CA2009024A1

CA2009024A1 - Optical oxygen sensor

Info

Publication number: CA2009024A1
Application number: CA002009024A
Authority: CA
Inventors: Richard Barner; Walter Huber; Josef Hubscher; Francis Muller
Original assignee: Richard Barner; Walter Huber; Josef Hubscher; Francis Muller; Hoffmann-La Roche (F.) Ag
Current assignee: F Hoffmann La Roche AG
Priority date: 1989-02-03
Filing date: 1990-01-31
Publication date: 1990-08-03
Also published as: EP0381026A2; EP0381026A3; JPH02240552A

Abstract

Abstract There is described an optical sensor based on a transfer of electromagnetic energy from a donor to an acceptor which is characterized that the donor is a pyrene derivative and the acceptor is a perylene derivative.

Description

200902~

The present invention is concerned with an optical oxygen sensor. Such sensors frequently consist of a photo-conductive medium to which an oxygen-sensitive layer has been applied. Such sensors can be implanted in a patient and serve especially for monitoring the oxygen content in the case of intensive care patients.

Optical oxygen (2) sensors have been described in the patent literature and in the literature, see e.g.
European Patent Application, Publication No. 91,390, European Patent Application, Publication No. 252,578 and Journal of Optical Sensors, 1986, Vol. 1, No. 1, pp. 43-67.

For example, in the case of these sensors light can be coupled into a glass fibre (photoconductive medium) via an optic and a dichroic reflector. This activates the 02-indicator at the end of the glass fibre in the 02-sensitive layer. The fluorescent light of the 02-indicator is collected in the glass fibre and is led back by this to the input of the fibre. This fluorescent light is fed to the photomultiplier via the dichroic reflector, interference filter and lenses. Information relating to fluorescence intensity and, respectively, fluorescence lifetime is possible from the signal of the photomultiplier with the aid of an electronic evaluation.
30 The ~wo values can be related to the 02-concentration in the vicjnity of the 02-sensitive layer.

The 02-sensitive element of a pO2-sensor can be formed from two fundamentally different types.

Klt/27.11.89 ~,, s, ,~ . , . . , ., ., . ,,. : . . . , , . . . : -2t~ 02~

The O2-sensitive layer can be applied to the end of the fibre. The excitation light emerges from the end of the fibre and stimulates the fluoresence of the O2-indicators. Since the radiated fluorescent light is distributed isotropically, a portion thereof is coupled into the fibre and fed to the photomultiplier by the fibre.

The sensitive layer can replace the coating of the fibre over a certain distance. In this embodiment of the sensitive element, the excitation ]ight is carried in the core of the glass fibre over the entire region of the sensitive layer. The reciprocal action of the O2-indicators with the excitation light takes place via the so-called evanescent field (a part of the electro-magnetic field which in the case of total reflectioninfiltrates into the optically l:hinner medium). Of this excitation there are only affected indicators which are -~
situated within the range of this evanescent field. The coupling-in of the fluorescent light is effected here via the "evanescent" field. The O2-sensitive layer consist6 of O2-indicator molecllles. The O2-indicator molecules are dissolved in polymers, which are brought together under the collective term silicones. Polydimethylsiloxane is the simplest repr~sentative of this class. A large number of groups (e.g. alkyl, phenyl, trifluoropropyl, vinyl, hydrogen etc.) can replace methyl as the sub~tituent on the silicon. Furthermore, individual repeating units can be reelaced by branching points. This permits a cross-linking of individual linear chains. The 30 consequences of this cross-linking are high-mo]~cular silicon gums. Silicon is chosen as the carrier material for the O2-indicators because of its high O2-permeabi]ity and, respectively, O2-solubility.

