A calixarene is a macrocycle or cyclic In organic chemistry, a cyclic compound is a compound in which a series of carbon atoms are connected to form a loop or ring. Benzene is a well known example. The term "polycyclic" is used when more than one ring is formed in a single molecule for instance in naphthalene, and the term macrocycle is used for a ring containing more than a oligomer In chemistry, an oligomer consists of a limited number of monomer units , in contrast to a polymer which, at least in principle, consists of an unlimited number of monomers. Many oils are oligomeric, such as liquid paraffin. Plasticizers are oligomeric esters widely used to soften thermoplastics such as PVC. They may be made from monomers by based on a hydroxyalkylation product of a phenol Phenol, also known as carbolic acid, is a toxic, white crystalline solid with a sweet tarry odor, commonly referred to as a "hospital smell". Its chemical formula is C6H5O and an aldehyde An aldehyde is an organic compound containing a terminal carbonyl group. This functional group, which consists of a carbon atom bonded to a hydrogen atom and double-bonded to an oxygen atom , is called the aldehyde group. The aldehyde group is also called the formyl or methanoyl group [1]. The word calixarene is derived from calix or chalice A chalice is a goblet or footed cup intended to hold a drink. In general religious terms, it is intended for quaffing during a ceremony because this type of molecule resembles a vase and from the word arene An aromatic hydrocarbon or arene is a hydrocarbon, of which the molecular structure incorporates one or more planar sets of six carbon atoms that are connected by delocalised electrons numbering the same as if they consisted of alternating single and double covalent bonds. The term 'aromatic' was assigned before the physical mechanism determining that refers to the aromatic building block. Calixarenes have hydrophobic Hydrophobic molecules tend to be non-polar and thus prefer other neutral molecules and nonpolar solvents. Hydrophobic molecules in water often cluster together forming micelles. Water on hydrophobic surfaces will exhibit a high contact angle cavities that can hold smaller molecules or ions and belong to the class of cavitands known in Host-guest chemistry In supramolecular chemistry, host-guest chemistry describes complexes that are composed of two or more molecules or ions held together in unique structural relationships by hydrogen bonding or by ion pairing or by Van der Waals force other than those of full covalent bonds. Calixarene nomenclature IUPAC nomenclature is a system of naming chemical compounds and of describing the science of chemistry in general. It is developed and kept up to date under the auspices of the International Union of Pure and Applied Chemistry . The rules for naming organic and inorganic compounds are contained in two publications, known as the Blue Book and the is straightforward and involves counting the number of repeating units In polymer chemistry, a structural unit is a building block of a polymer chain, and related to the repeat unit. It is the result of a monomer which has been polymerized into a long chain. When different monomer are polymerized, a copolymer is formed. It is a routine way of developing new properties for new materials in the ring and include it in the name. A calix[4]arene has 4 units in the ring and a calix[6]arene has 6. A substituent In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon. The terms substituent, side chain, group, branch, or pendant group are used almost interchangeably to describe branches from a parent structure, though certain distinctions are made in the in the meso position Rb is added to the name with a prefix C- as in C-methylcalix[6]arene.
