WO1993005028A1 - Receptor compounds based on 1,7-dioxa-4,10-diazacyclododecane - Google Patents

Abstract

Crown ether compounds which can function as receptor molecules for species such as alcohols, especially for ethanol, and other materials capable of forming hydrogen bonds. The compounds are based on 1,7-diaza-12-crown-4 group, substituted on the diaza groups with alkaryl groups as in formula (I) or with bridges extending to diaza groups on another 1,7-diaza-12-crown-4 group as in formula (II).

Description

RECEPTOR COMPOUNDS BASED m l,7-DIOXA-»_t10-DIAZACYCL0_)0DECANE.

This invention relates to receptor molecules, which can be used as molecular receptors for species capable of forming hydrogen bonds, for example for molecules which include alcohol or amine groups, to methods of making receptor molecules and to uses thereof.

Crown ethers having the structure

-N N- K

which is of the type referred to generically as a l,7-diaza-12- crown-4, are known. The crown ether of this type in which the nitrogen atoms are substituted with benzyl groups has been found to be capable, when protonated on one of its nitrogen atoms, of forming hydrogen bonds to a molecule of methanol. The present invention provides receptor molecules in which the alcohol receptor properties of such crown ether structures are improved.

In one aspect, the invention provides a receptor molecule having the structure I

in which R¹ and R² separately comprise -(CR³ ₂)_nPh, where n is from 2 to 4 and R³ is hydrogen or C_! to C₄ alkyl.

Preferably, R³ is hydrogen in each of R¹ and R². Preferably, n has a value of 2 in each of R¹ and R². Most preferably, R¹ or R² or each of R¹ and R² is -(C__₂)₂Ph.

It has been found that the association constants of certain alcohols with the materials specified above is improved significantly compared with the values of those constants with the corresponding material in which the value of n is 1.

In another aspect, the invention provides a receptor molecule having the structure II

PL ~ Q> ^%

N N ^π

in which

(i) A¹ and A² are each alkyl, ether or thioether divalent radicals, having a chain length of from 1 to 5 atoms; and

(ii) B¹ includes at least one of:

(a) -X-Ph-,

(b) -Ph-X-Ph-,

(c) -X-Ph-X-,

(d) -CX-Ph-,

(e) -X-B²-X- where B² is a divalent alkyl or aryl radical providing a chain length of from 2 to 7 atoms;

(f) -(B³)₂X where B³ is a divalent radical providing a chain length of from 1 to 4 atoms; and (g)

bonded directly or indirectly to the said phenyl group, where X is oxygen or sulphur.

It is believed that the receptor molecules of the type specified above can be used as receptors for alcohols, by virtue of the ability of the hydroxyl group an alcohol molecule to form a pair of hydrogen bonds to the nitrogen atoms of the crown ether ring, one of which has been protonated. The structure provided by -Aι-Ph-B,-A₂- can restrict access to the nitrogen atoms of the crown ether ring, so that the compound can be arranged to act as a selective receptor for certain alcohol species having no more than a certain steric requirement.

B¹ may include -(X(CR⁴ ₂)₂)₂.X where R⁴ is hydrogen or C_t to C₄ alkyl. For example, B¹ may be -O. (CR⁴ ₂)₂.0. (CR⁴ ₂)₂.0-, where R⁴ is generally hydrogen. B¹ might otherwise be, for example, -0. (CR⁴ ₂)₅.C—, again where R⁴ is generally hydrogen.

Examples of molecules which include components B¹ of this general type include:

7,10,13,22,27-pentaoxa-l,19-diazatetracyclo[15.5.5.2^3,6.2¹⁴'¹⁷] tritriaconta-3,5,14,16,30,32-hexaene

and

7,10,22,27-tetraoxa-l,19-diazatetracyclo[17.5.5.2³-⁶.2^14,17] tritriconta-3,5,14,16,30,32-hexaene

The formation of a molecule in which B¹ contains a crown ether ring, so that the molecule as a whole contains two such rings, is believed to allow the molecule to act as a receptor for a pair of molecules simultaneously or, significantly, for a molecule which presents two sites for forming hydrogen bonds such as a diol or a diamine.

The provision of phenyl groups between the components A¹ and A² of the molecule has the advantage that the structure of the molecule remains more rigid, which is believed to enhance the ability of the molecule to act as a receptor for specified molecules. Preferably, the component B¹ includes a terminal phenyl group through which the component is bonded to the component A². It can be advantageous for the component B¹ to include phenyl groups when the structure provided by the components -A^Ph-B^A²- is required to be large to admit, for example, a large molecule or a plurality of small molecules, to the crown ring ether, in order to enhance the rigidity of the resulting structure further. For example, the component B¹ might include the components -O.Ph-, -CO.Ph-, or -CO.Ph.CO.Ph-. The incorporation of these components is particularly advantageous when the component B¹ also includes a crown ether ring, so that the molecule includes two such rings, since the rings can be maintained a required distance apart, while retaining a certain degree of rigidity in order for the molecule to be able to receive alcohol or other molecules.

