AU777625B2 - Cucurbiturils and method for synthesis - Google Patents

Description

PCT/AU00/00412 Received 27 February 2001 1 CUCURBITURILS AND METHOD FOR SYNTHESIS The present invention relates to a method for preparing cucurbit[n]urils and cucurbit[s,u]urils. The present invention also relates to cucurbit[n]urils, to cucurbit[s,u]urils, and to a method of separating cucurbit[n]urils and/or cucurbit[s,u]urils. The present invention also relates to novel compounds used in the preparation of cucurbit[n]urils and cucurbit[s,u]urils.

Cucurbituril is the name given to a cyclic oligomer formed by linking six (6) glycoluril units via methylene bridges. Cucurbituril was first described in the literature in 1905 in a paper by R. Behrend, E. Meyer and F. Rusche, Leibigs Ann.

Chem. 339, 1, 1905. The macrocyclic structure of cucurbituril was first described in 1981 by W.A. Freeman et. al., "Cucurbituril", J. Am. Chem. Soc., 103 (1981), 7367-7368. Cucurbituril has a chemical formula of C 36

H

36

N

24 0 1 2 and is a macrocyclic compound having a central cavity. An AMI minimised structure of cucurbituril is shown in Figure 1.

The internal cavity of cucurbituril has a diameter of about 550 pm, a depth of 650 pm with portals at either end about 400 pm across. This rigid cavity has been shown to have high selectively in binding a variety of medium-small molecules and in this regard reference is made to Cintas, J. Inclusion Phenomena and Molecular Recognition in Chemistry; 17, 205, 1994.

The preparation of cucurbituril has generally followed the procedure first described in the article by R. Behrend et. al. published in 1905.

In German patent no. DE 196 03377, published 7 August 1997, a process for synthesising cucurbituril is described. This process includes dissolving acetylene diurea (glycoluril) in an aqueous solution of a strong mineral acid in the presence of excess formaldehyde, with warming. The water is evaporated from the mixture to completely eliminate the water from the mixture. The remaining polymer mixture is then heated to a temperature up to 145°C to complete the reaction. The applicants for this patent have stated that a yield of up to 82.4% of the theoretical yield can be obtained.

AMENDED

SHEET

IPAIAU

2 In German patent no. DE 4001139. the use of cucurbituril to remove organic compounds with hydrophobic groups, dyes. decomposition products from dyes and/or heavy metals from aqueous solutions is described. The patent actually states that a cyclic oligomer which is obtained by condensation of urea, thiourea, derivates of urea and/or derivatives of the thiourea with dialdehydes and formaldehyde is used. Although the patent states that the degree of polymerisation, n. of the cyclic oligomer varies between about 3 and about 8, the examples of the patent showing cylcic oligomers having a degree of polymerisation, n, only of 6.

Example 1 shows the preparation of cucurbituril by heating glycoluril under reflux with formaldehyde.

Experiments conducted by the present inventors in following the procedure of Example 1 of DE 4001139 have shown that cucurbituril having 6 glycoluril units joined together is formed. In the words of DE 4001139, n=6 for this product. No evidence was found of any cyclic oligomer having a degree of polymerisation, n, other than 6. Indeed, a paper by Buschmann et. al., Inorgica Chimica Acta. 1992, 193, 93 states that under the synthetic conditions as described in DE 400 1139, only cucurbituril having a degree of polymerisation, n, of 6 is formed.

The present inventors have now developed a method for producing cucurbiturils having a degree of polymerisation of 4 to 12. To assist in S 20 differentiating such compounds. the present inventors have adopted the terminology "cucurbit[n]uril", where n is a number from 4 to 12, to denote the different compounds. For example, a cyclic oligomer having 4 basic glycoluril (substituted or unsubstituted) units joined together would be denoted as "cucurbit[41uril".

In a first aspect, the present invention provides a method for producing S 25 a mixture of two or more cucurbit[n]urils, where n is from 4 to 12, comprising mixing substituted and/or unsubstituted glycoluril with an acid and a compound that can form methylene bridges between glycoluril units, and heating the mixture to a temperature of from 20°C to 120 0 C to thereby form cucurbit[n]urils.

Preferably, n is from 5 to In a second aspect, the present invention provides a method for producing a cucurbit[n]uril, where n is 4, 5, 6, 7, 8, 9, 10, 11 or 12, excluding unsubstituted cucurbit[6]uril and decamethylcucurbit[5]uril, comprising mixing substituted and/or unsubstituted glycoluril with an acid and a compound that can form methylene bridges between glycoluril units, and heating the mixture to a temperature of from 200 to 120 0 C to thereby form a cucurbit[n]uril.

Preferably, the method of the present invention further comprises adding a salt to the mixture.

It has been found that adding a salt to the mixture assists in achieving the synthesis of a variety of cucurbit[n]urils of differing unit sizes.

o *o• Without wishing to be bound by theory, it is believed that an ion templating effect may be occurring. Thus, selection of the particular salt can control the amount of a derived cucurbit[n]uril in the product.

It has also been found that a number of other compounds can be added to the mixture in place of the salt. or in combination with the salt, to achieve the templating effect described above. The templating effect causes the relative amount of cucurbit[n]urils of differing unit sizes to be altered if the salt or other compound is added to the mixture. For example, the salt or other compound, when added to the reaction mixture, may alter the ratio of, say, cucurbit[5]uril to cucurbit[6]uril, when that ratio is compared with the ratio of cucurbit[5]uril to cucurbit[6]uril that is produced using reaction mixtures having no salt or other compound added thereto but otherwise reacted under identical conditions.

For ease of description, such salts and other compounds will be described hereinafter throughout this specification as "templating compounds". In a preferred embodiment the method of the first aspect of .the present invention further comprises adding one or more templating compounds to the mixture.

The templating compounds can be selected from a large number of compounds and indeed any compound that can alter the ratio of cucurbit[njurils of different unit sizes produced in the method of the present invention can be used as a S 20 templating compound. The templating compound may be an organic compound, a salt of an organic compound, or an inorganic compound. Suitable compounds that may be used as a templating compound include ammonium chloride, lithium chloride, sodium chloride, potassium chloride, rubidium chloride, caesium chloride, ammonium chloride, lithium bromide, sodium bromide, potassium bromide, 25 rubidium bromide, caesium bromide, lithium iodide, sodium iodide. potassium S. iodide, rubidium iodide, caesium iodide, potassium sulfate, lithium sulfate, tetrabutylammonium chloride, tetraethylammonium chloride, o-carborane, thioacetamide, N-(l-napthyl) ethylenediamine, 2,2'-biquinoline, p-bromoaniliie, taurine, blue tetrazolium, 2-amino-3-methyl benzoic acid, indol-3-aldehyde, cysteine, 4-acetamidoaniline, p-aminophenol, 4 acetamide, 4-aminoacetophenone, 4-dimethylaminobenzaldehyde, 2aminobenzimidazol, bis-(4,4'-bipyridyl) a'-p-xylene, red phosphorus, and lithium p-toluenesulfonate. The present inventors believe that a large number of other compounds could be suitable for use as templating compounds and therefore the above list should not be considered to be exhaustive. The anions of the acid may also be considered to be a template.

The templating compounds may be added singly to the reaction mixture or two or more templating compounds may be added to the reaction mixture.

If a salt is used as the templating compound salt that is added to the mixture is preferably a metal halide. ammonium halide, or the corresponding sulphates, or metal tosylates. It is preferred that the anion of the salt corresponds to the anion of the acid used. For example, where the acid used is hydrochloric acid, a metal chloride or ammonium chloride is the preferred salt. If sulphuric acid is used, metal sulphate or ammonium sulphate is the preferred salt. Similarly, iodide-containing salts are preferably used where hydriodic acid is the acid, and bromide-containing salts are preferably used where hydrobromic acid is used.

2 The acid is preferably a strong mineral acid or a strong organic acid. In principle, any acid can be used. The acid acts to catalyse the reactions taking place.

S-0 Preferred acids for use in the method of the first or second aspects of the present invention include sulfuric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, deuterated sulfuric acid, phosphoric acid, p-toluenesulfonic acid, and methane sulfonic acid. It will be appreciated that this list is not exhaustive and that any acid that can catalyse the reaction may be used in the method of the 25 first aspect of the present invention.

It is especially preferred that the acid has a concentration of at least 5 M.

In some embodiments of the first or second aspects of the present invention, a solvent may also be added to the reaction mixture. The solvent is preferably selected from trifluoroacetic acid, methanesulfonic acid and 1,1,1trifluorethanol.

WO 00/68232 PCT/AUOO/00412 The compound that can form methylene bridges between gycoluril units is most preferably formaldehyde, paraformaldehyde. trioxane or one or more precursors for formaldehyde. For convenience, the invention will hereinafter be described with reference to the case where formaldehyde is used.

The mixture is preferably heated to temperature of from 20 0 C to 110 0 C, more preferably 60 0 C to 110°C, most preferably from 80 0 C to 110 0 C. It is preferred that boiling of the mixture is avoided. Heating under reflux, as required in the prior art, is not required (but may be used). Such temperature conditions are much milder than those utilised in the prior art synthesis process that led to the formation of cucurbit[6]uril. The prior art processes involved heating the mixture under reflux followed by heating to temperatures of up to 145 to 165 0 C. At room temperatures the present inventors have found that, cucurbit[n]uril was formed only if concentrated sulphuric acid was used as the acid. It has been found that the mixture should generally be heated to a temperature of 60 0 C and above to produce cucurbit[n]urils, with increased yields being obtained at temperatures on the range of 80 0 C to 100 0

C.

The glycolurils that are used in the present invention have an unsubstituted structure as shown in formula 1 below: 0 H.N) NH Hot..- H HY 0 (Formula 1) The general structure for the cucurbit[n]urils synthesised in accordance with the process of the present invention is shown in formula 2 below: SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCTAUO/00412 6

HC-CH

wherein n 4 to 12, preferably 4 to (Formula 2) Substituted and unsubstituted glycolurils, or a mixture thereof, may be used to synthesise cucurbit[n]uril in accordance with the present invention. Substituted glycolurils have the general formula as shown in formula 3 below:

O

HN NH R1 R2 HN NH 0 (Formula 3) wherein R, and R, are the same or different and selected from an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical or RI and

R

2 form a cyclic hydrocarbon radical. The hydrocarbon radical for substituents R, and R 2 may include alkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals. There are large numbers of substituted glycolurils known in the literature. Particular reference is made to a review article by Harro Petersen in Synthesis, 1973, 243-293, which contains a list of about 30 substituted glycolurils. The entire contents of this review article are hereby expressly incorporated into this specification by cross reference. The literature since the SUBSTITUTE SHEET (RULE 26) RO/AU Petersen article has disclosed several other examples of substituted glycolurils and it is believed that essentially any a- or /-diketone could be used to make a glycoluril.

.Investigations conducted by present inventors have shown that. cucurbit[n]uril-like systems can be svnthesised with many of the substituted glycolurils, preferably when used in conjunction with unsubstituted glycolurils. The following substituted glycoluril compounds have been prepared and used to synthesise substituted cucurbit[n]urils: (Formula 4) (Formula H H H HN H 0 0 o 0 H H

H

H H H H o 0 (Formula 6) (Formula 7) The compounds of formulae 5, 6 and 7 above are novel and accordingly, in another aspect, 15 the present invention provides a substituted glycoluril compound of formula 5, formula 6 or formula 7.

The synthesis of substituted cucurbit[n)urils opens the possibility of being able to chemically link the substituted cucurbit[njuril to a substrate or to chemisorb them onto a substrate. The solubility characteristics of the product may also be manipulated, by 20 selection of appropriate substituents.

e 8 As mentioned earlier, unsubstituted cucurbit[6]uril was first characterised and synthesised in 1905. The present inventors believe that cucurbit[n]uril, where n 4, 7, 8, 9, 11 or 12 has never previously been synthesised. In a further aspect, the present invention provides cucurbit[n]uril, where n 4 to 12, excluding unsubstituted cucurbit[6]uril and Preferably, n 5, 7, 8, 9 or The present invention provides substituted cucurbit[n]urils, where n 4, 5, 6, 7, 8, 9, 11 or 12. In order to clarify nomenclature when substituted cucurbiturils are formed, the present inventors have proposed that substituted cucurbiturils in accordance with the present invention be identified by the scheme "cucurbit[s,u]uril", where s the number of substituted glycoluril units and u the number of unsubstituted glycoluril units in the cucurbituril. Using this nomenclature, the present invention provides substituted cucurbiturils of the formula cucurbit[s,u]uril, where s and u are as defined above and s+u 4 to 12, preferably 5 to excluding In all of the experimental work conducted by the present inventors to date in relation to substituted cucurbiturils,, the substituted cucurbiturils have incorporated both substituted and unsubstituted glycoluril units into the cucurbituril structure. Thus, it is preferred that u does not equal zero. If s equals zero, cucurbit[s,ujuril is equivalent to unsubstituted cucurbit[n]uril! The substituted cucurbit[n]urils are preferably synthesized from substituted glycoluril or a mixture of substituted and unsubstituted glycoluril. The substituents may be as described above.

In order to show the structure of cucurbit[n]uril in cases where n 4, 5, 7 or 8, minimised chemical structures were prepared using PC-Spartan, a molecular modelling and visualisation package. The minimised structures are shown as formulae 8 to 11 in Figures 2 to 2* The minimised structures of Formulae 8 to 11 clearly show the inner cavity of the cucurbituril. As the value of n increases, the size of the inner cavity increases, which enables different compounds to fit into the inner cavity.

The reaction product of the process of the present invention contains a mixture of different cucurbit[n]urils or cucurbit[s,u]urils. There are several methods that could be used to separate and purify these products and these are described below: *.i PCT/AU00/00412 Received 20 August 2001 9 Successive Recrystallisation All of the cucurbit[n]urils that have been observed are apparently soluble in acid solutions. Cucurbit[5 or 7 or 8 or 10]uril have been purified by successive recrystallisations from acid solutions. Because of the similar nature of the cucurbiturils, this is a slow process with more than 10 recrystallisations required to purify cucurbit[7]uril. As shown in the German patents cucurbit[6]uril can be obtained in a relatively pure state from a single recystallisation process.

Selective dissolution/precipitation We have been able to demonstrate that different cucurbiturils have markedly different solubilities in various salt solutions. It is possible to separate cucurbit[6]uril and cucurbit[7]uril from a mixture containing cucurbit[5-8]urils by dissolving cucurbit[6 or 7]uril out of the complex mixture using a 0. 1M Na 2

SO

4 solution.

We have also demonstrated the use of selective precipitation as a purification method. A solution of cucurbit[6]uril and cucurbit[7]uril was mixed with bis(4,4'dipyridyl)-,a'-p-xylene. 'H NMR showed a decrease in signal due to the cucurbit[7]uril and bis(4,4'-dipyridyl)-a,a'-p-xylene with several crystals depositing out of the sample.

