Ratiometric fluorescent Zn2+ and In3+ receptors of fused pyrazine with an aminopropanol chain in acetonitrile

Article abstract of DOI:10.1039/c3nj00750b

A series of new potential intramolecular charge transfer ICT fluorescent receptors of Zn²⁺, Cd²⁺, Hg²⁺, Ga³⁺, In³⁺, and Tl³⁺ ions based on N-aryl or N-alkyl variously fused pyridopyrrolopyrazine or pyrrolo[2,3-b]quinoxaline with an integrated donor group, such as 3-aminopropanol, were synthesized and verified. Among [N, N, O] tridentate donors 4a, 6a-d, 10a, 12e, and 14e, only the integrated fluorophore-receptors with the nitrogen atom at the N-5 position of heterocyclic systems, pyrido[2,3-b]pyrrolo[2,3-e]pyrazine 6a, selectively respond to zinc and indium with significant fluorescent enhancement and different mechanisms of binding. The first example of Z to E interconversion of enaminone forms of a ligand responsible for Zn²⁺ complex fluorescence enhancement was documented. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2014.

Full text of DOI:10.1039/c3nj00750b

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Ratiometric fluorescent Zn2+ and In3+ receptors of
fused pyrazine with an aminopropanol chain in
Cite this: DOI: 10.1039/c3nj00750b
acetonitrile†
Katarzyna Ostrowska,*a Alicja Ka´zmierska,a Maria Ra˛pała-Kozikb and
a
´
Justyna Kalinowska-Tłuscikz
A series of new potential intramolecular charge transfer ICT fluorescent receptors of Zn2+, Cd2+, Hg2+
,
Ga3+, In3+, and Tl3+ ions based on N-aryl or N-alkyl variously fused pyridopyrrolopyrazine or pyrrolo-
[2,3-b]quinoxaline with an integrated donor group, such as 3-aminopropanol, were synthesized and
verified. Among [N, N, O] tridentate donors 4a, 6a–d, 10a, 12e, and 14e, only the integrated fluoro-
phore-receptors with the nitrogen atom at the N-5 position of heterocyclic systems, pyrido[2,3-b]-
pyrrolo[2,3-e]pyrazine 6a, selectively respond to zinc and indium with significant fluorescent enhancement
and different mechanisms of binding. The first example of Z to E interconversion of enaminone forms of a
ligand responsible for Zn2+ complex fluorescence enhancement was documented.
Received (in Montpellier, France)
7th July 2013,
Accepted 10th October 2013
DOI: 10.1039/c3nj00750b
www.rsc.org/njc
quinoline,14–20 quinoxaline,21,22 acridine,23–27 indole,28–30 and
carbazole31,32 are usually used as fluorogenic sensor compo-
Introduction
One of the most challenging fields in organic and supramolec-
ular chemistry is development of the fluorescent molecular
sensors, especially for heavy and transition metal ions.1–11
Current fluorescent molecular sensors for metal ions usually
contain a fluorophore and a receptor, which can form an
integrated or a spaced fluorophore–receptor system. Receptors
include N-, O-, or S-donor groups, which are responsible for
selective metal ion binding. The fluorophores with conjugated
p-electron systems change their photophysical properties upon
complexation, signalling binding with metal ions. The emitted
signals are detected as the enhancement of fluorescent emis-
sion with a red or blue shift of the emitted band or the
quenching of the fluorescence. Azaheteroarenes, containing
one or more heterocyclic nitrogen atoms, such as pyridine,12,13
nents. These heterocyclic systems with separated or integrated
receptor units containing amino, imino, amido, hydroxy,
alkoxy, carbonyl, or carboxyl groups and a metal ion form five-
or six-membered chelate rings with binding mode 1 : 1, 2 : 1, or
even 3 : 1.33 The connection between the ionophore and the
fluorophore is essential for signalling and recognition function.
The cation-induced photophysical changes are mainly based
on photoinduced electrons, protons or charge transfer and
excimer formation. The general classification of fluorescent
sensors is connected with the origin of photoinduced changes
such as photoinduced electron transfer cation sensors (PET) or
photoinduced charge transfer cation sensors (ICT). Usually the
cation sensors (ICT) contain conjugated electron-donating and
electron-withdrawing groups forming an intramolecular push–
pull electronic system. During the formation of the complex the
metal cation interacts with the donor or acceptor moiety, which
affects the efficiency of intramolecular charge transfer upon
excitation by light.
a
´
Faculty of Chemistry, Jagiellonian University, R. Ingardena 3, PL-30060 Krakow,
Poland. E-mail: ostrowsk@chemia.uj.edu.pl; Fax: +48-12-63-40-515
b Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University,
8-arylsulphonamide (Zinquin)13 or 8-carboxamide deriva-
tives of quinoline (AQZ)15 are the most widely used ICT fluor-
escent sensors for zinc cations in biological samples (Fig. 1).
Sensors contain electron-acceptor amido groups and electron-
´
Gronostajowa 7, PL-30387 Krakow, Poland
† Electronic supplementary information (ESI) available: 2D fluorescence spectra
of 4a, 4a-Hg, 6a, 6a-Zn, 6a-In, 6a-Hg, 12e, and 14e. Fluorescence spectra of 4a, 6,
10a, 12e, and 14e (10 mM) in CH3CN with 1 equiv. of Cd2+. Fluorescence spectra of
4a, 6, 10a, 12e, and 14e (10 mM) in CH3CN with 1 equiv. of Hg2+. Fluorescence
titration of 6a with Zn(acac)2, Zn(OAc)2, and ZnCl2. 1H and 13C NMR spectra of donors with the N-1 quinoline nitrogen atom. When the metal
compounds 6a–d, 8a, 9a, 10a, 12e,f, and 14e,f. Partial 1H NMR titration spectra of
ion is bound to an electron-withdrawing amido group, the
complexation is associated with the deprotonation of the amine
leading to an enhanced ICT process from the donor to the
6a with Zn(acac)2 in CD3CN and DMSO-d6. Conformational and intermolecular
interaction analysis of crystal structures of 6a and 12e. CCDC 890198 and 890197.
For ESI and crystallographic data in CIF or other electronic format see DOI:
acceptor upon excitation by light. The replacement of hydrogen
by the zinc ion and the formation of a five-membered chelate
10.1039/c3nj00750b
‡ For crystal structure information, e-mail: kalinows@chemia.uj.edu.pl.
c
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Fig. 1 General structures of the studied chemosensors.
ring broaden the conjugation of the p-system resulting in positive charge on iminium ions, or the electron-withdrawing
Stokes red-shift of the absorption spectra. In addition to this group could increase the positive charge and enhance the
shift a 300-fold increase in their fluorescence intensity upon dipole moment of 4a. Deprotonation and coordination of the
chelation of zinc is observed.34
zinc atom, more electropositive than hydrogen, to the nitrogen
We previously designed ICT integrated fluorophore–receptor of the conjugated enaminone moiety and the N-4 nitrogen
sensors 1a–4a for zinc ions, with (E/Z)-3-[(alkylamino)phenyl- donor of quinoxaline changes the distribution of electronic
methylidene]-pyrrolo[2,3-b]quinoxaline as the fluorogenic com- charge in the push–pull system. Formation of the six-membered
ponent and amino, hydroxyl, aminoalkyl or hydroxyalkyl groups as chelate ring extends p-conjugation resulting in a cation-induced
additional receptors (Fig. 1).35 Among these [N, N, N] or [N, N, O] red shift of the absorption spectrum and fluorescence emission
tridentate ligands 1a–4a, compound 3a showed the ratiometric upon excitation by light.
turn-on fluorescence response toward zinc cations within the
In this paper, we report the syntheses and photophysical
working zinc concentration range of Kd = 3.77 ꢀ 0.51 mM and a properties of various new fluorophores: aryl or alkylphenyl
binding stoichiometry of 1 : 1. This push–pull (E/Z)-enamine substituted at the N-1 position of pyridopyrrolopyrazine (6),36
undergoes deprotonation while binding zinc cations, yielding a (10), (12),37 and pyrrolo[2,3-b]quinoxaline-7-carboxylic acid (14),37
red-shifted excitation wavelength with induced charge transfer integrated with 3-aminopropan-1-ol upon complexation with bio-
signal transduction (ICT).35
logically12–20,25,26,28,31,38–40 and environmentally20,24,27,32,38,39
The electronegativity of the oxygen atom in the carbonyl important metal ions, such as Zn2+, Cd2+, Hg2+, Ga3+, In3+,
group of imide causes the delocalization of N-1 or enamine and Tl3+
nitrogen’s lone pairs into the p system, leading to formation of
zwitterions A or B, respectively (Scheme 1). Form B is stabilised
.
