WO2009066115A1

WO2009066115A1 - Colorimetric sensors for detection of the fluoride anion in solution and gel

Info

Publication number: WO2009066115A1
Application number: PCT/HR2008/000016
Authority: WO
Inventors: Zoran Dzolic; Mladen Zinic; Massimo Cametti; Antonella Dalla Cort; Luigi Mandolini
Original assignee: Ruder Boskovic Institute
Priority date: 2007-05-15
Filing date: 2008-05-15
Publication date: 2009-05-28
Also published as: HRP20070225A2

Abstract

The invention relates to oxalamide derivatives of anthraquinone with general formula (I) their preparation procedure and use for binding fluoride anions in solution and gel causing change in colour of solution and change in colour and morphology of gel (phase change from gel to liquid).

Description

COLORIMETRIC SENSORS FOR DETECTION OF THE FLUORIDE ANION IN

SOLUTION AND GEL

Technical field:

This invention relates to oxalamide derivatives of anthraquinone, their preparation procedure, use of compounds described herein in detection of fluoride anion in suspension and gel. The invention furthermore relates to intermediates in preparation procedures of oxalamide derivatives of anthraquinone.

Prior art:

Anions play an important role in chemical and biological processes. Amongst various anions, fluoride anion is extremely important for the preservation of bone stability and firmness of teeth enamel. Excessive dose of fluoride anion may, especially in children, cause damage and change in colour of teeth enamel, loss of hair and skin inflammation. (M. Kleerekoper, Endocrinol. Metab. Clin. North. Am., 1998, 27, 441-452; C. B. Black, B. Andrioletti, A. C. Try, C. Ruiperez and J. L. Sessler, J. Am. Chem. Soc, 1999, 121, 10438-10439). Thus establishing the quantity of fluoride in natural and waste waters is inevitable.

Anion sensors have been the subject of intensive research in the recent years with an aim of developing new highly selective anion sensors. Development of new colorimetric anion sensors (chemosensors) is especially important because visible detection enables qualitative and quantitative information without use of expensive instruments. (P. A. Gale and R. Quesada, Coord Chem. Rev., 2006, 250, 3219-3244; V. Amendola, M. Bonizzoni, D. Esteban-Gόmez, L. Fabbrizzi, M. Licchelli, F. Sancenόn and A. Taglietti, Coord. Chem. Rev., 2006, 250, 1451-1470; P. A. Gale, Ace. Chem. Res., 2006, 39, 465-475; T. Gunnlaughsson, M. Glynn, G. M. Tocci, P. E. Kruger and F. M. Pfeffer, Coord. Chem. Rev., 2006, 250, 3094-3117; V. Amendola, D. Esteban- Gomez, L. Fabbrizzi and M. Licchelli, Ace. Chem. Res., 2006, 39, 343-353; D. Esteban-Gomez, L. Fabbrizzi and M. Licchelli, J. Org. Chem., 2005, 70, 5717-5720; J. Sessler, B. Andrioletti, A. C. Try and C. Black, US 6,482,949 Bl November 19, 2002; R. Martinez-Manez and F. Sancenon, Chem. Rev., 2003, 103, 4419-4476; C. Suksai and T. Tuntulani, Chem. Soc. Rev., 2003, 32, 192-202). Sensors are mostly compounds containing amide, urea or thiourea groups, which act as a multiple hydrogen bond donors thus enabling target anion binding.