According to another aspect, the present invention comprises separating a mixture of cucurbit[n]urils, where n 4 to 12, by mixing the mixture of cucurbit[n]urils with a salt solution in which at least one of the cucurbit[n]urils, but not all of the cucurbit[n]urils, dissolves and separating solids from the solution. Preferably, the method further comprising recovering at least one of the dissolved at least one cucurbit[n]urils from the solution. This method may also be used to separate mixtures of different substituted cucurbit[s,u]urils.

As an example, lithium chloride in hydrochloric acid solutions selectively assists the crystallisation of cucurbit[6]uril and cucurbit[8]uril leaving cucurbit[5]uril and cucurbit[7]uril in solution.

Potassium chloride in hydrochloric acid solutions selectively assists the crystallisation of cucurbit[5]uril and cucurbit[8]uril leaving cucurbit[6]uril and cucurbit[7]uril in solution.

AMENDED SHEET

IPEAAU

WO 00/68232 PCT/AUOO/00412 Any of the salt complexed cucurbit[n]urils can be separated from their salt by a process of desalting on ion exchange resins such as Dowex 50. Dissolved in formic acid water, the mixtures are loaded onto the resin and the salts eluted with dilute hydrochloric acid/formic acid solutions until satisfactory salt removal and then the final recovery of the cucurbit[n]uril is achieved by elution with 5M or higher of aqueous hydrochloric acid.

Chromatographic Separation Both Thin Layer Chromatography (TLC) and High Pressure Liquid Chromatography (HPLC) have demonstrated ability to separate out various oligomers of cucurbit[n]uril. Both of these systems are under continuing investigation. TLC using a silica stationary phase and 0.1M Hydrochloric acid as the mobile phase resulted in a mixture of cucurbit[n]urils separating into several bands. HPLC separation has been attempted using a C-18 stationary phase and 0.5M NaSO 4 mobile phase. The retention times of recrystallised samples of cucurbit[6]uril and cucurbit[7]uril were comparable with peaks found in mixed samples of crude cucurbit[n]urils.

In a further aspect, the present invention provides a method for separating a mixture of cucurbit[n]urils, where n 4 to 10, by dissolving the mixture of cucurbit[n]urils and subjecting the thus-formed solution of cucurbit[n]urils to chromatographic separation.

This method may also be used to separate mixtures of cucurbit[s,u]urils.

In addition, polymer resins as chromatographic supports, such as, Dowex or Sephadex ion exchange columns or polyamines are effective in the purification of cucurbit[n]urils. The eluant most commonly used was 30-50% aqueous formic acid or a mixture of formic acid 98% and aqueous hydrochloric acid 0.5M in a ratio of 1:2 respectively. Samples sizes of 1 to 2 gm were able to be purified on a bed of 25cm of resin.

In order to more fully understand the present invention, the proposed reaction mechanism will be discussed hereunder. It is to be understood that the following reaction mechanism is a proposed mechanism and the present invention should not be considered to be limited thereto. The proposed reaction mechanism hereunder should be read in conjunction with Figures la, lb, Ic and Id.

The synthesis of cucurbit[n]uril or substituted cucurbit[n]uril (where n equals the number of glycouril units marking up cucurbituril) is an acid catalysed process. In the mechanism detailed below the first important intermediate 1 has been isolated and is the SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 11 reaction of a glycoluril with four equivalents of formaldehyde. The dehydration of this tetrol to the cyclic diether 2 has been demonstrated by the isolation of pure 2 where R phenyl. The intermediates A or B are both produced through a series of acid catalysed steps. This mechanism is not prescriptive, as it is possible for either A or B to be produced without going through 1 or 2. Similarly, it is possible for glycoluril units to begin linking on one side prior to reaction with formaldehyde on the other. This is a dynamic process with multiple reversible reaction steps. The mechanism shown here is only to be considered representative of the many possibilities.

The reaction from glycoluril to cucurbit[n]uril involves a number of intermediates produced through reversible reaction steps. The influences acting on the balance of these reversible steps are many and some can be manipulated at a variety of points there by effecting the out come of the reaction.

Examples The following examples illustrate preferred embodiments of the present invention: Example 1 Synthesis of cucurbit[n]urils g glycoluril 6.9 ml mineral acid (hydrochloric 36%, hydrobromic 48%, hydriodic 47% or sulphuric acid 98% or 50%) or organic acid (para toluene sulphonic acid) ml aqueous formaldehyde 5 mmol of the corresponding alkali metal halide, ammonium halide or the corresponding sulphates in the case of sulphuric acid or alkali metal tosylates 600 mg red phosphorus (this was added to reaction mixtures when hydriodic acid was used).

The glycoluril (1.5gm, 10.6mmol) was dissolved or suspended in the appropriate acid (6.9ml). Then in the cases where a salt was used to manipulate reaction products the alkali metal ion or ammonium salt (5mmol) with the corresponding anion appropriate to the acid was added. To this mixture at room temperature was added formaldehyde and within 5-10min, the mixture set as a gel (note After standing 3 hrs (note heat was applied raising the temperature to 100 0 C (note 3) whereby the gel liquefied. Heating SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 12 and stirring was maintained for 2-3 hr (note The reaction mixtures were cooled and in the case of HC1 and HBr all volatiles were removed in vacuo at temperatures no higher than 50 0 C. The residues were dissolved in the appropriate acid and evaporated again, this was repeated twice (note For remaining acids, the products were isolated by adding methanol (10ml) and collecting the resultant precipitate by filtration. The solid material was washed with methanol and acetone and air dried. The red phosphorus was removed by filtration before the addition of methanol.

Products have been isolated by a process of recyrstallisation using hydrochloric acid or hydrobromic acid at varying concentrations to effect crystallisation. The total yield was >90% except in the case of hydriodic acid where yields were 30-80% depending on the salt used. In all cases the range of isomers was produced ie cucurbit[n]urils with n= 4, 6, 7, 8, 9. etc. The maximum production of each of these was achieved as follows:n 4, in varying amounts under all conditions, n 5, 55-75%, with Nal, KI, or RbI in hydriodic acid, n 6, 80%, with CsCI in hydrochloric acid, n 7, 52-65%, with no salts or with Lil in hydriodic acid, n 8, with LiBr, or RbBr in hydrobromic acid, or LiOTs in aqueous pTsOH, n 9, with NH 4 CI in hydrochloric acid, in varying amounts under all conditions.

Notes A 1. Following the addition of formaldehyde there is an exothermic reaction. On larger scale the reaction mixture is cooled in an ice bath. Formaldehyde can be substituted by paraformaldehyde or trioxane or any formaldehyde producing precursor.

SUBSTITUTE SHEET (RULE 26) RO/AU 2. Proceeding to the next stage of the reaction procedure after lhr or 1 month at room temperature makes little difference to the out come except in the case of concentrated sulphuric acid where the reaction continues to cucurbit(nurils at room temperature.

3. A reaction temperature of 60 0 C and above is sufficient to give. cucurbit[n]urils but at the lower temperatures with extended reaction times to achieve completion, up to The given yields above for the larger unit cucurbit[>=7]uril are on average increased a further 50% on the tabled yields.

4. In some cases pressure was generated during heating. In the event of a pressure build up the pressure was released The repeated dissolving and evaporation was prir rily carried out to .remove excess formaldehyde and volatile formaldehyde by products.

Examle 2 Synthesis Cucurbit[s,ulurils The same templating .controls are applied to substituted cucurbir[n]urils either by the above method where glycoluril used is substituted or as described below.

A mixture of tetracyclic ether mmol) and glycoluril (0.355 gm, 2.5 mmol) was dissolved or suspended in the appropriate acid (6.9ml) (note Then in the cases where a salt was used to manipulate reaction products the alkali metal ion or ammonium salt (5mmol) with the corresponding anion appropriate to the acid was added. Heat was then applied to the reaction mixture, which was maintained at a temperature of 100 0 C for 3hrs (Note The reaction mixture was cooled to room temperature and the products were 'isolated by adding methanol (10ml) and collecting the resultant precipitate by filtration. The solid material was washed with methanol and acetone and air dried. Further purification was effected by recrystalisation from aqueous hydrochloric acid or hydrobromic acid or dissolving in formic acid and precipitating by the addition of water.

The composition of these mixed substituted cucurbit[n)urils was determined by Electrospray Mass Spectroscopy.

e e o go* *o~ *o 14 Notes B 1. The tetracyclic ether refers to a compound of the formula shown in box 2 in Figure Ila where the substituents R are alkyl, aryl, phenanthroline or pyridyl.

2. Para toluene suiphonic acid was the acid of choicefor the tetracyclic ethers whert.

*R equals aryl or Dyridyl and the temperature of the reaction mixture was maintained at 110 0

C.

3.

Exanle 3 Analysis of Cucurbituril Mlixture The analysis-of the aucurbituril reaction mixture is routinely carried out by 1 3 C NMR. The rese-nt- inventors have been able to achieve the x-ray crystal structure- for cucu cucurbit[B3uril and aucurbit[IO~uril. These are shown in Fi-gure 5a, in which.Formula 12 is cucurbit[5]uril, Formula 13 is cucufbit[g)uril and Formula 14 is cucurbit[l03uril. Waters, salts etc of crystallisation are not shown.

(Cucurbit[6)uril. is well established in the literature.) Solutions of pure- cucurbit[7])uri, as determine-d by 1 3 C NMR have been prepared and Electro-Spray Mass Spectroscopy has confirmed the presence of oly cucurbit[7]uril. (While pure cucurbizf7]uril is a crystalline material it is-dfficalr to grow crystals of X-ray quality.) From these pure- compounds the inventors have observed a trend, in the 1C NMR chemical shift of both the nethylene and methine carbons of the cucurbit[n)uril. This trend has allowed us to identif~y cucurbit[9)uril. cucurbitll1 iuril and cucurbit[12)uril in the reaction mixture. The table 25 below shows -the observed 13 C -cehmical shifts for the unambAig-uou sly identified cucurbit[6)uril, cucurbit[7]uuil, cucurbit[8)uri] and cucurbit[I1O~uril. The pre-dicted and observed values for cucurbit[9]uril, cucurbit[l liuril, cucurbit[12)uril and cucurbit[ 13) uril are also provided.

WO 00/68232 PCT/AUOO/00412 Methine C Methine C Methylene C Methylene C Curcurbit[n]uril Observed* Calc'd Observed* Calc'd n= (ppm) (ppm) (ppm) (ppm) 4 68.54 48.75 69.84 69.87 50.58 50.68 6 70.98 70.96 52.29 52.17 7 71.90 71.88 53.48 53.43 8 72.70 72.68 54.49 54.53 9 73.38 55.49 73.98 74.01 56.32 56.35 11 74.58 57.13 12 75.10 57.84 13 75.58 58.50 *These values were recorded on pure isolated materials.

The results of this Table are graphically shown in Figures 6 and 7.

Using this information the inventors have now identified cucurbit[9]uril (methine carbon 73.45 ppm and methylene carbon 55.42 ppm) in standard reaction mixtures.

Cucurbit[1 l]uril and cucurbit[12]uril have only been observed by the methylene carbon when 3 C labelled formaldehyde was used as a reactant. Under these conditions the cucurbit[ll]uril methylene carbon was observed at 56.86 ppm and the cucurbit[12]uril methylene carbon was observed at 57.75 ppm.

The inventors have routinely used the integration of 3 C NMR over the methine region of the spectra to determine the relative amounts of each cucurbit[n]uril in the mixture. In doing so it was assumed that the signal response for each species is related to the number of methine carbons for that cucurbit[n]uril and that there is little difference in signal response between the different cucurbit[n]urils. The integration-percent is then directly proportional to the mass percent of each component.

SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 16 Example 4 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (250 mg) and hydrochloric acid (36 w/v,2000 mL) were placed in a reaction flask. Formalin (40% w/v) (250 gpL) was added in one portion and the reaction mixture heated to 100°C for 15 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator.

Yield -30 by NMR Approximate Yields by 3 C NMR of recovered product) 58% cucurbit[6]uril 42% cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril <1% cucurbit[ 10] uril <1% cucurbit[1 l]uril <1% Example Synthesis of cucurbit[n]urils in sulfuric acid.

Glycoluril (500 mg) and sulfuric acid (9 M. 500 mL) were placed in a reaction flask.

Formalin (40% w/v) (250 p.L) was added in one portion and the reaction mixture heated to 100 0 C for 15 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and Yield -85 by NMR Approximate Yields by NMR of recovered product) 21% cucurbit[6]uril 64% cucurbit[7]uril 14% cucurbit[8]uril 1% cucurbit[9]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 17 <1% cucurbit[ ll]uril <1% Example 6 Synthesis of cucurbit[n]urils in sulfuric acid.

Glycoluril (1.5 g) and sulfuric acid (9 M, 6.9 mL) were placed in a reaction flask. Formalin w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were analysed by "C NMR.

Yield >98 by NMR Approximate Yields by NMR of recovered product) 26% cucurbit[6]uril 49% cucurbit[7]uril 19% cucurbit[8]uril 6% cucurbit[9]uril <1% <1% cucurbit[ 1l]uril <1% Example 7 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (77 mg) and hydrochloris acid (10 M, 0.4 mL) were placed in a reaction flask.

Paraformaldehyde (33 mg) was added in one portion and the reaction mixture heated to 105 0 C for 2.5 hours. The reaction mixture was cooled and the products were analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR of recovered product) 19% cucurbit[6]uril 54% cucurbit[7]uril 21% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 18 cucurbit[8]uril 6% cucurbit[9]uril <1% <1% cucurbit[1l]uril <1% Example 8 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (77 mg) and hydrochloric acid (9 M, 0.4 mL) were placed in a reaction flask.

Paraformaldehyde (33 mg) was added in one portion and the reaction mixture heated to 105 0 C for 2.5 hours. The reaction mixture was cooled and the products were analysed by "C NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR of recovered product) 18% cucurbit[6]uril 56% cucurbit[7]uril 19% cucurbit[8]uril 6% cucurbit[9]uril <1% cucurbit[ 10]uril <1% cucurbit[1 l]uril <1% Example 9 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (77 mg) and hydrochloric acid (8 M, 0.4 mL) were placed in a reaction flask.

Paraformaldehyde (33 mg) was added in one portion and the reaction mixture heated to 105 0 C for 2.5 hours. The reaction mixture was cooled and the products were analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by NMR of recovered product) SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 19 cucurbit[6]uril 58% cucurbit[7]uril 23% cucurbit[8]uril 4% cucurbit[9]uril <1% <1% cucurbit[ l]uril <1% Example Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (77 mg) and hydrochloric acid (7 M, 0.4 mL) were placed in a reaction flask.

Paraformaldehyde (33 mg) was added in one portion and the reaction mixture heated to 105 0 C for 2.5 hours. The reaction mixture was cooled and the products were analysed by "C NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR of recovered product) 18% cucurbit[6]uril 57% cucurbit[7]uril 23% cucurbit[8]uril 3% cucurbit[9]uril <1% cucurbit[ 10]uril <1% cucurbit[ll]uril <1% Example 11 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (77 mg) and hydrochloric acid (5 M, 0.4 mL) were placed in a reaction flask.