Results and discussion
by an internal hydrogen bond. The positive charge on iminium
ions in form A may be modulated by electron-donating or Ligands 6, 10, 12, and 14 were efficiently synthesised according
electron-withdrawing character of these groups attached to to our previously published procedure, using ketones 5, 9a, 11f,
N-1. The electron-donating group could decrease and stabilize 11e and salt of the latter or a regioisomeric mixture of keto
Scheme 1 Zwitterionic resonance structures of receptor 4a.
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starting materials at 50 1C for 3 h. Compounds 6c and 14f
crystallise with one molecule of aminopropanol.
According to our previous results, we obtained mixtures of
the E/Z diastereoisomers of 6a–6d, 10a, 12e, 12f and 14e, 14f,
with E-isomers predominating in solution (Table 1). The
presence of a nitrogen atom at N-5 for 6 effectively shifts the
E/Z equilibrium in CDCl3 to E-form, plausibly due to formation
of an additional intramolecular hydrogen bond between the
N-5 nitrogen atom and the hydroxyl group in solution. In the
case of the mixture of regioisomeric 6- and 7-carboxylic acids of
3-benzoylpyrrolo[2,3-b]quinoxaline 13, only the regioisomeric
7-substituted products 14e and 14f were isolated.
X-ray structure analysis41–48 of (E)-6a and (E)-12e showed the
stabilisation of the configuration in the solid. For both struc-
tures, an intramolecular hydrogen bond N30–H30ꢁ ꢁ ꢁN4 is
observed H30ꢁ ꢁ ꢁN4 = 2.16(3) Å, N30ꢁ ꢁ ꢁN4 = 2.837(3) Å and
N30–H30ꢁ ꢁ ꢁN7 = 137(3)1 for 6a (Fig. 2) and H30ꢁ ꢁ ꢁN4 =
2.162(17) Å, N30ꢁ ꢁ ꢁN4 = 2.894(1) Å and N30–H30ꢁ ꢁ ꢁN7 =
138.0(14)1 for 12e (Fig. 3).
Fig. 2 Crystal structure of 6a as a monohydrate, showing the atom labelling
The absorption and emission data for the studied com-
scheme. Displacement ellipsoids of non-hydrogen atoms are drawn at the 30%
probability level. H atoms are presented as small spheres with an arbitrary radius. pounds are listed in Table 2. The quantum yields (Fn) for
Dashed lines represent a hydrogen bond system observed within the asymmetric
compounds 5a,d, 6a,d and 9a, 10a, 12e,f, and 14e,f were
determined in chloroform and acetonitrile using 1 mM stock
unit.
solution prepared in DMSO. The lifetimes (tn) for all of the
analysed compounds were obtained in chloroform. The solubi-
acids 13 with 3-aminoalkohol as reagents (Scheme 2).35 Regio-
isomer 9a was obtained using a multistep method exploiting
the exo-enol tautomerism of 7a in CH2Cl2 to furnish 3-amino-
N-(2-amino-3-pyridyl)-pyrrolidinedione 8a, which was then
cyclized in EtOH. Aminoalcohol was used in excess, acting as
both reagent and solvent and reacting regioselectively at the
benzoyl carbon atom. The reaction was carried out at room
temperature for 5 days while the product precipitated. To
shorten the reaction time for 6a, we modified this procedure
by adding propanol to the reaction mixture and heating the
lity of the compounds was the basis of the solvent selection. In
principle, no significant differences were observed in the
absorption and emission spectra in the two solvents for com-
pounds 6a, 9a, 10a, 12e, and 14e. The UV/Vis spectra of
all enamines 6, 10a, 12e,f, and 14e,f exhibited two maxima
(376–388 and 393–402 nm) with equal molar absorption
coefficients.
All enamines exhibit weak fluorescence properties regard-
less of the various azaheteroarene fluorophores. To verify the
sensing abilities of integrated fluorophore–receptor sensors for
divalent and trivalent Zn2+, Cd2+, Hg2+, Ga3+, In3+, Tl3+ ions, we
performed a detailed spectrophotometric study. The most
effective turn-on fluorescence response among N-aryl or N-alkyl
variously fused pyridopyrrolopyrazine or pyrrolo[2,3-b]quinoxa-
line for Zn2+ and In3+ is exhibited by 6a (Fig. 4a and b). Trivalent
indium and divalent zinc ions have comparable Pauling’s ionic
radius and electronegativity. Additionally these ions have con-
fined d10 electron shells. Thus, the trivalent indium cation
should form a more stable complex with 6a in comparison
with divalent zinc ions.49 Different emission profiles for 6a-Zn2+
and 6a-In3+ suggest, however, different mechanisms of com-
plexation responsible for fluorescence enhancement.
We detected very low fluorescence response of all azahetero-
arenes to Cd2+, and Hg2+ ions (ESI†) and lack of any changes for
Ga3+, Tl1+, and Tl3+ ions.
The [N, N, O] tridentate ligands 6a, 6b are fluorescent for
zinc ions, most likely due to the electronic effect of the most
electron-withdrawing phenyl and 4-chlorophenyl groups at the
N-1 position and the additional integrated nitrogen donor at
the N-5 position of the fused heterocyclic system. The presence
of the less electron-withdrawing methyl and ethoxyl group at
Fig. 3 Crystal structure of 12e, specifically, the more abundant conformation
with an occupancy of 88.4%, showing the atom labelling scheme. Displacement
ellipsoids of non-hydrogen atoms are drawn at the 30% probability level.
H atoms are presented as small spheres of an arbitrary radius. The dashed line
represents an intramolecular hydrogen bond.
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Scheme 2 N-Alkyl enamination of 3-benzoylpyridopyrrolopyrazine 5a–d, 9a, 11e,f and pyrrolo[2,3-b]quinoxaline-7-carboxylic acid derivatives 13e,f.
Table 1 The results of N-alkyl enamination leading to an (E/Z) equilibrium of 6,
the 4-substituted phenyl substituent for 6c and 6d amplifies the
electron-donating character of the amide nitrogen atom. That
10a, 12e,f, and 14e,f in CDCl3, DMSO-d6, and CD3CN
reduces the dipole moment of the fluorophore and degree of
Yield E/Z ratio E/Z ratio
E/Z ratio
[%]
CDCl3
DMSO-d6 CD3CN
charge transfer upon excitation of light which is in accordance
with the literature.50
6a Ar = Ph
98
98
82
51
10 : 1
8.7 : 1
8.7 : 1
7.1 : 1
2 : 1
2 : 1
2.6 : 1
2.7 : 1
3.2 : 1
3 : 1
2.6 : 1
In contrast to the photooptical properties of reported 6b Ar = C6H4(4-Cl)
N-methylnaphthalimide51,52 or N-methylindole53 derivatives, the
6c Ar = C6H4(4-Me)
6d Ar = C6H4(4-OEt)
2.9 : 1
1.9 : 1
2.1 : 1
2.2 : 1
2.2 : 1
2.8 : 1
electron-donor group at the N-1 position, such as benzyl for 12e
and 14e reduces the degree of charge transfer responsible for 12e Ar = Bn
fluorescence enhancement. The possible explanation for that
difference in photooptical properties of fused N-alkyl imides may
be connected not only with the electron-donating character of alkyl
substituents but also with the restriction of p-conjugation. It seems
probable that extended p-conjugation of the pyridopyrrolopyrazine
with the aryl group at the N-1 position is essential for switching
10a Ar = Ph, R = (CH2)3OH 75
35
21
42
31
12f Ar = CH2CH2Ph
14ea Ar = Bn
14fa Ar = CH2CH2Ph
a
Compound is barely soluble in CDCl3.
