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Article

Macrocyclic Compounds Comprising Tris(3-Aminopropyl)Amine Units and Fluorophore Moieties: Synthesis and Spectroscopic Studies in the Presence of Metal Salts

by
Daria S. Kuliukhina
,
Nataliya M. Chernichenko
,
Alexei D. Averin
*,
Anton S. Abel
,
Olga A. Maloshitskaya
and
Irina P. Beletskaya
Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia
*
Author to whom correspondence should be addressed.
Chemosensors 2023, 11(3), 186; https://doi.org/10.3390/chemosensors11030186
Submission received: 1 February 2023 / Revised: 4 March 2023 / Accepted: 7 March 2023 / Published: 10 March 2023
(This article belongs to the Special Issue Advances in Fluorescence Sensing)
Browse Figures
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Abstract

:
The synthesis of a variety of polyazamacrocyclic compounds comprising structural units of tris(3-aminopropyl)amine (TRPN) and oxadiamines, decorated with one or two fluorophore groups (dansyl or quinoline) at different nitrogen atoms, was carried out using Pd(0)-catalyzed amination. The dependence of the yields of the macrocycles on the synthetic path was observed. The spectrophotometric and fluorescent properties of the target compounds were studied, and their coordination with metal cations using UV–vis, fluorescence spectra as well as NMR titration was investigated. The stoichiometry and binding constants of several complexes with Cu(II), Zn(II), Cd(II), Pb(II) and Hg(II) were established. Three of the six studied macrocycles can be judged as prospective detectors of Zn(II) cations due to the substantial enhancement of fluorescence.

Graphical Abstract

1. Introduction

Tetrapodal tetraaza ligands formed on the basis of tris(2-aminoethyl)amine (TREN) and tris(3-aminopropyl)amine (TRPN) attract the interest of the researchers, as they can play a role in the construction of various functional molecules and materials, e.g., macrocyclic and cryptand compounds comprising such structural units can be used for the molecular recognition of cations, anions and small organic molecules [1,2,3,4]; thus, the strategies for the construction of such compounds attract researchers [5]. Thus, a macrocycle with two TREN moieties and two 2,6-disubstituted pyridines decorated with two 1-naphthyl fluorophores connected by aminomethyl linkers was studied for the complexation with Cu(II) and Zn(II) [6] as well its analog with 4-quinolinyl fluorophores [7]. Several TREN derivatives were reported as efficient chelators of lanthanide ions [8]. TREN was also used for the end-capping of the hemicryptophane molecule comprising numerous polyoxysubstituted phenyl fragments. The compound is water-soluble, and its complex with Gd(III) is used as contrast agent in MRT [9]. A review on the manganese complexes with branched polyaza ligands (macrocyclic and open-chain) has been published recently [10].
TRPN is far less studied than TREN, and the majority of its derivatives do not contain macrocyclic moieties. Depending on the nature of the substituents at the nitrogen atoms, metal complexes of various structures and with different applications were obtained [11,12,13,14]. Enough simple acyclic receptors on the basis of urea and thiourea were synthesized from TRPN and studied in binding inorganic anions [15]. Some derivatives of this branched amine were investigated as antimalarial agents, e.g., tris(quinoxaline) [16] and tris(phenanthroline) [17] derivatives of TRPN showed antiparasitic activity. Other tripodal receptors were synthesized using 4-nitrophenyl isothiocyanate, 4-nitrophenylsulphonyl chloride and 4-nitrophenylbenzoyl chloride [18]. Such ligands demonstrate good selectivity towards cyanide anions. N-substituted derivatives of TRPN and their complexes were reported for the recognition of the azide-anion [19,20]. More sophisticated complex structures with TRPM structural fragments were reported for sensing N-Acetyl-β-d-glucosaminidase [21]. There are some examples of the use of TRPN derivatives as building blocks for the construction of MOFs [22]. Functional materials on the basis of TRPN are prospective for CO2 binding [23,24]. Complexes of cyclic and bicyclic ligands with transition metals containing TRPN moieties find application as catalysts [25], and they can also bind with DNA [26]. Quite rare are examples where TRPN was used for the construction of macrocyclic systems. Cryptands synthesized by the reaction of TRPN with trialdehyde [27] or 2,5-furandialdehydes have been reported [28]. A macrocycle on the basis of 1,8-disubstituted anthracene with TRPN was studied for the detection of Hg(II) and Cu(II) using fluorescent spectroscopy [29].
In the present work, we propose a convenient synthetic route to polyazamacrocycles comprising structural fragments of tris(3-aminopropyl)amine (TRPN) and oxadiamines bearing fluorophore groups at different nitrogen atoms (endocyclic and exocyclic). Previously, we accumulated substantial experience in the synthesis of various N- and O-containing macrocycles [30] and polymacrocycles [31], including those with fluorophore groups as well as chiral moieties [32], and demonstrated the wide possibilities of Pd(0)-catalyzed amination for this purpose. The main peculiarity of the proposed TRPN-derived macrocycles is the presence of the exocyclic 3-aminopropyl substituent and the possibility of varying the position of the fluorophore group (such as 5-(dimethylamino)naphthalene-1-sulfonyl (dansyl), 6- or 3-quinolinyl) by attaching it to either the endocyclic or exocyclic nitrogen atom. Special attention is paid to the investigation of the coordination of metal cations and the possibilities of using these macrocycles for spectrophotometric and fluorescent detection.