Paraformaldehyde (33 mg) was added in one portion and the reaction mixture heated to 105 0 C for 2.5 hours. The reaction mixture was cooled and the products were analysed by "C NMR.

SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 Yield >98 by NMR Approqximate Yields by 1 3 C NMR M% of recovered product) cucurbit[6]uril cucurbit[7]uril 27% cucurbit[8]uril 3% cucurbit[9]uril <1% <1% cucurbit[1I1]Iuril <1% PCT/AUOO/004 12 Example 12 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (2.4 g) and hydrochloric acid (36 wlv, 2 mL) were placed in a reaction flask.

Formalin (40% w/v) (2.4 mL) was added in one portion and the reaction mixture heated to 1 10'C for 3 hours. The reaction mixture was cooled and the products were analysed by 1 3

C

NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR of recovered product) 6% cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril 3% cucurbit[9]uril <1% cucurbit[ l0]uril <1% cucurbit[ I I]uril <1% SUBSTITUTE SHEET (RULE 26) RU/AU WO 00/68232 PCT/AUOO00412 21 Example 13 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (2.4 g) and hydrochloric acid (36 w/v, 2 mL) were placed in a reaction flask.

Formalin (40% w/v) (2.4 mL) was added in one portion and the reaction mixture heated to 110 0 C for 18 hours. The reaction mixture was cooled and the products were analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields b cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril cucurbit[1l]uril y 3C NMR of recovered product) 6% 2% <1% <1% <1% Example 14 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (2.1 g) and hydrochloric acid (36 w/v, 3 mL) were placed in a reaction flask.

Paraformaldehyde (887 mg) was added in one portion and the reaction mixture heated to 110°C for 18.hours. The reaction mixture was cooled and the products were analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by NMR of recovered product) 9% cucurbit[6]uril 52% cucurbit[7]uril 29% cucurbit[8]uril 8% cucurbit[9]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 cucurbit[ 10]uril cucurbit[11]uril <1% <1% Example Synthesis of cucurbit[n]urils in hydrobromic acid.

Glycoluril (2.1 g) and hydrobromic acid (48 w/v, 3 mL) were placed in a reaction flask.

Paraformaldehyde (887 mg) was added in one portion and the reaction mixture heated to 100 0 C for 18 hours. The reaction mixture was cooled and the products were analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields b cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril cucurbit[11]uril y 13C NMR of recovered product) 8% 29% 12% <1% <1% <1% Example 16 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (105 mg) and hydrochloric acid (36 w/v, 0.4 mL) were placed in a reaction flask. Formalin (40% w/v) (105 p.L) was added in one portion and the reaction mixture heated to 60 0 C for 65 hours. The reaction mixture was cooled and the products were analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR of recovered product) 4% cucurbit[6]uril 64% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUO/00412 23 cucurbit[7]uril 23% cucurbit[8]uril 9% cucurbit[9]uril <1% <1% cucurbit[ 1l]uril <1% Example 17 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (77 mg) and hydrochloric acid (8 M, 0.4 mL) were placed in a reaction flask.

Paraformaldehyde (33 mg) was added in one portion and the reaction mixture heated to 105 0 C for 2.5 hours. The reaction mixture was cooled and the products were analysed by 'C NMR.

Yield >98 by NMR Approximate Yields by 13C NMR of recovered product) 13% cucurbit[6]uril cucurbit[7]uril 23% cucurbit[8]uril cucurbit[9]uril <1% <1% cucurbit[l l]uril <1% Example 18 Synthesis of cucurbit[n]urils in phosphoric acid.

Glycoluril (1.5 g) and phosphoric acid (conc, 6.9 mL) were placed in a reaction flask.

Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 18 hours. The reaction mixture was cooled and the products were analysed by 3 C NMR.

Yield >98 by NMR SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 24 Approximate Yields by 1 3 C NMR of recovered product) cucurbit[6Iuril cucurbit[7]uril 28% cucurbit[8]uril <1% cucurbit[9]uril <1% cucurbit[I0]uril <1% cucurbit [II] urilI <1% Example 19 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (1.02 g) and hydrochloric acid (36 w/v, 0.6 mL) were placed in a reaction flask. Paraformaldehyde (430 mg) was added in one portion and the reaction mixture heated to 100'C for 15 hours. The reaction mixture was cooled and the products were analysed by 1 3 C NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR of recovered product) cucurbit[5]uril 4% cucurbit[6]uril 53% cucurbit[7]uril 27% cucurbit[8]uril cucurbit[9]uril <1% cucurbitf I0]uril <1% cucurbit[l I uril <1% Example Synthesis of cucurbit[n]urils in deuterated sulfuric acid.

Glycoluril (78 mg) and deuterated sulfuric acid (conc, 0.4 mL) were placed in a reaction flask. Formalin (40% w/v) (73 gQL was added in one portion and the reaction mixture SUBSTITUTE SHEET (RULE 26) ROMA WO 00/68232 PCT/AUOO/00412 heated to rt°C for 2 months. The reaction mixture was cooled and the products were analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields b cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril cucurbit[l1]uril y 3 C NMR of recovered product) <1% <1% <1% <1% <1% <1% Example 21 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (108 mg) and hydrochloric acid (36 w/v, 0.4 mL) were placed in a reaction flask. Formalin (40% w/v) (108 gL) was added in one portion kept at room temperature for 1 month. The products were analysed by 3 C NMR.

Yield -No cucurbiturils present NMR suggests oligomeric product.

Example 22 Synthesis of cucurbit[n]urils in hydrochloric acid.

Glycoluril (1000 g) and hydrochloric acid (36 w/v, 1420 mL) were placed in a reaction flask. Paraformaldehyde (422 g was added in one portion and the reaction mixture heated to 105 0 C for 18 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator.

Yield quantitative mass recovery and >98 cucurbit[n]urils by NMR Approximate Yields by NMR of recovered product) 19% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AU00/00412 cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril cucurbit[ 10]uril cucurbit[ll]uril 47% 27% 6% <1% <1% <1% Example 23 Synthesis of cucurbit[n]urils in p-toluenesulfonic acid.

Glycoluril (1 g) and p-toluenesulfonic acid (-90 w/w, 6.9 g) were placed in a reaction flask. Formalin (40% w/v) (1 mL mg) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields b cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril cucurbit[ll]uril y 1 3 C NMR of recovered product) 6% 68% <1% <1% <1% Example 24 Synthesis of cucurbit[n]urils in methane sulfonic acid.

Glycoluril (146.5 mg) and methane sulfonic acid (neat, 1.5 mL) were placed in a reaction flask. Paraformaldehyde (65.5 mg) was added in one portion and the reaction mixture heated to 90 0 C for 22 hours. The reaction mixture was cooled and the collected using a centrifuge.The collected solid was then dried at 80 0 C overnight.

SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 27 Yield >98 by NMR Approximate Yields by 1 3 C NMR of recovered product) 6% cucurbit[6]uril 52% cucurbit[7]uril 33% cucurbit[8Iuril 9% cucurbit[9Iuril <1% cucurbit[1IO]uril <1% cucurbit[I I] uril <1% Example Synthesis of cucurbit[n]urils in methane sulfonic acid.

Glycoluril (197.6 mg) and methane sulfonic acid (neat, 1.5 mL) were placed in a reaction flask. Paraformaldehyde (91.1 mg) was added in one portion and the reaction mixture heated to 90'C for 23.5 hours. The reaction m-ixture was cooled and the collected using a centrifuge.The collected solid was then dried at 80"C overnight.

Yield >98 by NMR Approximate Yields by' 3 C NMR of recovered product) 8% cucurbit[6Iuril 54% cucurbit[7]uril cucurbit[8]uril 8% cucurbit[9]uril <1% cucurbit[ 1O]uril <1% cucurbit[ II Juril <1% Example 26 Synthesis of cucurbit[nlurils in methane sulfonic acid.

Glycoluril (302.6 mg) and methane sulfonic acid (neat, 1.5 mL) were placed in a reaction flask. Paraformaldehyde (130.3 mg) was added in one portion and the reaction m-ixture SUBSTITUTE SHEET (RULE 26) ROMA WO 00/68232 PCT/AUOO/00412 28 heated to 90 0 C for 23.5 hours. The reaction mixture was cooled and the collected using a centrifuge.The collected solid was then dried at 80 0 C overnight.

Yield >98 by NMR Approximate Yields by 3 C NMR of recovered product) 3% cucurbit[6]uril 54% cucurbit[7]uril 32% cucurbit[8]uril 11% cucurbit[9]uril <1% cucurbit[ 10]uril <1% cucurbit[11]uril <1% Example 27 Synthesis of cucurbit[n]urils in methane sulfonic acid.

Glycoluril (497.3 mg) and methane sulfonic acid (neat, 1.5 mL) were placed in a reaction flask. Paraformaldehyde (204.0 mg) was added in one portion and the reaction mixture heated to 90 0 C for 25 hours. The reaction mixture was cooled and the collected using a centrifuge.The collected solid was then dried at 80 0 C overnight.

Yield >98 by NMR Approximate Yields by 1 3 C NMR of recovered product) 0% cucurbit[6]uril 77% cucurbit[7]uril 23% cucurbit[8]uril 0% cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 29 Example 28 Synthesis of cucurbit[n]urils in methane sulfonic acid.

Glycoluril (144.6 mg) and methane sulfonic acid (neat, 1.5 mL) were placed in a reaction flask. Paraformaldehyde (61.3 mg) was added in one portion and the reaction mixture heated to 70 0 C for 22.5 hours. The reaction mixture was cooled and the collected using a centrifuge.The collected solid was then dried at 80 0 C overnight.

Yield >98 by NMR Approximate Yields by 3 C NMR of recovered product) 0% cucurbit[6]uril 49% cucurbit[7]uril 34% cucurbit[8]uril 17% cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Example 29 Synthesis of cucurbit[n]urils in methane sulfonic acid.

Glycoluril (145.2 mg) and methane sulfonic acid (neat, 1.5 mL) were placed in a reaction flask. Paraformaldehyde (62.9 mg) was added in one portion and the reaction mixture heated to 80 0 C for 24 hours. The reaction mixture was cooled and the collected using a centrifuge.The collected solid was then dried at 80 0 C overnight.

Yield >98 by NMR Approximate Yields by 3 C NMR of recovered product) cucurbit[5]uril 4% cucurbit[6]uril 56% cucurbit[7]uril 28% cucurbit[8]uril 11% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Example Synthesis of cucurbit[n]urils in methane sulfonic acid.

Glycoluril (142.5 mg) and methane sulfonic acid (neat. 1.5 mL) were placed in a reaction flask. Paraformaldehyde (60.7 mg) was added in one portion and the reaction mixture heated to 100 0 C for 25 hours. The reaction mixture was cooled and the collected using a centrifuge.The collected solid was then dried at 80 0 C overnight.

Yield >98 by NMR Approximate Yields by 3 C NMR of recovered product) cucurbit[5]uril 3% cucurbit[6]uril 59% cucurbit[7]uril 32% cucurbit[8]uril 6% cucurbit[9]uril <1% cucurbit[10]uril <1% cucurbit[ l]uril <1% Example 31 Synthesis of cucurbit[n]urils in methane sulfonic acid.

Glycoluril (148.3 mg) and methane sulfonic acid (neat, 1.5 mL) were placed in a reaction flask. Paraformaldehyde (60.2 mg) was added in one portion and the reaction mixture heated to 110?C for 27 hours. The reaction mixture was cooled and the collected using a centrifuge.The collected solid was then dried at 80°C overnight.

Yield >98 by NMR Approximate Yields by 13C NMR of recovered product) 0% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 31 cucurbit[6]uril 93% cucurbit[7]uril 7% cucurbit[8]uril 0% cucurbit[9]uril 1% cucurbit[ 1O1uril 1 cucurbit[1 I1]Iuril <1% Example 32 Synthesis of cucurbit[nlurils in methane sulfonic acid using o-carborane as an added template.

Glycoluril (146.9 mg), methane sulfonic acid (neat, 1.5 mL) and o-carborane (-18 mgy) were placed in a reaction flask. Paraformaldehyde (64.2 mg) was added in one portion and the reaction mixture heated to 90'C for 22.5 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and collected using a centrifuge.The collected solid was then dried at 80'C overnight and analysed by 1 3 C NMR.

Yield >98 by NMR Approximate Yields by1 3 C NMR (mass of recovered product) cucurbit[5]urii cucurbit[6]uril 52% cucurbit[7]uril 33% cucurbit[8]uril cucurbit[9]uril <1% cucurbit[10]uril <1% cucurbit[1 luril <1% Example 33 Synthesis of cucurbit[n]urils in methane sulfonic acid using o-carborane as an added template.

Glycoluril (200.5 mg), methane sulfonic acid (neat, 1.5 mL) and o-carborane (102.7 mg) were placed in a reaction flask. Paraformaldehyde (94.2 mg) was added in one portion and SUBSTITUTE SHEET (RULE 26) RD/A WO 00/68232 PCT/AUOO/00412 32 the reaction mixture heated to 90 0 C for 24 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and collected using a centrifuge.The collected solid was then dried at 80°C overnight and analysed by "C NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 8% cucurbit[6]uril 53% cucurbit[7]uril 29% cucurbit[8]uril cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Example 34 Synthesis of cucurbit[n]urils in methane sulfonic acid using o-carborane as an added template.

Glycoluril (299.0 mg), methane sulfonic acid (neat, 1.5 mL) and o-carborane (152.4 mg) were placed in a reaction flask. Paraformaldehyde (126.2 mg) was added in one portion and the reaction mixture heated to 90 0 C for 24 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and collected using a centrifuge.The collected solid was then dried at 80 0 C overnight and analysed by "C NMR.

Yield >98 by NMR Approximate Yields by 3C NMR (mass of recovered product) 3% cucurbit[6]uril 57% cucurbit[7]uril 33% cucurbit[8]uril 7% cucurbit[9]uril <1% <1% cucurbit[11]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 33 Example Synthesis of cucurbit[n]urils in methane sulfonic acid using o-carborane as an added template.

Glycoluril (501.9 mg), methane sulfonic acid (neat, 1.5 mL) and o-carborane (166.2 mg) were placed in a reaction flask. Paraformaldehyde (207.9 mg) was added in one portion and the reaction mixture heated to 90 0 C for 25 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and collected using a centrifuge.The collected solid was then dried at 80 0 C overnight and analysed by 'C NMR.

Yield >98 by NMR Approximate Yields by 1 C NMR (mass of recovered product) 0% cucurbit[6]uril 63% cucurbit[7]uril 28% cucurbit[8]uril 9% cucurbit[9]uril <1% <1% cucurbit[11]uril <1% Example 36 Synthesis of cucurbit[n]urils in methane sulfonic acid using o-carborane as an added template.