To study the influence of anions on the fluorescent spectra
upon binding the zinc ion. However, confirmation of this photo- of 6a-Zn, we performed experiments between 6a (10 mM, Fig. 5)
optical phenomenon requires additional study. Other pyridopyrrolo- and different salts such as ZnSO4, ZnCl2, Zn(NO3)2, Zn(OTf)2,
pyrazine derivatives 10a and pyrrolo[2,3-b]quinoxaline 4a as Zn(OAc)2, and Zn(acac)2 (10 mM). The experiment showed that
[N, N, O] tridentate ligands do not exhibit a turn-on fluorescence the fluorescent enhancement of 6a-Zn increases in accordance
response. The quite similar behaviour of these tridentate ligands is with the basicity of anions. When anions are bound to metals
not surprising because the receptor component, 3-aminopropanol in complexes their basicity may modulate the fluorescence
and lack of additional donor nitrogen at N-5, are the same.
intensity via changing the electron density on the donor group
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Table 2 Photophysical properties of the analysed compounds
e [103 Mꢂ1 cmꢂ1
]
lem [nm]
Fn
tn [s]
a
b,c
c,d
labs [nm]
5a
5b
5c
5d
6a
6b
6c
6d
9a
10a
12e
12f
14e
14f
396d
24.16 ꢀ 1.71
26.84 ꢀ 1.54
29.62 ꢀ 2.31
30.18 ꢀ 2.53
28.25 ꢀ 2.31
22.69 ꢀ 2.88
14.35 ꢀ 2.69
27.87 ꢀ 1.77
27.61 ꢀ 1.72
31.17 ꢀ 1.99
30.80 ꢀ 5.07
28.54 ꢀ 3.30
28.25 ꢀ 1.38
31.40 ꢀ 1.83
456
456
n.f.
n.f.
444
444
444
444
457
440
438
438
438
440
0.023 ꢀ 0.0006
0.007 ꢀ 0.0010
5.38 ꢃ 10ꢂ10 ꢀ 1.01 ꢃ 10ꢂ11
5.08 ꢃ 10ꢂ10 ꢀ 7.58 ꢃ 10ꢂ12
n.f.
400d
396d
—
396d
—
n.f.
388, 408d
388, 408d
388, 408d
388, 408d
396e
0.0077 ꢀ 0.0005
0.0083 ꢀ 0.0004
0.0073 ꢀ 0.0005
0.0027 ꢀ 0.0008
0.0560 ꢀ 0.0008
0.0021 ꢀ 0.0005
0.0018 ꢀ 0.0006
0.0015 ꢀ 0.0004
0.0010 ꢀ 0.0005
0.0021 ꢀ 0.0004
5.36 ꢃ 10ꢂ10 ꢀ 7.92 ꢃ 10ꢂ11
2.17 ꢃ 10ꢂ10 ꢀ 1.01 ꢃ 10ꢂ11
2.57 ꢃ 10ꢂ10 ꢀ 4.05 ꢃ 10ꢂ12
2.21 ꢃ 10ꢂ10 ꢀ 7.60 ꢃ 10ꢂ12
8.34 ꢃ 10ꢂ10 ꢀ 1.24 ꢃ 10ꢂ11
3.27 ꢃ 10ꢂ10 ꢀ 5.75 ꢃ 10ꢂ11
1.03 ꢃ 10ꢂ10 ꢀ 2.51 ꢃ 10ꢂ12
1.01 ꢃ 10ꢂ10 ꢀ 2.89 ꢃ 10ꢂ11
3.92 ꢃ 10ꢂ10 ꢀ 7.09 ꢃ 10ꢂ12
1.74 ꢃ 10ꢂ10 ꢀ 9.12 ꢃ 10ꢂ11
382, 398e
376, 393e
376, 393e
376, 392e
386, 402e
a
b
n.f.: non-detectable fluorescent emission. The fluorescence quantum yields (Fn) were estimated from the corrected fluorescence spectra using
c
d
e
9,10-diphenylanthracene in cyclohexane (Fs = 0.90) as the standard. Average of three measurements. Measurements in CHCl3. Measurements
in CH3CN.
Fig. 4 (a) Fluorescence spectra of 4a, 6a–d, 10a, 12e, and 14e (10 mM) in CH3CN with 1 equiv. of Zn2+ (lex = 415 nm, voltage 400 V), (b) fluorescence spectra of 3a, 6a,
10a, 12e, and 14e (10 mM) in CH3CN with 1 equiv. of In3+ (lex = 425 nm, voltage 550 V).
The basicity of anions should also affect the equilibrium of
complex formation. The stronger bases such as acetate and
acetylacetonate anions may more easily deprotonate the ligand
6a than other weaker bases under study, especially the chloride
anion, so the stronger bases should shift the equilibrium
towards the formation of products. The fluorescence titration
data confirmed that emissions for 6a-Zn at lex = 415 nm are
saturated with 1.2 equiv. of Zn(acac)2, 1.6 equiv. of Zn(OAc)2,
and 2.0 equiv. of ZnCl2, respectively (Fig. 6a, ESI†).
As shown in Fig. 6b, UV-Vis spectra of 6a exhibited two
maximal absorptions at 385 and 403 nm. Upon addition of
Zn(OAc)2, the absorbance at these peaks decreased, whereas the
new two absorption peaks appeared at 407 and 435 nm with an
isosbestic point at 409 nm. The photometric titration for 6a-Zn
is saturated with 0.6 equiv. of Zn2+.
Fig. 5 Fluorescence spectra of 6a (10 mM) in CH3CN with 1 equiv. of Zn(acac)2,
Zn(OAC)2, Zn(OTf)2, Zn(NO3)2, ZnSO4, and ZnCl2 (lex = 415 nm, voltage 400 V).
To determine the binding stoichiometry of 6a with
Zn(acac)2, the absorption of 6a at 435 nm was plotted as a
of the fluorophore. Furthermore, acetate and acetylacetonate function of the molar fraction of 6a under a constant total
anions may also interfere with the fluorescent probe, despite concentration of 6a and Zn2+. The resulting Job plot is shown in
the fact that 6a-Zn(OAc)2 and 6a-Zn(acac)2 have similar fluores- Fig. 6b. The maximum absorbance was reached when the molar
cent profiles to 6a-ZnCl2.
fraction was 0.5, which indicates a 1 : 1 ratio for 6a-Zn.
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Fig. 6 (a) Increase in fluorescence intensity of 6a (10 mM) in CH3CN as the function of Zn2+ concentration for Zn(acac)2 at lex/lem = 415/482 nm (400 V), Zn(OAc)2 at
ex/lem = 415/482 nm (450 V), and for ZnCl2 ex/lem = 415/464 nm (550 V). (b) Absorption titration of 6a (50 mM) in CH3CN with 0.2 equiv. of Zn(OAc)2. Inset: Job’s
l
l
plot for the binding of 6a with Zn(OAc)2 at l = 435 nm in CH3CN.
To evaluate the E/Z equilibrium during the formation of an L2Zn complex with a 2 : 1 binding mode. Further addition of
6a-Zn and confirm its binding mode, a detailed 1H NMR zinc ions from 0.6 to 1.4 equiv. revealed the reorganisation of
titration was performed (Scheme 3, Fig. 7, ESI†). We used zinc the complex to 6a-Zn-acac with a 1 : 1 binding mode of the
1
acetylacetonate as a counter salt in H NMR titration because ligand and zinc. This reorganisation was indicated by the
the characteristic chemical shifts of the CH proton for the enol appearance of the new set of broadened signals. In the diag-
tautomer of acetylacetonate makes it possible to track the nostic alkene region two additional signals appeared at d = 5.67
progress of complex formation.