Examples of molecules which include a second crown ether ring as part of the component B¹ include:

4,9,15,21,26,32,37,42-octaoxa-l,12,18,29-tetraazapentacyclo [27.5.5.5^12>18.2⁵-⁸.2²²-²⁵]octatetraconta-5,7,22,25,45,47-hexaene

N N— 7,16,25,34, 44-hexaoxa-l, 13 , 19 , 31-tetraazaheptacyclo [29.5.5 _ 5¹³-¹⁹.2³'⁶.2²¹-²⁴.2²⁶*²⁹] tetrapentaconta-3 ,5,8,10,21,23, 26,28,47,49,51,53-dodecane

and

7 _r12 , 30, 35-tetraoxo-21,44 , 49 , 54-tetraoxa-l , 18 , 24 , 41- tetraazanonacyclo [39.5.5.5¹⁸-²⁴.2³-⁶.2⁸-¹¹.2¹³-¹⁶.2^26,29.2³¹-³⁴.2³⁶-³⁹] OCtahexaconta-3,5,8,10,13,15,26,28,31,33,36,38,57,59,61,63,65, 67-octadecane

The structure of the components A¹, A² and B¹ of the molecule can be selected to ensure that the steric requirements of the molecule which is to be received by the molecule are met. This can be achieved for example by selecting the length of the chains of the components A¹ and A² appropriately. For small alcohol or other molecules. A¹ or A² can have relatively short chains, for example of just one or two atoms, for example -CH₂- , -(CH₂)₂-, or -O.CH₂-. Longer chains for the components A¹ and A² can be appropriate for larger alcohol or other molecules, in which case the chain length can be upto five atoms. When A¹ or A² is an ether or a thioether radical, the heteroatom will preferably be terminal, providing the site for bonding to the phenyl group.

The bonds to the or each phenyl group will generally be located in the 1, 4 positions on the ring, in order to optimise the structure of the molecule. However, it is envisaged that the bonds may be located in other ways relative to one another, for example, in the 1, 3 positions.

The carbon atoms on the crown ether ring structure may be substituted, for example with lower alkyl groups, or halogen atoms. Phenyl groups which form part of the structure may also be substituted, for example to enhance the ability of the molecule to act for a receptor for a desired molecule.

It will generally be preferred that the molecular structure of the materials of the invention to be substantially symmetrical about the plane provided by the oxygen atoms of the crown ether ring structure, so that, for example in structure I, R¹ and R² are the same.

The materials of the invention can conveniently be prepared from the crown ether whose structure is shown on page 1 of this specification, by reaction with compounds which can provide the group or groups which are required to bond to the nitrogen atoms of the crown ether rings. Those compounds will generally be provided with groups which can be eliminated with the hydrogen atoms on the nitrogen atoms of the crown ether ring; for example, halogen atoms, especially bromine atoms may be provided for elimination with the hydrogen atoms.

Suitable solvents for the elimination reaction include acetonitrile, dimethyl formamide, dimethylsulphoxide and nitromethane.

The materials provided by the present invention find application as receptors for molecules which are capable of forming hydrogen bonds. The materials are particularly appropriate for forming such bonds when one of the nitrogen atoms on the (or each) crown ether ring is protonated. Protonation of the (or each) nitrogen is preferably carried out by reacting the material with one equivalent of an ammonium salt, most preferably in alcoholic solution. In another aspect, the invention provides an alcoholic solution of

(a) a compound of the type discussed above; and

(b) one mole equivalent of an ammonium salt.

Suitable ammonium salts include those of acids which have soft anions, for example, PF₆ ^" and B(Ph)₄ ^".

Complexation of the materials of the invention with molecules such as alcohols has been found to be affected by the solvent in which the complexation takes place. It has been found that apolar solvents are preferred for strong complexes to be formed, for example di- and tri-chloromethane and diethyl ether; especially suitable solvents include carbon tetrachloride, hexane and petroleum ethers.

The materials of the invention can be used to remove alcohols, or other molecular species capable of forming hydrogen bonds, for example for purification of such species, or for removal of the species from a solution. The materials of the invention might be provided on a solid support to allow their use in chromatographic systems, for example for use in the separation of alcohols or other species capable of forming hydrogen bonds. The materials might be incorporated into membranes to allow the selective transport of alcohols or other species between the opposite sides of the membrane.

The invention is illustrated by the following examples.

Preparation of starting materials

(a) 1,7-dioxa-4,10-diazacyclododecane

3-oxa-l,5-pentanediamine (6 g, 57.6 mmol) and 3-oxapentadioyl dichloride (4.92 g, 28.8 mmol), each dissolved in sodium dried benzene (160 ml) , were added simultaneously during a 3 hour period to a flask containing dry benzene (800 ml) . An atmosphere of dry nitrogen, room temperature, and vigorous stirring (ca. 1200 rpm) were the conditions maintained during the whole reaction procedure. The white precipitate which appeared was filtered off and washed with chloroform (2 x 200 ml) . After removal of the solvent, a white solid resulted which was further purified by use of a short chromatography column [Si0₂ with CH₃0H:CH₂C1₂ (10:100 v/v)]. The product obtained was characterised as 5,9-dioxo-l,7-dioxa-4,10- diazacyclododecane.

