Redox mediators
View Patent ↗The present invention relates to ruthenium and osmium complexes of Formula [M(A) w (B) x (C) y ] m (X z ) n , per se and the use of ruthenium and osmium complexes of Formula I as redox mediators in electrochemical biosensors.
1. A method for measuring an amount or concentration of an analyte, comprising:
(a) contacting a sample which contains the analyte with a solution containing an enzyme that acts on the analyte and a redox mediator of Formula I
[M(A) w (B) x (C) y ] m (X z ) n Formula I
wherein
M is ruthenium or osmium and has an oxidation state of 0, 1, 2, 3 or 4;
each of w, x, and y is an integer independently selected from the integers 1 to 4;
m is an integer selected from the integers −5 to +4;
n is an integer selected from selected from the integers 1 to 5;
z is an integer selected from the integers −2 to +1;
A is a monodentate 5- or 6-membered aromatic ligand containing 1, 2 or 3 nitrogen atoms which is optionally substituted by 1 to 8 substituents each selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, or aryl groups, —F, —Cl, —Br, —I, —NO 2 , —CN, —CO 2 H, —SO 3 H, —NHNH 2 , —SH, aryl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, —OH, alkoxy, —NH 2 , alkylamino, dialkylamino, alkanoylamino, arylcarboxamido, hydrazino, alkylhydrazino, hydroxylamino, alkoxyamino and alkylthio or A is NCS;
B is a bi-, tri-, tetra-, penta- or hexadentate ligand which is linear having the formula R 1 RN(C 2 H 4 NR) w R 1 or cyclic having the formula (RNC 2 H 4 ) v , (RNC 2 H 4 ) p (RNC 3 H 6 ) q or [(RNC 2 H 4 )(RNC 3 H 6 )] s , wherein
w is an integer selected from the integers 1-5,
v is an integer selected from the integers 3-6,
each of p and q is an integer independently selected from the integers 1-3 whereby the sum of p and q is 4, 5 or 6,
s is either 2 or 3;
and each of R and R 1 is independently hydrogen or alkyl;
C is a ligand other than B; and
X is a counter ion, wherein the number of coordinating atoms is 6, with the exception of [Ru III (Me 3 tacn)(acac)(py)](NO 3 ) 2 );
(b) incubating the contacted sample under conditions that cause the enzyme to act on the analyte;
(c) subjecting the incubated sample of step (b) to conditions which result in a change in a measurable signal; and
(d) measuring the measurable signal to determine the amount or concentration of the analyte in the sample.
2. The method of claim 1 , wherein ligand A is selected from the group consisting of NCS, imidazole, pyrazole, thiazole, oxazole, isoquinoline, substituted pyridyl, and isomers thereof.
3. The method of claim 1 , wherein ligand A is selected from the group consisting of guanine, adenine, a 5-membered heteroaromatic comprising three nitrogen atoms in the ring, a 6-membered heteroaromatic comprising three nitrogen atoms in the ring, imidazole, pyrazole, thiazole, oxazole, and isomers thereof.
4. The method of claim 1 , wherein ligand A is substituted by one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and halogen.
5. The method of claim 4 , wherein ligand A is substituted by one or more substituents selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, t-butyl, methoxy, ethoxy, ethenyl, propenyl, butenyl, ethynyl and propynyl.
6. The method of claim 1 , wherein ligand B is selected from the group consisting of a linear ligand of formula R 1 RN(C 2 H 4 NR) w R 1 , a cyclic ligand of formula (RNC 2 H 4 ) v , a cyclic ligand of formula (RNC 2 H 4 ) p (RNC 3 H 6 ) q , and a cyclic ligand of formula [(RNC 2 H 4 ))(RNC 3 H 6 )] s , wherein w is an integer selected from 1-3, v is 3 or 4, p and q are integers independently selected from 1-3, wherein the sum of p and q is 4, and s is 2 or 3.
7. The method of claim 1 , wherein B is selected from the group consisting of 1,4,7-trimethyl-1,4,7-triazacyclononane, 1,1,4,7,10,10-hexamethyltriethylenetetramine, 1,2-dimethylethylenediamine and 1,1,2,2-tetramethylethylenediamine.
8. The method of claim 1 , wherein ligand C is selected from the group consisting of NH 2 , CO, CN, a halogen, acetylacetonate (acac), 3-bromo-acetylacetonate (Bracac), oxalate, pyridine and 5-chloro-8-hydroxyquinoline.