2. Materials and Methods

1H and 13C NMR spectra were recorded with a Bruker Avance-400 spectrometer in CDCl3, and residual peaks of the solvent were as used as standards (δ 7.26 ppm and 77.0 ppm, respectively). UV–vis spectra were recorded with an Agilent Cary 60 spectrophotometer, and the spectra of fluorescence were obtained with a Hitachi F2700 spectrofluorometer using acetonitrile UHPLC grade (Fluka). MALDI-TOF mass spectra were obtained with a Bruker Autoflex II spectrometer with dithranol as the matrix and (polyethylene) glycols as the internal standards. Tris(3-aminopropyl)amine (1), dioxadiamine 12, 5-(dimethylamino)naphthalene-1-sulfonyl chloride (dansyl chloride), 6-bromoquinoline, 3-bromoquinoline and the phosphine ligands rac-BINAP, DavePhos, tBuDavePhos, tBuONa and K2CO3, were purchased from Sigma-Aldrich Co and ACBR Co and used without special purification. Column chromatography was performed using silica gel 40–63 μm from Macherey-Nagel Co, 1,4-dioxane was purified by distillation over sodium under argon, acetonitrile for the syntheses was distilled over CaH2 and dichloromethane and methanol were freshly distilled prior to use. Pd(dba)2 was synthesized using a known procedure [33], and N,N’-di(3-bromophenyl)-substituted dioxadiamine 6 and N,N’-di(3-bromophenyl)-substituted trioxadiamine 17 were obtained by a described method [34]. A description of the syntheses of compounds 2–5, 7–11, 13–16 and 18–25 and their spectral data are given in the Supplementary Materials.
An investigation of the ability of the macrocycles 7, 8, 16, 22, 23 and 25 to detect metal cations by means of UV–vis and fluorescent spectroscopies was carried out as follows. The spectrofluorimetric quartz cuvette (l = 1 cm) was charged with 3 mL of the solution of the corresponding ligand in MeCN (UHPLC grade) with the following concentrations: 4.8 μM (7), 23.0 μM (8), 17.5 μM (16), 14.3 μM (22), 21.2 μM (23) and 12.3 μM (25). Solutions of each of the metal perchlorates (Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II) and Ag(I)) or the nitrates (Ga(III), In(III) and Y(III)) in MeCN (UHPLC grade) with concentrations of 0.01 M were added with a Hamilton syringe directly to the spectrofluorimetric cuvette successively (to make 1, 2, 3, 5 and 10 equiv. of each metal); UV–vis and fluorescence spectra were registered after each addition. Spectrophotometric and spectrofluorimetric titrations were carried out by adding metal perchlorates in increments of 0.05 equiv. with the following concentrations of the ligands: 318 μM (16, UV–vis titration), 191 μM (22, UV–vis titration), 39 μM (22, spectrofluorimetric titration), 252 μM (23, UV–vis titration), 160 μM (25, UV–vis titration). Stability constants were calculated using nonlinear least squares analysis by means of HYPERQUAD software after the factor analysis of the combined datasets [35]. NMR titrations were carried out by adding metal perchlorates (C = 0.2 M in CD3CN) in increments of 0.1 equiv. to the solutions of the corresponding macrocycles in CD3CN with the following concentrations of the ligands: 0.041 M (16), 0.036 M (22) and 0.046 M (25). The compositions of the complexes and binding constants were calculated using the EQNMR [36] and BindFit [37] programs.

