Cucurbituril

  Cucurbiturils are macrocyclic molecules consisting of glycoluril repeat units. These compounds are particularly interesting to chemists because they are molecular containers that are capable of binding other molecules within their cavities. The name is derived from the resemblance of this molecule with a pumpkin of the family of Cucurbitaceae. The cavity of cucurbit[6]uril has nanoscale dimensions with an approximate height of 9.1 Å, outer diameter 5.8 Å and inner diameter 3.9 Å.^[1]

Cucurbiturils were first synthesized in 1905 by Behrend^[2] but their structure was not elucidated until 1981.^[3] To date cucurbiturils composed of 5, 6, 7, 8, and 10 repeat units have all been isolated,³ which have internal cavity volumes of 82, 164, 279, 479, and 870 ų respectively. A cucurbituril composed of 9 repeat units has yet to be isolated. Other common molecular capsules that share a similar molecular shape with cucurbiturils include cyclodextrins and calixarenes.

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Synthesis

Cucurbiturils are aminals and synthesized from urea 1 and a diketone (e.g., glyoxal 2) via a nucleophilic addition to give the intermediate glycoluril 3. This intermediate is condensed with formaldehyde to give hexamer cucurbit[6]uril above 110 °C. Ordinarily, multifunctional monomers such as 3 would undergo a step-growth polymerization that would give a distribution of products, but due to favorable strain and an abundance of hydrogen bonding, the hexamer is the only reaction product isolated after precipitation.^[4]

Decreasing the temperature of the reaction to between 75 and 90 °C can be used to access other sizes of cucurbiturils including CB[5], CB[7], CB[8], CB[9], and CB[10]. CB[6] is still the major product; the other ring sizes are formed in smaller yields. The isolation of sizes other than CB[6] requires fractional crystallization and dissolution. CB[5], CB[6], CB[7], and CB[8] are all currently commercially available. The larger sizes are a particularly active area of research since they can bind larger and more interesting guest molecules, thus expanding their potential applications.  

Cucurbit[10]uril is particularly difficult to isolate. It was first discovered by Day and coworkers in 2002 as a inclusion complex containing CB[5] by fractional crystallization of the cucurbituril reaction mixture. ^[5] The CB[10]•CB[5] was unambiguously identified by single crystal X-ray structural analysis that revealed the complex resembled a molecular gyroscope. In this case the free rotation of the CB[5] within the CB[10] cavity mimics the independent rotation of a flywheel within the frame of a gyroscope.

Isolation of pure CB[10] could not be accomplished by direct separation methods since the compound has such a high affinity for CB[5]. The strong binding affinity for the CB[5] can be understood since it has a complementary size and shape to the cavity of the CB[10]. Pure CB[10] was isolated by Isaacs and coworkers in 2005 by introducing a more strongly binding melamine diamine guest that is capable of displacing the CB[5]. ^[6] The melamine diamine guest was then separated from the CB[10] by reaction with acetic anhydride that converted the positively charged amine groups to neutrally charged amides. Cucurbiturils strongly bind cationic guests, but by removing the positive charge from the melamine diamine guest reduces the association constant to the point it can be removed by washing with methanol, DMSO, and water. The CB[10] with its unusually large cavity (870 ų) free and capable of binding extraordinarily large guests including a cationic calix[4]arene.

Applications

Supramolecular host molecules

 Cucurbiturils are efficient host molecules in molecular recognition and have a particularly high affinity for positively charged or cationic compounds. High association constants with positively charged molecules are attributed to the carbonyl groups that line each end of the cavity and can interact with cations is a similar fashion to crown ethers. The affinity of cucurbiturils can be very high. For example the affinity equilibrium constant of cururbit[7]uril with the positively charged 1-aminoadamantane hydrochloride is experimentally determined at 4.23*10¹².^[7]

Host guest interactions also significantly influence solubility behavior of cucurbiturils. Cucurbit[6]uril dissolves poorly in just about any solvent but solubility is greatly improved in a solution of potassium hydroxide or in an acidic solution. The cavitand forms a positively charged inclusion compound with a potassium ion or a hydronium ion respectively which have much greater solubility that the uncomplexed neutral molecule.^[8]

CB[10] is large enough to hold other molecular hosts such as a calixarene molecule. With a calixarene guest different chemical conformations (cone, 1,2-alternate, 1,3-alternate) are in rapid equilibrium. Allosteric control is provided when an adamantane molecule forces a cone conformation with a calixarene - adamantane inclusion complex within a CB[10] molecule.