9. The method of claim 1 , wherein the complex of Formula I is selected from the group consisting of
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(N-methylimidazole)](NO 3 ) 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(4-methylpyridine)]Cl 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(3-chloropyridine)](NO 3 ) 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(isonicotinamide)](NO 3 ) 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)pyrazine](NO 3 ) 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(4-methoxypyridine)](NO 3 ) 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(4-dimethylaminopyridine)](NO 3 ) 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(4-t-butyl-pyridine)](NO 3 ) 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(isoquinoline)](NO 3 ) 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(tropolone)(pyridine)](NO 3 ) 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(tropolone)(4-t-butyl-pyridine)](NO 3 ) 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(3,4-dimethylpyridine)](CF 3 SO 3 ) 2 ,
[Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(3-hydroxypyridine)](NO 3 ) 2 , and
[Ru III (1,4,8,11-tetramethyl-1,4,8,11-tetra-azacyclotetradecane)(NCS) 2 ](ClO 4 ).
10. The method of claim 1 , wherein the complex of Formula I is selected from the group consisting of [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(N-methylimidazole)](PF 6 ) 2 and [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(N-methylimidazole)](NO 3 ) 2 .
11. A complex according to Formula I
[M(A) w (B) x (C) y ] m (X Z ) n Formula 1
wherein
M is ruthenium or osmium and has an oxidation state of 0, 1, 2, 3 or 4;
each of w, x, and y is an integer independently selected from the integers 1 to 4;
m is an integer selected from the integers −5 to +4;
n is an integer selected from selected from the integers 1 to 5;
z is an integer selected from the integers −2 to +1;
A is a monodentate 5- or 6-membered aromatic ligand containing 1, 2 or 3 nitrogen atoms which is optionally substituted by 1 to 8 substituents each selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, or aryl groups, —F, —Cl, —Br, —I, —NO 2 , —CN, —CO 2 H, —SO 3 H, —NHNH 2 , —SH, aryl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, —OH, alkoxy, —NH2, alkylamino, dialkylamino, alkanoylamino, arylcarboxamido, hydrazino, alkylhydrazino, hydroxylamino, alkoxyamino and alkylthio;
B is a bi-, tri-, tetra-, penta- or hexadentate ligand which is linear having the formula R 1 RN(C 2 H 4 NR) w R 1 or cyclic having the formula (RNC 2 H 4 ) v , (RNC 2 H 4 ) p (RNC 3 H 6 ) q or [(RNC 2 H 4 )(RNC 3 H 6 )] s , wherein
w is an integer selected from the integers 1-5,
v is an integer selected from the integers 3-6,
each of p and q is an integer independently selected from the integers 1-3 whereby the sum of p and q is 4, 5 or 6,
s is either 2 or 3 and
each of R and R 1 is independently hydrogen or alkyl;
C is a ligand other than A or B; and
X is a counter ion,
wherein the number of coordinating atoms is 6, with the exception of [Ru III (Me 3 tacn)(acac)(Py)](NO 3 ) 2 ; and
wherein the complex is selected from the group consisting of [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(N-methylimidazole)](NO 3 ) 2 , [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(4-methylpyridine)]Cl 2 , [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(3-chloropyridine)](NO 3 ) 2 , [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(isonicotinamide)](NO 3 ) 2 , [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)pyrazine](NO 3 ) 2 , [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(4-methoxypyridine)](NO 3 ) 2 , [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(4-dimethylaminopyridine)](NO 3 ) 2 , [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(4-t-butyl-pyridine)](NO 3 ) 2 , [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(isoquinoline)](NO 3 ) 2 , [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(tropolone)(pyridine)](NO 3 ) 2 , [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(tropolone)(4-t-butyl-pyridine)](NO 3 ) 2 , [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(3,4-dimethylpyridine)](CF 3 SO 3 ) 2 , and [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(3-hydroxypyridine)](NO 3 ) 2 .
12. A complex according to Formula I
[M(A) w (B) x (C) y ] m (X Z ) n Formula 1
wherein
M is ruthenium or osmium and has an oxidation state of 0, 1, 2, 3 or 4;
each of w, x, and y is an integer independently selected from the integers 1 to 4;
m is an integer selected from the integers −5 to +4;
n is an integer selected from selected from the integers 1 to 5;
z is an integer selected from the integers −2 to +1;
A is a monodentate 5- or 6- membered aromatic ligand containing 1, 2 or 3 nitrogen atoms which is optionally substituted by 1 to 8 substituents each selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, or aryl groups, —F, —Cl, —Br, —I, —NO 2 , —CN, —CO 2 H, —SO 3 H, -NHNH 2 , —SH, aryl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, —OH, alkoxy, —NH2, alkylamino, dialkylamino, alkanoylamino, arylcarboxamido, hydrazino, alkylhydrazino, hydroxylamino, alkoxyamino and alkylthio;
B is a bi-, tri-, tetra-, penta- or hexadentate ligand which is linear having the formula R 1 RN(C 2 H 4 NR) w R 1 or cyclic having the formula (RNC 2 H 4 ) v , (RNC 2 H 4 ) p (RNC 3 H 6 ) q or [(RNC 2 H 4 )(RNC 3 H 6 )] s , wherein
w is an integer selected from the integers 1-5,
v is an integer selected from the integers 3-6,
each of p and q is an integer independently selected from the integers 1-3 whereby the sum of p and q is 4, 5 or 6,
s is either 2 or 3 and
each of R and R 1 is independently hydrogen or alkyl;
C is a ligand other than A or B; and
X is a counter ion,
wherein the number of coordinating atoms is 6, with the exception of [Ru III (Me 3 tacn)(acac)(Py)](NO 3 ) 2 ; and
wherein the complex is selected selected from the group consisting of [Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(N-methylimidazole)](PF 6 ) 2 and Ru III (1,4,7-trimethyl-1,4,7-triazacyclononane)(acac)(N-methylimidazole)](NO 3 ) 2 .