3. Results and Discussion

3.1. Synthesis of the Macrocycles Comprising a Sructural Unit of Tris(3-Aminopropyl)Amine

The main idea of the synthetic approach to the fluorescent macrocyclic compounds comprising endocyclic tris(3-aminopropyl)amine fragments was the combination of this unit with the oxadiamine structural units via 1,3-phenylene linkers and the introduction of fluorophore groups such as dansyl (5-dimethylaminonaphthalene-1-sulfonyl) and quinoline to nitrogen atoms of the macrocycles at various positions. The extensive application of the Buchwald–Hartwig amination reaction for constructing C-N bonds is characteristic of this approach. At first, we attempted the synthesis of the macrocycles bearing fluorophore groups at the exocyclic nitrogen atom of the 3-aminopropyl group (Scheme 1). For this purpose, N-dansyl and N-quinolin-6-yl-substituted tris(3-aminopropyl)amines 2 and 4 were synthesized from free tris(3-aminopropyl)amine (1) (Scheme 1). The reaction with dansyl chloride was carried out by a very slow addition of the reagent to an excess of the tetraamine taken as a dilute (0.065 M) solution in MeCN. The yield of the target monodansyl derivative 2 was 50%, while the side product—the didansylated tetraamine 3—was isolated in 25% yield. The heteroarylation of 1 with 6-bromoquinoline was conducted using a universal catalytic system Pd(dba)2/BINAP (8/9 mol%) (dba = dibenzylidene acetone, BINAP = rac-2,2′-diphenylphoshino-1,1′-binaphthalene) in dioxane in the presence of tBuONa as a base. The application of a twofold excess of 1 in this case was also important to promoting the formation of the monoquinolinyl-substituted product 4 (48% yield), though the diquinolinyl derivative 5 was also obtained (24% yield). The attempt to apply the diminished amount of the catalyst (4/4.5 mol%) failed, as the conversion of 6-bromoquinoline reached only 50%.
To afford the desired macrocycles, the reactions of macrocyclization were carried out between dansyl or quinolinyl derivatives (2 or 4) and N,N’-di(3-bromophenyl)-substituted dioxadiamine 6, which was prepared from the free dioxadiamine in accordance with the previously described method [34] (Scheme 2). The reactions were run in the presence of Pd(dba)2/tBuDavePhos (16/18 mol%) (tBuDavePhos = 2-(ditert-butylphosphino)-2′-dimethylaminobiphenyl). This ligand, like its analog DavePhos, promotes the diamination of aryl halides and is efficient, especially under dilute conditions (in the macrocyclization reactions, we employ 0.02 M solutions of the reagents in dioxane). It was found that the reaction of 6 with the dansyl derivative 2 was inefficient, and the desired macrocycle 7 could not be isolated; however, the reaction with the quinolinyl derivative 4 was successful, and the yield of the corresponding macrocycle 8 was 38%.
The alternative route to the macrocycle 7 used a three-step procedure. At first, branched tetraamine 1 was converted into its N,N’-di(3-bromophenyl) derivative 9 by the reaction with two equiv. of 1,3-dibromobenzene (Scheme 3). The main side product in this process was the triarylated compound 10, which was isolated in a comparable yield; however, attempts to increase the yield of the target compound 9 and to hamper the formation of 10 by varying the stoichiometry of the process and the catalyst loading did not improve the result. The slow reaction of compound 9 with strictly one equiv. of dansyl chloride in MeCN/CH2Cl2 (10:1) helped to avoid the formation of various polydansylated derivatives, and monodansyl compound 11 was obtained in 67% yield. At the last step, macrocyclization with a free dioxadiamine 12 (1.5 equiv.) gave rise to the target macrocycle 7 in a 23% yield. Here, the use of 1.5-fold excess of the diamines in the macrocyclization reactions was shown to slightly increase the yields of the desired products. The attempt to synthesize compound 11 by an alternative procedure, using the Pd-catalyzed arylation of the monodansyl derivative 2 with 1,3-dibromobenzene, was unsuccessful.
The synthesis of the macrocycles comprising triamine and dioxadiamine chains and 6-quinolinyl substituents at the nitrogen atoms of the macrocycle was achieved according to Scheme 4. At the first step, the Pd-catalyzed heteroarylation of compound 7 with 6-bromoquinoline (3 equiv.) was carried out, which produced N,N’-di(quinolin-6-yl) derivative 13 in 34% yield, and the monoquinolinyl product 14 was isolated in 18% yield. The macrocyclization step employed the reaction with a branched tetraamine 1 (1.5 equiv.) and produced target macrocycles with two and one quinolinyl substituents 15 and 16, respectively.
To compare the binding properties towards various cations of the macrocycles with various sizes of the macrocyclic cavity, we synthesized several macrocycles starting from the N,N’-di(3-bromophenyl) derivative of trioxadiamine 17, which possesses a longer chain (Scheme 5). We also were interested in the effect of the isomeric fluorophore group, i.e., 3-quinolinyl substituent, which could alter the binding abilities of the macrocycle due to a different orientation of the aromatic nitrogen with respect to a macrocyclic moiety. The compound 17 (which was obtained in accordance with the described method [34]) was reacted with three equiv. of either 6- or 3-bromoquinoline in the presence of Pd(dba)2/BINAP (16/18 mol%). In both cases, di- and monoheteroarylated derivatives were obtained; moreover, the yields of the monoquinolinyl products 19 and 21 were somewhat higher than those of the diquinolinyl compounds 18 and 20. This may be due to substantial hindrances in the formation of N,N,N’,N’-tetraaryl derivatives of di- and polyamines. Only the monoquinolinyl products 19 and 21 were further introduced in the macrocyclization reaction with the tetraamine 1. Macrocycle 22 with 6-quinolinyl substituent was obtained in 17% yield, while its isomer 23 was synthesized in 28% yield.
At last, the synthesis of the dansyl-substituted macrocycle with the triamine and trioxadiamine endocyclic chains was undertaken (Scheme 6). For this purpose, compound 17 was decorated with two dansyl groups forming intermediate product 24 in 70% yield, and afterwards, the macrocyclization reaction with the branched tetraamine 1 afforded the target macrocycle 25 in 26% yield. Thus, we have obtained a series of seven macrocycles differing by the cavity size, type and position of fluorophore groups, which also possess additional donor sites that are able to participate in binding metal cations.