The preparation of the silicon matrix is effected e.g.
starting from so-called prepolymers which harden e.g.
under the influence of atmospheric humidity. Thus, the -~(~090Z~

prepolymer is dissolved in a solvent which contains the O2-indicator molecule. This solution is applied to the glass substrate in a thin layer. The hardening of the polymer takes place in contact with environmental humidity. As an alternative thereto, the polymerization can also be effected in the absence of the Oz--indicators. These can subsequently be incorporated by using a solvent in which the polysilicone swells up.

In accordance with the invention the O2-sensitive layec does not consist of a single indicator molecule, but of a donor-acceptor pair, such as is described e.g. in Applied Spectroscopy, Vol. 4Z, No. 6, 1988 (1009-1011).
The combination of pyrene and perylene described there possesses the ideal spectral requirements which are needed on a donor-acceptor pair for an O2-detection. The excited state of the pyrene is quenched very efficiently by oxygen. The emission spectrum of the pyrene (donor) overlaps well with the absorption spectrum of the perylene. Perylene itself has an emission maximum at , 440 and 470 nm. Excitation wavelengths foe the donor (pyrene) and emission wavelengths of the acceptor (perylene) are thus .~eparated from one another by more than 100 nm.

The only disadvantage of this donor-acceptor pair lies in the low solubility of pyrene and perylene in silicon (<10 mol/dm ). The decisive value for an efficient transfer of energy is the distance between donor and acceptor. The suitable distance can be adjusted by means 30 of the concentration when the corresponding molecules have an adequate solubility (10 mol/dm ). A high concentration of pO2--indicator is also required for the signal-noise ratio, miniaturization of the sensitive layer ~ -and durability of the s(?nsor.
~-~
In the scope of the present invention it has now b~en found that by suitable substitution of the pyrene and of ~," ' ' ' ~ '' . ', ~',''"'. ~' ~" ', " ,,, ' ' ' ',' :

2(~0~02~

the perylene there can be obtained donor-acceptor pairs ~ ~
which on the one hand have a better so].ubility than pyrene . and perylene in silicon and which on the other hand retain the O2-indicator properties. -The present invention is therefore concerned with an - -~
optical oxygen sensor based on a transfer of electro-magnetic energy from a donor to an acceptor, which is ~ ~
characterized in that the donor is a pyrene derivative of ~ ~ :
10 the general formula :~

~

wherein R signifies an alkyl group with up to 30 C-atoms, -C~2-OR, -R'-O-R " or -OR, whereby n signifies a whole number of 1-10, R' is an alkylene group of 1-29 C-atoms and R'' is an alkyl group of 1-29 C-atoms, with the proviso that R' and R'' have a maximum of 30 C-atoms, and in that the acceptor is a perylene derivative of the gene~al formula :

~ ',' .

( R ) ,~

:~:

,: , , . . . .
,, i. :- - , :: - : . , :

i~,, , ' :
~ ~ ' ' ~ ' . . , , ' 1,... ... . . .
",; ~,, , , ' '' ', '' ' ' " '; ', . ~ :. ~ ' t02~

wherein R and n have the said significance.

As donors there come into consideration especially dioctadecylpyrene, tetraoctadecylpyrene, l-(methoxy-methyl)pyrene as well as l-(octadecyloxymethyl)pyrene.
Especially suitable acceptors are dioctadecylperylene, tetraoctadecylperylene as well as 3-(octadecyloxymethyl)-perylene. With the exception of l-(methoxymethyl)pyrene these compounds are novel and form a part of the present invention.

The compounds of formulae I or II in which R
represents an alkyl group with up to 30 C atoms can be prepared in a manner known per se by alkylating pyrene or perylene with the corresponding alkyl halide in a Friedel-Crafts reaction using aluminium chloride as the catalyst in an inert solvent such as carbon tetrachloride or methylene chloride or in a deactivated liquid aromatic such as nitrobenzene or chlorobenzene, preferably methylene chloride, at 0-30, preferably room tempeeature.
The introduction of the alkyl groups is effected according to the substitution pattern of the electrophilic substitution which is characteristic for the particular aromatic. After the usual working-up with ice-water/hexane the alkylation product can be separated by chromatography into the di-tetra- and higher-alkylated compounds.

