Synthesis and Coordination Chemistry of Hexadentate Picolinic Acid

Article pubs.acs.org/IC

Synthesis and Coordination Chemistry of Hexadentate Picolinic Acid Based Bispidine Ligands Peter Comba,*,† Laura Grimm,† Chris Orvig,‡ Katharina Rück,† and Hubert Wadepohl† †

Universität Heidelberg, Anorganisch-Chemisches Institut and Interdisciplinary Center for Scientific Computing, INF 270, D-69120 Heidelberg, Germany ‡ Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada S Supporting Information *

ABSTRACT: The synthesis and CuII, NiII, ZnII, CoII, and GaIII coordination chemistry of the two isomeric hexadentate N5O ligands 6-[[9-hydroxy-1,5-bis(methoxycarbonyl)-7-methyl-6,8-bis(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl]methyl]picolinic acid (Hbispa1a) and 6-[[9-hydroxy-1,5-bis(methoxycarbonyl)-7-methyl-2,4-bis(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl]methyl]picolinic acid (Hbispa1b), picolinic acid-appended bispidines, are described. The two ligands are highly preorganized for octahedral coordination geometries and are particularly well suited for tetragonal symmetries, i.e., for Jahn− Teller labile ground states. This is confirmed by all data presented: solid-state structures, solution spectroscopy, electrochemistry, and CuII complex stabilities. Differences in the preorganization of the two isomers for the Jahn−Teller labile CuII centers are thoroughly analyzed on the basis of the crystal structures and an angular-overlap-model-based ligand-field analysis.

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INTRODUCTION A large variety of bispidine derivatives (3,7-diazabicyclo[3.3.1]nonanes) together with diverse applications of their transitionmetal complexes have been reported, and the coordination chemistry of tetra-, penta-, and hexadentate bispidines has been thoroughly investigated.1 Characteristic for bispidines is their rigid adamantane-derived backbone that results in a highly preorganized binding pocket for coordination to metal ions, with a high complementarity for the Jahn−Teller labile CuII ion.2,3 In recent years, bispidine derivatives were established as promising bifunctional chelators (BFCs) for 64CuII positron emission tomography (PET) imaging.4−11 Among other efficient ligand systems for the labeling of CuII radionuclides are functionalized tri- and tetraazamacrocycles,12−14 hexaazasarcophagine (sar)-type cage ligands,15,16 and bisthiosemicarbazones like diacetylbis(N 4 -methylthiosemicarbazone) (ATSM),17−19 see Chart 1. On the basis of the tri- and tetraazamacrocycles 1,4,8,11-tetraazacyclotetradecane (cyclam), 1,4,7,10-tetrazacyclododecane (cyclen), and 1,4,7-triazacyclononane (tacn), a broad variety of systems have been developed, with the carboxylic acid substituted frameworks 1,4,8,11© XXXX American Chemical Society

tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) being the most popular ones.13,20 The substitution pattern of the macrocycles is not limited to carboxylic acids but also includes other donors like phosphonic acids and picolinic acids.13,21−24 For CuII-based radiopharmaceuticals, the crossbridged derivatives CB-TE2A,25 CB-TE1A1P,22 and CBTE2P21,22 are especially interesting because they show improved in vivo stability and radiolabeling kinetics in comparison to TETA.26 In this paper, we focus on bispidine ligands, which fulfill many important requirements for BFCs, i.e., (i) high stability, (ii) fast complexation, (iii) easy functionalization for coupling to targeting vectors, and (iv) a cost-effective, easy, and modular synthetic route.4−8,11,27−29 There are different possible sites for the introduction of a vector moiety at the bispidine scaffold, i.e., at the ester groups,4 at the hydroxy group at C9,29 or at one of the donor groups.5 Received: August 1, 2016

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DOI: 10.1021/acs.inorgchem.6b01787 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry Chart 1. Structures of the Ligands Discussed in This Publication

examined. While CuII and GaIII are of importance for radiopharmaceutical applications, complexation with the other metal ions was studied due to either their high bioavailability or their occurrence as impurities during the production of 64 CuII.44,45 The isolated metal complexes were investigated with a range of techniques, including nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), UV−vis−near-IR (NIR) spectroscopy, cyclic voltammetry (CV), electron paramagnetic resonance (EPR) spectroscopy, single-crystal X-ray structure analysis, and potentiometric titrations.