5,9-dioxo-l,7-dioxa-4,10-diazacyclododecane (1.9 g, 9.4 mmol) was placed in the thimble of a Soxhlet apparatus that was connected to a flask containing a suspension of lithium aluminium hydride (2 g, 52.7 mmol) in tetrahydrofuran (250 ml) freshly dried and distilled from lithium aluminium hydride. The reaction mixture was heated under reflux for 66 hours by holding the bath temperature at 95°C. The completion of the reaction was signalled by TLC [A1₂0₃ with CH₃OH:CH₂C1₂ (10:100 v/v)]. After cooling to room temperature, the flask was placed in an ice-bath. Then, dropwise, 1.2 ml of water, 4 ml of tetrahydrofuran (4 x 40 ml) . After removal of the solvent, a white solid resulted which was further purified by sublimation (90°C, 0.05 mm Hg) . The long, colourless needles thus obtained were characterised as 1,7-dioxa 4,10-diazacyclododecane.

(b) 1,5-bis (p-bromomethylphenoxy)-3-oxapentane

3-oxapentamethylenebis(p-toluensulphonate) (14.5 g, 35 mmol), dissolved in anhydrous acetonitrile (110 ml) , was added dropwise to a stirred refluxing mixture of p-cresol (8.0 g, 75 mmol, 8% excess) and anhydrous potassium carbonate (12.3 g, 89 mmol, 27% excess) in acetonitrile (100 ml) . During the addition, a new precipitate formed and more acetonitrile (100 ml) was added. The progress of the reaction was followed by TLC^" [Si0₂ with Et-0:CHC1₃ (4:100 v/v)]. After ca. 29 h, the reaction mixture was allowed to cool down to room temperature before being filtered. The solid material was then washed with chloroform (4 x 75 ml) and the filtrates were combined. After removal of the solvent in vacuo, a solid formed which was crystallised from methanol. The pure product was characterised as 1,5-bis(p-methylphenoxy)-3-oxapentane.

l,5-bis(p-methylphenoxy)-3-oxapentane (3.22 g, 11 mmol), N- bromosuccinimide (4.0 g, 22 mmol), and dibenzoyl peroxide (ca. 10 mg) were mixed together with stirring in refluxing carbon tetrachloride (75 ml) . At the beginning of the reaction, all the suspended solid (ZΫ-bromosuccinimide) was to be found at the bottom of the flask but, after ca . 18 h, it was observed floating on a top of slightly yellowish solution, which was then filtered while hot. On cooling down to room temperature, a white solid crystallised out. It was filtered off and then washed with water (10 ml) and methanol (10 ml) . The product was charactersied as pure 1,5-bis (p-bromomethylphenoxy)-3- oxapentane (3.25 g, 66%), m.p. 126-127°C.

(c) 1,5-bis(p-bromomethylphenoxy)pentane p-cresol (5.5 g, 51 mmol) and anhydrous potassium carbonate (12.0 g, 87 mmol) were suspended in anhydrous acetonitrile (50 ml) in a round bottom flask fitted with a condenser, a dropping funnel, and a CaCl- tube. 1,5-dibromopentane (5.3 g, 23 mmol) in acetonitrile (10 ml) was added dropwise to the stirred refluxing mixture. The progress of the reaction was followed by TLC [Si0₂ with CH₂C1₂:CC1₄ (50:50 v/v)]. More acetonitrile (20 ml) was added. After ca. 24 h, the reaction mixture was allowed to cool down to room temperature before it was filtered and the solid material was washed with dichloromethane (3 x 10 ml) . The solvent was removed from the filtrates in vacuo and the solid residue was extracted with diethyl ether (60 ml) and washed with water (3 x 15 ml) . After drying the ethereal phase (MgS0₄) and removing the solvent, a solid resulted which was washed further with methanol. The resulting material was characterised as pure l,5-bis(p-methylphenoxy)pentane.

1,5-bis(p-methylphenoxy)pentane (33) (4 g, 14 mmol) and N- bromosuccinimide (5 g, 28 mmol) were mixed together in anhydrous carbon tetrachloride (60ml) . The apparatus was equipped with a condenser and a CaCl₂ tube. Dibenzoyl peroxide (ca . lOmg) was added to the stirred refluxing suspension. After ca. 2 h, a white solid was observed floating on the carbon tetrachloride surface. The reaction mixture was filtered of whilst it was still hot. On cooling down to room temperature, colourless crystals formed which were filtered off and washed thoroughly with water and methanol. The solid was recrystallised from carbon tetrachloride. It was characterised as 1,5-bis(p-bromomethylphenoxy) pentane (3.30 g, 53%). m.p. 113-116°C.

(d) Hydroquinone bis(2-bromomethyl) ether

Triphenylphosphine (53.2 g, 0.2 mol) was suspended in anhydrous acetonitrile (200 ml) contained in a flask fitted with a thermometer, an overhead stirrer (glass rod) , and a pressure- equalising addition funnel. The flask was cooled in an ice- bath. Bromine (32 g, 0.2 mol) was added dropwise at such a rate that the supernatant solution remained colourless. During the addition, the reaction mixture was maintained at 0-4°C. Then, the ice-bath was removed and fine, powdered hydroquinone bis(2-hydroxyethyl) ether was added. After ca. 15 min, total dissolution of the precipitate had occurred. After another ca . 2 h, a new precipitate started to form. After yet another 2 h, the reactiron mixture was filtered, the solvent was removed in vacuo, and the resulting solid was crystallised from methanol. The pure product was characterised as hydroquinone bis(2- bromoethyl) ether.