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Synthesis
The aromatic components are derived from phenol Phenol, also known as carbolic acid, is a toxic, white crystalline solid with a sweet tarry odor, commonly referred to as a "hospital smell". Its chemical formula is C6H5O , resorcinol Resorcinol is a chemical compound from the dihydroxy phenols. It is the 1,3-isomer of benzenediol, and is also known with a variety of other names, including: m-dihydroxybenzene, 1,3-benzenediol, 1,3-dihydroxybenzene, 3-hydroxyphenol, m-hydroquinone, m-benzenediol, and 3-hydroxycyclohexadien-1-one or pyrogallol, For phenol, the aldehyde most often used is simply formaldehyde Formaldehyde is a chemical compound with the formula CH2O. It is the simplest aldehyde. Formaldehyde also exists as the cyclic trimer trioxane and the polymer paraformaldehyde. It exists in water as the hydrate H2C(OH)2. Aqueous solutions of formaldehyde are referred to as formalin. "100%" formalin consists of a saturated solution of, while larger aldehydes (acetaldehyde Acetaldehyde is an organic chemical compound with the formula C , or larger) are generally required in condensation reactions with resorcinol and pyrogallol. The chemical reaction A chemical reaction is a process that always results in the interconversion of chemical substances. The substance or substances initially involved in a chemical reaction are called reactants. Chemical reactions are usually characterized by a chemical change, and they yield one or more products, which usually have properties different from the ranks under electrophilic aromatic substitutions Electrophilic aromatic substitution or EAS is an organic reaction in which an atom, usually hydrogen, appended to an aromatic system is replaced by an electrophile. The most important reactions of this type that take place are aromatic nitration, aromatic halogenation, aromatic sulfonation, and acylation and alkylating Friedel-Crafts reactions followed by an elimination of water and then a second aromatic substitution. The reaction is acid An acid is traditionally considered any chemical compound that, when dissolved in water, gives a solution with a hydrogen ion activity greater than in pure water, i.e. a pH less than 7.0. That approximates the modern definition of Johannes Nicolaus Brønsted and Martin Lowry, who independently defined an acid as a compound which donates a hydrogen catalysed or base In chemistry, a base is most commonly thought of as an aqueous substance that can accept hydrogen ions. A base is also often referred to as an alkali if OH− ions are involved. This refers to the Brønsted-Lowry theory of acids and bases. Alternate definitions of bases include electron pair donors , as sources of hydroxide anions (Arrhenius). In catalysed Catalysis is the process in which the rate of a chemical reaction is either increased or decreased by means of a chemical substance known as a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. The catalyst may participate in multiple chemical transformations. Catalysts. Calixarenes are difficult to produce because it is all too easy to end up with complex mixtures of linear and cyclic oligomers with different numbers of repeating units. With finely tuned starting materials and reaction conditions synthesis can also be surprisingly easy. In 2005, research produced a pyrogallol[4]arene by simply mixing a solvent-free dispersion of isovaleraldehyde with pyrogallol and a catalytic amount of p-toluenesulfonic acid TsOH is a strong organic acid, about a million times stronger than benzoic acid. It is one of the few strong acids that is solid and, hence, conveniently weighed. Also, unlike some of the strong mineral acids , TsOH is non-oxidizing in a mortar and pestle A mortar and pestle is a tool used to crush, grind, and mix substances. The pestle is a heavy stick whose end is used for pounding and grinding, and the mortar is a bowl. The substance is ground between the pestle and the mortar [2]. Calixarenes as parent compounds are sparingly soluble and are high melting crystalline solids [3].
Structure
Calixarenes are characterised by a three-dimensional basket, cup or bucket shape. In calix[4]arenes the internal volume The volume of any solid, liquid, plasma, vacuum or theoretical object is how much three-dimensional space it occupies, often quantified numerically. One-dimensional figures and two-dimensional shapes such as square geometry squares are assigned zero volume in the three-dimensional space. Volume is commonly presented in units such as mililitres or is around 10 cubic nanometers A nanometre (Greek: νάνος, nanos, "dwarf"; μέτρον, metrοn, "unit of measurement") is a unit of length in the metric system, equal to one billionth of a metre (i.e., 10-9 m or one millionth of a millimetre). 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 Hydroxyl in chemistry stands for a molecule consisting of an oxygen atom and a hydrogen atom connected by a covalent bond . The neutral form is a hydroxyl radical and the hydroxyl anion is called a hydroxide. When the oxygen atom is linked to a larger molecule the hydroxyl group is a functional group (OH) . Hydroxide (HO¯ or ¯OH anion) is a 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 In chemistry, conformational isomerism is a form of stereoisomerism in which molecules with the same structural formula exist as different conformational isomers or conformers in 3-D due to rotations about one or more σ bonds. Conformations are not superimposable in three dimensions and can be characterized by their dihedral angles, the angle because rotation around the methylene bridge is not difficult. In calix[4]arene 4 up-down conformations exist: cone ( point group In mathematics, a point group is a group of geometric symmetries leaving a point fixed C2v,C4v), partial cone Cs, 1,2 alternate C2h and 1,3 alternate D2d. The 4 hydroxyl groups interact by hydrogen bonding A hydrogen bond is the attractive force between one electronegative atom and a hydrogen covalently bonded to another electronegative atom. It results from a dipole-dipole force with a hydrogen atom bonded to nitrogen, oxygen or fluorine . The energy of a hydrogen bond (typically 5 to 30 kJ/mole) is comparable to that of weak covalent bonds (155 kJ/ and stabilize the cone conformation. This conformation is in dymamic 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 [1].
