Covalently immobilized fluoroionophores for optical ion sensors

Details Covalently immobilized fluoroionophores for optical ion sensors Covalently immobilized fluoroionophores for optical ion sensors

1999-01-21

2001-09-25

Warden, Jill (Department: 1743)

Chemistry: analytical and immunological testing

Optical result

With fluorescence or luminescence

C436S164000, C436S800000, C549S346000, C549S347000

Reexamination Certificate

active

06294390

ABSTRACT:

This application is a 371 of PCT/EP97/03913 filed Jul. 21, 1997.
The present invention relates to monomeric fluoroionophores that comprise a fluorophore, an ionophore and a functional group covalently bound either directly or via a bridging group to a trivalent organic radical; to homo- and co-polymers of those monomeric fluoroionophores; to processes for the preparation of the monomeric fluoroionophores and polymers thereof; to a coating composition comprising a solvent and a homo- or co-polymer of the monomeric fluoroionophores; to a coated material comprising a support and a layer of the homo- or co-polymers of the monomeric fluoroionophores; to a sensor for the determination of ions, polar substances or lipophilic substances especially in aqueous solutions that comprise the immobilised fluoroionophores in the active layer; to a fluorescence-optical method for the qualitative or quantitative determination of ions, polar substances or lipophilic substances especially in aqueous solutions using the sensor; and to the use of the homo- or co-polymers of those monomeric fluoroionophores as the active layer in fluorescence-optical sensors.
The optical determination of ions has recently gained greater importance, the presence or concentration of ions being measured, for example, by means of a change in the absorption or fluorescence of a suitable dye. The sensors, also called optrodes, generally consist of a transparent support material and an active layer. The active layer normally comprises a transparent hydrophobic polymer and a lipophilic plasticiser for the purpose of obtaining adequate diffusion of the ions and adequate solubility of the active components. Active components are a specific ionophore as a complexing agent for ions, a counter-ion for maintaining electrical neutrality, and an indicator substance which, as a result of a chemical change or a physical change in the environment, emits a measurable optical signal. The disadvantages of many such optical sensors are, for example, that their response times are too long, they are not sufficiently stable, they are pH-dependent, and the active constituents are washed out, so that their useful life is too short or they have to be recalibrated during use.
The response times may be shortened by covalent linkage of ionophore and fluorophore to form the so-called fluoroionophores. Such fluoroionophores are known from WO 89/00997 and U.S. Pat. N. 4,367,072. Even with the use of those fluoroionophores, however, the problem of washing out cannot be fully overcome.
In
J. Mater. Chem.
4(1), (1994), pp. 145-151, Perez-Jimenez et al. describe two novel fluoroionophores that comprise four anthracene units covalently bound to calix[4]arene via an amide or ester bond. Disadvantageous fluorescence-quenching effects may occur as a result of the close adjacency of the four anthracene units in the molecule.
Shortreed et al. describe in
Anal. Chem.
(1996), 68, p. 1414-1418 a calcium-sensitive fluoroionophore that contains a vinyl group bound to the ionophore and that is immobilised at the distal end of an optical fibre by photopolymerisation in acrylamide. Washing out is prevented by that method. The ionophores must, however, contain two functional groups to construct the monomers, which substantially limits the possible choices, since the ion affinity can be substantially reduced by such structural changes.
It has now been found that monofunctionalised ionophores and fluorophores can be covalently bound either directly or via a bridging group to a trifunctional group, which can then be polymerised or bonded to an inorganic or organic material. The immobilised materials are, surprisingly, still suitable for fluorescence detection of ions because the complexing of ions by way of interactions between fluorophore and ionophore still results in a measurable change in fluorescence, and consequently a measurement that is substantially independent of pH is possible. As a result, a direct analysis of ions in body fluids (for example blood, urine, serum), natural waters, waste water or liquid mixtures from chemical reaction processes is possible in which disadvantages, such as washing out of the active components of a sensor, are avoided and, surprisingly, long useful lives and also a high degree of accuracy of measurement are achieved, even with repeated use.
This idea in addition embraces a modular construction of the building blocks (fluorophore, ionophore and functional group) that are to be covalently bound to a trivalent radical, representing a great simplification in synthesis and rendering possible a high degree of flexibility and range of variation resulting from the possibility of interchanging the individual building blocks. In addition, optimisation to the particular intended purpose is possible by means of the choice of building blocks, the nature and length of the bridging groups and the nature of the base materials used for the immobilisation.
The invention relates firstly to compounds of formula (I),
wherein
I is the monovalent residue of an ionophore,
F is the monovalent residue of a fluorophore,
G is a functional group,
T is a trivalent organic radical and
R
01
, R
02
and R
03
are each independently of the others a direct bond or a bridging group.
Preferably, R
01
, R
02
and R
3
are each independently of the others a bridging group.
The ionophores may be natural or synthetic organic compounds that contain a plurality of mostly alternating electron-rich hetero atoms, such as, for example, S, N and especially O, in an open-chained or cyclic carbon chain, and that enable the ions to be measured to be complexed selectively. Such ionophores are described, for example, in U.S. Pat. No. 4,645,744.
The monovalent ionophores from which I in formula (I) is derived may be substances that have an oligoether, polyether, oligoester, polyester, oligoamide or polyamide structure. Examples of such suitable substances may be crown ethers, coronandenes, cryptandenes, calixarenes, podandene or derivatives thereof, also cyclic peptides, for example valinomycin or nonactin, peptides such as gramicidin, and peptides that in the presence of the ion to be determined change their secondary, tertiary or quaternary structure for bonding the ion. It is also possible to use tetrahydrofuran-containing macrolides bonded via ester bridges, and analogous substances that are able to regulate transport in biological systems, or cyclic oligosaccharides, such as, for example, cyclodextrins or cyclophanes.
The functional group G may be carboxy or sulfonic acid, carboxy or sulfonic acid halide, carboxy or sulfonic acid amide, carboxy or sulfonic acid ester, thiol, amine, hydroxyl, cyanate, isocyanate, oxime, aldehyde or ketone groups, or polymerisable groups, such as, for example, olefinically unsaturated groups. Halide denotes preferably chloride or bromide.
The functional group G is preferably a hydroxyl, thiol, isocyanate, carboxyl, carboxamide, carboxyhalide, carboxyalkoxy or amine group.
The functional group G may also be a polymerisable group and in that case is preferably a vinyl group that is unsubstituted or substituted by C
1
-C
4
alkyl. Further examples of polymerisable groups are: diol, diamine, diisocyanate, dicarboxylic acid, dicarboxylic acid dihalide, dicarboxylic acid diamide and dicarboxylic acid diester groups.
The polymerisable group is bonded to the trivalent radical T preferably via the bridging group R
03
. The polymerisable radical may be selected from the group —O—R
8
, —S—R
8
, —NR
7
R
8
, —NR
7
C(O)R
8
, —OC(O)R
8
, —C(O)OR
8
, —C(O)NR
7
R
8
, —CH═N—O—R
8
and —NH—C(O)—NR
7
R
8
, wherein R
7
is H or C
1
-C
4
alkyl and R
8
is an olefinic group having from 1 to 12 carbon atoms, preferably from 1 to 4 carbon atoms, it being possible for those groups to be bonded to the trivalent radical T directly or via a bridging group R
03
, for example C
1
-C
20
alkylene. Those radicals are preferably —NR
7
C(O)R
8
wherein R
7
is H and R
8
is an olefinic group having preferably from 2 to 20, especially from 2 to 12, and more especia

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