To further improve the bispidine ligands, we now have incorporated picolinic acid groups, known as excellent metalbinding moieties.23,24,30−38 The introduction of an oxygen donor might facilitate the coordination of hard metal ions such as GaIII. 68Ga is of interest for nuclear medicine because it has suitable properties for PET imaging and is easily available via a 68 Ge/68Ga generator.39,40 Amine-substituted picolinates are rigid tridentate ligands and reduce the overall charge of metal complexes, and this might have an impact on the biodistribution of the corresponding system.41 A crucial factor for the application in nuclear medicine is the stability of the metal complexes under physiological conditions,42 and first insights on the complex stability can be obtained by potentiometric titration and, specifically for CuII, by electrochemical investigations.43 Here, we report the syntheses of the two isomeric picolinic acid based bispidine ligands Hbispa1a and Hbispa1b and their metal complexes. In Hbispa1a, the picolinic acid group is linked to N7 of the bispidine scaffold, whereas in Hbispa1b, the group is attached to N3 (see Chart 2 for the numbering scheme). The coordination chemistry of these new hexadentate bispa ligands with various metal ions (CoII, NiII, CuII, ZnII, and GaIII) was

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RESULTS AND DISCUSSION Syntheses. The synthetic route to the hexadentate bispa ligands Hbispa1a and Hbispa1b starts with the preparation of the tert-butyl ester protected picolinic acid derivative 2 in two steps (Scheme 1).46 Therefore, the commercially available starting material 6-methylpicolinic acid was first esterified to 1 using tert-butyl-2,2,2-trichloroacetimidate and then transformed to the alkyl bromide derivative 2 with N-bromosuccinimide (NBS) and azobis(isobutyronitrile) (AIBN) as radical initiators. This fragment is later coupled to a secondary amine of the B


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Inorganic Chemistry Chart 2. Hexadentate Bispidine Ligands and the Respective Metal Complexes Discussed in This Publication

protonated. It is probably for this reason and due to the carboxylic acid group, which allows for hydrogen bonding, that in the crystal structure of Hbispa1a even the pyridine donors and the picolinic acid point toward the metal binding site (Figure 1). Selected experimental structural data of Hbispa1a and Hbispa1b as well as of the corresponding metal complexes are presented in Tables 1 and 2. Suitable crystals of the metal complexes for X-ray diffraction were obtained either by diffusion of diethyl ether into methanolic complex solutions or by slow evaporation of the complex solution in a mixture of MeOH and water (2:1). The structures of the metal complexes are as expected, and all are similar to each other with distorted octahedral coordination geometries (see Tables 1 and 2). [Because of the frequent presence of different types and the amounts of crystal solvent, there is no unique packing motif for the complexes even with the same type of ligand (see the packing diagrams in the Supporting Information).] Figure 2 shows the molecular cations of the CuII complexes of Hbispa1a and Hbispa1b. Both complexes display the expected pseudoJahn−Teller elongation. In the case of [CuII(bispa1a)]+, the distortion is along the N7−Cu−Opic axis, whereas in [CuII(bispa1b)]+, the axis Npy1−Cu−Npy2 is elongated. The structures of the other complexes also appearing in Tables 1 and 2 are plotted in the Supporting Information. An interesting and, from structural, spectroscopic, and theoretical studies, expected observation is that the bispa-type ligands are, similar to the tetra-, penta-, and hexadentate bispidines, very rigid and preorganized for tetragonally distorted complexes, in particular for Jahn−Teller-active systems such as CuII.1,57−59 In general, the bond from the metal center to N7 is more flexible (part of two six-membered chelates) than that to N3 (part of two rigid five-membered chelates), and this usually leads to a longer and more flexible bond for M−N7 compared to N−N3. Although for the bispa1abased complexes (and the corresponding pentadentate all-N ligands),1,57−59 the flexibility of the M−N7 bond is restricted by a five-membered chelate ring to the third pyridine group (picolinate−pyridine in bispa1a), the elongation along M−N7 is