Rotaxane macrocycles

Given their high affinities to form inclusion complexes cucurbiturils have been employed as the macrocycles component of a rotaxane. After formation of the supramolecular assembly or threaded complex with a guest molecule such as hexamethylene diamine the two ends of the guest can be reacted with bulky groups that will then act as a stoppers preventing the two separate molecules from dissociating.^[9]

In another rotaxane system with a CB[7] wheel, the axle is a 4,4'-bipyridinium or viologen subunit with two carboxylic acid terminated aliphatic N-substituents at both ends.^[10] In water at concentration higher than 0.5 M complexation is quantitative without need of stoppers. At pH = 2 the carboxylic end-groups are protonated and the wheel shuttles back and forth between them as evidenced by the presence of just two aromatic viologen protons in the proton NMR spectrum. At pH = 9 the wheel is locked around the viologen center.

Drug delivery vehicles

Cucurbituril's host-guest properties have been explored for drug delivery vehicles. The potential of this application has been explored with cucurbit[7]uril that forms an inclusion compound with the important cancer fighting drug oxaliplatin. CB[7] was employed despite the fact that it is more difficult to isolate since it has much greater solubility in water and its larger cavity size can accommodate the drug molecule. The resulting complex was found to have increased stability and greater selectivity that may lead to less side effects.^[11]

Supramolecular catalysts

Cucurbiturils have also been explored as supramolecular catalysts. Larger cucurbiturils, such as cucurbit[8]uril can bind multiple guest molecules. CB[8] forms a complex 2:1 (guest:host) with (E)-diaminostilbene dihydrochloride which is accommodated by CB[8]’s larger internal diameter of 8.8 angstrom and height 9.1 angstrom.^[12] The close proximity and optimal orientation of the guest molecules within the cavity enhances the rate of the photochemical cyclization to give cyclobutane dimer with a 19:1 stereoselectivity for the syn configuration when bound to CB[8]. In the absence of CB[8] the cyclization reaction does not occur, but only the isomerization of the trans isomer to the cis isomer is observed.^[13]

Related compounds

Inverted cucurbiturils or iCB[x] are CB analogues with one glycoluril repeating unit inverted.^[14] In this unit the methine protons actually point into the cavity and this makes the cavity less spacious. Inverted cucurbiturils form as a side-product in CB-forming reactions, with yields between 2 and 0.4%. Isolation of this type of CB compound is possible because it is more difficult to form inclusion compounds that ordinarily form with regular CB's. Inverted cucurbiturils are believed to be the kinetically controlled reaction products because the addition of deuterated hydrochloric acid or DCl to iCB[6] results in a mixture of CB[5], CB[6] and CB[7]in a 24:13:1 ratio.

A cucurbituril cut in half along the equator is called a hemicucurbituril.

Nomenclature

Cucurbiturils are commonly written as cucurbit[#]uril, where the number of repeat units is indicated within the brackets. A common abbreviation is CB[#] where again the number of repeat units is included within the brackets.

Systematic name

Cucurbit[6]uril goes by the systematic name of Dodecahydro-1H, 4H, 14H, 17H-2, 16:3, 15-dimethano-5H, 6H, 7H, 8H, 9H, 10H, 11H, 12H, 13H, 18H, 19H,20H, 21H, 22H, 23H, 24H, 25H, 26H-2, 3, 4a, 5a, 6a, 7a, 8a, 9a, 10a, 11a, 12a, 13a, 15, 16, 17a, 18a, 19a, 20a,21a, 22a, 23a, 24a, 25a, 26a-tetracosaazabispentaleno[1’’’, 6’’’:5’’, 6’’, 7’’]cycloocty[1’’, 2’’, 3’’:3’,4’]pentaleno (1’, 6’:5, 6, 7) -cycloocta (1, 2, 3-gh:1’, 2’, 3’-g’h’) cycloocta (1, 2, 3-cd:5, 6, 7-c’d’) dipentalene-1, 4,6, 8, 10, 12, 14, 17, 19, 21, 23, 25-dodecone ^[15]. Cucurbituril is considerably easier to remember.

References