(e) di-p-(bromomethyl)phenyl ether

tf-bromosuccinimide (2.32 g, 13.0 mmol) was added in portions during a period of 1 h to a refluxing solution of di-p-tolyl ether (1.14 g,5.7 mmol) in dry benzene (30 ml) and dibenzoyl peroxide (ca. 30 mg) . The solution was then heated under reflux for an additional 30 min before being allowed to cool down to room temperature. The resulting suspension was filtered and the solvent was removed in vacuo. The white precipitate which remained was washed with an aqueous solution of sodium hydroxide and then crystallised from benzene/light petroleum (b.p. 60-80°C) . The crystals were identified as di-p-(bro omethyl)phenyl ether (1.02 g, 51%), m.p. 95-96°C.

(f) p-bis[4-(bromomethyl)benzoyl]benzene

Aluminium trichloride (13.3 g, 0.1 mol) was suspended in distilled (from CaCl₂) toluene (50 ml) in a flask fitted with a pressure-equalising addition funnel, a mechanical overhead stirrer, a condenser, and a hydrochloric acid gas trap. The flask was immersed in an ultrasonic bath. Terephthaloyl dichloride (10.1 g, 0.05 mol) in toluene (50 ml) was added dropwise to the reaction mixture. After ca. 90 min, the sonic bath was replaced by a cold water bath. Then, water was added slowly with the purpose of destroying the carbonyl aluminium chloride complex. The water phase was discarded and the organic phase was filtered. The remaining solid was crystallised from ethyl acetate and the compound obtained was characterised as p-di-p-toluoylbenzene (8.5 g) . After washing the filtrates with 0.4 N Na₂C0₃ solution, drying them with MgS0₄, and removing the solvent in vacuo, a solid resulted which, after column chromatography (Si0₂ with CH₂C1₂) yielded more of the compound.

p-di-p-toluoylbenzene (3 g, 9.5 mmol) was dissolved in refluxing carbon tetrachloride (75 ml) . Λr-Bromosuccinimide (3.4 g, 19.1 mmol) and dibenzoyl peroxide (ca . 10 mg) were added to the reaction medium. After 3 h, all the suspended solid was floating on the surface of the carbon tetrachloride. The reaction mixture was filtered whilst hot. When the combined filtrates had cooled down to room temperature, a precipitate formed which consisted of a mixture of several compounds. Separation of these compounds was achieved by medium pressure liquid chromatography (MPLC) [Si0₂ with CH₂Cl₂:Hexane (10-20:100 v/v)]. One of the isolated compounds was identified as p-bis[4-(bromomethyl)benzoyl]benzene (1.83 g, 26%) , .p. 209 - 211°C.

Example 1

l,7-dioxa-4,10-diazacyclododecane (see (a) above) (300 mg, 1.7 mmol) and andhydrous sodium carbonate (1.2g, 11.3 mmol) were suspended in dry acetonitrile (40ml). (2-bromoethyl)benzene (624 mg, 3.5 mmol) dissolved in dry acetonitrile (5 ml) was then added dropwise to the stirred refluxing mixture. The progress of the reaction was followed by TLC (Si0₂, 0.1% ammonia 35% solution, 8.3% methanol, 25% diethyl ether, and 66.6% chloroform). The reaction was left overnight and a slight excess of (2-bromoethyl)benzene was added. After ca. 24 h, the reaction mixture was allowed to cool down to room temperature and then filtered. The solvent in the filtrate was removed in vacuo and the resulting oil was extracted with boiling hexane (3 x 100 ml) . The hexane solution was concentrated in vacuo to ca. 50ml and then it was placed inside an ice-box. This cooling procedure caused the crystallisation of long colourless needles which were subsequently filtered and washed with cold hexane (3 x 10 ml) . After drying in vacuo, the compound was characterised as N,N'-diphenethyl-l,7-dioxa- 4,10-diazacyclododecane (244 mg, 37%), m.p. 58-60°C; (Found : m/z (EIMS) 382, M⁺.

requires M, 382); δ_H (CDC1₃, 250 MHZ), 2.70-2.80 (16H, m 2 X Ar(CH₂)₂N and 4 X NC CH-O) , 3.61 (8H, t,³ _H4.5 Hz, 4 x NCH2CH ) , 7.15-7.31 (10H, m, aromatic protons); δ_c (CDC13, 100.6 MHz, J mod), 33.7 (2 x ArCH₂CH₂tf) , 55.2 (4 x NCH₂CH₂N) , 55.2 (4 X NCH₂CH₂0) , 59.2 (2 X

, 69.7 (4 x CH_jCH ) , 125.8 (2 x aromatic HC(CH)₂(CH)₂CC) , 128.3 and 128.7 (2 x aromatic HC(CH)₂(CH)₂CC and 2 x aromatic HC(CH)₂(CH)₂CC) 140.5 (2 x aromatic HC(CH)₂(CH)₂CC) ;i/max (KBr disc), 1495, 1450, 1120, 750, and 700 cm"¹.