3.2. Spectroscopic Investigations

The investigation of the ability of the synthesized macrocycles to act as fluorescent detectors of metal cations was carried out using a panel of 21 salts: 18 perchlorates (Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II) and Ag(I)) and 3 nitrates (Ga(III), In(III) and Y(III)). The UV–vis and spectra of fluorescence were registered in MeCN, and the spectroscopic properties of the potential detectors 7, 8, 15, 16, 22, 23 and 25 are presented in Table 1. Metal salt (perchlorate or nitrate) was added gradually to a ligand under investigation in the spectrofluorimetric cuvette (1, 2, 5, 10 equiv.), and upon each addition, the UV–vis and spectra of fluorescence were registered. For convenience, all figures present the data corresponding to five equiv. of metals salt added. In the case in which the changes in the spectrum caused by a certain ion were different from the changes observed with other metals, spectrophotometric and spectrofluorimetric titrations were conducted; in several cases, they were accompanied by the NMR titrations. As the macrocycles under investigation contain many N- and O-binding sites differing in their ability to form coordination bonds with metal cations, one may suppose that they will give complexes of different stabilities with various metals; moreover, complexes with different ligand-to-metal ratios can be formed with a certain cation, especially those characterized by a high coordination number. This will ensure different changes in absorption and fluorescence spectra that are crucial for the needs of detection.
The addition of metal salts to the macrocycle 7 containing tris(3-aminopropyl)amine and dioxadiamine fragments and one dansyl group attached to an exocyclic amine caused either the quenching (Li(I), K(I), Cu(II), Hg(II)) or enhancement (other ions) of fluorescence—in some cases, with small bathochromic shifts in the emission maximum (by 10–15 nm) (Figure 1a). The changes in the absorption spectrum were not observed in the presence of the majority of cations, except for Cu(II), Hg(II) and Fe(III) (Figure S1). The addition of the copper perchlorate resulted in the disappearance of the absorption maximum at 310 nm, while in the presence of Hg(II) cations, two new, weakly manifested maxima at 315 and 350 nm emerged (Figure S2). As for Fe(ClO4)3, its addition simply caused an increase in the optical density of the specimen, which is likely due to the partial hydrolysis of this salt. The peculiarity of this salt, as well of Mn(ClO4)2, was also observed in further experiments and will not be discussed specially. In fact, macrocycle 7 did not show any selective response to the metal cations added and cannot serve for their detection.
The change in the dansyl fluorophore for the quinolin-6-yl substituent in the same compound fully changed the response of macrocycle 8 to the addition of the metal cations. In(III), Ga(III) and Cu(II) caused strong fluorescence quenching, while the addition of Al(III) and Pb(II) led to full emission quenching (Figure 1b). Moreover, in the presence of these cations, we observed a new emission band at ca 540 nm, which is only characteristic of these metals. Notable changes in the absorption spectrum were registered in the case of the following cations: Cu(II), Hg(II), Zn(II), Pb(II) and Al(III) (Figures S3 and S4). The addition of the copper perchlorate resulted in the disappearance of both absorption maxima at 300 and 365 nm; the same is true for Hg(ClO4)2, though in the case of Cu(II), the optical density increased throughout the whole spectrum. The changes caused by Zn(II) cations were less pronounced, but the addition of both Al(III) and Pb(II) salts gave rise to a new absorption band at 420 nm (Figure S4), while the initial maximum at 365 nm disappeared. The observed spectral changes allow for the proposal of macrocycle 8 as a potential dual-channel (colorimetric and fluorimetric) probe for Al(III) and Pb(II) cations as well as a colorimetric probe for Cu(II) cations.
The change in the position of the aminoquinolin-6-yl fluorophore group in the macrocycle in compound 16 (in which it is attached to an endocyclic nitrogen atom) leads to a dramatic change in the spectral response of the macrocycle to the presence of metal cations (Figure 2). The addition of some salts led to fluorescence quenching, while others promoted a moderate increase in the emission intensity, often with a small hypsochromic shift of the maximum (ca 10 nm, like with Pb(II) or Mg(II)). The addition of Cd(II) caused both a bathochromic shift by 10 nm and some enhancement of fluorescence, while in the presence of Zn(II) perchlorate, this enhancement was much more pronounced (five times with five equiv.). In the UV–vis spectrum of 16 (Figures S5 and S6), it is clearly seen that the addition of Fe(III) and Mn(II) led to an increase in the optical density without changes in the shape (the probable reason is discussed above), the addition of Cu(II) ions resulted in a 10 nm hypsochromic shift of the maximum (from 370 to 360 nm). More interesting were the changes associated with the presence of Pb(II) and Al(III) cations, as they gave rise to a new absorption band at 440 nm. For this reason, we carried out spectrophotometric titration of the ligand with Pb(ClO4)2 (Figure S7) and calculated the binding constants for the L4M, L2M and LM complexes: lgβ = 17.5(3), lgβ = 10.27(1) and lgβ = 5.05(1), respectively. Figure S7b (absorption at 300 nm) shows that the local maximum corresponds to the