The compounds of formulae I or II in which R signifies -CH2-OR, -R'-O-R''- or OR can be prepared by converting 30 the corresponding hydroxy compound into the alcoholate by deprotoni~ation with sodium hydride at 0 to room ~ -~
temperature in an inert solvent which is favourable for ~-the subsequent alkylation, ~uch as tetrahydrofuran or N,N-dialkylformamide, and reaction (aftec the 35 H2-evolution has ceased) with the corresponding alkyl halide at room temperature to give the alkoxy compound.

.,, . , ~ . . . .

' ' '' , ', "
~' . ' " " ' ~ ' '' ' .

21~0~)2~

The ~ollowing Examples illustrate the invention:

Example 1 -:
2.5 g (10 mmol) of peeylene were added dropwise as a solution in lO ml of dey methylene chloride to a suspension of 3.5 g (lO.5 mmol) of l-bromooctadecane and 1 g (8 mmol) Oe aluminium chloride in 10 ml of methylene chloride and the mixture was stirred at room temperature for 5 hours. It was hydrolyzed with ice-water, extracted with hexane and concentrated. The crude product was chromatographed on silica gel with hexane. There were thus obtained 1.2 g (15.9%) of dioctadecylperylene and 2.1 g (16.6%) of dioctadecylperylene (as a mixture of isomers in addition to educt and other alkylation products) as a yellow oil. TLC (silica gel/hexane) Rf (educt) = 0.3 Rf (dioctadecylperylene/tetraoctadecylperylene) = 0.6/0.7 Mol(C20H12) = Z52.32 Mol(C56H84) = 757.29 Mol(C92H156) = 1262.27.

Example 2 20 g (100 mmol) of pyrene were added dropwise as a solution in 100 ml of dry methylene chloride were added dropwise to a suspension of 35 g (105 mmol) of 1-bromo-octadecane and 5 g (40 mmol) of aluminium chlocide in 10 ml of methylene chloride and the mixture was stirred at room temperature for 5 hours. It was hydrolyzed with 30 ice-water. extracted with hexane and concentrated. The crude product was chromatographed on silica gel with hexane. There were thus obtained 16 g (22.6%) of diocta~
decylpyrene and 19 g (15.7%) of dioctadecylpyrene (as a mixtu~e of isomers in addition to educt and other 35 alkylation products) as a yellow oil. The products were characterized by IR, NMR and MS and microanalysis. TLC
(silica gel/hexane) Rf (educt) = 0.4 Rf (dioctadecyl-", .. . . ....

~`

2~30~2~

pyrene/tetraoctadecylpyrene) = 0.7/0.8 Mol(C16H10) = 202.26 -~
Mol(C52H82) = 707.23 Mol(C88H154) = 1212.21.

ExamDle 3 :
232 mg (1 mmol) of l-hydroxymethylpyrene were dissolved in 2 ml of dry THF and treated with 30 mg (1.2 mmol) of sodium hydride (80% in mineral oil) and stirred at room temperature for 30 minutes. Then, 1 ml (about 1 mmol) of methyl iodide was added dropwise and the mixture was stirred at room tempecature for 3 hours. It was treated with ice-water, extracted with toluene and the organic phase was filtered through silica gel and concentrated. There were obtained 243 mg (99%) of l-(methoxymethyl)pyrene as a brownish oil which was characterized by MS. TLC (silica gel/toluene) Rf (educt) =
0.1 Rf (product) = 0.5. ~ -ExamDle 4 A solution of 186 mg (0.8 mmol) of l-(hydroxymethyl)-pyrene in dry N,N-dimethylformamide (DMF) was tceated at 25 0C while stirring with 100 mg of a 55-60% suspension of ~ ~
sodium hydride in mineral oil (about 2 mmol of sodium -hydride) and, after the evolution of hydrogen had ceased, the mixture was stirred at room temperature for a further 30 minutes. A solution of 270 mg (0.8 mmol) of octadecyl bromide in 1 ml of dry DMF was added dropwise, while sl:irring, to the solution obtained and the reaction mixture was subsequently stirred overnight (room temperature). The salts were separated by filtration over "Hyflo" and the filtrate was chromatographed directly on ~
35 silica gel, whereby th~ee were obtained 363 mg (85%) of ~ ~-l-(octadecyloxymethyl)pyrene in crystalline form: m.p. =
67-69.
.