Glycoluril (145.0 mg), methane sulfonic acid (neat, 1.5 mL) and o-carborane (53.4 mg) were placed in a reaction flask. Paraformaldehyde (62.5 mg) was added in one portion and the reaction mixture heated to 70 0 C for 22.5 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and collected using a centrifuge.The collected solid was then dried at 80 0 C overnight and analysed by "C NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 WO 0068232PCT/A UOOI 00412 cucurbit[6] uril cucurbit[7] uril cucurbit[8] uril cucurbit[9]uril uril cucurbit[1I luril 0% 48% 32% <1% <1% <1% Example 37 Synthesis of cucurbit[n]urils in methane sulfonic acid using o-carborane as an added template.

Glycoluril (146.9 mg), methane sulfonic acid (neat, 1.5 mL) and o-carborane (53.4 mg) were placed in a reaction flask. Paraformaldehyde (64.0 mg) was added in one portion and the reaction mixture heated to 80'C for 24 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and collected using a centrifuge.The collected solid was then dried at 80'C overnight and analysed by NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) 4% cucurbit[6]uril 48% cucurbit[7]uril 29% cucurbit[8Iuril 19% cucurbit[9]uril <1% cucurbit[ 1 Ouril cucurbit[I I] uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 Example 38 Synthesis of cucurbit[n]urils in methane sulfonic acid using o-carborane as an added template.

Glycoluril (142.7 mg), methane sulfonic acid (neat. 1.5 mL) and o-carborane (48.6 mg) were placed in a reaction flask. Paraformaldehyde (60.7 mg) was added in one portion and the reaction mixture heated to 100 0 C for 25 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and collected using a centrifuge.The collected solid was then dried at 80 0 C overnight and analysed by 1 C NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 2% cucurbit[6]uril 53% cucurbit[7]uril 31% cucurbit[8]uril 14% cucurbit[9]uril <1% <1% cucurbit[ l]uril <1% Example 39 Synthesis of cucurbit[n]urils in methane sulfonic acid using o-carborane as an added template.

Glycoluril (145.5 mg), methane sulfonic acid (neat, 1.5 mL) and o-carborane (49.9 mg) were placed in a reaction flask. Paraformaldehyde (60.7 mg) was added in one portion and the reaction mixture heated to 110 0 C for 27 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and collected using a centrifuge.The collected solid was then dried at 80 0 C overnight and analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by '3C NMR (mass of recovered product) 0% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 36 cucurbit[6]uril cucurbit[7]uril 26% cucurbit[8]uril 9% cucurbit[9] uril cucurbitfl10] uril 1 cucurbit[ II]uril <1% Example Synthesis of cucurbit[n~urils in hydrochloric acid using thioacetamide as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v. 0.7 mL) and thioacetamide (12.8 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95'C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by

NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) cucurbit[5]uril 0% cucurbit[6]uril 64% cucurbit[7] uril 36% cucurbit[8]uril 0% cucurbit[9juril <1% cucurbit[1l0]uril 1 cucurbit[ II]uril <1% Example 41 Synthesis of cucurbit[n]urils in hydrochloric acid using N-(1-napthyl)ethylenediamine as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and N-(1napthyl)ethylenediamine (44.1 mg) were placed in a reaction flask. Paraformaldehyde SUBSTITUTE SHEET (RULE 26) ROIAU WO 00/68232 PCT/AUOO/00412 37 (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 4 hours.

The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 12% cucurbit[6]uril 53% cucurbit[7]uril 23% cucurbit[8]uril 12% cucurbit[9]uril <1% cucurbit[ 10]uril <1% cucurbit[ l]uril <1% Example 42 Synthesis of cucurbit[n]urils in hydrochloric acid using 2,2'-biquinoyl as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and 2,2'-biquinoyl (43.6 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by

NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 6% cucurbit[6]uril 62% cucurbit[7]uril 26% cucurbit[8]uril 6% cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 38 Example 43 Synthesis of cucurbit[n]urils in hydrochloric acid using p-bromoaniline as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and p-bromoaniline (29.3 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 11% cucurbit[6]uril 36% cucurbit[7]uril 36% cucurbit[8]uril cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Example 44 Synthesis of cucurbit[n]urils in hydrochloric acid using tetrabutylammonium chloride as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and tetrabutylammonium chloride (47.3 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCr/AUOO/00412 cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril cucurbit[ll]uril <1% <1% <1% Example Synthesis of cucurbit[n]urils in hydrochloric acid using taurine as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and taurine (21.3 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by

NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) cucurbit[5]uril 16% cucurbit[6]uril 51% cucurbit[7]uril 23% cucurbit[8]uril cucurbit[9]uril <1% cucurbit[10]uril <1% cucurbit[ll]uril <1% Example 46 Synthesis of cucurbit[n]urils in hydrochloric acid using blue tetrazolium as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and blue tetrazolium (123.7 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 and the reaction mixture heated to 95°C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 7% cucurbit[6]uril cucurbit[7]uril 23% cucurbit[8]uril cucurbit[9]uril <1% cucurbit[ 10]uril <1% cucurbit[1l]uril <1% Example 47 Synthesis of cucurbit[n]urils in hydrochloric acid using 2-amino-3-methyl benzoic acid as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and 2-amino-3-methyl benzoic acid (25.7 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 41 Example 48 Synthesis of cucurbit[n]urils in hydrochloric acid using indol-3-aldehyde as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and indol-3-aldehyde (24.7 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) 3% cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril 2% cucurbit[9]uril <1% <1% cucurbit[1 l]uril <1% Example 49 Synthesis of cucurbit[n]urils in hydrochloric acid using cystine as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and cystine (40.9 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by

NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 42 cucurbit[6Iuril cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril 1% cuc urbit[ cucurbit[1 I ]url <1% Example Synthesis of cucurbitlinlurils in hydrochloric acid using p-acetamidoaniline as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 wlv, 0.7 mL) and p-acetam-idoaniline (25.5 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95'C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) cucurbit[5]urii cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril <1 cucurbit[1O]uril 1 cucurbit[l I uril <1% Example 51 Synthesis of cucurbit[n]urils in hydrochloric acid using p-aminophenol as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 ml-) and p-aminophenol (18.6 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion SUBSTITUTE SHEET (RULE 26) ROIAU WO 00/68232 PCT/AUOO/00412 43 and the reaction mixture heated to 95 0 C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) 13% cucurbit[6]uril 39% cucurbit[7]uril 36% cucurbit[8]uril 12% cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Example 52 Synthesis of cucurbit[n]urils in hydrochloric acid using acetamide as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and acetamide (10.0 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by

NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 9% cucurbit[6]uril 31% cucurbit[7]uril 39% cucurbit[8]uril 17% cucurbit[9]uril <1% cucurbit[ 10]uril <1% cucurbit[ l]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 44 Exmaple 53 Synthesis of cucurbit[n]urils in hydrochloric acid using 4-aminoacetophenone as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and 4-aminoacetophenone (23.0 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) 9% cucurbit[6]uril 44.5% cucurbit[7]uril cucurbit[8]uril 12% cucurbit[9]uril <1% cucurbit[ 0]uril <1% cucurbit[ll]uril <1% Example 54 Synthesis of cucurbit[n]urils in hydrochloric acid using 4dimethylaminobenzaldehyde as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and 4dimethylaminobenzaldehyde (25.4 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 4 hours.

The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232PCAUO042 PCT/AUOO/00412 cucurbit [51 uril cucurbit[6juril cucurbit[7]uril cucurbit[8]uril cucurbit u Il cucurbitf 101uril cucurbitli I uril <1% <1% Example Synthesis of cucurbit[n]urils in hydrochloric acid using 2-aminobenzimadazol as an added template.

Glycoluril (142.1 mng), hydrochloric acid (36 w/v, 0.7 mL) and 2-aminobenzimadazol (22.6 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95'C for 2 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 13 C NMR (mass of recovered product) 9% cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril 11% cucurbit[9]uril 1 uril <l cucurbit II]urilI <1% Example 56 Synthesis of cucurbit[n]urils in hydrochloric acid using bis-(4,4'-ipyridyl)-ax, cx-pxylene as an added template.

SUBSTITUTE SHEET (RULE 26) RO/A WO 00/68232 PCT/AU00/00412 46 Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and bis-(4,4'-bipyridyl)-oa, a'-p-xylene (110.8 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 2 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 3C NMR (mass of recovered product) 8% cucurbit[6]uril 42% cucurbit[7]uril 46% cucurbit[8]uril cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Example 57 Synthesis of cucurbit[n]urils in hydrochloric acid using tetraethylammonium chloride as an added template.

Glycoluril (142.1 mg), hydrochloric acid (36 w/v, 0.7 mL) and tetraethylammonium chloride (28.2 mg) were placed in a reaction flask. Paraformaldehyde (60.0 mg) was added in one portion and the reaction mixture heated to 95°C for 2 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) 0% cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril 18% cucurbit[9]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCr/AUOO/00412 47 cucurbit[ 10]uril <1% cucurbit[11]uril <1% Example 58 Synthesis of cucurbit[n]urils in hydrochloric acid using ammonium chloride as an added template.

Glycoluril (1.49 hydrochloric acid (36 w/v, 6.9 mL) and ammonium chloride (280 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) cucurbit[6]uril 62% cucurbit[7]uril cucurbit[8]uril 3% cucurbit[9]uril <1% <1% cucurbit[ 1l]uril <1% Example 59 Synthesis of cucurbit[n]urils in hydrochloric acid using lithium chloride as an added template.

Glycoluril (1.49 hydrochloric acid (36 w/v, 6.9 mL) and lithium chloride (211 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 48 Yield >98 by NMR Approximate Yields by 1' 3 C NMR (mass of recovered product) 7% cucurbit[6]uril 68% cucurbit[7]uril 22% cucurbit[8]uril 3% cucurbit[9]uril <1% cucurbit[ IO~uril <1% cucurbit[1 I1]uril 1 Example Synthesis of cucurbit[n]urils in hydrochloric acid using sodium chloride as an added template.

Glycoluril (1.49 hydrochloric acid (36 wlv, 6.9 mnL) and sodium chloride (292 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 m.L) was added in one portion and the reaction mixture heated to 100'C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) 3% cucurbit[6]uril 73% cucurbit[7]uril 21% cucurbit[8]uril 3% cucurbit[9]uril <1% cucurbit[ iQjuril <1% cucurbit[11 iluril 1 SUBSTITUTE SHEET (RULE 26) RD/A WO 00/68232 PCT/AUOO/00412 49 Example 61 Synthesis of cucurbit[n]urils in hydrochloric acid using potassium chloride as an added template.

Glycoluril (1.49 hydrochloric acid (36 w/v, 6.9 mL) and potassium chloride (372 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 24% cucurbit[6]uril 61% cucurbit[7]uril 14% cucurbit[8]uril 2% cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Example 62 Synthesis of cucurbit[n]urils in hydrochloric acid using rubidium chloride as an added template.

Glycoluril (1.49 hydrochloric acid (36 w/v, 6.9 mL) and rubidium chloride (604 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100°C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 14% cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril <1% cucurbit[9]uril <1% cucurbitlllOluril 1 cucurbit[ II]uril <1% Example 63 Synthesis of cucurbit[nlurils in hydrochloric acid using caesium chloride as an added template.

Glycoluril (1.49 hydrochloric acid (36 w/v, 6.9 ml-) and caesium chloride (842 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 ml-) was added in one portion and the reaction mixture heated to 1 00'C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) 4% cucurbit[6]uril 79% cucurbit[7]uril 16% cucurbit[8]uril I1% cucurbit[9]uril 1 cucurbit[ l0]uril <1% cucurbit[1 ]uril 1 Example 64 Synthesis of cucurbit[njurils in hydrobromic acid using ammonium bromide as an added template.

SUJBSTITUTE SHEET (RULE 26) ROMA WO 00/68232 PCT/AUOO/00412 51 Glycoluril (1.49 hydrobromic acid (48 w/v, 6.9 mL) and ammonium bromide (490 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 8% cucurbit[6]uril 66% cucurbit[7]uril 23% cucurbit[8]uril 3% cucurbit[9]uril <1% <1% cucurbit[1l]uril <1% Example Synthesis of cucurbit[n]urils in hydrobromic acid.

Glycoluril (1.49 g) and hydrobromic acid (48 w/v, 6.9 mL) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by "C NMR (mass of recovered product) cucurbit[6]uril 59% cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCr/AUOO/00412 52 Example 66 Synthesis of cucurbit[n]urils in hydrobromic acid using lithium bromide as an added template.

Glycoluril (1.49 hydrobromic acid (48 w/v, 6.9 mL) and lithium bromide (435 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 7% cucurbit[6]uril 49% cucurbit[7]uril 36% cucurbit[8]uril 7% cucurbit[9]uril <1% <1% cucurbit[1ll]uril <1% Example 67 Synthesis of cucurbit[n]urils in hydrobromic acid using sodium bromide as an added template.

Glycoluril (1.49 hydrobromic acid (48 w/v, 6.9 mL) and sodium bromide (515 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 53 16% cucurbit[6]uril 44% cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril <1% cucurbit[ l~luril <1% cucurbit[1 I uril <1% Example 68 Synthesis of cucurbit[nlurils in hydrobromic acid using sodium bromide as an added template.

Glycoluril (1.49 hydrobromic acid (48 w/v, 6.9 ml-) and sodium bromide (5000 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 1 NMR (mass of recovered product) cucurbit[6]uril 51% cucurbit[7]uril 9% cucurbit[8]uril 1 cucurbit[9]uril 1 cucurbit[ IlOjuril <1% cucurbit[ IIluril <1% Example 69 Synthesis of cucurbit[nlurils in hydrobromic acid using potassium bromide as an added template.

SUBSTITUTE SHEET (RULE 26) RD/AU WO 00/68232 PCr/AUOO/00412 54 Glycoluril (1.49 hydrobromic acid (48 w/v, 6.9 mL) and potassium bromide (595 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 36% cucurbit[6]uril 44% cucurbit[7]uril 18% cucurbit[8]uril 2% cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Example Synthesis of cucurbit[n]urils in hydrobromic acid using rubidium bromide as an added template.

Glycoluril (1.49 hydrobromic acid (48 w/v, 6.9 mL) and rubidium bromide (827 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) cucurbit[6]uril 43% cucurbit[7]uril 24% cucurbit[8]uril 8% cucurbit[9]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCr/AUOO/00412 <1% cucurbit[11]uril <1% Example 71 Synthesis of cucurbit[n]urils in hydrobromic acid using caesium bromide as an added template.

Glycoluril (1.49 hydrobromic acid (48 w/v, 6.9 mL) and caesium bromide (1070 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by NMR (mass of recovered product) cucurbit[6]uril 59% cucurbit[7]uril 23% cucurbit[8]uril 3% cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Example 72 Synthesis of cucurbit[n]urils in hydrochloric acid using ammonium chloride as an added template.

Glycoluril (1.49 hydrochloric acid (36 w/v, 6.9 mL) and ammonium chloride (280 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 60 0 C for 60 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCr/AUOO/00412 56 Yield >98 by NMR Approximate Yields by 13 C NMR (mass of recovered product) 11% cucurbit[6Iuril cucurbit[7]uril 21% cucurbit[8]uril 8% cucurbit[9]uril 1 cucurbit[ l~juril <1% cucurbit[ 1 I uril 1 Example 73 Synthesis of cueurbit[nlunls in hydrobromic acid using rubidium bromide as an added template.