L4M complex, the local minimum of absorption corresponds to the L2M composition and the formation of the LM complex brings the graph to a plateau. In Figure S7c, depicting the absorption at 440 nm, one may observe an increase in the absorption after the formation of the L2M complex (0.5 equiv. Pb(II)). These data give evidence of a different coordination of lead cations at different titration steps. One may suppose that, at first, the coordination takes place at the aliphatic nitrogen atoms (NH2 and NH), which lead to rather small changes in the absorption spectrum (calculated absorption spectra for L4M and L2M shown in Figure S8b), and more profound changes occur when the heterocyclic nitrogen from the quinoline moiety takes part in coordination with the Pb(II) cation, leading to a great bathochromic shift from 370 to 440 nm (calculated absorption spectrum for LM depicted in Figure S8b).
The attempt to proceed with the spectrofluorimetric titration of compound 16 with the Zn(II) perchlorate was unsuccessful, probably due to a partial oxidation of the diaminobenzene moiety in a dilute solution, but the changes in its UV–vis spectrum upon the addition of the same salt were helpful for obtaining data from its spectrophotometric titration (Figure S9a). The calculated binding constants for the L2M, LM and LM2 complexes are lgβ = 11.88(3), lgβ = 8.31(1) and lgβ = 12.2(3), respectively. Changes in the absorbance at 320 nm (Figure S9b) demonstrate a local minimum corresponding to the L2M composition of the first complex, followed by a local maximum corresponding to the LM complex, but the changes in the absorbance intensity are quite small. The calculated UV–vis spectra (Figure S10a) show that it is the complex LM2 that differs substantially from L, L2M and LM by its spectrum, and it is characterized by a strong bathochromic shift of the absorption maximum from 370 to 440 nm (as was the case with Pb(II)). This suggests the participation of the fluorophore group (quinoline) in the coordination of the metal cation. However, the intensity of this new maximum is higher for the Pb(II) complex than for the Zn(II) complex.
The NMR titration of macrocycle 16 with the Zn(II) perchlorate provides additional information about a successive formation of complexes with different ligand-to-metal ratios (Figure 3). Though it is clearly seen that the signals broaden upon the addition of Zn(II) salt, especially in the aliphatic part of the spectrum (Figure 3a), one may follow the changes of the chemical shifts of the protons belonging to quinoline moiety. The formation of the L2M complex is evidenced from the inflection at ca 0.5 equiv. Zn(II) for the H26 proton (Figure 3b) and the maximum at 0.5 equiv. Zn(II) for the H24 proton (Figure 4c). After the addition of one equiv. of the salt, the graphs approach the plateau. We tried to calculate the binding constants from NMR titration, but they were found to be much higher than the limit of this method (lgβ ≤ 5). Graphs of the changes in the chemical shifts as experimental and calculated points are given in Figure S29; they correspond to the formation of ML2 and ML complexes.
To conclude, macrocycle 16 can be judged as a potential fluorescent chemosensor for Zn(II) due to a described unique enhancement of emission in the presence of this cation, but its response in the UV–vis spectrum is quite similar for a number of cations and shows no selectivity.
Macrocycle 22 possesses a larger cavity compared to compound 16 due to the incorporation of the trioxadiamine structural unit instead of the dioxadiamine one. This unexpectedly resulted in a substantial red-shifted emission maximum (485 nm instead of 440 nm), but the general picture of the compound’s response to the presence of the metal cations did not change dramatically (Figure 4). While the majority of metal salts caused either moderate fluorescence quenching or enhancement, only Cd(II) and, especially, Zn(II) led to a substantial increase in the emission intensity: the addition of five equiv. Cd(II) gave rise to 2.5-fold enhancement, and that of five equiv. Zn(II) resulted in a ninefold increase in the emission intensity. In both cases, a small hypsochromic shift of 10–15 nm was observed. The spectrofluorimetric titration of macrocycle 22 with Zn(ClO4)2 was successful (Figure S13) and revealed the formation of the complexes L4M and L2M with the corresponding binding constants lgβ = 28.2(1) and lgβ = 14.69(7). The calculated emission spectra (Figure S14a) demonstrate that the enhancement of the intensity of fluorescence is mainly associated with the L2M complex. The qualitative limit of spectrofluorimetric detection for Zn(II) by compound 22 was estimated as 13 μM.
The changes in the UV–vis spectrum of ligand 22 in the presence of metal salts are shown in Figure S11. They are very close to those observed for its analog 16, and certain changes can also be found upon the addition of Cu(II), Hg(II), Zn(II), Pb(II) and In(III); however, only in the presence of the Cu(II) and Hg(II) cations were reasonable changes in the shape of the absorption spectrum observed (Figure S12). In the case of Cu(II), the gradual addition of the salt led to a disappearance of the absorbance at 380 nm and the formation of a new maximum at 440 nm, which is clearly seen from the titration spectra (Figure S15a). The binding constants for the LM, LM2 and LM3 complexes were calculated to be lgβ = 8.45(8), lgβ = 16.1(1) and lgβ = 21.1(2). While the LM complex, according to its calculated absorption spectrum, possesses similar absorption maxima as the initial ligand 22, the spectra of LM2 and LM3 are quite different and are characterized by the absorbance at 440 nm (Figure S16a). This may be explained by the fact that more than one copper cation can bind to a macrocycle with a big enough cavity comprising five nitrogen and three oxygen atoms and which additionally possesses the exocyclic 3-aminopropyl substituent and 6-quinolinyl moiety. It is plausible to suggest that, in the LM2 and LM3 complexes, the coordination of Cu(II) also takes place at the nitrogen atom of the fluorophore quinoline fragment, because, in these complexes, a strong bathochromic shift is observed. Macrocycle 22 can be proposed as a potential fluorescent chemosensor for Zn(II) ions.