Certain organic molecules of low molecular mass (gelators) can thermoreversibly gelate water and numerous organic solvents. Gels are created by dissolving small amounts of gelator molecules in hot solvent and then cooling down below the gelation temperature. This causes an immobilisation of total solvent volume and loss of fluidity. Interest for preparation of these compounds has increased due to their microscopic and macroscopic properties and great application possibilities in various areas: biomedicine, different technologies and environment protection. (Low Molecular Mass Gelators. Design, Self -Assembly, Function, editor F. Fages, Top. Curr. Chem., 2005; L. A. Estroff and A. D. Hamilton, Chem. Rev., 2004, 104, 1201-1218; (c) O. Gronwald, E. Snip and S. Shinkai, Curr. Opin. Colloid Interface Sci., 2002, 7, 148-156; J. H. van Esch and B. L. Feringa, Angew. Chem., Int. Ed, 2000, 39, 2263-2266; P. Terech and R. G. Weiss, Chem. Rev., 1997, 97, 3133-3159). Gelators con taining chromophoric groups a re capable of binding in new and unusual way during the gelation process. Introduction of anthraquinone chromophoric group into the basic structure of oxalamide gelators gives rise to the molecules which retain gelation properties. However, at the same time they can act as gel system with chemical sensor properties. For these reasons new oxalamide derivatives of anthraquinone were prepared and tested for their application in anion detection in solution and gel. Oxalamide moiety is incorporated in known chiral amino acid and amino alcohol organo- and hydrogelators. (Z. Dzolic, K. Wolsperger and M. Zinic, New J. Chem., 2006, 30, 141 1-1419; S. Miljanic, L. Frkanec, T. Biljan, Z. Meic and M. Zinic, Langmuir, 2006, 22, 9079-9081; S. Miljanic, L. Frkanec, Z. Meic and M. Zinic, Eur. J. Org. Chem., 2006, 1323-1334; S. Miljanic, L. Frkanec, Z. Meic and M. Zinic, Langmuir, 2005, 21, 2754-2760; J. Makarevic, M. Jokic, Z. Raza, V. Caplar, D. Katalenic, Z. Stefanic, B. Kojic-Prodic and M. Zinic, Croat. Chem. Acta, 2004, 77, 403-414; J. Makarevic, M. Jokic, Z. Raza, Z. Stefanic, B. Kojic-Prodic and M. Zinic, Chem. Eur. J., 2003, 9, 5567-5580; J. Makarevic, M. Jokic, B. Peric, V. Tomisic, B. Kojic-Prodic and M. Zinic, Chem. Eur. J., 2001, 7, 3328-3341 ; X. Luo, C. Li and Y. Liang, Chem. Commun., 2000, 2091-2092). Several scientific papers regarding use of antraquinone derivatives with amide, urea and thiourea groups as chemosensors able to recognise and detect anions in solution have been published (S. J. Brooks, L. S. Evans, P. A. Gale, M. B. Hursthouse and M. E. Light, Chem. Commun., 2005, 734- 736; D. A. Jose, D. K. Kumar, B. Ganguly and A. Das, Org Lett., 2004, 6, 3445-3448; D. Jimenez, R. Martinez-Manez, F. Sancenon and J. Soto, Tetrahedron Lett., 2002, 43, 2823-2825;

S. O. Kang, S. Jeon and K. C. Nam, Supramol. Chem., 2002, 14, 405-410; H. Miyaji and J. L. Sessler, Angew. Chem. Int. Ed, 2001, 40, 154-157).

Subject of the Invention;

Subject of the present invention relates to new oxalamide derivatives of anthraquinone, their preparation procedure and their usage in recognition and detection of fluoride anion in solvent and gel. The subject of this invention furthermore relates to the intermediates in preparation of oxalamide derivatives of anthraquinone: oxamate amino acid derivatives and oxalamide amino acid derivatives and their preparation procedures.

Detailed Description of the Invention;

Oxalamide derivatives of anthraquinone are presented with general formula I:

wherein:

Ri is a branched or straightchained Ci_-6 alkyl group, phenyl, benzyl or^-hydroxybenzyl, R₂ is a hydrogen, branched or straightchained C)_-6 alkyl group, benzyl or M⁺, and n represents an integer from 1 to 9 and their optical isomers and mixtures.