bispidine scaffold. The bispidine system is usually built up by two consecutive double Mannich reactions.47 The syntheses of piperidones 348 and 749 as well as of bispidones 450 and 851 have been described. To prevent ligand decomposition by a retro Mannich reaction, the bispidones 4 and 8 were reduced with sodium borohydride to the alcohols 5 and 9, respectively.1,52,53 The required secondary amine can be introduced directly at position N3 by choosing ammonia in the first Mannich reaction (synthesis of the piperidone 7). To obtain a free amine at N7, a benzyl protecting group has to be inserted (Scheme 1).54 Therefore, benzylamine was used as the amine component to build up the bispidone 4. Then the protecting group was removed by hydrogenation with palladium on activated charcoal.55 Both bispidols [secondary amine at N7 (6) or N3 (9)] were then separately coupled to fragment 2 via nucleophilic substitution, yielding the respective ester-protected ligand precursors (tBu)bispa1a and (tBu)bispa1b. By hydrolysis of these precursors with trifluoroacetic acid, the new ligands Hbispa 1a and Hbispa1b were obtained as trifluoroacetate (TFA) salts. With these ligands, complexation reactions with CoII, NiII, CuII, ZnII, and GaIII were undertaken. Equimolar solutions of Hbispa1a or Hbispa1b and the respective metal salt in methanol (MeOH; CoII, NiII, CuII, and ZnII) or in a mixture of methanol and water (GaIII) were combined and stirred at room temperature (rt; CoII, NiII, CuII, and ZnII) or at 60 °C (GaIII). In the case of the colored complexes, an immediate color change was observed. Molecular Structures. With the protected precursor (tBu)bispa1a and the ligands Hbispa1a and Hbispa1b, suitable crystals for X-ray crystal structure determination were obtained by recrystallization from hot acetonitrile (MeCN) or MeOH. These bispidol systems crystallize in a chair−chair conformation, where the pyridine donors adopt the favored equatorial position with respect to the six-membered N3 azacyclohexane. Bispidine ligands in general are highly preorganized for complexation to metal ions.1,56 As the bispa ligands were isolated as TFA salts, one of the amine functions, namely, N7 is C


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Inorganic Chemistry Scheme 1. Synthetic Routes to the Hexadentate bispa Ligandsa

a (i) BF3·etherate, CH2Cl2, rt, 24 h; (ii) NBS, AIBN, CCl4, 80 °C, 6 h; (iii) THF, reflux, 30 min (Hbispa1a) or 3 h (Hbispa1b); (iv) NaBH4, 1,4dioxane/water (3:1), −5 and 0 °C, overnight; (v) H2, Pd/C, EtOAc, 90 °C, overnight; (vi) Na2CO3, MeCN, reflux, 24 h; (vii) TFA, CH2Cl2, rt, 24 h.

accompanied the structural studies,57,59 with the structures of bispa1a presented in Table 1, it appears that for bispa1a the situation is very similar to the standard bispidine ligands. For bispa1b, the situation is somewhat different, i.e., for all five structures of the metal complexes, the differences of the bond distances from the metal center to N3 and N7 are smaller than those for bispa1a, and for CuII, ZnII, and GaIII, the bond to N3 is larger than that to N7 (see Table 2). This situation has been observed and discussed in detail for bispidine ligands; i.e., there are two locations for the metal ion in the rigid bispidine cavity,

clearly shown for all structures of bispa1a; see Table 1. Obviously, for CuII, this leads to an electronic stabilization, and for CoII, this is not unfavorable, but for NiII, ZnII, and GaIII, it is. Therefore, for the pentadentate bispidines, a stability order in contrast to that predicted by the Irving−Williams series60,61 was observed, with the stability of the CuII complex being the largest and that of the CoII complex being larger than that of NiII.59 Comparing these stabilities and the overall shape resulting from the structural analyses of the penta- and hexadentate bispidines, where computational modeling has D