Example 2

Solutions (0.016M) of l_r7-dioxa-4,10-diazacyclododecane (see (a) above) (524 mg, 3.1 mmol) and 1,5-bis(p- bromomethylphenoxy)-3-oxapentane (see (b) above) (1.38 g, 3.1 mmol) in anhydroys dimethyl formamide were added simultaneously to a suspension of anhydrous potassium carbonate (2.15 g, 15.5 mmol) in dimethyl formamide. The temperature of the reaction was maintained at 50-60°C while it was stirred vigorously (σa.1200 rpm) . The progress of the reaction was followed by TLC (Si0₂, 0.07% ammonia 35% solution, 20.7% methanol, 24% diethyl ether, 55.1% chloroform) . After ca . 40 h, the reaction mixture was allowed to cool to room temperature before it was filtered through celite. The solvent from the filtrate was removed in vacuo leaving an oily residue which was then partitioned between water (4 ml) and dichloromethane (15 ml) . The water phase was discarded and the organic layer was dried over molecular sieves 4 k. After removal of the solvent, the oily residue was passed through three neutral A1₂0₃ columns (First : A1₂0₃, 70 g, eluent: 1.4% methanol, 9.0% diethyl ether. and 89.6% dichloromethane . Second: A1₂0₃, 70 g, eluent : 2.2% methanol, 8.9% diethyl ether, and 88.9% dichloromethane. Third : A1₂0₃, 3 g, 1.4% methanol, 9.0% diethyl ether, and 89.6% dichloromethane) . The crystalline compound thus obtained was recrystallised from methanol. It was characterised as

7,10,13,22, 27-pentaoxa-l , 19-diazatetracyclo [ 15.5.5.2^3,6.2^14, ] tritriaconta-3,5,14,16,30,32-hexaene (208 mg, 15%), m.p. 129- 129.5°C; (Found : C, 67.96; H, 7.91; N, 5.89%; m/z (EIMS) 456, M⁺. Calc. for C^NA : C, 68.40; H, 7.95; N, 6.13%; M, 456); _Η(CDC13, 250 MHZ), 2.58 (4H, br dd, ²JAB 14 Hz, 4 x NCH_AH_BCH_XH_YO) , 2.85 (4H, br dd, ²JBA 14 Hz, ³JBY 8 Hz, 4 x NCH_AH_BCH_xH_γO) , 2.85 (4H, br dd, ²JXY 11 Hz, 4 x NCH_AH_BCHχH_γO) , 3.56 (4H, 2, 2 x ArCH₂N) , 3.64 (4H, br dd, ²JYX 11 Hz, ³JYB 8 Hz, 4 X NCH_AH_BCHχH_γO0 , 3.80 (4H, m, ³JAX 3 Hz , ³JAX' 6 Hz , 2 X ROCH_AH_A.CHxHx.OAr), 4.25 (4H, m, ³JXA 3 Hz, ³JXA' 6 Hz, 2 X ROCH_AH_A.CHχH_χ.OAr) , 6.97 (4H, m, ³JAX' 1 Hz , 2 x aromatic OC (CH_ACH_A-) (CH_xCHχ.)CC) , 7.42 (4H, m, ³JXA 9 Hz , ³JXA' 1 Hz, 2 X aromatic OC(CH_ACH_A.) (CHχCH_x.)CC) ; δ_c (CDC13, 62.9 MHz, J mod), 55.6 (4 x NCH₂CH₂0) , 59.9 (2 x NCH₂Ar) , 69.0, 70.3, and 70.4 (2 x ArOCH-CH₂CH₂0 , and 4 x NCH^H ,), 114.9 (2 x aromatic CC(CH)₂(CH)₂C0) , 126.6 (2 x aromatic CC(CH)₂(CH)₂C0) , 133.6 (2 x aromatic CC(CH)₂(CH)₂CO) , 158.0 (2 x aromatic CC(CH)₂(CH)₂CO) .