Glycoluril (1.49 hydrobromic acid (48 wlv, 6.9 mL) and rubidium bromide (827 mg) were placed in a reaction flask. Formalin (40% wlv) (1.5 ml-) was added in one portion and the reaction mixture heated to 60'C for 84 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) 34% cucurbit[6]uril 39% cucurbit[7]uril 19% cucurbit[8]uril 9% cucurbit[9Iuril <1% cucurbit[ lOluril <1% cucurbit[1 luril <1% SUBSTITUTE SHEET (RULE 26) RD/AU WO 00/68232 PC/AUO/00412 57 Example 74 Synthesis of cucurbit[n]urils in hydrochloric acid using potassium chloride as an added template.

Glycoluril (250 hydrochloric acid (36 w/v, 1200 mL) and potassium chloride (62 g) were placed in a reaction flask. Paraformaldehyde (110 g) was added in one portion and the reaction mixture heated to 95°C for 4 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by

NMR.

Yield >98 by NMR Approximate Yields by 'C NMR (mass of recovered product) 39% cucurbit[6]uril 36% cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril <1% cucurbit[ 10]uril <1% cucurbit[ll]uril <1% Example Synthesis of cucurbit[n]urils in hydrochloric acid using potassium chloride as an added template.

Glycoluril (8 hydrochloric acid (36 w/v, 70 mL) and potassium chloride (2.1 g) were placed in a reaction flask. Paraformaldehyde (3.5 g) was added in one portion and the reaction mixture heated to 100 0 C for 3.5 hours. The reaction mixture was cooled and the products were collected by the removal of solvent on a rotary evaporator and analysed by

NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 58 26% cucurbit[6]uril 56% cucurbit[7]uril cucurbit[8]uril 3% cucurbit[9]uril 1 <1% cucurbit[l I Iuril 1 Example 76 Synthesis of cucurbit[nlurils in hydrobromic acid using lithium bromide as an added template.

Glycoluril (1.49 hydrobromic acid (48 w/v, 6.9 mL) and lithium bromide (4.3 g) were placed in a reaction flask. Formalin (40% wlv) (1.5 ml-) was added in one portion and the reaction mixture heated to 1 00'C for 3 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) cucurbit[5]uril 13% cucurbit[6Iuril 63% cucurbit[7]uril 22% cucurbit[8]uril 3% cucurbit[9Iuril <1% cucurbit[10]uril <1% cucurbit[1 I uril 1 Example 77 Synthesis of cucurbit[nlurils in hydroiodic acid.

Glycoluril (1.49 g) and hydroiodic acid (57 w/v, 6.9 mL) were placed in a reaction flask.

Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 59 100 0 C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield 2.2 g Approximate Yields by 3 C NMR (mass of recovered product) 3% cucurbit[6]uril 72% cucurbit[7]uril 22% cucurbit[8]uril 3% cucurbit[9]uril <1% cucurbit[ 0]uril <1% cucurbit[ll]uril <1% Example 78 Synthesis of cucurbit[n]urils in hydroiodic acid using lithium iodide as an added template.

Glycoluril (1.49 hydroiodic acid (57 w/v, 6.9 mL) and lithium iodide (665 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield 0.9 g Approximate Yields by 3C NMR (mass of recovered product) cucurbit[5]uril 16% cucurbit[6]uril 28% cucurbit[7]uril 56% cucurbit[8]uril <1% cucurbit[9]uril <1% cucurbit[10]uril <1% cucurbit[11]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 Example 79 Synthesis of cucurbit[n]urils in hydroiodic acid using sodium iodide as an added template.

Glycoluril (1.49 hydroiodic acid (57 w/v, 6.9 mL) and sodium iodide (745 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 3C NMR (mass of recovered product) 19% cucurbit[6]uril cucurbit[7]uril 17% cucurbit[8]uril 9% cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Example Synthesis of cucurbit[n]urils in hydroiodic acid using potassium iodide as an added template.

Glycoluril (1.49 hydroiodic acid (57 w/v, 6.9 mL) and potassium iodide (825 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) 67% cucurbit[6uril 22% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCTAUO/00412 61 cucurbit[7]uril cucurbit[8]uril 1% cucurbit[9]uril <1% cucurbit[ 10]uril <1% cucurbit[ 1 ]uril <1% Example 81 Synthesis of cucurbit[n]urils in hydroiodic acid using rubidium iodide as an added template.

Glycoluril (1.49 hydroiodic acid (57 w/v, 6.9 mL) and rubidium iodide (1060 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100°C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 34% cucurbit[6]uril 18% cucurbit[7]uril 48% cucurbit[8]uril <1% cucurbit[9]uril <1% <1% cucurbit[11]uril <1% Example 82 Synthesis of cucurbit[n]urils in hydroiodic acid using caesium iodide as an added template.

Glycoluril (1.49 hydroiodic acid (57 w/v, 6.9 mL) and caesium iodide (1300 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AUOO/00412 62 Yield >98 by NMR Approximate Yields by 13 CNMR (mass %of recovered product) 8% cucurbit[6]uril 36% cucurbit[7]uril 53% cucurbit uril 3% cucurbit[9luril <1% 1 cucurbit[ II]uril <1% Example 83 Synthesis of' cucurbit[nlurils in hydroiodic acid using red phosphorous as an added template.

Glycoluril (1.49 hydroiodic acid (57 w/v, 6.9 mL) and red phosphorous (1 g) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 1 3 CNMR (mass of recovered product) 3% cucurbit[6]uril cucurbit[7]uril 23% cucurbit[8]uril 4% cucurbit[9]uril zl cucurbit(IOluril 1 cucurbit[1 I uril 1 SUBSTITUTE SHEET (RULE 26) ROMA WO 00/68232 PCT/AUOO/00412 63 Example 84 Synthesis of cucurbit[n]urils in hydroiodic acid using lithium iodide and red phosphorous as an added template.

Glycoluril (1.49 hydroiodic acid (57 w/v, 6.9 mL) and lithium iodide and red phosphorous (665 mg and 650 mg respectively) were placed in a reaction flask. Formalin w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 23% cucurbit[6]uril 6% cucurbit[7]uril cucurbit[8]uril 6% cucurbit[9]uril <1% cucurbit[ 10]uril <1% cucurbit[1l]uril <1% Example Synthesis of cucurbit[n]urils in hydroiodic acid using sodium iodide and red phosphorous as an added template.

Glycoluril (1.49 hydroiodic acid (57 w/v, 6.9 mL) and sodium iodide and red phosphorous (745 mg and 650 mg respectively) were placed in a reaction flask. Formalin w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vaccum filtration.

Yield >98 by NMR Approximate Yields by 13 C NMR (mass of recovered product) SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCT/AU00/00412 cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril cucurbit[9]uril cucurbit[l l]uril 57% 9% 29% <1% <1% <1% Example 86 Synthesis of cucurbit[n]urils in hydroiodic acid using potassium iodide and red phosphorous as an added template.

Glycoluril (1.49 hydroiodic acid (57 w/v, 6.9 mL) and potassium iodide and red phosphorous (825 mg and 650 mg respectively) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) cucurbit[6]uril 11% cucurbit[7]uril cucurbit[8]uril 3% cucurbit[9]uril <1% cucurbit[ 10]uril <1% cucurbit[1lluril <1% Example 87 Synthesis of cucurbit[n]urils in hydroiodic acid using rubidium iodide and red phosphorous as an added template.

SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PPr/AUO/00412 Glycoluril (1.49 hydroiodic acid (57 w/v, 6.9 mL) and rubidium iodide and red phosphorous (1060 mg and 650 mg respectively) were placed in a reaction flask. Formalin w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 13 C NMR (mass of recovered product) 58% cucurbit[6]uril cucurbit[7]uril cucurbit[8]uril 2% cucurbit[9]uril <1% <1% cucurbit[1l]uril <1% Example 88 Synthesis of cucurbit[n]urils in hydroiodic acid using caesium iodide and red phosphorous as an added template.

Glycoluril (1.49 hydroiodic acid (57 w/v, 6.9 mL) and caesium iodide and red phosphorous (1300 mg and 650 mg respectively) were placed in a reaction flask. Formalin w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 2 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtation.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) 21% cucurbit[6]uril 28% cucurbit[7]uril 46% cucurbit[8]uril cucurbit[9]uril <1% SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 PCr/AUOO/00412 66 cucurbit[ 0]uril <1% cucurbit[l l]uril <1% Example 89 Synthesis of cucurbit[n]urils in sulfuric acid using potassium sulfate as an added template.

Glycoluril (1.49 sulfuric acid (9 M, 6.9 mL) and potassium sulfate (436 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) cucurbit[5]uril cucurbit[6]uril 66% cucurbit[7]uril 18% cucurbit[8]uril 1% cucurbit[9]uril <1% cucurbit[10]uril <1% cucurbit[l l]uril <1% Example Synthesis of cucurbit[n]urils in sulfuric acid using potassium sulfate as an added template.

Glycoluril (1.49 sulfuric acid (9 M, 6.9 mL) and potassium sulfate (871 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) SUBSTITUTE SHEET (RULE 26) RO/AU PCTAUOO/00 4 1 2 WO 00/68232 67 11% cucurbit[6]uril cucurbit[7luril cucurbitiL'O1urii <1% cucurbit[91uril <1% cucurbitll 1 0)uril <1% cucurbit[ I Iluril <1% ExAMple 91 frcai sn oasul uft sa de Synthesis of cucurbitllflurils in sulficadusnposimslatasnade temiplate.

Glycoluril (1.49 ).sulfuric acid (9 M, 6 .9 mL) and potassium sulfate (1307 mg) were placed in a reaction flask. Formalin (40% wlv) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) cucurbit[5j1uril 33% cucurbit[6)uril 49% cucurbit[7j1uril 16% cucurbitF8luril 2% cucurbit[9luril <1% cucurbitF1Ojuril <1% cucurbitti I 1uril <1% Example 92 Synthesis of cucurbittinlurils in sulfuric acid using potassiumn sulfate as an added temlplate.

Glycoltiril (1.49 sulfuric acid (9 M, 6.9 mL) and potassium sulfate (4350 mg) were placed in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the SUBSTITUTE SHEET (RULE 26)

ROMA

pCrIAUOOIOO 4 1 2 WO 00/68232 68 reaction mixture heated to IO 0 oC for 3 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMIR Approximate Yields by 1 3 C NMR (mass of recovered product) cucurbit[5j1uril 23% cucurbit[6junll 64% cucurbit[7]uril 13% cucurbit[gluril <1% cucurbit[91Iuril <1% cucurbit[lIOlurit <1% cucurbit[l 1]uril <1% Sytei ofccri~~r~i ulfuric acid using lithium sulfate as an added template.

Glycoluril (1.49 sulfuric acid (9 M, 6.9 mL) and lihuIuftD27 g eepae in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) cucurbit[5luril 4% cucurbit[6juril 71% cucurbit[7)uril 24% cucurbit 181uril 1% cucurbit[9]uril <1% cucurbitil~lUril <1% cucurbit[ I hun 1 <1% sUjBsTIT1TE SHEET (RULE 26)

RO/A

PCTIAUOO00412 WO 00/68232 69 Sof cucurbituri in sulfuric acid using lithium sulfate as an added template.

Glycouril (1.49 sufuric acid (9 M, 6.9 mL) and lithium sulfate (2750 mg) were placed Glycoluril (1.49 sulfurc acid m L was a n onon in a reaction flask. Formalin (40% w/v) (1.5 mL) was added in one portion and the reaction mixture heated to 100 0 C for 3 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by "3C NMR (mass of recovered product) cucurbit[6]uril 51% cucurbit[7uril 23% cucurbit[8]uril 1% cucurbit[9]uril <1% cucurbit[101uril <1% cucurbit[ll luril <1% ExamPle 95 Synthesis of cucurbit[nurils in hydrochloric acid using lithium chloride as an added template.

Glycoluril (5 hydrochloric acid (36 w/v, 20 mL) and lithium chloride (746 mg) were placed in a reaction flask. Paraformaldehyde (2.2 g) was added in one portion and the reaction mixture heated to 100C for 4 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield >98 by NMR Approximate Yields by "C NMR (mass of recovered product) 22% cucurbit[6]uril 37% SUBSTITTE SHEET (RULE 26)

RO/AU

PCT/AU 00!004 12 WO 00/68232 cucurbit[7juril 29% cucurbitF8Puril 12% cucurbit[9juril <1% cucurbit[Il0)uril cucurbit[i I uril <1% Example 96usn ihn P Synthesis o .f cucurbit[fllurils in p.toluenesulfonic acid uig ltim

P

toluenesulfoflate as an added template.

(400 mg), ptoluenesulfonic acid (-95 3.5 g) and lithium ptoluenesulfonate (157 mg) were placed in a reaction flask. Formalin (40% w/v) (0.5 mL) was added in one portion and the reaction mixture heated to 1001C for 3 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and collected by vacuum filtration.

Yield 240 mg Approximate Yields by 3 C NMR (mass of recovered product) 18% cucurbitI6Lril cucurbit[7ljlril 26% cucurbitigluril 9% cucurbit[91uril <1% cucurbitil~luril <1% cucurbit[ I I jril <1% Example 7 Synthesis of cucurbitnlills with hydrochloric acid using trifluoroacetic acid as a solvent.

Glycoluril (144 mg), hydrochloric acid (36 w/v, I drop) and trifluoroacetic acid (1 mL) were placed in a reaction flask. ParaformaldehYde (63 mg) was added in one portion and the reaction mixture heated to 901C for 3 hours. The reaction mixture was cooled and the sUBSTIUE SHEET (RULE 26)

RD/M

PCTAUOOIOO

4 1 2 WO 00/68232 71 products were precipitated by addition of methanol and the collected solid was then dried at 90'C overnight and analysed by 1 3 C NMR.

Yild>9 by NMR Approximate Yields by 1 3 C NMR (mass of recoverdpout 46% cucurbit[6juril 54% cucurbit[7]uril <1% cucurbit18luril <1% cucurbitI9]uril <1% cucurbiti i0juril <1% cucurbitil 111uril <1% Exampe 98 iacduigtilooctcaiasaove.

Synthesis of cucurbittfllurils with sulfurcaiusntiflraetccdasaovn.

Glycoluril (144 mg), sulfuric acid (98 w/v, 2 drops) and trifluoroacetic acid (I mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 4 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 80 0 C overnight and analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) cucurbit[5luril <1% cucurbit[ 6 Luril 100% cucurbit[7Iuril <1% cucurbitigluril <1% cucurbit[9juril <1% cucurbit[ 10luril <1% cucu rbit[IlI juril <1% SUBSTITUTE SHIEET (RULE 26)

ROIAJ

PCTIAUO00412 WO o0068232 72 Example 99 Synthesi of cucrbiturils with hydrochloric acid using trifluoroacetic acid as a solvent.