The subject of the invention also relates to the preparation procedure of the oxalamide derivatives of anthraquinone, shown in the reaction scheme (scheme 1), which includes reaction of amino acid and ethyl oxalyl chloride, reaction of oxamate amino acid derivative with N-benzyl dialkylamine, hydrogenation of oxalamide amino acid derivative, condensation of amine of oxalamide amino acid derivative with ethyl-N-1-anthraquinone oxamate and isolation of oxalamide derivative of anthraquinone from reaction mixture through precrystallization, which is defined by the below mentioned general preparation procedure:

III

Scheme 1. Preparation of oxalamide derivatives of anthraquinone (I).

General preparation procedure of oxalamide derivatives of anthraquinone with general formula

wherein:

Ri is a branched or straightchained Ci_-6 alkyl group, phenyl, benzyl or/7-hydroxybenzyl, R₂ is a hydrogen, branched or straightchained Ci_-6 alkyl group, benzyl or M⁺, and n represents an integer from 1 to 9 and their optical isomers and their mixtures include the following steps: Step a) preparation of oxamate amino acid derivatives with general formula II

In a reaction flask 1 equivalent of amino acid is dissolved in a suitable organic solvent and 2.1 1 equivalent of base is added, preferably triethylamine. The reaction mixture is cooled down to 0⁰C and the solution of 1.1 equivalent of ethyl oxalyl chloride in a suitable organic solvent is added dropwise. The reaction mixture is then stirred for 18 hours at room temperature. Reaction is terminated by addition of water and suitable organic solvent that is non-miscible with water, preferably dichloromethane, is added to the mixture. The layers are then separated and aqueous layer is extracted twice with suitable organic solvent. Combined organic extracts are washed with aqueous ammonium chloride solution and with water. The organic layer is dried over anhydrous drying agent including CaCl₂, MgSO₄ or Na₂SO₄. After filtration, organic solvent is evaporated by distillation under reduced pressure to obtain the products of general formula II.

Step b) preparation of oxalamide amino acid derivatives with general formula III

In a reaction flask 1 equivalent of oxamate amino acid derivative II and 1.1 equivalent of N- benzyl dialkylamine are dissolved in a suitable organic solvent. The reaction mixture is stirred under nitrogen overnight at room temperature. The reaction progress is monitored by thin layer chromatography on silica gel. After disappearance of oxamate amino acid derivative, water is added to the reaction mixture, followed by suitable organic solvent that is non miscible with water, preferably dichloromethane. The layers are then separated and aqueous layer is extracted twice with the suitable organic solvent. Combined organic extracts are washed with aqueous ammonium chloride solution and then again with water. The organic layer is dried over anhydrous drying agent including CaCl₂, MgSO₄ or Na₂SO₄. After filtration, organic solvent is evaporated by distillation under reduced pressure. Obtained crude product III is purified by column chromatography on silica gel using CH₂C1₂/CH₃OH as eluent.

Step c) preparation of oxalamide derivatives of anthraquinone (I)

In a reaction flask 1 equivalent of oxalamide amino acid derivative III is dissolved in a suitable organic solvent. Catalyst is added to this solution and reaction mixture is hydrogenated under hydrogen stream at room temperature for at least one hour. The reaction progress is monitored by thin layer chromatography on silica gel. After filtration through Celite, organic solvent is evaporated by distillation under reduced pressure. Isolated amine of oxalamide amino acid derivative is used without further purification. In a suitable organic solvent 1 equivalent of ethyl- N-I -anthraquinone oxamate is dissolved. To this solution, the solution of obtained amine of oxalamide amino acid derivative is added at room temperature under nitrogen. Reaction mixture is stirred at least for 48 hours at room temperature. Precipitated product is filtered off and purified by precrystallisation from organic solvent.

The subject of this invention is also the use of compounds with general formula I for fluoride anion detection. Oxalamide derivatives of anthraquinone shown herein are binding fluoride anion in solution and gel. The binding of fluoride anion in solution is demonstrated by UV-Vis titration and shown in test of anion binding in solution. This phenomenon is accompanied by visible colour change from yellow into red (Figure 1). The binding of fluoride anion in gel is shown in test of fluoride anion binding and the diffusion of Bu₄NF solution through gel prepared from oxalamide derivative of anthraquinone I. The presence of fluoride anion results in changes in gel colour and morphology (phase change from gel to liquid) caused by specific recognition of fluoride anion. Compounds with general formula I and mixtures containing at least one of the mentioned compounds are also used for extraction of anions.