In addition, the NMR titration of macrocycle 22 with Cd(ClO4)2 was carried out. The titration curve shown in Figure 5 for the H4(Quin) proton clearly shows the inflection at 0.5 equiv. of Cd(II) corresponding to the formation of the L2M complex, and after the addition of one equiv. of the salt, the chemical shift comes to a plateau. The binding constants for the L2M and LM complexes were calculated to be lgβ = 2.7(3) ± 0.31 and lgβ = 3.1(2) ± 0.24 by the EQNMR program. Graphs of the changes in the chemical shifts as experimental and calculated points are given in Figure S30.
Compound 23 possesses the same macrocyclic cavity as 22 decorated with the isomeric quinolin-3-yl fluorophore group. The fluorescence of this macrocycle is quenched to various degrees by the majority of the metal ions (Figure 6), but the addition of Cd(II) and, especially, Zn(II) salts leads to the enhancement of the emission intensity, with a notable hypsochromic shift of the maximum (by 15 and 30 nm, respectively). In the absorption spectra (Figure S17) of this compound in the presence of various metals, our attention was drawn to Zn(II) and Hg(II), as the changes caused by the addition of these metals were the most meaningful at the wavelength around 370 nm (the absorption maximum with the largest wavelength) (Figure S18). Spectrophotometric titration with Zn(ClO4)2 (Figure S19a) provided the binding constants lgβ = 21.34(5) for the Zn(II) complex of the L4M composition and lgβ = 11.46(2) for the L2M complex (Figure S20). Changes in the absorbance at 380 nm (Figure S19b) explicitly show the maximum at 0.25 equiv. of Zn(II), corresponding to the formation of the L4M complex. The titration with Hg(ClO4)2 (Figure S21) revealed the formation of the following complexes: L4M, L2M, LM and LM2. Their binding constants were calculated as lgβ = 22.94(8), lgβ = 13.23(7), lgβ = 7.80(5) and lgβ = 12.3(1), respectively (Figure S22). The changes in the UV–vis spectrum are complex, e.g., at 305 nm absorbance, it has a minimum at 0.25 equiv. of Hg(II) and a maximum at 1 equiv. of Hg(II), suggesting the formation of at least two complexes: L4M and LM (Figure S21b). The calculated UV–vis spectra for different complexes show that these are LM and, especially, LM2, which are characterized by the most important changes in the spectrum (Figure S22a). One may suggest that, with the ligand 23, as in the above-described cases, at first, the most sterically accessible exocyclic NH2 group can participate in binding with metal cations, giving rise to L4M complexes, and further, upon the addition of more salt, the quinolinyl fluorophore group begins to take part in coordination, providing substantial changes in the absorption spectrum. It is even more plausible for the complexes with a metal-to-ligand ratio over 1. Thus, macrocycle 23 can be proposed as a dual-channel (UV and fluorescent) molecular probe for Zn(II) cations.
It was found that macrocycle 25, featuring two dansyl fluorophore groups, exhibits a totally non-selective fluorescent response towards metal cations (Figure 7), like the above-described monodansyl macrocycle 7. More distinguishable were the changes in its absorption spectrum upon the addition of several metal cations (Figure S23), including Zn(II) and Pb(II) (Figure S24). We carried out spectrophotometric titration with Zn(II) perchlorates (Figure S25). It was possible to calculate the binding constants for the L4M and L2M complexes with Zn(II) (lgβ = 25.3(1) and lgβ = 13.49(5)) (Figure S26). In the case of titration with Pb(ClO4)2 (Figure S27a), the absorbance in the interval of 310–340 nm first gradually increased up to 0.33 equiv. of Pb(II) and then began to diminish (Figure S27a,b). The calculation of the binding constants gave the following values for the L3M, LM and LM2 complexes: lgβ = 19.48(5), lgβ = 7.74(2) and lgβ = 12.1(1) (Figure S28). However, the overall changes in the UV spectra are small enough, and, thus, macrocycle 25 cannot serve for the colorimetric detection of cations.
The NMR titration of macrocycle 25 with Hg(ClO4)2 was carried out as an alternative to spectrofluorimetric titration. The corresponding titration curve is shown in Figure 8 for the H4(Np) proton, and it features a maximum at 0.5 equiv. of Hg(II), corresponding to the formation of the L2M complex. After this maximum, the chemical shifts gradually diminish but still do not approach the plateau at 1.5 equiv. of Hg(II) salt. The binding constants for the L2M and LM complexes were calculated to be lgβ = 2.5(2) and lgβ = 3.8(2) by the BindFit program. Graphs of the changes in the chemical shifts as experimental and calculated points are given in Figure S31.
The data for the composition of the complexes and their binding constants are summarized in Table 2.