Glycoluril (144 mg), hydrochloric acid (36 w/v, 5 drops) and trifluoroacetic acid (1 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 5 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 80 0 C overnight and analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by "C NMR (mass of recovered product) <1% cucurbit[6]uril 100% cucurbit[7]uril <1% cucurbit[8uril <1% cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Examle s w i h h y d r oc hlori c a ci d u sin g t ri fluoroacetic ac id as a Synthesis of cucurbit[nurils with hydrochloric acid using trifluoroacetic acid as a solvent.

Glycoluril (144 g) and trifluoroacetic acid mL) were placed in a reaction flask. Dry hydrochloric acid gas was then bubbled into the solution for 15 minutes. paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 20.5 hours.

The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 80 0 C overnight and analysed by 3

C

NMR.

Yield >98 by NMR SUBSTITUTE SHEET (RULE 26)

ROAU

PCT/AUOO/OO

412 WO 00/68232 7 Approximate Yiel ds by 1 3 C NMR (mass of recovered product) <1% cucurbit[6luril 100% cucurbit[7jIuril <1% cucurbitFgluril <1% cucurbit[9luril <1% cucurbit~l Ouril <1% cucurbitt II juri <1% ExMa~le 101I Synthesis of cucurbitinlurils with hydrochloric acid using trifluoroacetic acid as a solvent.

Glycoluril (144 mg) trifluoroacetic acid (2 mL) were placed in a reaction flask. Dry hydrochloric acid gas was then bubbled into the solution for 15 minutes. Paraformaldehyde (63 mg) was added In one portion and the reaction mixture heated to 90 0 C for 25 hours.

The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 80 0 C overnight and analysed by 1 3 c

NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) cucurbit[51uril <1% cucurbit[6juril 100% ctacurbit[7]uril <1% cucurbitiI8luril <1% cucurbit[9juril <1% cucurbit~ll0uril <1% cucurbiti I I uril <1% Sythei of0 cubitnIflw isufuric acid using trifluoroacec acid as a solvent.

SUjBSTITUTE SHEET (RULE 26)

ROMAI

PCTAUOOIOO

4 1 2 WO 00/68232 74 Glycl~rl (44 g),suluri acd (99 wlv, I drop) and trifluoroacetic acid (1.5 MnL) wereplaed n areation flask. ParaformaldehYde (63 mg) wsaddi n oto n the reaction mixture heated to 90 0 C for 23 hours. The reacinmxuewsoldadth products were precipitated by addition of methanol and the collected solid was then dried at 80 0 C overnight and analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) <1% cucurbit[6juril 37% cucurbit[7jIuril 39% cucurbitF8luril 24% cucurbit[9)uril <1% cucurbit[ l0luril <1% cucurbit[ I uril <1% Synthe of0 cubtfluls with sulfuric acid using trifluoroacetic acid as a solvent.

Glycolufll (144 mg), sulfuric acid (98o w/v, 2 drops) and trifluoroacetic acid (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 23 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and he collected solid was then dried at 0 C overnight and analysed by 1 3 C NMR.

Yield >98 by NMR Approximate Yields by C NMR (mass of recovered product) <1% cucurbit[6juril 100% cucurbit[7]uril <1% cucurbit[8)uril <1% cucizrbit[9juril <1% cucurbitt~l0juril <1% U8STITUTE SHIEET (RULE 26)

ROIMJ

PCT/AU00100 4 1 2 WO 00/68232 cucurbit[ll]uril <1% Synthesis of cucurbitnrils with sulfuric acid using trifluoroacetic acid as a solvent.

Glyc ril (144 sulfuric acid (9 wv, 5 drops) and trifluoroacetic acid (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to C for 23 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 80 0 C overnight and analysed by 13C

NMR.

Yield >98 by NMRdt) Approximate Yields by C NMR (mass of recovered product) <1% cucurbit[6]uril 48% cucurbit[71uril 32% cucurbit[8]uril cucurbit[9]uril <1% cucurbit[ 10uril <1% cucurbit[l l]uril <1% Synthesis of cucurbit[nurils with sulfuric acid using trifluoroacetic acid as a solvent.

Gycouri (144 sulfuric acid (9 w/v, 5 drops) and trifluoroacetic acid (1.5 mL) Glycoluril (144 mg), sulfuric ac iarfmdey (63 mg) was added in one portion and were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90C for 3 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 80 0 C overnight and analysed by 13C NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) <1% SUBSTITUTE SHEET (RULE 26)

RO/AU

PCII/AUOOIOO

4 1 2 Wo 00/68232 cucurbit[61uil cucurbit[7luril cucurbit[8)uril cucurbit[9]Iuril cucurbit~ IOluril cucurbit[i I Ijuril 57% 28% <1% Example 106 frcai sn rfuroccai saslet Synthesis of cucurbitllnlurils with sulfrcai sn rfurae~cai saslet 0 Glycoluril (144 mg), sulfuric acid (fuming, 3 drops) and trifluoroacetic acid (1.5 mL) were placed in a reaction flask. ParaformaldehYde (63 mg) was added in one portion and the reaction mixture heated to 90-C for 25.5 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 90 0 C overnight and analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) <1% cucurbit[6juril 47% cucurbit[71uril 34% cucurbit[8)uril cucurbit[91urii <1% cucurbiti I0juril <1% cucurbit[l IlI uril <1% Synthei fcuubt07rswt sulfuric acid using methanesulfonic acid as a solvent.

Glycoluril (144 mg), sulfuric acid (98 w/v, 1 drop) and methaflesulfonic acid (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90'C for 26 hours. The reaction mixture was cooled and the SiUBSTIfIfTE SHEET (ROLE 26)

ROMA

PCT/AU 00100412 WO 00/68232 7 products wrpeiitated by addition of ethanol and the collected solid was then dried at '0 0 C overnight and analysed by 1 C NMR.

Yield >98 by NMRR(msofrcvedpdut Approximate Yields by 3 C NMR ms frcvrdpout cucurbitl6luril 62% cucurbit[71uril 33% cucurbit[8luril <1% cucurbitt9luril <1% cucurbit~ 1 Quril <1% cucurbit[ I I uril <1% Snhe of cuubi lrs with sulfuric acid using methafleulfonic acid as a solvent.

Glycoluril (144 mg), sulfuric acid (986 w/v, 5 drops) and methaflesulfonic acid (1.5 mL) wre placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and te ratomitrheedto 90 0 C for 26 hours. The reaction mixture was cooled and the p0trducto we xtre eiated byadto f ethanol and the collected solid was then dried at go 0 C overnight and analysed by' 3 C NMR.

Yield >98 by NMR 3sofrcvedpdut Approximate Yields by 1 C NMR (mass frcvrdpout 7% cucurbit[6Iuril 61% cucurbit[7)uril 32% cucurbitII8luril <1% cucurbit[9]uril <1% cucurbit[l0juril <1% cucurbit[i I Iuril <1% SUBSTITUTE SHEET (RULE 26)

ROIM&

PCT/AU00/00412 WO 00/68232 78 Example 109 Synthesis of cucurbit[n]urils with sulfuric acid using trifluoroacetic acid as a solvent.

Glycoluril (144 mg), sulfuric acid (fuming, 3 drops) and trifluoroacetic acid (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 26 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and the collected solid was then dried at 0 C overnight and analysed by 'C NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) <1% cucurbit[6]uril 47% cucurbit[7]uril cucurbit[8]uril 17% cucurbit[9]uril <1% <1% cucurbit[l l]uril <1% Example 110 Synthesis of cucurbit[n]urils with sulfuric acid using trifluoroacetic acid as a solvent Glycoluril (144 mg), sulfuric acid (fuming, 3 drops) and trifluoroacetic acid (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 26 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and the collected solid was then dried at 0 C overnight and analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) <1% cucurbit[6]uril 47% SUBSTITUTE SHEET (RULE 26) RO/AU

PCTAUOO/OO

4 1 2 wo 00/68232 cucurbiti7juril cucurbit[gluril cucurbit[9luril cucurbit[lOluril cucurbitl I Iluril 32% 21% <1% <1% <1% Synthesis of cucurbitIfliurils withsufrcaiuin iiitifortholsa solvent G0 cl~i (14m) nufrc acid (98 wlv, I drop) and i,,1-trifluoroethanol (1.5 mL) were placed in a reaction flask. ParaformaldehYde (63 mg) was added in one porto an the reaction mixture heated to 90 0 C for 25 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and the collected solid was then dried at 80 0 C overnight and analysed by 3 C NMR.

Yield >98 by NMR 3pout Approximnate Yields by 'C NMR (mass of recovered pout 17% cucurbitll6]uril 72% cucurbit[7]uril 11% cucurbit8gluril <1% cucurbit9]Lril <1% cucurbit[1O]uril <1% cucurbitt II uril <1% Synt-e of12 rbtnUr~wt sulfuric acid using ,l,1-trifluoroethanol as a solvent Glycoluril (144 mg), sulfuric acid (98 w/v, 5 drops) and 1,1,1-trifluoroethanol (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90'C for 25 hours. The reaction mixture was cooled and the SUBSTITUTE SHIEET (RULE 26)

ROMA

PCT/AUO004 12 WO 00/68232 products were pecipitated by addition of ethanol and the collected solid was then dried at 0 C overnight and analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) cucurbit[51uril 89% cucurbit[6]uril 11% cucurbit[7luril <1% cucurbitF8luril <1% cucurbit[91uril <1% cucurbitl lOuril <1% cucurbit[II hunl <1% Synthesis of cucurbit[nlurils with sulfuric acid using 19,1~~nlooehnla solvent.

Glycoluril (144 mg), sulfuric acid (98 w/v, I drop) and l,l,-trifluoroethanol (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 170 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and the collected solid was then dried at 90"C overnight and analysed by

NMR.

Yield >98 by NMR Approximate Yields by 3 C NMR (mass of recovered product) <1% cucurbittI61uril 100% cucurbit[7]uril <1% cucurbitigluril <1% cucurbit[9juril <1% cucurbitt~l0juril <1% cucurbit[i I I uril <1% SUBSTITUTE SHEET (RULE 26)

ROM/A

WO 00/68232 PCT/AU00/00412 81 Example 114 Synthesis of cucurbit[n]urils with sulfuric acid using 1,1,1-trifluoroethanol as a solvent.

Glycoluril (144 mg), sulfuric acid (98 w/v, 5 drops) and 1,1,1-trifluoroethanol (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 170 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and the collected solid was then dried at 80 0 C overnight and analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by "3C NMR (mass of recovered product) <1% cucurbit[6]uril 100% cucurbit[7]uril <1% cucurbit[8]uril <1% cucurbit[9]uril <1% <1% cucurbit[ll]uril <1% Example 115 Synthesis of cucurbit[n]urils with sulfuric acid using trifluoro acetic acid as a solvent and o-carborane as a template.

Glycoluril (144 mg), sulfuric acid (98 w/v, 1 drop), o-carborane (18 mg) and trifluoro acetic acid (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 25.5 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 80 0 C overnight and analysed by 13C NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) SUBSTITUTE SHEET (RULE 26) RO/AU WO 00/68232 82PCT/AUOO/0041 2 <1 cucurbit uril 57% cucurbit[7]uril 32% cucurbit[8juril 11% cucurbit[9]uril 1 cucurbit[ 1 Oluril <1% cucurbit[1 I Iuril <1% Example 116 Synthesis of cucurbittInlurils with sulfuric acid using trifluoro acetic acid as a solvent and o-carborane as a template.

Glycoluril (144 mg), sulfuric acid (98 w/v. 5 drops), o-carborane (18 mg) and trifluoro acetic acid (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90'C for 25.5 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 80'C overnight and analysed by 1 3 C NMR.

Yield >98 by NMR Approximate Yields by 1'3C NMR (mass of recovered product) 1 cucurbitll6]uril cucurbit[7]uril 32% cucurbit[8]uril 17% cucurbit[9]uril <1% cucurbit[ 1 0] uril <1% cucurbit[ II]uril <1% Example 117 Synthesis of cucurbitiniurils with sulfuric acid using trifluoro acetic acid as a solvent and o-carborane as a template.

SUBSTITUTE SHEET (RULE 26) RD/AU PC-TAUoo/ 0 0 4 1 2 WO 00/68232 83 GlycolUril (144 mg), sulfuric acid (98 wlv I drop), o-carborane (18 mg) and trifluoro acetic acid (1 .5 mL) were placed in a reaction flask. paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 20 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 90-C overnight and analysed by 3 c Yield >98 by NMR Approximate Yields by' 3 C NMR (mass of recovered product) <1% cucurbit1I6juril 51% cucurbitll7luril 39 cucurbitluril cucurbit[9]uril <1% cucurbiti 0]1unil <1% cucurbit[ I luril <1% ExaM2e 118 Synthesis of cucurbit[l~urils with sulfuric acid using tritluoro acetic acid as a solvent and o-carborane as a template.

Glycoluril (144 mg), ufrcai 9 w/v, 5 drops), o-carborane (18 mg) and trifluoro, acetic acid (1.5 ml-) were placed in a reaction flask. nc~fraleyd 63m) was added in one portion and the reaction mixture heated to 90 0 C for 20 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 8011C overnight and analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by 1 3 C NMR (mass of recovered product) <1% cucurbit[ 6 Puril 47% cucurbit[7buril 38% cucurbitE8luril cucurbit[9j1uril <1% SUjBSTITUTE SHEET (RULE 26) ROM WO 00/68232 84 PCT/AU00/00412 cucurbit[1 0]uril <1% cucurbit[ l]uril <1% Example 119 Synthesis of cucurbit[n]urils with sulfuric acid using trifluoro acetic acid as a solvent and o-carborane as a template.

Glycoluril (710 mg), sulfuric acid (98 w/v, 7.5 mL), o-carborane (18 mg) and trifluoro acetic acid (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 24.5 hours. The reaction mixture was cooled and the products were precipitated by addition of methanol and the collected solid was then dried at 80 0 C overnight and analysed by 3 C NMR.

Yield >98 by NMR Approximate Yields by 13C NMR (mass of recovered product) 3% cucurbit[6]uril 53% cucurbit[7]uril 33% cucurbit[8]uril 11% cucurbit[9]uril <1% cucurbit[l0]uril <1% cucurbit[ lluril <1% Example 120 Synthesis of cucurbit[n]urils with sulfuric acid using methanesulfonic acid as a solvent and o-carborane as a template.

Glycoluril (144 mg), sulfuric acid (98 w/v, 1 drop), o-carborane (18 mg) and methanesulfonic acid (7.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 22.5 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and collected using a centrifuge.The collected solid was then dried at 80 0 C overnight and analysed by 3 C NMR.