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solution with ZnII and GaIII, and these spectra are in agreement with the structures determined by X-ray crystallography. UV−Vis−NIR and EPR Spectroscopies. The spectroscopic and electrochemical data of the bispa complexes are given in Tables 3 and 4, together with the reported values for complexes of the known hexadentate bispidine N2py4.57 The solution electronic spectra were measured at rt in MeOH (NiII and CuII) or dimethyl sulfoxide (DMSO; CoII). The experimental spectra and deconvolution of unresolved transitions with Gaussian fits appear in the Supporting Information. For each metal center, the spectra of the complexes of the three ligands are as similar as expected, showing higher asymmetry for the bispa with respect to the N2py4 systems (the ligand-field parameters for pyridines and tertiary amines are very similar). Because of the significant π donation of the carboxylates, the ligand field emerging from the two isomeric bispa ligands is smaller than that of N2py4. The EPR spectra of the CuII complexes of Hbispa1a and Hbispa1b were recorded and simulated as frozen solutions (see the Supporting Information). In agreement with the crystal structures and the analysis of the electronic spectra, the spin Hamiltonian parameters derived by simulation of the EPR spectra (see Table 4) indicate that the solution structures are similar to those in the solid state and that [Cu(bispa1a)]+ has close to axial symmetry while [Cu(bispa1b)]+ has rhombic site geometry. Also, the angular overlap model (AOM) analysis is in agreement with the observed spin Hamiltonian parameters, i.e., with a stronger in-plane ligand field for [Cu(bispa1b)]+ than for [Cu(bispa1a)]+ (see below).64 For the two CuII complexes, an AOM-based ligand-field analysis of the electronic (and EPR) spectra was made in order to confirm that the structures in solution are similar to those in the crystals and to understand the differences in the degree of preorganization of the two isomeric ligands for the Jahn−Teller labile CuII ion (see the Supporting Information for details). The AOM eσ, eπ, and eds parameters, in principle, are not transferable, but in a series of studies, we have shown that the errors made by assuming transferability generally are acceptable.64−66 However, with published parameters for Cu− amine, Cu−pyridine, and Cu−carboxylate bonds (adjusted to

Figure 1. ORTEP plot of Hbispa1a. Ellipsoids are shown at the 50% probability level; cocrystallized solvent molecules, counterions, and hydrogen atoms are omitted for clarity. The following color code was used: C, gray; N, blue; O, red.

and the stability of the two isomers depends on the size and electronic structure of the metal ion.58 Also, for the CuII complexes of the pentadentate bispidines, Jahn−Teller isomers have been observed and thoroughly analyzed,62,63 and the structural trends observed in the complexes with bispa1b (see Table 2), which show for CuII an elongation along py1−Cu− py2 and similar bonds from CuII to N3 and N7 with similar overall shapes for the other metal ions, indicates that bispa1b is also highly preorganized and complementary for CuII. Solution Chemistry. NMR Spectroscopy. The newly synthesized bispidines as well as the metal complexes with the diamagnetic ZnII and GaIII ions were studied by 1H and 13C NMR spectroscopy (see the Experimental Section and Supporting Information). Two-dimensional correlation experiments (1H−1H and 1H−13C) were performed to allow the accurate assignment of all signals. A comparison of the NMR spectra of the free ligands and the respective metal complexes shows significant changes of the proton chemical shifts associated with coordination of the ligands to the metal ions. The spectra confirm the formation of a single complex in

Table 1. Selected Bond Distances and Angles of Hbispa1a, [CoII(bispa1a)]+, [NiII(bispa1a)]+, [CuII(bispa1a)]+, [ZnII(bispa1a)]+, and [GaIII(bispa1a)]2+

Distance [Å] M−N7 M−N3 M−Npy1 M−Npy2 M−Npic M−Opic N3···N7 Npy1···Npy2 Angle [deg] N3−M−N7 N3−M−Npy1 N3−M−Npy2 N3−M−Npic N7−M−Npy1 N7−M−Npy2 Npy1−M−Npy2 N7−M−Npic

Hbispa1a

[CoII(bispa1a)]+

[NiII(bispa1a)]+

[CuII(bispa1a)]+

[ZnII(bispa1a)]+

[GaIII(bispa1a)]2+

2.684(2) 4.922(3)

2.2503(17) 2.1203(18) 2.1203(18) 2.1398(18) 2.0209(18) 2.0912(16) 2.952(2) 4.142(3)

2.1625(11) 2.0850(12) 2.0936(11) 2.0798(11) 1.9660(12) 2.1359(10) 2.934(2) 4.088(2)

2.3280(13) 2.0097(13) 2.0229(14) 2.0347(13) 1.9893(13) 2.3127(12) 2.954(2) 3.999(2)

2.3465(17) 2.1477(16) 2.1516(18) 2.1314(18) 2.0444(17) 2.1441(15) 2.958(2) 4.148(3)

2.189(2) 2.0529(19) 2.068(2) 2.077(2) 1.962(2) 1.9830(17) 2.893(2) 4.052(3)

84.92(6) 78.15(7) 77.89(7) 162.95(7) 95.68(7) 94.47(7) 152.97(7) 78.73(7)

87.36(4) 79.69(4) 79.71(4) 168.75(4) 95.34(5) 94.46(5) 156.70(4) 81.84(4)

85.53(5) 81.89(5) 81.70(5) 165.43(5) 94.95(5) 94.16(5) 160.52(6) 80.25(5)