and 5.45 ppm with the simultaneous increase of population of
Upon gradual addition of 0–0.6 equiv. of Zn(acac)2 to a CH2 for the keto form of acetylacetone relative to the popula-
CD3CN solution of (E/Z)-6a, a new set of signals were observed tions of H-6 in the L2Zn complex at 8.40 ppm and 6a-Zn-acac at
with the simultaneous reduction of the NH signal, indicating 8.49 ppm. The protons at 5.67 ppm and 5.45 ppm were
the formation of a complex. The protons (E/Z)-H-6 of the free attributed to the CH fragment of acetylacetone chelating the
ligand are upfield shifted from dE-H-6 = 8.78 ppm and dZ-H-6
8.62 ppm to d = 8.40 ppm. Simultaneously, the protons (E)-H-8 tively. The H NMR study shows that the Z diastereoisomer of
and (Z)-H-8 are upfield and downfield shifted from dE-H-8 6a during the addition of zinc ion isomerises into its E-form,
=
zinc in 6a-Zn-acac and CH for zinc(II) acetylacetonate, respec-
1
=
8.11 ppm and dZ-H-8 = 8.01 ppm to d = 8.03 ppm, respectively which coordinates the metal cation simultaneously with depro-
(Fig. 7). These signals were attributed to the H-6 and H-8 of the tonation. The upfield shifted signals for (E/Z)-H-6 reveal that
complex. The CH and CH2 protons of two tautomeric forms of the nitrogen atom at the N-5 position in pyrido[2,3-b]pyrrolo-
acetylacetone also appeared at chemical shifts of d = 5.63 and [2,3-e]pyrazine derivatives 6a does not directly coordinate the
d = 3.61 ppm, respectively. The presence of only one signal in zinc cation during binding but probably facilitates the deproto-
the alkene region of the chemical shifts proved the formation of nation and formation of complex (E)-6-Zn-acac.
Scheme 3 Proposed binding modes of 6a with Zn(acac)2.
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Fig. 7 Partial 1H NMR spectra (600 MHz) of 6a (5 mM) in the presence of different concentrations of Zn(acac)2 in CD3CN. (Please see the ESI† for partial 1H NMR
spectra of 6a in the region 1–4 ppm.)
Reorganisation of the complex from L2Zn to L-Zn-acac is not for diagnostic protons H-6, H-7 and H-8, because of long range
observed in fluorometric and photometric titrations. However, the spin coupling of these protons with the 115In isotope. These
1H NMR experiment indicated that two equilibria were estabilished signals are shifted to 9.92, 8.55 and 8.43 ppm. Plausibly the
during the formation of the complex with binding mode 1 : 1.
indium ion binds to the N-5 nitrogen donor of the fluorophore.
1
Quite different equilibria are revealed by H NMR titration That coordination is possible for the Z-diastereoisomer of 6a
for E/Z-6a with InCl3 (ref. 54 and 55) (Scheme 4, Fig. 8). After because the N-5 nitrogen atom is easily accessible. The Z-NH
addition of 0.4 equiv. of indium ions probably two separate proton is upfield shifted and overlaps with the E-NH-form. The
complexes with E- and Z-diastereisomers of 6a, respectively, are second set shows the three-spin system ABM with three differ-
formed. Interconversion of Z-6a to E-form and deprotonation ent coupling constants JH-6,H-7 = 4.9 Hz, JH-7,H-8 = 8.1 Hz, and
during binding are not observed. Metal ions are consumed JH-6,H-8 = 1.4 Hz. Protons H-6, H-7, and H-8 are upfield shifted
immediately and two sets of new signals appear indicating to 8.95, 8.76, and 7.98 ppm, respectively. After addition of
formation of the L3M system. One set shows broadened signals 0.6 equiv. of salt the new equilibria start to establish with two
Scheme 4 Proposed binding modes of 6a with InCl3.
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Fig. 8 Partial 1H NMR spectra (600 MHz) of 6a (5 mM) in the presence of different concentrations of InCl3 in CD3CN.
broadened set of signals in the ratio 2 : 1 indicating reorganisa- The fluorescence titration data show that emissions for 6a-In at
tion and formation of the two new complexes with two N–H ex = 425 nm appear after addition of 0.6 equiv. of metal ions and
l
signals. Probably, two indium ions prefer binding to E/Z-6a at they are saturated with 3 equiv. of InCl3 (Fig. 9b). This indicates
N-5 and N-9 nitrogen donors and form E-6a-In2 and Z-6a-In2. All that 6a coordinates first with In3+, producing non-emissive
attempts to isolate these complexes failed.
complexes. Further addition of these ions leads to the formation
As shown in Fig. 9a, upon addition of InCl3 to 6a, the absor- of emissive complexes.
bance decreased and the new broaden absorption peak appeared
The metal ions except gallium and thallium affect the
at 427 nm with an isosbestic point at 408 nm. The spectral absorption spectral profile of 6a indicating the coordination
change for 6a-In terminates by the addition of 2 equiv. of In3+. of the ligand with Zn2+, Cd2+, Hg2+, and In3+ ions (Fig. 10a).
Fig. 9 (a) Absorption titration of 6a (50 mM) in CH3CN with 0.2 equiv. of InCl3. (b) Fluorescence titration (lex = 425 nm) of 6a (10 mM) in CH3CN with InCl3.
The concentration of In3+ was increased from 0 to 36 mM. Inset: increase in fluorescence intensity at lem = 488 nm as a function of In3+ concentration.
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Fig. 10 (a) Absorption spectra of 6a (50 mM) in CH3CN with 1 equiv. of Zn2+, Cd2+, Hg2+, Ga3+, In3+, Tl3+ and Tl1+. (b) Absorption spectra of 6a (50 mM) in CH3CN with
1 equiv. of Zn2+, Na+, Mg2+, Pb2+, Ni2+, Co2+ and Cu2+
.
The selectivity of 6a towards Zn2+ and other metal ions was do not compete in complexation with 6a. The most significant
examined, and the results are shown in Fig. 11. An extremely changes, indicating chelation, are observed upon the addition
low fluorescence emission intensity relative to that for Zn2+ was of Zn2+, Cd2+, Co2+, Cu2+, Hg2+and Ni2+ metal ions. The addition
observed upon the addition of Cd2+, Co2+, Hg2+, Mg2+, Na+, Ni2+, of 1 equiv. of Cd2+, Co2+, or Hg2+ into the complex 6a with Zn2+
and Pb2+ metal cations.
slightly reduces the emission peak at 480 nm, indicating that
To study the influence of other metal ions on the binding of the displacement of Zn2+ from the complex by Cd2+, Co2+, or
Zn2+ to 6a, we performed competitive experiments between Hg2+ ions is unfavourable. The competition experiment shows
Zn2+ (10 mM) and Cd2+, Cu2+, Co2+, Hg2+, Mg2+, Na+, Ni2+ Pb2+, excellent selectivity for Zn2+ over all metal ions under study
and In3+ (10 mM, Fig. 11a and b). The addition of Hg2+, Na+, and except In3+.
Pb2+ have a negligible effect on Zn2+ sensing. The fluorescence
The fluorescence properties of the new complexes are
of 6a with Zn2+ is slightly quenched by Co2+, Cd2+, and Hg2+ solvent-dependent, and the new complexes are non-fluorescent
ions. The great impact on the fluorescence emission of 6a with in the presence of water and in DMSO. To understand this
Zn2+ has the presence of one equiv. of indium ions, quenching phenomenon, we measured the 1H NMR spectra of 6a with 0.5,
the emission. Three equiv. of In3+ enhance the fluorescence 1.0, 1.5, and 2.0 equiv. of Zn(acac)2 in DMSO-d6. All spectra,
emission with the changes in the profile similar to 6a-In even that for the highest zinc cation concentration, show four
indicating the displacement of zinc by the indium metal ion.
sets of signals: E-, Z-diastereoisomers of 6a with E/Z-NH signals
Additionally, the absorption data detected for 6a and the and 2 : 1 and 1 : 1 complexes of 6a-Zn. This polar aprotic sol-
metal ions (Fig. 10b) show that the addition of Na+, Mg2+, and vent enhances solvation by hindering the deprotonation of
Pb2+ does not affect the absorption spectral profile of 6a. Thus, the enamino group and thus the further formation of the
these metal cations most likely do not bind to the receptor and complex (ESI†).
Fig. 11 (a) Fluorescence spectra of 6a (10 mM) in CH3CN with 1 equiv. of Cd2+, Co2+, Hg2+, Mg2+, Na+, Ni2+, Pb2+, Zn2+, and 3 equiv. of In3+ (lex = 415 nm). (b) Metal ion
selectivity profiles of 6a (10 mM) in CH3CN in the presence of various metal ions (10 mM) at lex/lem = 415/480 nm.