.~, . . . . . . .

, ~:,: " "
~ A , ' , ~

- 8 - 2~0~

The compound was characterized by mass spectroscopy (M = 484) TLC tsilica gel/toluene) Rf = 0.8 Rf (hydroxymethyl-pyrene) = 0.1 Mol(C35H480) = 484.78.
..
ExamPle 5 In analogy to Example 4, 115 mg (0.42 mmol) of 3-(hydroxymethyl)-perylene were reacted with octadecyl bromide to give 3-(octadecyloxymethyl)perylene (135 mg;
60%) m.p. = 101-103 MS: M = 534 TLC (silica gel/toluene) Rf = 0.9 Mol(C30H500) = 534.79.

Example 6 (Preparation of an 2 sensitive layer) 1 g of Elastosil E43 (Wacker Chemie) is dissolved in 1 ml of o-toluene solution containing the donor diocta-decylpyren (0.001 m) and the acceptor dioctadecylperylene (0,001 m). The resulting viscous mass is brought on to the substrate in the desired thickness. The hardening of the polymer takes place within 24 hours.

The figures l:a) and l:b) show schematically two optical oxygen sensors with an 02-sensitive layer according Example 6. ;~

:

~''' :~ ~ - ' ' ' ' ' ., ', ,'; ' " ' ' ' . ' ~'-' : , , . ' :
~," ., ,: ' ~'~ G ~
''',',,,, ~ ~ : ~ '' "',',, ^': ' ' ' ' " ' ~ . ' ` '"~'. '., :"
~:"' ' ' ' ~' ''' ''' , ', ' ' :
~' ' ': ' , ~ ' - ' , , ' . . . ' '., ~. . , ' ,

Claims

1. An optical oxygen sensor based on a transfer of electromagnetic energy from a donor to an acceptor, characterized in that the donor is a pyrene derivative of the general formula I
wherein R signifies an alkyl group with up to 30 C-atoms, -CH2-OR, -R'-O-R'' or -OR, whereby n signifies a whole number of 1-10, R' is an alkylene group of 1-29 C-atoms and R'' is an alkyl group of 1-29 C-atoms, with the proviso that R' and R'' have a maximum of 30 C-atoms, and in that the acceptor is a perylene derivative of the general formula II
wherein R and n have the said significance.

2. An optical oxygen sensor, characterized in that the donor is dioctadecylpyrene.

3. An optical oxygen sensor, charactecized in that the donor is tetraoctadecylpyrene.

4. An optical oxygen sensor, characterized in that the donor is 1-tmethoxymethyl)pyrene.

5. An optical oxygen sensor, characterized in that the donor is 1-(octadecyloxymethyl)pyrene.

6. An optical oxygen sensor, characterized in that the acceptor is dioctadecylperylene.

7. An optical oxygen sensor, characterized in that the acceptor is tetraoctadecylperylene.

8. An optical oxygen sensor, characterized in that the acceptor is 3-(octadecyloxymethyl)perylene.

9. Pyrenes and perylene derivatives, namely dioctadecylpyrene, tetraoctadecylpyrene, 1-(octadecyloxy-methyl)pyrene, dioctadecylperylene, tetraoctadecylperylene and 3-(octadecyloxymethyl)perylene.