82.18(6) 76.98(6) 77.18(6) 158.82(7) 98.23(6) 90.64(6) 151.20(7) 76.82(6)

85.92(7) 79.14(8) 79.43(8) 166.01(8) 95.23(8) 94.61(8) 155.67(8) 80.15(8)

E


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Table 2. Selected Bond Distances and Angles of Hbispa1b, [CoII(bispa1b)]+, [NiII(bispa1b)]+, [CuII(bispa1b)]+, [ZnII(bispa1b)]+, and [GaIII(bispa1b)]2+ Distance [Å] M−N7 M−N3 M−Npy1 M−Npy2 M−Npic M−Opic N3···N7 Npy1···Npy2 Angle [deg] N3−M−N7 N3−M−Npy1 N3−M−Npy2 N3−M−Npic N7−M−Npy1 N7−M−Npy2 Npy1−M−Npy2 N7−M−Npic

Hbispa1b

[CoII(bispa1b)]+

[NiII(bispa1b)]+

[CuII(bispa1b)]+

[ZnII(bispa1b)]+

[GaIII(bispa1b)]2+

2.664(2) 4.805(2)

2.0271(17) 2.0060(18) 2.1973(18) 2.1928(18) 1.8749(17) 2.0020(16) 2.855(2) 4.313(3)

2.0941(11) 2.0731(11) 2.1255(12) 2.1235(12) 1.9578(11) 2.0664(10) 2.921(2) 4.181(2)

2.0077(11) 2.0738(11) 2.4192(13) 2.3789(13) 1.9129(11) 2.0119(11) 2.882(2) 4.642(2)

2.1032(16) 2.2507(14) 2.1979(16) 2.2655(15) 2.0509(14) 2.0358(13) 2.963(2) 4.327(2)

2.0622(18) 2.1045(18) 2.0667(17) 2.1179(17) 1.9868(18) 1.9149(16) 2.907(3) 4.121(3)

90.12(7) 80.08(7) 80.34(7) 85.29(8) 94.57(7) 94.40(7) 158.44(7) 175.15(8)

89.01(4) 80.39(4) 80.61(4) 83.58(4) 93.60(4) 93.85(4) 159.45(4) 172.43(4)

89.83(4) 76.39(5) 76.76(5) 83.73(4) 95.73(5) 95.82(4) 150.65(4) 173.38(4)

85.70(5) 76.73(5) 75.87(5) 77.59(5) 95.29(6) 90.20(5) 151.53(5) 162.64(5)

88.46(7) 80.97(7) 79.74(7) 80.91(7) 93.12(7) 91.75(7) 159.96(6) 169.11(6)

Figure 2. ORTEP plot of the complex cations of [CuII(bispa1a)](TFA) (left) and [CuII(bispa1b)](TFA) (right). Ellipsoids are shown at the 50% probability level; cocrystallized solvent molecules, counterions, and hydrogen atoms are omitted for clarity. The following color code was used: C, gray; N, blue; O, red; Cu, orange.

the observed CuII-donor distances with 1/r6),67−69 and coordinates of the CuII center and the donor atoms based on the crystal structural coordinates, the computed and experimentally determined electronic transitions are only in fair agreement, but some modifications of the ligand-field parameters lead to acceptable predictions of the dd transitions and EPR g tensor parameters (see Table 4 and the Supporting Information for details). One reason for the discrepancy between the published and moderately adjusted AOM parameters is that those for the carboxylates are merely the result of an ad hoc parametrization for one particular set of complexes,68 while the parametrization for amines and pyridines emerged from a larger set of spectroscopic studies.64 Also, transferability is an assumption with limited applicability, and electron transfer from anionic ligands may be problematic in this context.70 In addition and most importantly, small structural changes upon dissolution of the complexes, in particular along the Jahn−Teller vibration, may lead to significant changes of the ligand field. However, while the adjustments to the AOM parameters seemed to be necessary for esthetic reasons, the qualitative interpretation that there are