4. Conclusions

In this research, we elaborated a synthetic route to N- and O-containing macrocycles comprising the structural fragments of tris(3-aminopropyl)amine (TRPN) and dioxa- or trioxadiamines with additional fluorophore groups such as 5-(dimethylamino)naphthalene-1-sulfonyl (dansyl), 6- or 3-quinolinyl. First of all, macrocylization reactions were carried out under Pd(0)-catalyzed amination conditions. The possibility of introducing either free or N-(quinoline-6-yl)-substituted TRPN and N,N’-di(3-bromophenyl)-substituted oxadiamines bearing one or two additional fluorophore groups in the catalytic macrocyclization reactions was demonstrated. The synthesized macrocycles differ not only by the cavity size and nature of fluorophores but also by their position (attached either to exocyclic 3-aminopropyl fragments or to endocyclic nitrogen atoms). Six macrocycles were investigated for their ability to change their spectra of absorption and fluorescence in the presence of 21 metals. Among them, judging by a unique character of the changes in UV–vis and emission spectra, macrocycle 8, bearing the 6-quinolinyl substituent at the exocyclic nitrogen atom, was shown to be a potential dual-channel (colorimetric and fluorimetric) probe for the Al(III) and Pb(II) cations as well as a colorimetric probe for Cu(II) cations. Isomeric macrocycle 16, with the same fluorophore attached to an endocyclic nitrogen atom, can be judged as a potential fluorescent chemosensor for Zn(II) due to a unique enhancement of emission in the presence of this cation. Macrocycle 22, with a larger cavity and 6-quinolinyl fluorophore substituent, can also be proposed as a potential fluorescent chemosensor for Zn(II) ions. Additionally, macrocycle 23, bearing 3-quinolinyl fluorophore, is capable of dual-channel (UV and fluorescent) molecular sensing for Zn(II) cations. Dansyl-substituted macrocycles 7 and 25 did not show enough selectivity in their response towards metals. UV–vis and spectrofluorimetric titrations were carried out for the macrocyclic ligands 16, 22, 23 and 25, and the composition of the complexes and binding constants were obtained for the Zn(II), Cu(II), Pb(II) and Hg(II) cations. It was shown that, in almost all cases, the formation of the complexes with a ligand-to-metal ratio over 1 takes place (L4M, L3M or L2M complexes). The studied macrocycles possess several types of coordination sites: the primary amino group in the 3-aminopropyl arm, N and O atoms of the macrocycle, quinoline nitrogen or the dimethylamino group of the dansyl fluorophore. Taking this fact into consideration, one may explain the formation of the complexes of different stoichiometries. The coordination of the metal cation with the NH2 group gives rise to MLx complexes, the further addition of the metal salt leads to ML complexes in which the coordination with macrocycle heteroatoms is possible and an excess of metal salt favors the formation of MxL complexes with the participation of the nitrogen atoms of the fluorophore groups. Such stepwise coordination is evidenced by UV and NMR spectra recorded over the course of titration experiments. Indeed, the calculated UV–vis spectra of the complexes suggest that profound changes in the spectra (strong bathochromic shifts of the absorption maxima) are associated with the complexes with smaller ligand-to-metal ratios (such as ML or ML2). This is probably due to the initial coordination of the NH2 group of the exocyclic substituent at a low metal concentration, followed by the involvement of the heterocyclic nitrogen atom of the fluorophore group in the coordination at higher concentrations of metal salts. The NMR titration of the compounds 16, 22 and 25 with Zn(II), Cd(II) and Hg(II) perchlorates, respectively, gave additional information on the composition and binding constants of the corresponding complexes.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemosensors11030186/s1, Figures S1 and S2: UV–vis spectra for compound 7 in the presence of metal salts; Figures S3 and S4: UV–vis spectra for compound 8 in the presence of metal salts; Figures S5 and S6: UV–vis spectra for compound 16 in the presence of metal salts; Figures S7 and S8: UV–vis titration of compound 16 with Pb(ClO4)2; Figures S9 and S10: UV–vis titration of compound 16 with Zn(ClO4)2; Figures S11 and S12: UV–vis spectra for compound 22 in the presence of metal salts; Figures S13 and S14: UV–vis titration of compound 22 with Cu(ClO4)2; Figures S15 and S16: spectrofluorimetric titration of compound 22 with Zn(ClO4)2; Figures S17 and S18: UV–vis spectra for compound 23 in the presence of metal salts; Figures S19 and S20: UV–vis titration of compound 23 with Zn(ClO4)2; Figures S21 and S22: UV–vis titration of compound 23 with Hg(ClO4)2; Figures S23 and S24: UV–vis spectra for compound 25 in the presence of metal salts; Figures S25 and S26: UV–vis titration of compound 25 with Zn(ClO4)2; Figures S27 and S28: UV–vis titration of compound 25 with Pb(ClO4)2; Figures S29–S31: Graphs of the changes in the chemical shifts as experimental and calculated points.

Author Contributions

Conceptualization, A.D.A. and I.P.B.; methodology, A.D.A. and A.S.A.; investigation, D.S.K., N.M.C. and O.A.M.; visualization, A.S.A. and O.A.M.; writing—original draft preparation, D.S.K. and N.M.C.; writing—review and editing, A.D.A., A.S.A. and I.P.B.; supervision, I.P.B.; project administration, A.D.A.; funding acquisition, A.D.A. All authors have read and agreed to the published version of the manuscript.