Test of anion binding in solution, UV-Vis titration: An aliquot of anion solution containing F^", Cl^", Br^', I^", CH₃COO^" or H₂PO₄ ^" (in the form of tetrabutylammonium salt) is added to DMSO solution of oxalamide derivative of anthraquinone I (c = 4.4 x 10^"5 M). After each aliquot UV-Vis spectra is recorded. Titrations are carried out at room temperature. Results obtained demonstrate the binding of fluoride anion only (Figures 1 and 2).

Figure 1 shows colour change of DMSO solution (c = 1 x 10^~3 M) of oxalamide derivative of anthraquinone with general formula I, wherein n = 1, Ri is isobutyl and R₂ is -CH₃, caused by addition of 10 equivalent of Bu₄NF. It also shows the absence of colour change of DMSO solution in case of Cl^", Br^" i I^" anions.

Figure 2 shows changes in UV- Vis spectra (DMSO) of oxalamide derivative of anthraquinone with general formula I, wherein n = 1, Ri is isobutyl and R₂ is -CH_3i with an increase of concentration of Bu₄NF. Fluoride anion binding is characterised by appearance of a new band at

481 nm and intensive change in colour of solution. Dependence of absorbance (at 520 nm) on concentration of added fluoride anion is also demonstrated.

Test of fluoride anion binding in: a) Gel in aromatic solvent: in two small flasks (10 mm inner diameter) 3.2 mg of oxalamide derivative of anthraquinone with general formula I, wherein « = 1, R₁ is isobutyl and R₂ is -CH₃₅ is added and dissolved in 0.05 cm³ of dimethylformamide by mild heating. After cooling down to room temperature, 2 cm³ of /7-xylene is added to one flask and 2 cm³ of solution of p-xylene containing 10 equivalents Of Bu₄NF is added to the other flask. Both solutions are heated. After cooling down, yellow-green gel is formed in the first flask, which does not contain fluoride anion (Figure 3a), while red solution is obtained in the other flask as a result of the interaction of oxalamide derivative of anthraquinone with fluoride anion (Figure 3b). b) Gel in polar solvent: in two small flasks (10 mm inner diameter) 3.2 mg of oxalamide derivative of anthraquinone with general formula I, wherein « = 1, Rj is isobutyl and R₂ is -CH_3, is added and dissolved in 0.20 cm³ of dimethylformamide by mild heating. After cooling down to the room temperature, 2.5 cm³ of ethanol is added to one flask and 2.5 cm³ of solution of ethanol containing 10 equivalent Of Bu₄NF is added to the other flask. Both solutions are heated. After cooling down, yellow-green gel is formed in the first flask, which does not contain fluoride anion, (Figure 4a), while orange gel is formed in the other flask as a result of the interaction of oxalamide derivative of anthraquinone with fluoride anion (Figure 4b). Diffusion of Bu₄NF solution through gel prepared from oxalamide derivative of anthraquinone: in a 10 mm inner diameter test tube 3.2 mg of oxalamide derivative of anthraquinone with general formula I, wherein Λ? = 1, R₁ is isobutyl and R₂ is -CH₃, is added and dissolved in 0,05 cm³ of dimethylformamide by mild heating. After cooling down to the room temperature, 2 cm³ of p-xyϊene is added and the solution is heated. Upon cooling yellow-green gel is formed in the test tube. To this gel sample 2 cm³ of solution of /7-xylene containing 50 equivalent of Bu₄NF is added. Immediately upon addition of the solution containing fluoride anion, visible change in colour (from yellow to red) appears on the gel surface. During the 4 hour period, diffusion OfBu₄NF solution through gel occurs and changes in colour and morphology of gel take place (Figure 5).