| Calix[4]arene with para-tert-butyl substituents | 3D representation of a cone conformation |
History
Adolf von Baeyer Johann Friedrich Wilhelm Adolf von Baeyer was a German chemist who synthesized indigo, and was the 1905 recipient of the Nobel Prize in Chemistry. Born in Berlin, he initially studied mathematics and physics at Berlin University before moving to Heidelberg to study chemistry with Robert Bunsen. There he worked primarily in August Kekulé's pioneered the chemistry of calixarenes although he was unable to determine its structure and did not realise its potential (he was pursuing dyes). In 1872 he mixed benzaldehyde Benzaldehyde is a chemical compound consisting of a benzene ring with an aldehyde substituent. It is the simplest representative of the aromatic aldehydes and one of the most industrially used members of this family of compounds. At room temperature it is a colorless liquid with a characteristic and pleasant almond-like odor: benzaldehyde is an with pyrogallol and a strong acid An acid is traditionally considered any chemical compound that, when dissolved in water, gives a solution with a hydrogen ion activity greater than in pure water, i.e. a pH less than 7.0. That approximates the modern definition of Johannes Nicolaus Brønsted and Martin Lowry, who independently defined an acid as a compound which donates a hydrogen and noted a red-brown resin Resin is a hydrocarbon secretion of many plants, particularly coniferous trees. It is valued for its chemical constituents and uses, such as varnishes and adhesives, as an important source of raw materials for organic synthesis, or for incense and perfume. Fossilized resins are the source of amber. Resins are also a material in nail polish with a marked viscosity Viscosity is a measure of the resistance of a fluid which is being deformed by either shear stress or extensional stress. In everyday terms , viscosity is "thickness". Thus, water is "thin", having a lower viscosity, while honey is "thick" having a higher viscosity. Viscosity describes a fluid's internal resistance to increase. He also used resorcinol Resorcinol is a chemical compound from the dihydroxy phenols. It is the 1,3-isomer of benzenediol, and is also known with a variety of other names, including: m-dihydroxybenzene, 1,3-benzenediol, 1,3-dihydroxybenzene, 3-hydroxyphenol, m-hydroquinone, m-benzenediol, and 3-hydroxycyclohexadien-1-one and formaldehyde Formaldehyde is a chemical compound with the formula CH2O. It is the simplest aldehyde. Formaldehyde also exists as the cyclic trimer trioxane and the polymer paraformaldehyde. It exists in water as the hydrate H2C(OH)2. Aqueous solutions of formaldehyde are referred to as formalin. "100%" formalin consists of a saturated solution of which he had to prepare from iodoform Iodoform is the organoiodine compound with the formula C himself because a commercial grade of formaldehyde at that time had not been realised yet. In 1894 the Lederer-Manasse hydroxyalkylation was invented as a synthetic tool for the preparation of hydroxylmethyl phenols, bringing calixarenes one step closer. In 1902 Leo Baekeland Leo Hendrik Baekeland (Sint-Martens-Latem , November 14, 1863 - February 23, 1944) was a Belgian chemist who invented Velox photographic paper (1893) and Bakelite (1907), an inexpensive, nonflammable, versatile, and popular plastic made phenol formaldehyde resins The earliest commercial synthetic resin is based on a Phenol formaldehyde resin with the commercial name Bakelite, and is formed from an elimination reaction of phenol with formaldehyde. Phenol is reactive towards formaldehyde at the ortho and para sites (sites 2, 4 and 6) allowing up to 3 units of formaldehyde to attach to the ring. This forms a a commercial success under the trade name Bakelite Bakelite is a material based on the thermosetting phenol formaldehyde resin polyoxybenzylmethylenglycolanhydride, developed in 1907–1909 by Belgian Dr. Leo Baekeland. Formed by the reaction under heat and pressure of phenol (a toxic, colourless crystalline solid) and formaldehyde (a simple organic compound), generally with a wood flour filler,. In these resins phenol and formaldehyde are exhaustively condensed with each other to form heavily cross-linked Cross-links are bonds that link one polymer chain to another. They can be covalent bonds or ionic bonds. "Polymer chains" can refer to synthetic polymers or natural polymers . When the term "cross-linking" is used in the synthetic polymer science field, it usually refers to the use of cross-links to promote a difference in the polymers A polymer is a large molecule (macromolecule) composed of repeating structural units typically connected by covalent chemical bonds. While polymer in popular usage suggests