26 (7–8): 454–479. doi:10.1080/10610278.2013.877137. S2CID   95769878.
  19. ↑ Hennrich, Gunther; Murillo, M. Teresa; Prados, Pilar; Song, Kai; Asselberghs, Inge; Clays, Koen; Persoons, André; Benet-Buchholz, Jordi; de Mendoza, Javier (2005-07-07). "Tetraalkynyl calix[4]arenes with advanced NLO properties". Chemical Communications (21): 2747–2749. doi:10.1039/B502045J. PMID   15917941 . Retrieved 2011-10-10.
  20. ↑ Fujita J, Ohnishi Y, Ochiai Y, Matsui S (1998-08-05). "Ultrahigh resolution of calixarene negative resist in electron beam lithography". Applied Physics Letters . 68 (9): 1297–1299. doi:10.1063/1.115958.
  21. ↑ Thallapally PK, Lloyd GO, Atwood JL, Barbour LJ (2005-06-20). "Diffusion of water in a nonporous hydrophobic crystal". Angewandte Chemie International Edition in English. 44 (25): 3848–3851. doi:10.1002/anie.200500749. PMID   15892031.
  22. ↑ Purse, BW; Gissot, A; Rebek Jr., J (2005). "A deep cavitand provides a structured environment for the menschutkin reaction" (PDF). Journal of the American Chemical Society . 127 (32): 11222–11223. doi:10.1021/ja052877+. PMID   16089433. S2CID   38364784.
  23. ↑ Subodh Kumar; Dharam Paul; Harjit Singh (2006). "Syntheses, structures and interactions of heterocalixarenes" (PDF). Arkivoc . 05-1699LU: 17–25.
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