13. A complex according to Formula 1
[M(A) w (B) x (C) y ] m (X Z ) n Formula 1
wherein
M is ruthenium or osmium and has an oxidation state of 0, 1, 2, 3 or 4;
each of w, x, and y is an integer independently selected from the integers 1 to 4;
m is an integer selected from the integers −5 to +4;
n is an integer selected from selected from the integers 1 to 5;
z is an integer selected from the integers −2 to +1;
A is a monodentate 5- or 6-membered aromatic ligand containing 1, 2 or 3 nitrogen atoms which is optionally substituted by 1 to 8 substituents each selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, or aryl groups, —F, —Cl, —Br, —I, —NO 2 , —CN, —CO 2 H, —SO 3 H, —NHNH 2 , —SH, aryl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, —OH, alkoxy, —NH2, alkylamino, dialkylamino, alkanoylamino, arylcarboxamido, hydrazino, alkylhydrazino, hydroxylamino, alkoxyamino and alkylthio;
B is a bi-, tri-, tetra-, penta- or hexadentate ligand which is linear having the formula R 1 RN(C 2 H 4 NR) w R 1 or cyclic having the formula (RNC 2 H 4 ) v , (RNC 2 H 4 ) p (RNC 3 H 6 ) q or [(RNC 2 H 4 )(RNC 3 H 6 )] s , wherein
w is an integer selected from the integers 1-5,
v is an integer selected from the integers 3-6,
each of p and q is an integer independently selected from the integers 1-3 whereby the sum of p and q is 4, 5 or 6,
s is either 2 or 3 and
each of R and R 1 is independently hydrogen or alkyl;
C is a ligand other than A or B; and
X is a counter ion,
wherein the number of coordinating atoms is 6, with the exception of [Ru III (Me 3 tacn)(acac)(Py)](NO 3 ) 2 ; and
wherein ligand A is selected from the group consisting of guanine, adenine, a 5-membered heteroaromatic comprising three nitrogen atoms in the ring, a 6-membered heteroaromatic comprising three nitrogen atoms in the ring, imidazole, pyrazole, thiazole, oxazole, and isomers thereof.
14. A complex according to Formula I
[M(A) w (B) x (C) y ] m (X Z ) n Formula 1
wherein
M is ruthenium or osmium and has an oxidation state of 0, 1, 2, 3 or 4;
each of w, x, and y is an integer independently selected from the integers 1 to 4;
m is an integer selected from the integers −5 to +4;
n is an integer selected from selected from the integers 1 to 5;
z is an integer selected from the integers −2 to +1;
A is a monodentate 5- or 6-membered aromatic ligand containing 1, 2 or 3 nitrogen atoms which is optionally substituted by 1 to 8 substituents each selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, or aryl groups, —F, —Cl, —Br, —I, —NO 2 , —CN, —CO 2 H, —SO 3 H, —NHNH 2 , —SH, aryl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, —OH, alkoxy, —NH2, alkylamino, dialkylamino, alkanoylamino, arylcarboxamido, hydrazino, alkylhydrazino, hydroxylamino, alkoxyamino and alkylthio;
B is a bi-, tri-, tetra-, penta- or hexadentate ligand which is linear having the formula R 1 RN(C 2 H 4 NR) w R 1 or cyclic having the formula (RNC 2 H 4 ) v , (RNC 2 H 4 ) p ,(RNC 3 H 6 ) q or [(RNC 2 H 4 )(RNC 3 H 6 )] s , wherein
w is an integer selected from the integers 1-5,
v is an integer selected from the integers 3-6,
each of p and q is an integer independently selected from the integers 1-3 whereby the sum of p and q is 4, 5 or 6,
s is either 2 or 3 and
each of R and R 1 is independently hydrogen or alkyl;
C is a ligand other than A or B; and
X is a counter ion,
wherein the number of coordinating atoms is 6, with the exception of [Ru III (Me 3 tacn)(acac)(Py)](NO 3 ) 2 ; and
wherein B is selected from the group consisting of 1,4,7-trimethyl-1,4,7-triazacyclononane, 1,1,4,7,10,10-hexamethyltriethylenetetramine, 1,2-dimethylethylenediamine and 1,1,2,2-tetramethylethylenediamine.