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and 6 and acetonitrile for 9a, 10a, 12e, 12f, 14e, and 14f using a
1 mM stock solution prepared in DMSO. The fluorescence
lifetimes were determined using a 20 mM stock solution in
chloroform. The absorption spectra of compounds 5, 6, 9a, 10a,
12e, 12f, 14e, and 14f (Table 2) were recorded on a Microplate
Reader Infinite M200 (Tekan) spectrophotometer in 1 cm cells
at 25 1C.
We have designed and verified the sensing abilities of inte-
grated azaheteroarene fluorophores, such as N-aryl or N-alkyl
pyrido[2,3-b]pyrrolo[2,3-e]pyrazine (6), pyrido[2,3-b]pyrrolo[3,2-e]-
pyrazine (10), pyrido-[3,4-b]pyrrolo[3,2-e]pyrazine (12), and
pyrrolo[2,3-b]quinoxaline-7-carboxylic acid (14), integrated with
3-aminopropan-1-ol upon complexation with Zn2+, Cd2+, Hg2+,
Ga3+, In3+, and Tl3+ metal ions. We have shown that the [N, N, O]
tridentate ligands 6a, 6b, and 6c with the nitrogen atom at N-5
and N-aryl groups selectively respond to zinc and 6a to indium
ions in acetonitrile. The benzyl and (4-ethoxy)phenyl groups at
the N-1 position weaken the acceptor character of the amide
carbonyl group in fluoroionophore systems and quench ICT
fluorescence enhancement for 6d, 12e, and 14e. An additional
nitrogen donor at N-7 or N-8 changes the electron density in
ICT azaheteroarene indicators and that should also influence
the dipole moment of fluorophores. Pyrido[2,3-b]pyrrolo[3,2-e]-
pyrazine derivative 10a with the nitrogen atom at N-8 does not
exhibit fluorescence emission with Zn2+, Cd2+, Hg2+, Ga3+, In3+,
and Tl3+ metal ions. 1H NMR titration showed two different
mechanisms of binding Zn2+ and In3+ to 6a. The Z-diastereoisomer
of 6a during the addition of the zinc ion isomerises to its E-form,
which coordinates metal cations simultaneously with deproto-
nation in acetonitrile. Indium ions form two separate com-
plexes with (E)-6a and (Z)-6a without deprotonation. Although
ligands under study do not operate in aqueous media, further
functionalisation of the receptor unit will allow us to obtain
sensors with desirable physicochemical properties which will
be reported in due course.
The fluorescence measurements for all analysed compounds
were done using a Hitachi F-4500 spectrofluorometer. All
spectra were recorded at 25 1C with an excitation slit width of
5 nm, an emission slit of 10 nm and a PMT voltage of 700 V.
The fluorescence quantum yields of the analysed com-
pounds were determined using 9,10-diphenylanthracene
(Fs = 0.90 in cyclohexane) as a standard. The fluorescence
lifetimes were determined using a time-correlated single-
photon counting system based on the Horiba Jobin Yvon IBH
lifetime spectrofluorometer system components, which con-
sisted of a picosecond single-photon-detection TBX-04 module
integrated with a fast photomultiplier, high-voltage power
supply, GHz preamplifier and picosecond-timing discrimina-
tor. A picosecond pulsed laser diode (NanoLED-11, Horiba
Jobin, Yvon) was used as a light source. The specimens were
excited at 372 nm with a 1 MHz repetition rate. The fluores-
cence decays were observed through a cut-off filter of 475 nm
(Andover Corporation Optical Filter). To avoid pulse pile-up, the
power of the diode was adjusted to an appropriately low level
using a neutral gradient filter. The excitation pulse diode laser
profile, required for the deconvolution analysis, was measured
using a diluted glycogen suspension without a filter. For the
data acquisition and decay analysis, the Jobin Yvon IBH data
station and DAS6 software were used. All measurements were
performed at 25 1C, and each recorded lifetime was averaged
from five independent decay measurements.
Experimental
Materials and instrumentation
The Job plots for 6a with Zn(acac)2 and absorption spectra of
All of the solvents for the UV and fluorescence spectra were 6a (50 mM) in CH3CN with respective 1 equiv. of metal cations
obtained from Sigma-Aldrich or Merck and were of spectro- were recorded on a Hitachi U-3900H spectrophotometer. The
scopic purity. The solution metal ions were prepared from fluorescence measurements (Fig. 4, 5, 6a, 9b, 11a and b) were
ZnCl2, ZnSO4, Zn(NO3)2, Zn(OTf)2, Zn(acac)2, Zn(OAc)2, Ga(acac)3, also recorded using a F-7000 FL spectrophotometer (25 1C,
InCl3, TlNO3, Tl(OAc)3, Cu(acac)2, Ni(acac)2, Co(acac)2, Cd(acac)2, excitation and emission slit width of 5 nm, 400 V and 550 of
Hg(OAc)2, NaOAc, Pb(OAc)2, Mg(OAc)2. Melting points were deter- PMT voltage). The fluorescence spectra were obtained using a
mined on a Boetius PHMK 05 melting point apparatus. IR spectra 1 mM stock solution prepared in DMSO for compounds 4a, 10a,
were measured on a Thermo Scientific Nicolet IR200 FT-IR. The 12e, and 14e.
1H NMR and 13C NMR spectra were recorded using Bruker Avance
Substrates 5a–d, 7a, 11e,f, and 13e,f were synthesised
III 600 and II 300 spectrometers at 300 K. The chemical shifts (d) according to previously reported procedures.35,36
are reported in parts per million (ppm) on a d scale downfield
1
X-ray structure analysis of 6a and 12e
from TMS. The H NMR spectra were referenced internally to
the residual proton resonance in CDCl3 (d 7.26 ppm), DMSO-d6 Crystals of 6a were obtained from acetonitrile solution by
(d 2.49 ppm), and CD3CN (d 1.96 ppm). The 13C NMR spectra were slow evaporation of the solvent under ambient conditions.
referenced to CDCl3 (d 77.0 ppm), or, DMSO-d6 (d 39.7 ppm). The The crystal suitable for X-ray diffraction experiment was a
coupling constants (J) are reported in Hertz (Hz). Mass spectra yellow plate of dimensions: 0.3 ꢃ 0.1 ꢃ 0.03 mm. X-ray
were recorded on a Finnigan Mat 95 (EI, 70 eV) and ESI spectro- diffraction data were collected at 130 K using a Nonius Brucker
meters. Microanalyses were performed with a Vario Micro Tube KappaCCD diffractometer with MoKa radiation (l = 0.71073 Å),
CHNS; the results agreed with the calculated values.
with the software Collect.41 Data were processed using HKL
For the determination of e and quantum yields indicated in SCALEPACK42 and HKL DENZO.42 The phase problem was
Table 2, the analysed compounds were diluted in selected solved by direct methods using SHELXS-9743 program. The
solvents to prepare 20 mM stock solutions: chloroform for 5 model parameters were refined by full-matrix least-squares
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on F2 using SHELXL-97.43 All non-hydrogen atoms were refined and then diluted with cold H2O (100 mL). The precipitated solid
anisotropically. H atoms attached to N and O atoms were was collected by filtration, washed with H2O, and crystallised
located on the difference Fourier map. These in the hydroxyl from acetonitrile.