only minor structural changes upon dissolution of the complexes does not change with the two sets of parameters used (see Table 4). The structural data suggest that [CuII(bispa1a)]+ is elongated along the N7−Cu−Opic axis, while the elongation observed in [CuII(bispa1b)]+ is along Npy1−Cu−Npy2, and this is, based on both sets of AOM parameters, confirmed to also be the structure in solution and has some implications for the relative stabilities (see below). The splitting of the three dπ orbitals is not resolved for either isomer, but from the relative line width of the dxz,yz,xy → dx2−y2 transitions, it appears that the splitting is slightly larger for [CuII(bispa1a)]+, and this agrees with the geometry observed in the crystals, which for [CuII(bispa1a)]+ has the carboxylate π-donor interacting with the CuII dxz,yz orbitals. The in-plane carboxylate in [CuII(bispa1b)]+ leads to a relative destabilization of the dπ orbitals and a stabilization of the dx2−y2 orbital with respect to [CuII(bispa1a)]+ with an axial carboxylate, emerging in a generally lower ligand field but a higher energy dz2 → dx2−y2 transition. The conservation of the solid-state structures in solution (i.e., the different orientation of the pseudo-Jahn−Teller axes) is also well supported by the F


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shape that is highly complementary for CuII. For the N2py3type isomers similar to Hbispa1a and Hbispa1b, this leads to distinct stability differences between the two corresponding isomeric CuII complexes and an interesting CuII selectivity for one of the two isomers.59 However, “Jahn−Teller isomerism” was observed for the CuII complexes of a number of bispidine derivatives,62,63 and the ligand-field properties (see Table 4) of the two isomers [CuII(bispa1a)]+ and [CuII(bispa1b)]+ as well as the stronger CuII−Ocarboxylate interaction in [CuII(bispa1b)]+ suggest that this isomer might lead to a slightly more stable CuII complex. CV. The electrochemical measurements of the metal complexes were perfomed at ambient temperature in dimethylformamide (DMF; see Table 3 and also the Supporting Information for the cyclic voltammograms). With the bispa complexes of NiII (CoII), two signals corresponding to the NiII/I (CoII/I) and NiIII/II (CoIII/II) couples were detected, and for the CuII systems, a single wave for CuII/I was observed in the measurable range given by the solvent. It is known that the stability constants of CuI complexes are relatively uniform, while those of CuII vary over a wide range. Therefore, CuII/I redox potentials are linearly correlated to the thermodynamic stability of the corresponding CuII complexes,71 and this correlation has been used to predict the approximative stability constants of CuII bispidine complexes.28,59 In comparison to other CuII bispidine systems only bearing nitrogen donors, the reversible redox potentials of [Cu(bispa1a)]+ (E1/2 = −1.02 V vs fc/fc+) and [Cu(bispa1b)]+ (E1/2 = −1.17 V vs fc/fc+) are significantly lower, indicating higher CuII complex stabilities, in particular compared to the hexadentate [Cu(N2 py 4 )] 2+ system,57 and [Cu(bispa1b)]+ is predicted to be slightly more stable than [Cu(bispa1a)]+, in agreement with the spectroscopic analysis. When the bispidine complexes of all three investigated metal ions are compared, there is a general trend observed with the N2py4 complexes having significantly higher redox potentials than the bispa systems, whereas the values for the bispa1b isomers are slightly more negative than the respective bispa1a complexes, i.e., [M(N2py4)]+ > [M(bispa1a)]+ > [M(bispa1b)]+. Potentiometric Titrations. The stability of the CuII(bispa) complexes was investigated by potentiometric titration, and the determined protonation and stability constants are listed in Table 5. To measure the protonation constants of the bispa ligands, potentiometric titrations in aqueous solution at 25 °C and the ionic strength of 0.1 M KNO3 were performed. Hexadentate bispa ligands have six basic centers consisting of five nitrogen donors (two tertiary amines and three pyridines) and one carboxylic acid group. Therefore, the compounds possess six pKa values but, because the fully protonated ligands are expected to be very strong acids, not all of these constants are accessible by potentiometric titration (pKa values: 7.73, 3.94, and ∼1.83 for Hbispa1a and 9.05 and 6.10 for Hbispa1b). The first protonation of the ligand occurs at a pKa value of about 8 for Hbispa1a and 9 for Hbispa1b and is associated with proton addition to one of the tertiary amines of the bispidine scaffold. This is confirmed by the X-ray crystal structures of the protonated bispa ligands. The stability constants of the CuII(bispa) complexes were determined under experimental conditions similar to those used in the protonation experiments. Because the stability constants were not accessible via direct potentiometry, ligand/ligand competition titrations were performed in a ratio of 1:1:1 [CuII/L/L′, with L = Hbispa1a or Hbispa1b and L′ = ethylenediaminetetraacetic acid (EDTA)].