EXAMPLE 1

Ethyl 7V-(L-Leucine methyl ester)oxamate (1). Ethyl oxalyl chloride (3.35 cm³, 30 mmol) in anhydrous dichloromethane (20 cm³) is added dropwise to the mixture of L-leucine methyl ester hydrochloride (5 g, 27.5 mmol) and triethylamine (8.1 cm³, 58 mmol) in anhydrous dichloromethane (100 cm³) over 1 hour at 0⁰C. The mixture is stirred for 18 h at room temperature and then successively washed with water (2 x 50 cm³), saturated aqueous solution of ammonium chloride (3 x 50 cm³) and again with water (2 x 50 cm³). Organic layer is dried over anhydrous magnesium sulphate, solvent is evaporated and colourless oily product 1 (6.2 g, 92%) is obtained.

[α]_D ²² = -10 (c = 1.48 u CH₂Cl₂); ¹H NMR (CDCl₃): δ = 7.51 (d, J= 8.2, 2H, NH), 4.65 (m, IH, C^*H), 4.36 (q, J= 7.1, 2H, CH₂), 3.75 (s, 3H, OCH₃), 1.68 (m, 3H, CH_γ + CH_2β), 1.40 (t, J= 7.1, 2H, CH₃), 0.95 (d, J = 4.7, 6H, 2 x CH₃); ¹³C NMR (CDCl₃): δ = 14.1, 21.8, 22.9, 24.9, 41.4, 51.3, 52.6, 63.4, 156.3, 160.3, 172.4; IR (KBr): v = 3344, 2956, 2873, 1747, 1703, 1521 cm^"1.

EXAMPLE 2 iV-(L-Leucine methyl ester)-iV'-(7V-benzylethylenediamine)oxalamide (2). Mixture of ethyl N- (L-Leucine methyl ester)oxamate 1 (2 g, 8.2 mmol) and N-benzylethylendiamine (1.37 g, 9.1 mmol) is stirred in anhydrous dichloromethane (50 cm³) overnight at room temperature under nitrogen atmosphere. The reaction mixture is successively washed with water (2 x 20 cm³), saturated aqueous solution of ammonium chloride (2 x 20 cm³) and water (3 x 20 cm³). Organic layer is dried over anhydrous natrium sulphate and solvent is evaporated. Crude product is purified by column chromatography on silica gel (CH₂Cl₂ZCH₃OH 3:1) to obtain compound 2 (2.5 g, 87%).

t.t. = 39-40 ⁰C; [α]_D ²² = -13 (c = 1 u CH₂Cl₂); ¹H NMR (CDCl₃): δ = 7.85 (br t, IH, NH), 7.75 (d, J = 8.7, IH, NH), 7.31 (m, 5H, -Ph), 4.60 (m, IH, C^*H), 3.81 (s, 2H, -CH₂Ph), 3.74 (s, 3Η, OCH₃), 3.42 (q, J= 5.9, 2H, -CH₂), 2.83 (t, J= 5.9, 2H₃ -CH₂), 1.85 (br s, IH, NH), 1.67 (m, 3H, CH_γ + CH_2β), 0.95 (d, J = 6.2, 6H, 2 x CH₃); ¹³C NMR (CDCl₃): δ =21.8, 22.9, 24.9, 39.4, 41.2, 47.5, 51.2, 52.5, 53.4, 127.3, 128.3, 128.6, 139.6, 159.6, 159.8, 172.2; IR (KBr): v = 3302, 2958, 2871, 1751, 1655, 1518 cπT¹.