SUBSTITUTE SHEET (RULE 26) RO/AU PC-T/AUOO/0O 4 1 2 WO 00168232 yield >98 by NMR 1 frcvrdpout Approximate Yields by 'C NMR (mass %ofrcvedpdc) cucurbit[5j1uril 7% cucurbit[6juril 53% cucurbitt7l1uril cucurbitI8lufll cucurbi[91uril <1% cucurbiti IlOluril <1% cucurbit[ II lufl <1% Synthei of2 cuuritnurils with sulfuric acid using nethaflesulfonic acid as a solvent and o-carborafle as a template.

abrn 1 g n Glycoluril (144 mg), sulfuric acid (98 w/v, 5 drops), o-Crbrn (1 Vg n methanesulfonic acid (1.5 mL) were placed in a reaction flask. Paraformaldehyde (63 mg) was added in one portion and the reaction mixture heated to 90 0 C for 22.5 hours. The reaction mixture was cooled and the products were pecipitated by addition of ethanol and collected using a centrifuge.The collected solid was then dried at 90 0 C overnight and analysed by 13C

NMR.

Yield >98 by NMR Approximate Yields by '1C NMR (mass of recovered product) 6% cucurbit[6juril 56% cucurbitllflunll cucurbit8gIufll 8% cucurbit[I91uril <1% cucurbit~l0juril <1% cucurbit[ I I lril <1% SUBlSVTIUTE SHEE-T (RULE 26)

ROMA

PCT/AU00/0041 2 WO 00/68232 86 Examples 122 Preparation of Substituted Cucurbiturils Substituted glycolurils of the following formulae were used in this synthesis: Examples of mixed cucurbit[s,u]urils 0 0

O

Rp-N N 0R' 0 'tetracyclic diether' R=R'=CH 3 dimethyl;

R=R'=C

6 Hs, diphenyl; dihydrophenathroline.

A mixture of the dimethyl tetracyclic diether (107mg) and caesium chloride (71mg) in concentrated hydrochloric acid (0.5ml) was heated at 100°c for lhr 40mins. to give a >85% yield of the decamethylcucurbit[5]uril and of the other sizes.

A mixture of the dimethyl tetracyclic diether (97 mg) and glycoluril (54mg) in concentrated hydrochloric acid (0.5ml) was shaken at room temperature for 1hr then heated at 100 0 C for lhr 40 mins., at which time reaction was complete. The yield was determined by 3 C NMR to be >95% for a mixture of the methyl substituted cucurbit[s,u]urils, where s,u equalsl, 4 2,3; 3,2; 4,1; 1,5; 2,4; 3,3; 4,2; 5,1; 1,6; 2,5; 3,4; 4,3; 5,2; 6,1; and s represents the unit carrying the substitution. The composition of s to u was determined by ES-MS.

A mixture of the dimethyl tetracyclic diether (119mg), glycoluril (66mg) and caesium chloride (78mg) in concentrated hydrochloric acid (0.5ml) was shaken at room temperature for 1 hr then heated at 100°C until the reaction was complete at lhr SUBSTITUTE SHEET (RULE 26) RO/AU 87 The yield by t 3 C NMR was near quantitative. The composition of s to u was observed to be different but not accurately determined.

The diphenyl tetracyclic diether (1.9gm), gylcoluril (0.71gm) and para toluene sulphonic acid (10.4gm) were combined and heated to 120°C for 3hr. While still .hot the mixture was poured into methanol (150ml) and precipitate collected by filtration. The solid material collected was dissolved in a minimum volume of hot.formic acid and this solution was poured into hot water and the precipitate collected to give 1.32gm of the phenyl substituted cucurbit[s,u]urils, where s,u equals 1,4; 2,3; 2,4; 3,3 and s represents the unit carrying the substitution.

To a suspension of the dihydrophenathroline glycoluril (530mg) in aqueous formaldehyde was added 8M hydrochloric acid (1.8ml) and the mixture stirred at room temperature for 5hr. Then glycoluril (253mg) was added and the mixture heated at 100°C for 3hr. 13C NMR of the mixture indicated a 20-30% formation of the dihydrophenanthroline substituted cucurbit[s,u]urils.

Variations of these methods could conceivably be applied to any substituted glycoluril where the side chain is stable to the reaction conditions.

Template function The controlling factors for achieving the synthesis of a variety of cucurbiturils of differing unit sizes are postulated to be primarily derived from a templating effect. For 25 example, an anidfn is apparenfly'hela'ri p6sision bya nietil.cation or the anmmonium ion.

The metal cations coordinate to the carbonyls of the forming cucurbituril intermediates (such as F, G1 and G2) or in the case of the ammonium cation is held through hydrogen bonding to the carbonyls of these intermediates. The larger iodide anion and its tight pairing with the lithium cation favours cucurbit[7]uril but for the more diffuse.ion pairs of sodium, potassium, or rubidium, iodide does not control the size by templating around the anion but rather templating is predominantly controlled by the cation although this effect diminishes as the anion decreases in size. There has been found a common trend where the equilibrium shifts by varying combinations of anion and cations. The proton from the acid not only serves as a catalyst but also acts as a cation capable of hydrogen bonding to the **oo PCT/AU00/00412 WO 00/68232 88 carbonyls of the forming cucurbit[n]uril and also controlling the placement of anions. The degree of the competing influence between these protons and any added cations affects the equilibrium and hence the product distribution. Cucurbit[n]urils where n>7 appears to be controlled by a templating around a cation/anion cluster rather than a single ion pair.

Electrospray mass spectroscopy of larger cucurbiturils supports this showing multi charged cationic complexes.

Further influences upon the equilibrium and hence the product out come is the precipitation of product complexes. For example increasing the concentration by 10 times of a cation such as lithium in sulphuric acid changes the relative proportion of cucurbit[5]uril from 5% to 25% as a consequence of the precipitation of the lithium complexes.

In addition to equilibrium shifts caused by changes to the cation concentration the equilibrium is also affected by the formation of the cucurbit[6]uril iodine complex which occurs under the reaction conditions where hydriodic acid is used and hydriodic acid decomposes to form iodine. The addition of red phosphorus eliminates this effect by the in situ reduction of the iodine generated.

In addition, we have found that a wide range of other inorganic and organic compounds can be used as templates. These affect the equilibrium through a variety of subtle effects including ion-dipole, diople-diople and hydrogen bonding, hydrophobic and weak Van der Waals interactions. In essence, any material or compound stable to the reaction conditions could act as a potential template.

Industrial applicability The potential uses for cucurbit[n]urils are large with academic, industrial, analytical and pharmaceutical applications. As a class these molecules can be favourable compared to the cyclodextrins because both molecular systems posses a hydrophobic cavity with polar end caps. Cyclodextrins have been used in a wide range of applications including slow release drugs, odour entrapment agents in plastic films, and enzimimics for synthesis.

It is believed that cucurbit[n]urils will be of use in similar areas where benefit can be taken of the ability of the cucurbit[n]urils to take up molecules or compounds into there central cavity. Such potential uses may include: SUBSTITUTE SHEET (RULE 26) RO/AU PCT/AU00100 4 1 2 WO 00/68232 89 Environmental (water and soil Remediation by the binding of polluting products and their removal: Preventative, eg, by binding of potential pollutants before wastes are released to the environment; Uses in biodegradable polymers.

Domestic and Public Incorporation into polymers as odourisers, releasing fragrances slowly over time; Or incorporated into polymers to trap unpleasant odours or toxic vapours Encaptulation of bleaching and whitening agents.

Food Flavour enhancers; Flavour optimisers. hence hiding unpleasant flavours: Polyphenol removal to reduce discolouration of juices.

pharmaceutical Slow release drugs, limiting side effects and reducing the frequency of doses; Increasing drug stability in vivo or on the shelf; Detoxification, for example, decreasing stomach irritations, or the treatment of chemical allergens by encaptulation.

SUBSTITUTE SHEET (RULE 26)

RO/AU

pCTIAUOO0041 2 WO 00/68232 Agricultural/horticultural Slow release of herbicides and pesticides; Stabilisation of agricultural chemicals against light and heat Manufacturnng Enzyme/catalyst mimics; Regioselective control over reaction products; Manipulation of paint and polymer products; Chromatographic columns for chemical purification; Analytical tools and devices; Printing and photography.

Miscellaneous Volatility reduction, for storage, safety, or use; Uses for insensitive munitions manufacture; Forensic science.

Cucurbit[nlurils are thermally more robust than cyclodextrins and are stable to strong acid solutions unlike cyclodextrins.

The present inventors have also found that cucurbit[6uril and cucurbit[7]uril can both bind dioxane aqueous solutions. This dioxane binding property can form the basis of processes for the removal of dioxane. According to a further aspect of the present invention, the SUBSTWIT SHEET (RULE 26)

RO/AU

PCTIAUOO/0 041 2 WO 00/68232 91 present invention provides a process for removing dioxane from a fluid comprising contacting the fluid with cucurbit[6]uril and/or cucurbit[7]uril.

The physical removal of dioxane could take place using one of the following techniques: Cucurbit[ 6 or 7]uril bound to a non-reactive solid support (silica or alumina) where the dioxane would bind to the cucurbit[ 6 or 7]uril and then be removed from solution by simple filtration to collect the solid support.which wo SA solution of cucurbit[ 6 or 7]uril placed in dialysis tubing which would allow the passage of dioxane into the solution where it would be bound by the cucurbit[ 6 or Incorporation of the cucurbit[ 6 or 7uril into a solid clay support and use filtration techniques to remove bound dioxane.uld be entrapped by the Incorporation into a polymer film. In this case the dioxane would be entrapped by the cucurbit[ 6 or 7uril inside the polymer film. When the capacity of the film has been reached it is simply removed from contact with the product stream.

In all cases the material itself could be regenerated for repeated use.

If the dioxane is contained in the solid, for example in dioxane/contaminated soil, rthe further step of washing the soil the process of this aspect of the invention may comprise the further step of washing the soil with a fluid to thereby cause the dioxane to go into the fluid and subsequently treating the fluid in accordance with this aspect of the invention.

has shown uptake of carbon monoxide. Accordingly, the invention further provides a method for removing carbon monoxide from a liquid or vapour containing carbon monoxide by contacting the liquid or vapour with The present invention provides a method for producing a range of cucurbit[n]urils and cucurbit[s,u]urils- The synthesis method results in the production of a number of cucurbit[njurils and cucurbit[s,u]urils that have never before been produced or isolated.

Separation is possible via chromatography and/or selective precipitation. The product Separation is possible via c reaction conditions over a cucurbitfn]urils and cucurbit[s,uurils are stable to vigorous reaction conditions over a wide range of PH values. They are soluble in aqueous acid or aqueous salt solutions. The SUBSTITUTE SHEET (RULE 26)

RO/AU

92 method gives cucurbiturils in much larger yields than previously possible. The use of templating compounds allows a degree of control over the relative amounts of the different cucurbit[n]urils being produced.

Those skilled in the art will appreciate that the invention described herein may be susceptible to variation and modifications other than those specifically described. It is to be understood that the present invention encompasses all such variations and modifications that fall within its spirit and scope.

It is to be understood that a reference herein to a prior art document does not constitute an admission that the document forms part of the common general knowledge in the art in Australia.

Claims (72)