group and the water molecule were refined using the DFIX
(E/Z)-3-[(3-Hydroxypropylamino)-phenylmethylidene]-1,3-
restraint with a target bond length of 0.82 Å, within an assumed dihydro-2H-1-phenylpyrido[2,3-b]pyrrolo[2,3-e]pyrazin-2-one
estimated standard deviation of 0.02 Å. For the water molecule the 6a. Yellow needles (228 mg, 98%), m.p. 198 1C. E/Z = 10 : 1
DANG restraint was applied with an H1wꢁꢁꢁH2w distance of (CDCl3), E/Z = 2.7 : 1 (DMSO-d6), E/Z = 2.6 : 1 (CD3CN). IR (ATR):
1.35 Å, within an assumed estimated standard deviation of 3335, 3207, 3070, 2927, 2875, 1704, 1596 cmꢂ1. 1H NMR (300.13
0.04 Å. Positions of hydrogen atoms attached to C atoms were MHz, DMSO-d6): d = 1.69 (quint, 2H, J = 6.0 Hz, Z-CH2), 1.76
calculated with C–H = 0.95 Å for aromatic, C–H = 0.99 Å for (quint, 2H, J = 6.0 Hz, E-CH2), 3.31 (s, H2O) 3.41 (m, 6H,
methylene and were refined using the riding model with the E/Z-CH2NH, Z-CH2OH), 3.54 (q, 2H, J = 6.0 Hz, E-CH2OH),
isotropic displacement parameter Uiso = 1.2 Ueq of the parent 4.62 (t, 2H, J = 6.0. Hz, E/Z-OH), 7.37–7.62 (m, 22H, E/Z-H-Ar),
atom. Crystal data: moiety formula C25H21N5O2 H2O, Mr = 441.48, 8.04 (d, J = 8.2 Hz, Z-H-8), 8.14 (dd, 1H, J = 1.8 Hz, J = 8.2 Hz,
monoclinic, space group P21/c, a = 11.2202(2) Å, b = 6.1966(4) Å, c = E-H-8), 8.58 (d, 1H, J = 4.3 Hz, Z-H-6), 8.74 (dd, 1H, J = 1.8 Hz,
31.8009(10) Å, b = 109.409(2)1, V = 2085.48(15) Å3, Z = 4, Dc = J = 4.3 Hz, E-H-6), 10.69 (br. s, 1H, Z-NH), 10.89 (br. s, 1H, E-NH).
1.406 g cmꢂ3, m(MoKa) = 0.10 mmꢂ1, F(000) = 928; 14 239 collected 13C NMR (75.47 MHz, DMSO-d6): d = 32.91, 42.05, 57.85, 89.49,
reflections, 4696 unique (Rint = 0.057), 3177 observed (I > 2s(I)). 122.29, 127.39, 127.49, 128.01, 128.54, 128.80, 130.15, 130.52,
For 313 refined parameters, the final R1 = 0.062 for reflections 133.53, 136.03, 148.29, 165.17, 166.48, 173.50. MS-ESI: m/z 424
with F2 > 2s(F2), wR2 = 0.186 for all unique reflections, S = 1.04.
Crystals of 12e were obtained from DMSO-d6 solution by N, 15.86%. Found: C, 67.99; H, 4.95; N, 15.71%.
slow evaporation of the solvent under ambient conditions. The (E/Z)-1-(4-Chlorophenyl)-3-[(3-hydroxypropylamino)-phenyl-
(M+ + 1). Anal. calcd for C25H21N5O2 + H2O: C, 68.01; H, 5.25;
crystal suitable for X-ray diffraction experiment was a yellow methylidene]-1,3-dihydro-2H-pyrido-[2,3-b]pyrrolo[2,3-e]pyrazin-
prism of dimensions: 0.45 ꢃ 0.3 ꢃ 0.3 mm. X-ray diffraction 2-one 6b. Yellow needles (246 mg, 98%), m.p. 175 1C. E/Z = 8.7 : 1
data were collected at 110 K using a SuperNova diffractometer (CDCl3), E/Z = 3.2 : 1 (DMSO-d6). IR (ATR): 3331, 3207, 3062,
with MoKa radiation (l = 0.71073 Å). Data were processed using 2957, 2923, 1702, 1593 cmꢂ1; 1H NMR (300.13 MHz, DMSO-d6);
CRYSALISPro 44
The phase problem was solved using direct d = 1.69 (quint, 2H, Z-CH2), 1.75 (quint, 2H, J = 6.3 Hz, E-CH2),
.
methods with SHELXS-9743 program. The model parameters were 3.43 (m, 4H, E/Z-CH2NH2), 3.56 (m, 4H, E/Z-CH2OH), 4.35 (t, 1H,
refined by full-matrix least-squares on F2 using SHELXL-97.43 All E-OH), 4.62 (t, 1H, Z-OH), 7.37–7.70 (m, 20H, E/Z-H-Ar), 8.03 (1H,
non-hydrogen atoms were refined anisotropically. H atoms d, J = 8.1 Hz, Z-H-8), 8.05 (1H, dd, J = 8.0 Hz, J = 1.7 Hz, E-H-8),
attached to N and O atoms were located on the difference Fourier 8.58 (1H, dd, J = 4.5 Hz, J = 1.7 Hz, Z-H-6), 8.75 (1H, dd, J =
map and refined independently. Positions of hydrogen atoms 4.5 Hz, J = 1.7 Hz, E-H-6), 10.69 (br. s, 1H, Z-NH), 10.89 (br. s, 1H,
attached to C atoms were calculated with C–H = 0.95 Å for E-NH). 13C NMR (75.47 MHz, DMSO-d6) d = 32.88, 42.10, 57.85,
aromatic, C–H = 0.99 Å for methylene and were refined using 89.41, 122.34, 128.01, 128.56, 128.79, 128.90, 130.20, 130.45,
the riding model with the isotropic displacement parameter 131.70, 132.42, 133.30, 136.04, 146.45, 148.19, 148.44, 164.93,
Uiso = 1.2 Ueq of the parent atom. Crystal data: moiety formula 166.54. MS-ESI: m/z 458 (M+ + 1). Anal. calcd for C25H20ClN5O2 +
C
26H23N5O2, Mr = 437.49, monoclinic, space group P21/c, H2O: C, 63.09; H, 4.66; N, 14.71%. Found: C, 63.17; H, 4.46; N,
a = 9.1766(1) Å, b = 11.1148(1) Å, c = 21.7846(2) Å, b = 106.341(1)1, 14.85%.
V = 2132.19(4) Å3, Z = 4, Dc = 1.363 g cmꢂ3, m(MoKa) = 0.09 mmꢂ1
(E/Z)-1-(4-Methylphenyl)-3-[(3-hydroxypropylamino)-phenyl-
,
F(000) = 920; 32 725 collected reflections, 5395 unique (Rint = 0.032), methylidene]-1,3-dihydro-2H-pyrido-[2,3-b]pyrrolo[2,3-e]pyrazin-
4494 observed (I > 2s(I)). For 323 refined parameters, the final 2-one 1-aminopropanol hydrate 6c. Yellow needles (198 mg, 83%),
R1 = 0.039 for reflections with F2 > 2s(F2), wR2 = 0.103 for all m.p. 198 1C. E/Z = 8.7 : 1 (CDCl3), E/Z = 3 : 1 (DMSO-d6). IR (ATR):
unique reflections, S = 1.03.
3435, 3282, 3040, 2925, 2890, 1709, 1607 cmꢂ1 1H NMR
.
WinGX45 software was used to prepare materials for publica- (300.13 MHz, CDCl3) for crude product 6c + NH2(CH2)3OH,
tion. Figures showing asymmetric units of 6a and 12e were H2O: d = 1.62 (m, 2H, J = 5.8 Hz, CH2), 1.90 (m, 4H, J = 5.8 Hz,
made using ORTEP-3 for Windows.46 For calculation of the E/Z-CH2), 2.36 (s, 3H, E-CH3), 2.44 (s, 3H, Z-CH3), 2.63 (br. s, 4H,
weighted least-squares planes through selected atoms program E/Z-OH, H2O) 2.97 (t, 2H, J = 5.8 Hz, CH2NH2), 3.44 (br. m, 2H,
PARST47,48 was used. Crystallographic data (excluding structure Z-CH2NH), 3.56 (t, 2H, J = 5.8 Hz, E-CH2NH), 3.78–3.88 (m, 6H,
factors) for the structures in this paper have been deposited J = 5.8 Hz, E/Z-CH2-OH; CH2OH), 7.23–7.66 (m, 20H, E/Z-H-Ar),
with the Cambridge Crystallographic Data Centre as supple- 8.09 (dd, 1H, J = 1.8 Hz, J = 8.1 Hz, Z-H-5), 8.19 (dd, 1H, J =
mentary publication nos. CCDC 890197 and 890198 for struc- 1.8 Hz, J = 8.1 Hz, E-H-7), 8.69 (dd, 2H, J = 4.4 Hz, J = 1.8 Hz,
ture of 12e and 6a, respectively.