Example 3

l,7-dioxa-4,10-diazacyclododecane (see (a) above) (0.50g, 2.87 mmol) dissolved in dry dimethyl formamide (150ml) and 1,5- bis(p-bromomethylphenoxy) pentane (see (c) above) (1.27 g, 2.87 mmol) dissolved in dry dimethyl formamide (150 ml) were added simultaneously to a suspension of anhydrous potassium carbonate (2 g, 14.5 mmol) in dimethyl formamide (150 ml). The suspension was stirred vigorously (ca. 1800 rpm) and warmed to 45°C. The process was followed by TLC (Si0₂, 0.1% ammonia 35% solution, 12.0% methanol, 24.0% diethyl ether, and 63.9% chloroform) . After ca. 40 h, the reaction mixture was filtered through celite and the solid was washed with dichloromethane. After removal of the solvent from the filtrates an oil was obtained which was partitioned between dichloromethane (30ml) and water (3 x 5 ml) . The water phase was discarded and the organic layer was dried (MgS0₄) and the solvent removed in vacuo. The resulting solid was shown by FABMS to consist of only one peak in the m/z 200-1000 mass range : m/z 455 (100%) assigned to [M + H] ⁺ for 26. The residue was then passed through a chromatography column (Si02 , 70 g; eluent, 0.1% ammonia 35% solution, 21.4% diethyl ether, 21.4% methanol, and 57.1% cholorof orm) . A white solid was obtained which was further triturated in methanol. The pure product was characterised as 7 , 10 , 22 , 27-tetraoxa-l , 19-diazatetracyclo [17.5.5.2^3,6.2^14,17] tritriconta-3 , 5 , 14 , 16 , 30 , 32-hexaene (157 mg, 12.1%) , m.p. 124-126°C; (Found : m/z (FABMS) 455, [M + H] ⁺ . requires M, 454) ; δ_H (CDC1₃, 250 MHz) , 1. 65 (2H, M, RCH-CH₂CH₂OAr) , 1.84 (4H, m, 2 X RCH₂CH_CH₂OAr) , 2 . 75 (8H, br S, 4 x OCH₂CH₂N) , 3 .57 (12H, br s , 4 X OCH₂CH₂N and 2 X ArCHjN) , 4. 07 (4H, 5, ³JH 6.9 Hz , 2 X RCH₂CH₂CI^OAr) , 6.85 (4H, m, 2 X aromatic OC (CH_ACH_A.) (CH_BCH ) CC) , 7.38 (4H, m, 2 x aromatic OC(CH_ACH_A (CH_BCH_B.) CC) ; &c (CDC1₃, 62 .9 MHz , J mod) , 21.2 (RCH₂GH₂CH₂OAr) , 27.4 (2 X RCH₂CH₂CH₂OAr) , 55.4 (4 X

, 59.9 (2 X NCH₂Ar) , 68. 1 and 70.2 (2 X RCH₂CH₂CH₂OAr) , 55.4 (4 X 0CH₂CH₂N) , 59.9 (2 X NCH₂Ar) , 68.1 and 70. 2 (2 X RCH^H^H Ar and 4 x OCH₂CH₂N) , 115.2 (2 X aromatic OC(CH₂) (CH₂) CC) , 129.8 (2 X aromatic OC(CH₂)ICH₂) CC) , 132.9 (2 x aromatic OC(CH₂) (CH₂) CC) , 157.6 (2 x aromatic OC(CH₂) (CH₂) CC) ; innax (KBr disc) 2940 , 2800 , 1612 , 1512 and 1238 cm^'1.

Example 4

Hydroquinone bis(2-bromoethyl) ether (see (d) above) (198 mg, 0.6 mmol) dissolved in dry acetonitrile (30 ml) was added dropwise with stirring to a refluxing suspension of anhydrous potassium carbonate (0.35 g, 5.0 mmol) and l,7-dioxa-4,10- diazacyclododecane (see (a) above) (214 mg, 1.2 mmol) in acetonitrile (25ml) . The progress of the reaction was followed by TLC (Si02, 0.1% ammonia 35% solution, 21.4% methanol, 21.4% diethyl ether, and 57.1% chloroform). After ca. 72h, the reaction mixture was allolwed to cool down to room temperature before being filtered. A sample was taken and shown by FABMS to consist of four main compounds in the 170-1200 mass range: m/z 175, assigned to the diaza crown used as starting material; m/z 337, assigned to [M+H]⁺ of the cyclic (1+1) oligomer; m/z

511, assigned to [M+H]⁺ of the lineal (2+1) oligomer with formula C^H^N^; and m/z 111 assigned to [M+K]⁺ of the cyclic

(2+2) oligomer, target compound. The acetonitrile solution was diluted to 65 ml and then added simultaneously with a solution of the dibromide (198 mg, 0.6 mmol) dissolved in acetonitrile

(65 ml) to a refluxing suspension of potassium carbonate (0.85 g, 6.1 mmol) in acetonitrile (100 ml). Again, the progress of the reaction was followed by TLC using the same system of adsorbant and eluant as before. After ca. 3 days, the reaction mixture was allowed to cool down to room temperature before it was filtered. The FABMS in the 170-1200 mass range of a sample taken consisted of two peaks : m/z 337 (100% intensity) , and m/z 111 (20% intensity) . The solvent in the filtrates was removed in vacuo and the residue was partitioned between water

(3 ml) and dichloromethane (10 ml) . The organic phase was dried (molecular sieves 4 A) and the solvent was removed, leaving a very dense oil. A suspension of this oil in ethyl acetate was encouraged, with the help of an ultrasonic bath, to afford a white solid which was shown to consist mainly of the desired (2+2) cyclic oligomer. It was purified by column chromatography (two neutral) A1₂0₃ columns, 0.3% ammonia 35% solution, 3.8% methanol, and 95.9% ethyl acetate). The compound was characterised as 4,9,15,21,26,32,37,42-octaoxa-

1,12,18, 29-tetraazapentacyclo [27.5.5.5^12,18.2^5>8.2²²-²⁵] octatetraconta-5,7,22,25,45,47-hexaene (50 mg, 12%), m.p. 169-