Funding

This work was accomplished in the frames of the State contract of the chair of organic chemistry of the Moscow State University entitled “Synthesis and study of physical, chemical and biological properties of organic and organometallic compounds”—CITIC No-AAAAA-A; 21-121012290046-4.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Chemosensors 11 00186 sch001 550
Scheme 1. The synthesis of dansyl- and 6-quinolinyl-substituted tris(3-aminopropyl)amine 2 and 4.
Scheme 1. The synthesis of dansyl- and 6-quinolinyl-substituted tris(3-aminopropyl)amine 2 and 4.
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Scheme 2. Synthesis of 6-quinolinyl-substituted macrocycle 8.
Scheme 2. Synthesis of 6-quinolinyl-substituted macrocycle 8.
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Scheme 3. Alternative synthesis of dansyl-substituted macrocycle 7.
Scheme 3. Alternative synthesis of dansyl-substituted macrocycle 7.
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Scheme 4. Synthesis of di- and monoquinolinyl-substituted macrocycles 15 and 16.
Scheme 4. Synthesis of di- and monoquinolinyl-substituted macrocycles 15 and 16.
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Scheme 5. Synthesis of monoquinolinyl-substituted macrocycles 22 and 23.
Scheme 5. Synthesis of monoquinolinyl-substituted macrocycles 22 and 23.
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Scheme 6. Synthesis of didansyl-substituted macrocycle 24.
Scheme 6. Synthesis of didansyl-substituted macrocycle 24.
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Figure 1. (a) Spectra of the fluorescence of compound 7 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 48 μM, λex 340 nm. (b) Spectra of the fluorescence of compound 8 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 23 μM, λex 365 nm.
Figure 1. (a) Spectra of the fluorescence of compound 7 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 48 μM, λex 340 nm. (b) Spectra of the fluorescence of compound 8 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 23 μM, λex 365 nm.
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Figure 2. Spectra of the fluorescence of compound 16 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 17.5 μM, λex 370 nm.
Figure 2. Spectra of the fluorescence of compound 16 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 17.5 μM, λex 370 nm.
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Figure 3. NMR titration of compound 16 with Zn(ClO4)2*6H2O in CD3CN, CL 0.041 M and CZn(II) 0.2 M. (a) NMR spectra of 16 after the addition of 0.5, 0.7 and 1 equiv. of Zn(ClO4)2; (b) changes in the chemical shift of the H4(Quin) proton; (c) changes in the chemical shift of the H2(Quin) proton.
Figure 3. NMR titration of compound 16 with Zn(ClO4)2*6H2O in CD3CN, CL 0.041 M and CZn(II) 0.2 M. (a) NMR spectra of 16 after the addition of 0.5, 0.7 and 1 equiv. of Zn(ClO4)2; (b) changes in the chemical shift of the H4(Quin) proton; (c) changes in the chemical shift of the H2(Quin) proton.
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Figure 4. Spectra of the fluorescence of compound 22 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 14.3 μM, λex 370 nm.
Figure 4. Spectra of the fluorescence of compound 22 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 14.3 μM, λex 370 nm.
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Figure 5. NMR titration of compound 22 with Cd(ClO4)2*6H2O; changes in the chemical shift of the H4(Quin) proton. CL 0.036 M, CCd(II) 0.2 M.
Figure 5. NMR titration of compound 22 with Cd(ClO4)2*6H2O; changes in the chemical shift of the H4(Quin) proton. CL 0.036 M, CCd(II) 0.2 M.
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Figure 6. Spectra of the fluorescence of compound 23 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 21.2 μM, λex 370 nm.
Figure 6. Spectra of the fluorescence of compound 23 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 21.2 μM, λex 370 nm.
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Figure 7. Spectra of the fluorescence of compound 25 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 12.3 μM, λex 340 nm.
Figure 7. Spectra of the fluorescence of compound 25 in the presence of Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Cr(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pb(II), Ag(I), Ga(III), In(III) and Y(III) (five equiv.). CL 12.3 μM, λex 340 nm.
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Figure 8. NMR titration of compound 25 with Hg(ClO4)2*6H2O; changes in the chemical shift of the H4(Np) proton. CL 0.046 M, CHg(II) 0.2 M.
Figure 8. NMR titration of compound 25 with Hg(ClO4)2*6H2O; changes in the chemical shift of the H4(Np) proton. CL 0.046 M, CHg(II) 0.2 M.
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Table
Table 1. Spectroscopic properties of the macrocycles 7, 8, 16, 22, 23 and 25.
Table 1. Spectroscopic properties of the macrocycles 7, 8, 16, 22, 23 and 25.
MacrocycleConcentration, μMλabs, nmlgελex, nmλem, nm
74.83054.47340508
3404.20
823.03004.08365430
3653.66
1617.53084.19370443
3733.80
2214.33094.28370485
3743.86
2321.23064.03370510
3703.68
2512.33133.96340516
3423.93
Table
Table 2. Composition and binding constants for selected complexes of the macrocycles 16, 22, 23 and 25.
Table 2. Composition and binding constants for selected complexes of the macrocycles 16, 22, 23 and 25.
MacrocycleMetalComplexlgβMethod
16Pb(II)L4M17.5(3)Spectrophotometry
L2M10.27(1)Spectrophotometry
LM5.05(1)Spectrophotometry
Zn(II)L2M11.88(3)Spectrophotometry
LM8.31(1)Spectrophotometry
LM212.2(3)Spectrophotometry
22Cu(II)LM8.45(8)Spectrophotometry
LM216.1(1)Spectrophotometry
LM321.1(2)Spectrophotometry
Zn(II)L4M28.2(1)Spectrofluorometry
L2M14.69(7)Spectrofluorometry
Cd(II)L2M2.7(3)NMR (EQNMR)
LM3.1(2)NMR (EQNMR)
23Zn(II)L4M21.34(5)Spectrophotometry
L2M11.46(2)Spectrophotometry
Hg(II)L4M22.94(8)Spectrophotometry
L2M13.23(7)Spectrophotometric
LM7.80(5)Spectrophotometric
LM212.3(1)Spectrophotometric
25Zn(II)L4M25.3(1)Spectrophotometric
L2M13.49(5)Spectrophotometric
Pb(II)L3M19.48(5)Spectrophotometric
LM7.74(2)Spectrophotometric
LM212.1(1)Spectrophotometric
Hg(II)L2M2.5(2) NMR (BindFit)
LM3.8(2)NMR (BindFit)
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Kuliukhina, D.S.; Chernichenko, N.M.; Averin, A.D.; Abel, A.S.; Maloshitskaya, O.A.; Beletskaya, I.P. Macrocyclic Compounds Comprising Tris(3-Aminopropyl)Amine Units and Fluorophore Moieties: Synthesis and Spectroscopic Studies in the Presence of Metal Salts. Chemosensors 2023, 11, 186. https://doi.org/10.3390/chemosensors11030186

AMA Style

Kuliukhina DS, Chernichenko NM, Averin AD, Abel AS, Maloshitskaya OA, Beletskaya IP. Macrocyclic Compounds Comprising Tris(3-Aminopropyl)Amine Units and Fluorophore Moieties: Synthesis and Spectroscopic Studies in the Presence of Metal Salts. Chemosensors. 2023; 11(3):186. https://doi.org/10.3390/chemosensors11030186

Chicago/Turabian Style

Kuliukhina, Daria S., Nataliya M. Chernichenko, Alexei D. Averin, Anton S. Abel, Olga A. Maloshitskaya, and Irina P. Beletskaya. 2023. "Macrocyclic Compounds Comprising Tris(3-Aminopropyl)Amine Units and Fluorophore Moieties: Synthesis and Spectroscopic Studies in the Presence of Metal Salts" Chemosensors 11, no. 3: 186. https://doi.org/10.3390/chemosensors11030186

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