1. 2. A method for producing a cucurbit[n] uril, where n is 4, 5,6, 7, 8,9, 10, 11 or 12, excluding unsubstituted cucurbit[6]uril and decamethylcucurbit[5]uril, comprising mixing substituted and/or unsubstituted glycoluril with an acid and a compound that can form methylene bridges between glycoluril units, and heating the mixture to a temperature of from 200 to 120'C to thereby form a cucurbit[nluril.
2. 3. A mtthod as claime d in claim 1 or claim 2 whcreini n is from 4 to
3. 4. A method as Claimed in any one of claims 1 to 3 f urther comprising adding a Ltmtilatiqg comapound to tht: mixture. A method as claimtd in claim 4 wherein said tremnplatirg compound is &elected fro im chlrieliu chloride. s~odium hoid-ptssunhlr rubidiumn chloride, caesium chloride, ammnonium chloride., lithium bromnide, sodium to bromnide-, potassium bromide, rubidium bromide-, ca5§Urn bromide, lithium iodide, sodiumn iodid=, potassium iodidt, rubidium iodide, c-atsium. iodlide, potassium sulfate, lithium .sulfate, rtrabutylainmoniurn chloride, teviaerhylammonum GOD:chloride, o-carborane, thioacetamide, I-napthyl) ethyl enediamine, 2,2' -biquinoline, p-bromoaniline, taurine, blue tetrazolium, 2 -amino-3-methyl benzoic acid, indol-3- cysteine, 4 -acetamidoaniline, p-aminophenol, acetamide, 4- aminoacetophenone, 4-dimethyl aminobenzaldehyde, 2 -aminobenzimidazol, bis-(4,4 bipyridyl)-ci, (x-p-xylene, red phosphorus, and lithium p-tolunsloae
4. 6. A rrtthcd as caiued in :lairm 4 wherein Lh._ enmpjati'cmono~ aL .94
5. 7. A method as claimned in claim 6 wh~ein tbe anion of the salt coITCspoDflz to Ct anion of the acid in-the itue R. A method as claimed in any, one of claims 3 to 7 whbercin two or more rcamplating compounds, arm added to the niixture.
6. 9. A rmethod as claimcrd in any one of the preceding claims wherei th= acid comprises a stroagmine=ral acid bo' a GrnOn organic acid.
7. 10. A method as claiied in any onc of tht p=eding claims whemrcin the acid is selected from sulfuric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, de-utzrattd sulfuric. acid, phosphoric. acid, p-toluenesdlfonic acid., and =mhne sulfonic acid.
8. 11. A method as claimed in any ont of the prcedAing claims furthe-r comprising adding a So] vent Mo reaction mixtura.
9. 12. A meT Lhod as claimetd in -claim 11 'wherein th-e- solvent is &electe iron trifluoroaceric acid-, methanes&ulfonic acid and l,1,4.-trdifuoroetbanol.
10. 013. A method as claimad in any one the Drecedingf -laims wherein the compound thai 0 ~can fortn nethb11en- bridges betwn glycoluril units comp'zists formaldrhyde. paraformaldehyde, trioxane or one or more precursors for formaldehyde. Ii 14. A metthod as-claimed in any one of the prectding claims wherein the mixture Is heated -to a Llrptrat=lr of from 20'C to I I O'C. A mthod as claimed in claim 24 whc-rein the mixture is hezatead to a tcmp:Tature oif fromOM to' 1] O'C. I 6. Amethod z: claimed6 in zlaim 14 -wherzin the mL'mtur hn-:d io a _MIDe5atUr cc frOM 90' LO II O.
11. 17. A method as claimed in any one of the preceding claims wherein the mixture is heated for between 1 hour and 24 hours.
12. 18. Cucurbit[n]uril, where n 4 to 12, excluding unsubstituted cucurbit[6]uril and
13. 19. A substituted cucurbituril of the formula cucurbit[s,u]uril, wherein s number of substituted glycoluril units and u number of unsubstituted glycoluril units and s u 4 to 12, but excluding A method for producing a substituted cucurbituril of the formula cucurbit[s,u]uril, where s number of substituted glycoluril units, u number of unsibstituted glycoluril units and s u 4 to 12, but excluding decamethylcucurbit[ 5 ]uril, comprising mixing substituted glycoluril and unsubstituted glycoluril with an acid and a compound that can form methylene bridges between glycoluril units and heating the 1 mixture to a temperature of from 20° to 120 0 C to thereby form a cucurbit[s,u]uril.
14. 21. A method as claimed in claim 20 wherein the substituted glycoluril has a formula C) SHNNH HN NH .0 wherein R 1 and R 2 are the same or different and are selected from an optionally 1substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon 2 radical or a heterocyclyl radical or Ri and R 2 form a cyclic hydrocarbon radical. 96
15. 22. A method as claimed in claim 21 wherein R, and R 2 are the same or different and are selected from alkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals.
16. 23. A mnethod as c*lairned in any one of claims 2D to 22 wherein s u 4 cc)
17. 24. A method as claimed in any one of claim 20 to 23 further comnprising adding a tonating com.Dound to tLhe rnixcture-
18. 25. a. a a A rethod a; clairmd in -claim 24 whmrein said teznplating compound is selzcted from ammoaniurn Chloride, lithium chloride-, sodium chloride, potaskiUrn chloridc, rubidlurn chloi-idz, caesium chloride, ammonium chloride, IIHiumbrorridt, sodium bromaide, potassium bromid-, rubidium bromidt, enesium bromidr., hliium iodide, soffium iodidt, potassium iodide, rubidium iodide,. =asium iodide, potassi~um .sulfate, lithium sulfatt, tetrabutylammoniurn chloride, T'traethylamrmonium chloride, o-carborane, thioacetamide, 1-napthyl) ethyl enediamnine, 2,2' -biquinoline, p-bromoaniline, taurine, blue tetrazolium, 2-amino-3-methyl benzoic acid, indol-3- aldeyde, cysteine, 4-acetamidoani line, p-aminophenol, acetamide, 4- aminoacetophenone, 4-dimethylaminobenzaldehyde, 2-aminobenzimidazol, bis-(4,4' bipyridyl)-cc, c'-p-xylene, red phosphorus, and lithium p-toluenesulfonate. A a a. a a a
19. 26. A metho~d as claimed inclairn 24 where said TentolaTing, compound is a salt.
20. 27. A method as clamed in claim 26 whercin -the an~ion of the salt CoCrrCSnonds to the anion of the acid in the mixture.
21. 29. .A method as claimed in any one- of clairis 24 to 27 wherein two or mnore- tenplating compounds are adde-d to dt mnixturt. 29' A mthod a- clairned in any one of claims 20 to 28 wherei'n tht acid comrast.L tsuion(g mirteraJ aid or a .;u-ong o=-rg_ald. Received 20 August 2001 A method as claimed in any one of claims 20 to 29 wherein the acid is selected from sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, deuterated sulfuric acid, phosphoric acid, p-toluenesulfonic acid, and methane sulfonic acid.
22. 31. A method as claimed in any one of claims 20 to 30 further comprising adding a solvent to the mixture.
23. 32. A method as claimed in claim 31 wherein the solvent is selected from trifluoroacetic acid, methane sulfonic acid and 1,1,1-trifluoroethanol.
24. 33. A method as claimed in any one of claims 20 to 32 wherein the compound that can form methylene bridges between glycoluril units comprises formaldehyde, paraformaldehyde, trioxane or one or more precursors for formaldehyde.
25. 34. A method as claimed in any one of claims 20 to 33 wherein the mixture is heated to a temperature of from 200 to 110 0 C.
26. 35. A method as claimed in claim 34 wherein the mixture is heated to a temperature of from 600 to 110 0 C.
27. 36. A method as claimed in claim 34 wherein the mixture is heated to a temperature of from 800 to 110 0 C.
28. 37. A method as claimed in any one of claims 20 to 36 wherein the mixture is heated for between 1 hour and 24 hours.
29. 38. A substituted glycoluril of the formula: AMENDED SHEE, IPEAAU PCT/AU00/00412 Received 20 August 2001
30. 39. A substituted glycoluril of the formula: 0 HN NH O A method for separating a mixture of cucurbit[n]urils, where n 4 to 12, by mixing the mixture of cucurbit[n]urils with a salt solution, in which at least one of the cucurbit[n]urils, but not all of the cucurbit[n]urils, dissolves, and separating solids from the solution.
31. 41. A method as claimed in claim 40 further comprising recovering at least one cucurbit[n]uril from the solids.
32. 42. A method as claimed in claim 40 further comprising recovering at least one cucurbit[n]uril from solution.
33. 43. A method as claimed in claim 42 further comprising passing the solution into contact with an ion exchange resin to thereby absorb dissolved cucurbit[n]urils onto the resin and subsequently eluting said cucurbit[n]urils from the resin. AMENDED SHEEI IPEAIAU PCT/AU00/00412 Received 20 August 2001 99
34. 44. A method for separating a mixture of cucurbit[n]urils, where n 4 to 10, by dissolving the mixture of cucurbit[n]urils and subjecting the thus-formed solution of cucurbit[n]urils to chromatographic separation.
35. 45. A method for separating a mixture of cucurbit[s,u]urils where s number of substituted glycoluril units, u number of unsubstituted glycoluril units and s u 4 to 12 comprising dissolving the mixture of cucurbit[s,u]urils and subjecting the thus-formed mixture of cucurbit[s,u]urils to chromatographic separation.
36. 46. A method as claimed in any one of claims 1 to 17 or 20 to 37 wherein the acid has a concentration of at least
37. 47. A method as claimed in any one of claims I to 17 or 20 to 37 or 46 wherein the mixture is allowed to stand at room temperature until a gel is formed prior to heating. AMENDED SHEL IPENAU 100 00396388]
38. 48. A cucurbit[n]urilofthe formula wherein n 4 to 12, and wherein, for each unit of the formula (II) 20 a 0 FI making up the cucurbit[n]uril, R and R 2 are independently selected from H, an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical or a heterocyclyl radical, or R 1 and R 2 form a cyclic hydrocarbon radical, but excluding unsubstituted cuicurbit[6]uril and
39. 49. A cucurbit[n]uril according to claim 48 wherein for each unit of the formula (II) making up the cucurbit[n]uril, RI and R 2 are both H, and n is 4, 5, 7, 8, 9, 10, 11 or 12. A cucurbit[n]uril according to claim 48 wherein for each unit of the formula (II) making up the cucurbituril, R 1 and R2 are both H, or Ri and R 2 are independently selected from an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical or a heterocyclyl radical, or Ri and R 2 form a cyclic hydrocarbon radical. 101 003963881
40. 51. A method for producing a cucurbit[n]uril of the formula as defined in claim 48, but excluding unsubstituted cucurbit[6]uril and decamethylcucurbit[5]uril, the method *comprising mixing a glycoluril of the formula (III), or two or more glycourils of the formula (III), HN NH R 2 (fl) IO HN. NH O wherein Ri and R 2 are independently selected from H, an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical or a heterocyclyl radical, or Ri and R 2 form a cyclic hydrocarbon radical, with an acid and a compound that can form methylene bridges between glycoluril units, and heating the mixture to a temperature of from 200 to 120 0 C to thereby form cucurbit[n]urils of formula
41. 52. A method as claimed in claim 51 wherein R 1 and R 2 are the same or different and are selected from alkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals.
42. 53. A method as claimed in claim 51 wherein R 1 and R 2 are H. 25 54. A method as claimed in any one of claims 51 to 53 wherein n 4 to
43. 55. A method as claimed in any one of claims 51 to 54 further comprising adding a templating compound to the mixture.
44. 56. A method as claimed in claim 55 wherein said templating compound is selected from ammonium chloride, lithium chloride, sodium chloride, potassium chloride, rubidium chloride, caesium chloride, ammonium chloride, lithium bromide, sodium bromide, potassium bromide, rubidium bromide, caesium bromide, lithium iodide, sodium iodide, potassium iodide, rubidium iodide, caesium iodide, potassium sulfate, lithium sulfate, 9*eo9S 102 003963881 tetrabutylammonium chloride, tetraethylammonium chloride, o-carborane, thioacetamide, N-(1-napthyl) ethylenediamine, 2,2'-biquinoline, p-bromoaniline, taurine, blue tetrazolium, 2-amino-3-methyl benzoic acid, indol-3-aldehyde, cysteine, 4-acetamidoaniline, p- aminophenol, acetamide, 4-aminoacetophenone, 4-dimethylaminobenzaldehyde, 2- aminobenzimidazol, bis-(4,4'-bipyridyl)-, a'-p-xylene, red phosphorus, and lithium p- toluenesulfonate.
45. 57. A method as claimed in claim 55 wherein said templating compound is a salt.
46. 58. .A method as claimed in claim 57 wherein the anion of the salt corresponds to the mion of the acid in the mixture.
47. 59. A method as claimed in any one of claims 55 to 58 wherein two or more templating compounds are added to the mixture. A method as claimed in any one of claims 51 to 59 wherein the acid comprises a strong mineral acid or a strong organic acid.
48. 61. A method as claimed in any one of claims 51 to 60 wherein the acid is selected 20 from sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, deuterated sulfuric acid, phosphoric acid, p-toluenesulfonic acid, and methane sulfonic acid.
49. 62. A method as claimed in any one of claims 51 to 61 further comprising adding a solvent to the mixture. S 63. A method as claimed in claim 62 wherein the solvent is selected from trifluoroacetic acid, methane sulfonic acid and 1,1,1-trifluoroethanol.
50. 64. A method as claimed in any one of claims 51 to 63 wherein the compound that can .2::30 form methylene bridges between glycoluril units comprises formaldehyde, paraformaldehyde, trioxane or one or more precursors for formaldehyde. A method as claimed in any one of claims 51 to 64 wherein the mixture is heated to a temperature of from 20" to 11 0"C. 103 003963881
51. 66. A method as claimed in claim 65 wherein the mixture is heated to a temperature of from 60" to 110OC
52. 67. A method as claimed in claim 65 wherein the mixture is heated to a temperature of from 80" to 110°C.
53. 68. A method as claimed in any one of claims 51 to 67 wherein the mixture is heated for between 1 hour and 24 hours.
54. 69. A method of binding a gas or volatile compound in a cucurbit[n]uril, where n 4 to 12, said method comprising contacting the gas or volatile compound with the cucurbit[n]uril to form a cucurbituril complex of the gas or volatile compound, provided that when the volatile compound is an organic molecule, the cucurbit[n]uril is not unsubstituted cucurbit[6]uril. A method for removing dioxane from a fluid, the method comprising contacting the fluid with unsubstituted cucurbit[6]uril, unsubstituted cucurbit[7]uril or a mixture of unsubstituted cucurbit[6]uril and unsubstituted cucurbit[7]uril, to form a cucurbituril complex of dioxane.
55. 71. A method for removing carbon monoxide from a liquid or vapour, the method comprising contacting the liquid or vapour with unsubstituted cucurbit[5]uril to form a cucurbituril complex of carbon monoxide.
56. 72. A method for producing a cucurbit[n]uril, where n is 4 to 12, comprising mixing a diether of the formula 2, or two or more diethers of the formula 2, R1 -N K- R2 (2) C* 0 0 Io oqf 104 003963881 104 wherein R 1 and R 2 are independently selected from H, an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical or a heterocyclyl radical, or R 1 and R 2 from a cyclic hydrocarbon radical, and optionally a glycoluril of the formula (III) or two or more glycolurils of the formula (in) 'O HN NH R2 wherein R 1 and R 2 are independently selected from H, an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical or a heterocyclyl radical, or R 1 and R 2 from a cyclic hydrocarbon radical, with an acid, and heating -the mixture to a temperature of from 200 to 120 0 C to thereby form cucurbit[n]urils.
57. 73. A method for producing a cucurbit[n]uril, where n 4 to 12, comprising mixing a tetrol of the formula 1, or two or more tetrols of the formula 1, 25 N 2 (1) HO OH .O0 wherein R 1 and R 2 are independently selected from H, an optionally substituted straight 30 chain, branched or cyclic, saturated or unsaturated hydrocarbon radical or a heterocyclyl radical, or R, and R 2 from a cyclic hydrocarbon radical, with an acid, and heating the mixture to a temperature of from 200 to 120 0 C to thereby form cucurbit[n]urils. *o* 105 003963881
58. 74. A method as claimed in claim 72 or 73. wherein Ri and R 2 are selected from alkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals. A method as claimed claim 72 or 73 wherein Ri and R 2 are H.
59. 76. A method as claimed in any one of claims 72 to 75 wherein n 4 to
60. 77. A method as claimed in any one of claims 72 to 76 further comprising adding a templating compound to the mixture.
61. 78. A method as claimed in claim 77 wherein said templating compound is selected from ammonium chloride, lithium chloride, sodium chloride, potassium chloride, rubidium chloride, caesium chloride, ammonium chloride, lithium bromide, sodium bromide, potassium bromide, rubidium bromide, caesium bromide, lithium iodide, sodium iodide, potassium iodide, rubidium iodide, caesium iodide, potassium sulfate, lithium sulfate, tetrabutylammonium chloride, tetraethylammonium chloride, o-carborane, thioacetamide, N-(l-napthyl) ethylenediamine, 2,2'-biquinoline, p-bromoaniline, taurine, blue tetrazolium, 2-amino-3-methyl benzoic acid, indol-3-aldehyde, cysteine, 4-acetamidoaniline, p- aminophenol, acetamide, 4-aminoacetophenone, 4-dimethylaminobenzaldehyde, 2- aminobenzimidazol, bis-(4,4'-bipyridyl)-a, a'-p-xylene, red phosphorus, and lithium p- toluenesulfonate.
62. 79. A method as claimed in claim 77 wherein said templating compound is a salt.
63. 80. A method as claimed in claim 79 wherein the anion of the salt corresponds to the anion of the acid in the mixture.
64. 81. A method as claimed in any one of claims 77 to 80 wherein two or more templating S: compounds are added to the mixture. 3
65. 82. A method as claimed in any one of claims 72 to 81 wherein the acid comprises a strong mineral acid or a strong organic acid. 106
66. 83. A method as claimed in any one of claims 72 to 82 wherein the acid is selected from sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, deuterated sulfuric acid, phosphoric acid, p-toluenesulfonic acid, and methane sulfonic acid.
67. 84. A method as claimed in any one of claims 72 to 83 further comprising adding a solvent to the mixture. A method as claimed in claim 84 wherein the solvent is selected from trifluoroacetic acid, methane sulfonic acid and 1,1,1-trifluoroethanol.
68. 86. A method as claimed in any one of claims 72 to 85 wherein the mixture is heated to a temperature of from 200 to 110 0 C.
69. 87. A method as claimed in claim 86 wherein the mixture is heated to a temperature of from 60 0 to 110°C.
70. 88. A method as claimed in claim 86 wherein the mixture is heated to a temperature of from 800 to 110 0 C.
71. 89. A method as claimed in any one of claims 72 to 88 wherein the mixture is heated i* for between 1 hour and 24 hours. A method according to claim 1 substantially as herein described with reference to any one of Examples 1, 2 or 4 to 122.
72. 91. A method according to claim 20 substantially as herein described with reference to Example 2 or Example 122. Dated this 9th day of April 2003 30 UNISEARCH LIMITED By their Patent Attorneys GRIFFITH HACK .*o.o