172°C; (Found : m/z 673 and 695, [M+H]⁺ and [M+Na]⁺. C^H^Og requires M, 672); 5_H (CDC1₃, 250 MHz) 2.77 (16H, t, ³JH 5 Hz. 8 x R₂NCH₂CH₂OR') , 2.90 (8H, t, ³JH 6.5 Hz, 4 X

, 3.56

(16H, t, 3JH 5 HZ, 8 x R2NCH2CH₂OR') , 4.01 (8H, t, ³JH 6.5 Hz,

24 x R"₂NCH₂CH₂OAr) , 6.81 (8H, s, 8 x aromatic CH) ; δ_c (CDC1₃,

100.6 MHz) 56.1 (8 X R₂NCH₂CH₂OR') , 56.6 4 X R'_NCH₂CH₂OAr) , 67.6

(4 X R"₂NCH₂CH₂OR') , 115.4 (8 X aromatic CH) , 152.9 (4 X aromatic CO); u max (KBr disc), 1510, 1470, 1230, and 830 cm^"1.

Example 5

l,7-dioxa-4,10-diazacyclododecane (see (a) above) (0.446 g, 2.56 mmol) dissolved in acetonitrile (30 ml) and di-p- ( romomethyl)phenyl ether (see (e) above) dissolved in acetonitrile (30ml) were added simlutaneously during 90 min to a suspension of anhydrous potassium carbonate (3.43 g, 24.8 mmol) in refluxing acetonitrile (70 ml) . A dry nitrogen atmosphere and stirring were provided. The reaction mixture was heated under reflux overnight and, after being allowed to cool to room temperature, it was filtered. The solid was washed three times with dichloromethane (3 x 20 ml) . The combined filtrates, together with the acetonitrile phase, were concentrated in vacuo resulting in a solid, which was mixture of several compounds. [Found im/z (FABMS) , glycerol) 737 (base peak for m/z > 300, assigned to [M + ]⁺ for cyclic (2+2) oligomer.

requires M, 736) , 369 (12% of base peak, assigned to [M + 1]⁺ for cyclic (1+1) oligomer. C^g ^ requires M, 368) , and 1105 (11% of base peak assigned to [M + 1]⁺ for cyclic (3+3) oligomer. C₆₆H₄N₆0₉ requires M, 1104)]. After column chromatography on silica gel using as eluent a mixture of chloroform (89.7%), diethyl ether (8%), methanol (2%), and (35%) ammonia solution (0.3%), the major product was isolated and crystallised from acetone. It was characterised as 7,16 ,25,3 ,44-hexaoxa-l,13,19,31-tetraazaheptacyclo [29.5.5.5¹³-¹⁹.2³-⁶.2^21,24.2^26>29]tetrapentaconta-3,5,8,10,21,23, 26,28,47,49,51,53-dodecane (159 mg, 18%), m.p. 236-237°C; (Found : m/z (FABMS, glycerol) 737, [M + 1]⁺. Calc. for C_MH_M A : M, 736), δ_κ (CDC1₃, 250 MHz) 2.73 (16H, m, 8 x NCH_AH_A.CH_BH_B.0) , 3.59 (16H, m, 8 X NCH_AH_A.CH_BH_BO) , 3.64 (8H, s, 4 x NCH₂Ar) , 6.95 (8H, m, 4 x aromatic OC (CH_ACH_A (CH_BCH_B.)CC) , 7.41 (8H, m, 4 x aromatic OC (CH_ACH_A.) (CH_BCH_B.)CC) ; δC (CDC1₃, 100.6 MHZ, J mod) 54.9 (8 X OCH-CHiN) - 60.3 (4 X ArCH₂N, 69.6 (8 X OCH₂CH₂N) , 118.5 ( 4 X aromatic CC(CH)₂(CH₂CO) , 130.0 (4 X aromatic CC(CH)₂(CH)₂C0) , 134.4 (4 x aromatic CC(CH)₂(CH)₂CO) , 156.1 (4 x aromatic CC(CH)₂(CH)₂CO) .

Example 6

A mixture of p-bis[4-(bromomethyl)benzoyl]benzene (see (f) above) (300 mg, 0.63 mmol) and l,7-dioxa-4,10- diazacyclododecane (see (a) above) (llOmg, 0.63 mmol) in acetonitrile (125 cm³) were added in ca . 15 min to a suspension of anhydrous K₂C0₃ (300 mg, 2.17 mmol) in refluxing acetonitrile (25 cm³) . After ca . 30 min, a new precipitate started to form. The reaction mixture was allowed to cool down to room temperature after 4 h. Then, it was filtered and the solid residue extracted into chloroform. The organic solution was washed with water and then dried (MgS0₄) before the solvent was removed in vacuo. A white solid was obtained whose FAB mass spectrum showed, in the m/s range of 420-1100, the peak 969 [assigned to (M + H)⁺ for the cyclic dimeric derivative] in 100% intensity and the peak at m/z 473 (18% intensity) assigned to the dibromide compound used as reactant. The TLC (Si0₂) [30 methanol : 30 diethyl ether : 80 chloroform : 0.1 ammonia (35%) ] showed a mixture of compounds with very close R_f (« 0.6) . The 'H NMR spectrum (CDC1₃, 220 MHz) showed signals corresponding to the starting dibromide material together with the signals expected for 7,12,30,35-tetraoxo-21,44,49,54- tetraoxa-1,18,24,41-tetraazanonacyclo [39.5.5.5¹⁸'²⁴.2³-⁶.2^8, u 2^Ϊ3<16.2²⁶-²⁹.2³¹-³⁴.2³⁶'³⁹]octahexaconta-3,5,8,10,13,15,26,28, 31,33,36,38,57,59,61,63,65,67-octadecane. [ δ_H 2.56 (16 H, br , 8, 0CH₂CH₂N) , 3.43 (16 H, , br m, 8 x 0CH₂CH₂N) , 3.55 (8 H, br s, benzyl CH₂N) , 7.80 and 7.82 (24 H, AA'XX' system and s respectively, aromatic protons) .