E/Z-H-6), 10.77 (br. s, 1H, Z-NH), 11.09 (br. s, 1H, E-NH). 13C
NMR (75.47 MHz, CDCl3) for crude product 6c + NH2(CH2)3OH,
H2O: d = 21.17, 32.53, 33.73, 41.43, 42.29, 59.12, 63.41, 90.27,
121.78, 126.59, 127.56, 128.74, 129.43, 130.25, 130.44, 134.15,
General procedure: synthesis of enaminone 6a–d, 10a, 12e, 12f,
14e, and 14f
A benzoyl-azaheteroarene derivative 5, 9, 11, or 13 (0.55 mmol) 136.91, 137.34, 147.28, 147.68, 148.54, 149.25, 166.14, 166.78.
was added to the amine (2 mL). The mixture was left for 5 days, 1H NMR (300.13 MHz, DMSO-d6) 6c: d = 1.69 (quint, 2H,
c
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J = 6.0 Hz, Z-CH2), 1.76 (quint, 2H, J = 6.0 Hz, E-CH2), 2.36 (q, 2H, J = 6.0 Hz, E-CH2-NH), 3.79 (t, 2H, J = 6.0 Hz, Z-CH2-OH),
(s, 3H, E-CH3), 2.44 (s, 3H, Z-CH3), 2.63 (br. s, 4H, E/Z-OH, H2O) 3.85 (t, 2H, J = 6.0 Hz, E-CH2-OH), 5.05 (s, 2H, E-CH2Bn), 5.23
2.97 (t, 2H, J = 5.8 Hz, CH2NH2), 3.44 (br. m, 2H, Z-CH2NH), (s, 2H, Z-CH2Bn), 7.20–7.63 (m, 22H, E/Z-H-Ar), 8.36 (d, 1H,
3.56 (t, 2H, J = 5.8 Hz, E-CH2NH), 3.78–3.89 (m, 6H, J = 5.8 Hz, J = 5.6 Hz, Z-H-6), 8.52 (d, 1H, J = 5.6 Hz, E-H-6), 9.13 (s, 1H,
E/Z-CH2-OH; CH2OH), 7.23–7.66 (m, 20H, E/Z-H-Ar), 8.09 Z-H-8), 9.20 (s, 1H, E-H-8), 10.61 (t, 1H, Z-NH), 10.78 (t, 1H,
(dd, 1H, J = 1.8 Hz, J = 8.1 Hz, Z-H-5), 8.19 (dd, 1H, J = E-NH). 13C NMR (75.47 MHz, CDCl3): d = 32.56, 41.94, 42.08,
1.8 Hz, J = 8.1 Hz, E-H-7), 8.69 (dd, 2H, J = 4.4 Hz, J = 1.8 Hz, 59.75, 104.89, 119.99, 127.43, 127.59, 127.87, 128.41, 128.60,
E/Z-H-6), 10.58 (br. s, 1H, Z-NH), 11.09 (br. s, 1H, E-NH). 128.69, 128.81, 130.25, 130.50, 136.98, 151.19, 166.33, 166.65.
MS-ESI: m/z 438 (M+ + 1). Anal. calcd for C26H23N5O2 + H2O: MS-ESI: m/z 438 (M+ + 1). Anal. calcd for C27H25N5O2 + H2O: C,
C, 68.56; H, 5.53; N, 15.37%. Found: C, 68.93; H, 5.28; N, 69.07; H, 5.80; N, 14.92%. Found: C, 68.77; H, 5.61; N, 14.73%.
14.90%.
(E/Z)-1-(2-Phenylethyl)-3-[(3-hydroxypropylamino)-phenyl-
(E/Z)-1-(4-Ethoxyphenyl)-3-[(3-hydroxypropylamino)-phenyl- methylidene]-1,3-dihydro-2H-pyrido[3,4-b]pyrrolo[3,2-e]pyrazin-
methylidene]-1,3-dihydro-2H-pyrido-[2,3-b]pyrrolo[2,3-e]pyrazin- 2-one 12f. Yellow needles (52 mg, 21%), m.p. 145 1C. E/Z = 2.6 : 1
2-one 6d. Yellow needles (130 mg, 51%), m.p. 208–209 1C. (CDCl3), E/Z = 2.2 : 1 (DMSO-d6). IR (ATR): 3414, 3056, 2944,
E/Z = 7.1 : 1 (CDCl3), E/Z = 2.9 : 1 (DMSO-d6). IR (ATR): 3445, 2826, 2748, 1697, 1609 cmꢂ1 1H NMR (300.13 MHz, CDCl3):
.
3275, 3076, 2978, 2937, 1714, 1642 cmꢂ1. 1H NMR (300.13 MHz, d = 1.87 (quint, 2H, J = 6.0 Hz, Z-CH2), 1.93 (quint, 2H, J =
CDCl3) for crude product 6d: d = 1.37–1.48 (m, 6H, J = 6.0 Hz, 6.0 Hz, E-CH2; 2H, E/Z-OH; H2O), 3.00–3.05 (m, 2H, E-CH2Ph),
E/Z-CH3), 1.85–1.97 (m, 4H, J = 6.0 Hz, E/Z-CH2), 3.46 (q, 2H, 3.12–3.18 (m, 2H, Z-CH2Ph), 3.47 (q, 2H, J = 6.0 Hz, Z-CH2NH),
J = 6.0 Hz, Z-CH2NH), 3.56 (q, 2H, J = 6.0 Hz, E-CH2NH), 3.80 3.51 (q, 2H, J = 6.0 Hz, E-CH2NH), 3.80 (t, 2H, J = 6.0 Hz, Z-CH2-OH),
(t, 2H, J = 5.8 Hz, Z-CH2OH) 3.87 (t, 2H, J = 5.8 Hz, E-CH2OH), 3.87 (t, 2H, J = 6.0 Hz, E-CH2-OH), 4.07–4.12 (m, 2H, E-CH2N),
4.01–4.14 (m, 4H, J = 6.0 Hz, E/Z-CH2O), 6.95 (d, 2H, J = 8.7 Hz, 4.25–4.31 (m, 2H, Z-CH2N), 7.25–7.63 (m, 22 H, E/Z-H-Ar), 8.36
E-H-30/50), 7.07 (d, 2H, J = 8.7 Hz, Z-H-30/50) 7.38–7.65 (m, 20H, (d, 1H, J = 5.6 Hz, Z-H-6), 8.52 (d, 1H, J = 5.6 Hz, E-H-6), 9.13 (s, 1H,
E/Z-H-Ar), 8.09 (dd, 1H, J = 1.9 Hz, J = 8.1 Hz, Z-H-5), 8.18 (dd, Z-H-8), 9.19 (s, 1H, E-H-8), 10.59 (t, 1H, Z-NH), 10.75 (t, 1H, E-NH).
1H, J = 1.8 Hz, J = 8.1 Hz, E-H-7), 8.70 (dd, 1H, J = 4.5 Hz, J = 13C NMR (75.47 MHz, CDCl3): d = 32.31, 32.55, 34.25, 39.81, 42.10,
1.8 Hz, E-H-6), 8.75 (dd, 1H, J = 4.4 Hz, J = 1.9 Hz, Z-H-6), 10.77 59.76, 90.94, 120.00, 126.35, 127.53, 127.92, 128.39, 128.48, 128.82,
(br. s, 1H, Z-NH), 11.06 (br. s, 1H, E-NH). 13C NMR (75.47 MHz, 128.94, 130.46, 138.56, 144.21, 149.14, 151.16, 166.49. MS-ESI: m/z
CDCl3) for crude product 6d: d = 14.77, 32.61, 42.33, 59.25, 452 (M+ + 1). Anal. calcd for C27H25N5O2 + H2O: C, 69.07; H, 5.80; N,
59.50, 63.65, 90.26, 114.75, 115.03, 121.79, 125.57, 127.57, 14.92%. Found: C, 68.77; H, 5.61; N, 14.73%.