plastic, the term actually refers to a large class of natural and synthetic materials with a variety of properties. The first attempt to control the reaction was made by Alois Zinke and Erich Ziegler in 1942. They employed para substituted phenols which inhibits crosslinking and should result in a linear polymer with formaldehyde. So in 1944 p-tert-butyl phenol with formaldehyde and sodium hydroxide Pure sodium hydroxide is a white solid; available in pellets, flakes, granules and as a 50% saturated solution. It is hygroscopic and readily absorbs carbon dioxide from the air, so it should be stored in an airtight container. It is very soluble in water with liberation of heat. It also dissolves in ethanol and methanol, though it exhibits lower in linseed oil Linseed oil, also known as "flax seed oil" is a clear to yellowish oil obtained from the dried ripe seeds of the flax plant . The oil is obtained by cold pressing, sometimes followed by solvent extraction as a solvent produced for the first time a crystalline solid with a high melting point rather than a resin. In the same year another duo by the names of Niederl and Vogel did something similar with a para substituted resorcinol Resorcinol is a chemical compound from the dihydroxy phenols. It is the 1,3-isomer of benzenediol, and is also known with a variety of other names, including: m-dihydroxybenzene, 1,3-benzenediol, 1,3-dihydroxybenzene, 3-hydroxyphenol, m-hydroquinone, m-benzenediol, and 3-hydroxycyclohexadien-1-one and they were the first to postulate a cyclic tetramer. In these days structure elucidation was limited to determination of molar mass Molar mass, symbol M, is the mass of one mole of a substance . It is a physical property which is characteristic of each pure substance. The base SI unit for mass is the kilogram but, for both practical and historical reasons, molar masses are almost always quoted in grams per mole (g/mol or g mol–1), especially in chemistry by freezing-point depression Freezing-point depression describes the phenomenon that the freezing point of a liquid is depressed when another compound is added, meaning that a solution has a lower freezing point than a pure solvent. This happens whenever a solute is added to a pure solvent, such as water. The phenomenon may be observed in sea water, which due to its salt and functional group In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of. However, its relative reactivity can be analysis.
John Cornforth was in 1955 the first to realize the potential of calixarenes as a basket analogue to enzymes Enzymes are biomolecules that catalyze chemical reactions. Nearly all known enzymes are proteins. However, certain RNA molecules can be effective biocatalysts too. These RNA molecules have come to be known as ribozymes. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into and repeated the work done by Zinke. He obtained a mixture of products and elicited the services of Dorothy Crowfoot Hodgkin Dorothy Hodgkin, born Dorothy Mary Crowfoot OM, FRS was a British chemist, credited with the discovery of protein crystallography for structure elucidation by X-ray crystallography X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and scatters into many different directions. From the angles and intensities of these scattered beams, a crystallographer can produce a three-dimensional picture of the density of electrons within the crystal but with limited success. First commercial success came to calixarenes in the nineteen fifties when the company Petrolite started a range of calixarene products as demulsifiers used in the oil industry.
The word calixarene was coined by David Gutsche [2] in 1975 who was also interested in this type of compound as biomimetic, since the molecule resembled the calyx krater vases of ancient Greece. It was by then established that unmodified calixarenes exhibit extensive conformational mobility so that the basket was not much of a basket after all. Donald J. Cram fixed this shortcoming by inventing a way of immobilizing calixarenes. He was able to freeze in a conformation by so called lower rim functionalization, replacing the hydroxyl groups by larger substituents. The acetate calixarene fixates the molecule as a partial cone, whereas the carbonate ester yields the full cone.
Host guest interactions
Calixarenes are efficient sodium ionophores and are applied as such in chemical sensors. With the right chemistry these molecules exhibit great selectivity towards other cations. 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. [3] Calix[5]arene and the C70 fullerene in p-xylene form a ball-and-socket supramolecular complex. [4] calixarenes also form exo-calix ammonium salts with aliphatic amines such as piperidine. [4]
See Host-guest chemistry.