Complexation with alcohols

Complexation constants of alcohols with materials prepared in accordance with the instructions set out above in the Examples, and for comparison with the crown ether having the structure shown on page 1 of this specification in which the nitrogen atoms are substituted with benzyl groups (N,N'-dibenzy1-1,7- diaza-4,10-diozacyclododecane) , were determinedwith a nitrogen atom on each of the crown ether rings protonated by treatment with NH₄PF₆. The results were as follows:

Claims

CLAIMS :

1. A receptor molecule having the structure I

in which R¹ and R² separately comprise -(CR³ ₂)_nPh, where n is from 2 to 4 and R³ is hydrogen or C, to C₄ alkyl.

2. A receptor molecule as claimed in claim 1, in which R¹ or R² or each of R¹ and R² is -(CH₂)₂Ph.

3. A receptor molecule having the structure II

Pt - _> • / \

_-0^ in which

(i) A¹ and A² are each C_ to C₄ alkyl or Cj to C₄ alkoxy,

(ii) B¹ includes at least one of:

(a) -X-Ph-,

(b) -Ph-X-Ph-,

(c) -X-Ph-X-,

(d) -CX-Ph-,

(e) -X-B²-X- where B² is to C, alkyl,

(f) -(B³)₂X where B³ is Cj to C₄ alkyl, and (g)

-N N-

bonded directly or indirectly to the said phenyl group, where X is oxygen or sulphur.

4. A receptor molecule as claimed in claim 3, in which B¹ includes -(X(CR₂)₂)₂X where R⁴ is hydrogen or C_t to C₄ alkyl.

5. A receptor molecule as claimed in claim 3, in which B¹ includes -X(CR₂)₅X-.

6. A receptor molecule as claimed in claim 3, in which B¹ includes -Ph-0-(CR⁴ ₂)_n- where n has a value of from 1 to 3.

7. A receptor molecule as claimed in any one of claims 3 to

6, in which A¹ provides a chain of at least 2 atoms between the nitrogen of the crown ether ring and the phenyl group.

8. A receptor molecule as claimed in any one of claims 3 to

7, in which A² provides a chain of at least 2 atoms between the nitrogen of the crown ether ring and B¹.

9. A receptor molecule as claimed in any one of claims 3 to

8, in which B¹ includes a terminal phenyl group through which it is bonded to A².

10. N,N -diphenethyl-l,7-diaza-4 ,10-dioxacyclododecane.

11. 7,10,13,22, 27-pentaoxa-l, 19-diazatetracyclo [15.5.5.2³-⁶.2¹⁴-¹⁷]tritriaconta-3,5,14,16,30,32-hexaene.

12. 7,10 ,22,27-tetraoxa-l,19-diazatetracyclo[17.5.5.2^3,6.2¹⁴-¹⁷] tritriconta-3 , 5 , 14 , 16 , 30 , 32-hexaene.

13. 4,9,15,21,26,32,37, 42 -octaoxa-1 , 12,18, 29-tetra azapentacyclo[27.5.5.5^12,18.2^5,8.2^22,25] octatetraconta- 5 , 7 , 22 , 25 , 45 , 47-hexaene .

14. 7, 16,25,34,44-hexaoxa-l, 13, 19, 31-tetraazaheptacyclo [29.5.5.5¹³-¹⁹.2 .2²¹-²⁴.2²⁶*²⁹] tetrapentaconta-3., 5,8,10,21,23, 26,28,47,49, 51, 53-dodecane.

15. 7 , 12 , 30 , 35-tetraoxo-21, 44 , 49 , 54-tetraoxa-l ,18,24,41- tetraazanonacyclo [39.5.5.5¹⁸-²⁴.2^3,6.2^8,u.2^13,16.2^26,29.2^31>34.2^36>39] octahexaconta-3,5,8,10,13,15,26,28,31,33,36,38,57,59,61,63,65, 67-octadecane .

16. An alcoholic solution of

(a) a compound as claimed in any one of claims 1 to 13,

(b) one mole equivalent of an ammonium salt.

17. Use of a compound as claimed in any one of claims 1 to 14 as a receptor for molecules which include an alcohol group.