EXAMPLE 3

2-({2-[(9,10-dioxo-9,10-dihydro-anthracene-l-ylaminooxalyl)-amino]-ethylaminooxalyl}- amino)-4-methyl-pentanoic acid methyl ester (3). N-(L-Leucine methyl ester)-N'-(N- benzylethylenediamine)oxalamide 2 solution (1 g, 2.9 mmol) in anhydrous CH₃OH (50 cm³) is hydrogenated under hydrogen stream using 10% Pd/C catalyst (100 mg) at room temperature overnight. The catalyst is removed by filtering over Celite, washed with methanol and the filtrate is evaporated. Obtained amine is dried under reduced pressure and used in the following step without further purification. Ethyl-N-1-anthraquinone oxamate (0.94 g, 2.9 mmol) is dissolved in dichloromethane (50 cm³) and solution prepared by dissolving amine in 20 cm³ of dry dichloromethane is added dropwise. Reaction mixture is stirred for 48 hours under nitrogen at room temperature. Precipitated product is then filtered off, washed with dichloromethane and precrystallised from dimethylformamide to obtain yellow crystals of compound 3 (1.18 g, 76 %).

t.t. = 282 ⁰C; [α]_D ²² = -17 (c = 0.3 u DMSO); ¹H ΝMR (DMSO-J₆): δ = 13.45 (s, IH, NH), 9.29 (br t, IH, NH), 9.06 (t, J= 8.3, IH, Ar-CH), 9.01 (s, IH, NH), 8.97 (br t, IH, NH), 8.24 (m, 2H, Ar-CH), 8.00 (m, 4H, Ar-CH), 4.36 (m, IH, C^*H), 3.62 (s, 3H, OCH₃), 3.39 (m, 4H, 2 x -CH₂), 1.83 (m, IH, CH_γ), 1.53 (m, 2H, CH_2β), 0.85 (2d, J = 5.9, 6H, 2 x CH₃); ¹³C NMR (DMSO-J₆, 353 K): δ =20.9, 22.1, 24.0, 38.1, 38.6, 39.1, 50.4, 51.4, 122.3, 124.8, 126.0, 126.6, 132.0, 133.3, 133.8, 134.2, 134.3, 135.1, 139.0, 158.9, 159.3, 159.5, 159.6, 171.3, 175.9, 181.6, 185.6; IR (KBr): v = 3300, 2956, 1750, 1698, 1668, 1657, 1521 cm^"1. Elemental analysis for C₂₇H₂₈N₄O₈:

C, 60.44; H, 5.26; N, 10.44. Found: C, 60.40; H, 5.32; N, 10.40.

Claims

PATENT CLAIMS

1. Compound with general formula I

Charecterised by:

- Ri is a branched or straightchained Ci_-6 alkyl group, phenyl, benzyl orp-hydroxybenzyl,

R₂ is a hydrogen, branched or straightchained Ci_-6 alkyl group, benzyl or M⁺, and n represents an integer from 1 to 9 and their optical isomers and their mixtures.

2. Compound according to the claim 1, characterised by Ri is isobutyl

- R₂ -CH₃ and n is 1

3. Procedure for preparation of oxalamide derivatives of anthraquionone with formula I

wherein:

- Ri is a branched or straightchained Ci_-6 alkyl group, phenyl, benzyl orp-hydroxybenzyl, R₂ is a hydrogen, branched or straightchained Ci_-6 alkyl group, benzyl or IVf⁺, and n represents an integer from 1 to 9

characterised by, including the following steps: a) reaction between amino acid and ethyl oxalyl chloride with the formation of oxamate derivative of amino acid with general formula II

wherein Ri and R₂ as previously defined

b) reaction of oxamate derivative of amino acid from the step a) with N- benzyldialkylamine with the formation of oxalamide derivative of amino acid with general formula III

wherein Ri and R₂ as previously defined

c) condensation of amino oxalamide derivative of amino acid from step b) with ethyl-N-l- anthraquinone oxamate and isolation of oxalamide derivative of anthraquinone by precrystallisation.

4. Compound according to the patent claim 3, characterised by the general formula II

5. Compound according to the patent claim 3, characterised by general formula III

6. Use of the compounds according to the patent claim 1 for detection of fluoride anion.

7. Use of the compounds according to the patent claim 1 for biding of fluoride anions in solution and gel.

8. Mixture, characterised by, containing at least one compound from patent claim 1.

9. Use of mixtures according to the claim 8 for extraction of anions.