128.01, 128.73, 130.25, 130.41, 134.16, 136.81, 147.36, 147.77,
(E/Z)-1-Benzyl-3-[(3-hydroxypropylamino)-phenylmethyli-
148.49, 149.27, 158.11, 166.28, 166.72. MS-ESI: m/z 468 (M+ + 1). dene]-1,3-dihydro-2H-pyrrolo[2,3-b]quinoxaline-7-carboxylic
Anal. calcd for C27H25N5O3: C, 69.36; H, 5.39; N, 14.98%. Found: acid 14e. Yellow needles (111 mg, 42%), m.p. 156 1C. E/Z =
C, 69.13; H, 5.28; N, 14.90%.
(E/Z)-3-[(3-Hydroxypropylamino)-phenylmethylidene]-1,3-
dihydro-2H-1-phenylpyrido[2,3-b]pyrrolo[3,2-e]pyrazin-2-one
2.2 : 1 (DMSO-d6). IR (ATR): 3211, 3058, 3034, 2927, 2878, 1690,
1
1614, 1591, 1573 cmꢂ1. H NMR (300.13 MHz, DMSO-d6): d =
1.71 (quint, 2H, J = 6.3 Hz, Z-CH2), 1.77 (quint, 2H, J = 6.3 Hz,
10a. Yellow needles (175 mg, 75%), m.p. 266 1C. E/Z = 2 : 1 E-CH2), 3.35–3.39 (m, 4H, Z/E-CH2NH), 3.47 (t, 2H, Z-CH2OH),
(CDCl3), E/Z = 1.9 : 1 (DMSO-d6). IR (ATR): 3235, 3059, 2862, 3.58 (t, 2H, E-CH2OH), 4.65 (s, 1H, Z-OH), 4.76 (s, 1H, E-OH),
1711, 1609, 1587, 1561 cmꢂ1 1H NMR (300.13 MHz, CDCl3): 4.93 (s, 2H, E-CH2Bn), 5.15 (s, 2H, Z-CH2Bn), 7.18–7.65 (m, 21H,
.
d = 1.83 (m, 2H, Z-CH2), 1.90 (m, 2H, E-CH2), 2.05 (br. s, 2H, E/Z-H-Ar), 7.84 (dd, 1H, J = 8.5 Hz, J = 1.9 Hz, Z-H-7), 7.95 (d, 1H,
E/Z-OH), 3.43–3.54 (m, 4H, E/Z-CH2NH), 3.77 (t, 2H, J = 5.8 Hz, J = 8.5 Hz, Z-H-8), 8.02 (dd, 1H, J = 8.5 Hz, J = 1.7 Hz, E-H-7), 8.25
Z-CH2OH), 3.83 (t, 2H, J = 5.8 Hz, E-CH2OH), 7.28–7.74 (m, 22H, (d, 1H, J = 1.9 Hz, Z-H-5), 8.31 (d, 1H, J = 1.7 Hz, E-H-5), 10.50
E/Z-H-Ar), 8.16 (dd, 1H, J = 1.7 Hz, J = 8.1 Hz, E-H-5), 8.66 (t, 1H, J = 5.6 Hz, Z-NH), 10.75 (t, 1H, J = 5.6 Hz, E-NH), 13.00
(dd, 1H, J = 1.7 Hz, J = 4.4 Hz, 1H, Z-H-7), 8.74 (dd, 1H, J = (s, 2H, COOH). 13C NMR (75.47 MHz, DMSO-d6): d = 32.31,
1.7 Hz, J = 4.4 Hz, 1H, E-H-7), 10.59 (br. s, 1H, Z-NH), 10.74 32.53, 41.28, 41.43, 42.25, 42.42, 58.27, 58.34, 89.44, 89.72,
(br. s, 1H, E-NH). 13C NMR (75.47 MHz, CDCl3): d = 32.32, 32.62, 125.60, 125.87, 127.30, 127.67, 127.85, 128.06, 128.21, 128.35,
42.01, 59.77, 90.16, 121.58, 126.72, 127.19, 127.63, 128.02, 128.53, 128.60, 129.13, 130.09, 130.21, 130.62, 130.94, 137.10,
128.68, 128.76, 128.99, 130.30, 132.74, 133.90, 135.20, 137.02, 137.33, 137.49, 137.69, 141.39, 142.14, 146.93, 147.00, 165.56,
148.86, 161.07, 166.08. MS-ESI: m/z 423 (M+ + 1). 424; anal. 165.61, 165.80, 167.23, 169.44. MS-ESI: m/z 481 (M+). Anal. calcd
calcd for C25H21N5O2 + H2O: C, 70.91; H, 5.0; N, 16.54%. Found: for C28H25N4O4: C, 69.84; H, 5.23; N, 11.64%. Found: C, 69.85;
C, 70.92; H, 5.03; N, 16.29%.
H, 4.95; N, 11.62%.
(E/Z)-1-Benzyl-3-[(3-hydroxypropylamino)-phenylmethyli-
dene]-1,3-dihydro-2H-pyrido[3,4-b]pyrrolo[3,2-e]pyrazin-2-one
1-Hydroxypropan-3-ammonium (E/Z)-1-(phenylethyl)-3-[(3-
hydroxy-propylamino)-phenylmethylidene]-1,3-dihydro-2H-pyrrolo-
12e. Yellow needles (85 mg, 35%), m.p. 221 1C. E/Z = 2.0 : 1 [2,3-b]quinoxaline-7-carboxylate hydrate 14f. Yellow needles
(CDCl3), E/Z = 2.1 : 1 (DMSO-d6). IR (ATR): 3411, 3241, 3060, (100 mg, 31%), m.p. 107 1C. E/Z = 2.8 : 1 (DMSO-d6). IR (ATR):
1
2937, 2870, 1703, 1612 cmꢂ1
.
1H NMR (300.13 MHz, CDCl3): 3350, 3210, 3031, 2928, 2870, 1672, 1585, 1557 cmꢂ1. H NMR
d = 1.87 (m, 2H, J = 6.0 Hz, Z-CH2), 1.92 (m, 2H, J = 6.0 Hz, (300.13 MHz, DMSO-d6) for 14f + NH2(CH3)2OH: d = 1.73 (m, 6H,
E-CH2; 2H, E/Z-OH), 3.46 (q, 2H, J = 6.0 Hz, Z-CH2-NH), 3.51 J = 6.85 Hz, CH2, E/Z-CH2), 2.87 (t, 4H, J = 7.04 Hz, E/Z-CH2Ph),
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2.96 (t, 2H, J = 7.7 Hz, CH2NH2), 3.10 (t, 1H, J = 7.5 Hz, OH), 3.33 was carried out using the equipment purchased thanks to the
(m, 4H, E/Z-CH2NH), 3.44–3.59 (m, 8H, E/Z-CH2OH, E/Z-CH2N), financial support from the European Regional Development
3.39 (t, 2H, CH2OH), 4.19 (t, 1H, E/Z-OH), 7.09–7.64 (m, 21H, Fund in the framework of the Polish Innovation Economy
E/Z-H-Ar), 7.82 (d, 1H, J = 8.5 Hz, E-H-8), 7.85 (dd, 1H, J = 1.9 Hz, Operational Program (contract no. POIG.02.01.00-12-023/08).
Z-H-7), 8.02 (dd, 1H, J = 8.5 Hz, J = 1.7 Hz, E-H-7), 8.23 (d, 1H,
J = 1.9 Hz, Z-H-5), 8.31 (d, 1H, J = 1.7 Hz, E-H-5), 10.36 (s, 1H,
Z-NH), 10.58 (s, 1H, E-NH). 13C NMR (75.47 MHz, DMSO-d6):
d = 31.36, 32.44, 33.67, 36.79, 42.02, 58.24, 89.73, 125.97,
References
126.39, 126.76, 128.14, 128.52, 128.76, 129.92, 130.83, 136.95,
137.79, 138.80, 139.36, 145.71, 146.52, 164.59, 165.65, 169.32.
MS-ESI: m/z 493 (M+ ꢂ 1). Anal. calcd for C32H37N5O6 (14f +
NH2(CH3)2OH + H2O): C, 65.40; H, 6.35; N, 11.92%. Found: C,
65.46; H, 6.30; N, 11.89%.
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.
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