Molecular self-assembly
Molecular self-assembly of resorcinarenes and pyrogallolarenes lead to larger supramolecular assemblies [5]. Both in the crystalline state and in solution, they are known to form hexamers that are akin to certain Archimedean solids with an internal volume of around one cubic nanometer (nanocapsules). (Isobutylpyrogallol[4]arene)6 is held together by 48 intermolecular hydrogen bonds. The remaining 24 hydrogen bonds are intramolecular. The cavity is filled by a number of solvent molecules. [5]
Applications
Calixarenes are applied in enzyme mimetics, ion sensitive electrodes or sensors, selective membrames, non-linear optics [6] and in HPLC stationary phase [7]. In addition, in nanotechnology calixarenes are used as negative resist for high-resolution electron beam lithography [8].
A tetrathia[4]arene is found to mimic aquaporin proteins [6]. 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 are able to 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 [7].
In heterocalixarenes the phenolic units are replaced by heterocycles [8], 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.
Calix[4]arene was used as scaffold to assemble a construct bearing four Tn-antigen unit, at upper rim, and the immunoadjuvant P3CS, at lower rim. The construct showed a cluster effect in the production of Tn specific IgG antibodies in mice when compared to an analogous monovalent construct. This reveals perspectives for potential applications in cancer immunotherapy [9].
Esthetics
Building esthetic molecules with calixarenes include thus far a molecular Football World Cup [9].
Inherent chirality
Calix[4]arenes with XXYZ or WXYZ substitution patterns at the upper rim are inherently chiral and their enantiomers can be resolved by chiral column chromatography.
References
- [1] a) Gutsche, C. David (1989). Calixarenes. Cambridge: Royal Society of Chemistry. ISBN 0-85186-385-X. ; b) International Union of Pure and Applied Chemistry (1995). "Calixarenes". Compendium of Chemical Terminology Internet edition.
- [2] Antesberger J, Cave GW, Ferrarelli MC, Heaven MW, Raston CL, Atwood JL (2005). "Solvent-free, direct synthesis of supramolecular nano-capsules". Chemical communications (Cambridge, England) . (7): 892–4. doi:10.1039/b412251h. PMID 15700072.
- [3] McMahon G, O’Malley S, Nolan K and Diamond D (2003). "Important Calixarene Derivatives – their Synthesis and Applications". Arkivoc Part (vii). Article
- [4] Nachtigall FF, Lazzarotto M and Braz FNJ (2002). "Interaction of Calix[4]arene and Aliphatic Amines: A Combined NMR, Spectrophotometric and Conductimetric Investigation". Journal of the Brazilian Chemical Society 13 (3). doi:10.1590/S0103-50532002000300002. Article
- [5] Atwood JL, Barbour LJ, Jerga A (2002). "Organization of the interior of molecular capsules by hydrogen bonding". Proceedings of the National Academy of Sciences 99 (8): 4837–41. doi:10.1073/pnas.082659799. PMID 11943875.
- [6] Thallapally PK, Lloyd GO, Atwood JL, Barbour LJ (2005). "Diffusion of water in a nonporous hydrophobic crystal". Angewandte Chemie (International ed. in English) 44 (25): 3848–51. doi:10.1002/anie.200500749. PMID 15892031.
- [7] Purse BW, Gissot A, Rebek J Jr (2005). "A deep cavitand provides a structured environment for the menschutkin reaction". Journal of the American Chemical Society 127 (32): 11222–3. doi:10.1021/ja052877. PMID 16089433.
- [8] Subodh Kumar, Dharam Paul, Harjit Singh (2006). "Syntheses, structures and interactions of heterocalixarenes". Arkivoc 05-1699LU: 17–25. Article
- [9] Geraci C, Consoli GML, Galante E, Bousquet E, Pappalardo M and Spadaro A (2008). "Calix[4]arene Decorated with Four Tn Antigen Glycomimetic Units and P3CS Immunoadjuvant: Synthesis,Characterization, and Anticancer Immunological Evaluation". Bioconjugate Chemistry 19 (3): 751–8. doi:10.1021/bc700411w.
Categories: Supramolecular chemistry
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