Table 3. Electronic Spectroscopic and Electrochemical Data of the CoII, NiII, and CuII Complexes of the Hexadentate Bispidine Ligands Hbispa1a, Hbispa1b, and N2py4

[Co(bispa1a)]+ [Co(bispa1b)]+

UV−vis−NIR (dd transitions)a

redoxb

λ [nm] (ε [M−1 cm−1])

E1/2 vs fc/fc+ [V]

[Ni(bispa1b)]+

470 (123), 557 (43), 993 (5) 475 (117), 516 (9), 544 (23), 584 (7), 677 (6), 920 (6) 397 (170), 493 (67), 551 (27) sh 515 (12), 558 (11), 819 (20), 923 (25) 512 (18), 796 (13), 877 (36)

[Ni(N2py4)]2+

304 (443) sh, 532 (18), 815 (30)

[Cu(bispa1a)]+ [Cu(bispa1b)]+ [Cu(N2py4)]2+

672 (93), 1284 (34) 651 (78), 904 (18) 620 (110)

[Co(N2py4)]2+ [Ni(bispa1a)]+

−0.37, −1.94 −0.52, −2.09 0.22 0.76 (irrev.), −2.18 0.71, −2.27 (irrev.) 1.39 (irrev.), −1.28 (irrev.) −1.02 −1.17 −0.66

ref 57

57

57

Measurements at 25 °C in MeOH (NiII and CuII complexes of Hbispa1a and Hbispa1b), DMSO (CoII complexes of Hbispa1a and Hbispa1b) or MeCN (N2py4). bMeasurements at 25 °C in DMF and 0.1 M (Bu4N)(ClO4) (Hbispa1a and Hbispa1b) or in MeCN and 0.1 M (Bu4N)(PF6)(N2py4). a

Table 4. Spectroscopic Data and AOM Analysis of the CuII Complexes of the Hexadentate Bispidine Ligands Hbispa1a and Hbispa1ba UV−vis−NIR (dd transitions)b λ [cm−1] [Cu(bispa1a)]+ exp AOMpubd AOMadjd [Cu(bispa1b)]+ exp AOMpubd AOMadjd [Cu(N2py4)]2+ exp

14880, 7790 17870, 17330, 15640, 9110 16131, 15668, 13421, 8114 15360, 11060 18530, 18260, 17440, 11200 17306, 16978, 15713, 10681 16130

EPRc gx, gy, gz 2.059, 2.059, 2.243 2.029, 2.038, 2.136 2.028, 2.046, 2.154 2.016, 2.068, 2.236 2.014, 2.055, 2.120 2.015, 2.060, 2.128 2.069, 2.069, 2.208

Ax, Ay, Az [×10−4 cm]

ref

13, 13, 164

27, 21, 145

−, −, 169

57

a

The experimental data for the N2py4 system appear for comparison. Measurements at 25 °C in MeOH (CuII complexes of Hbispa1a and Hbispa1b) or MeCN (N2py4). cMeasurements at 8 K in MeOH (Hbispa1a and Hbispa1b) or at 130 K in 2:1 DMF/water (N2py4). dFor AOMpub, published AOM parameters were used,67−69,81 and for AOMadj, these were moderately adjusted to better fit the observed spectroscopic parameters; see the text and Supporting Information. b

EPR g tensors, resulting from simulation of the frozen solution X-band EPR spectra (see below, Table 4): tertiary amines and pyridine donors have very similar ligand-field parameters,65,67 while those for carboxylate are significantly different and therefore lead to a larger in-plane asymmetry in [CuII(bispa1b)]+. The structural difference between N7 and N3 in the bispidine scaffold, which in metal complexes are part of the rather flexible six-membered and very rigid five-membered chelate rings, respectively,58 in general leads to long M−N7 and shorter M−N3 bonds and therefore to a rigid bispidine ligand G


Article

Inorganic Chemistry

Table 6. Comparison of the pKa, log KCuL, and pCu Values of bispa Ligands and Other Relevant Ligands from the Literature

Table 5. Protonation and CuII Complex Stability Constants of Hbispa1a and Hbispa1b equilibrium reactiona

overall constant log βxb,c

Hbispa1ad

Hbispa1bd

L + H ⇌ LH L + 2 H ⇌ LH2 L + 3 H ⇌ LH3

log β1 log β2 log β3 stability constant log Kc,f,g

7.73(3) 11.68(5) 13.50(12)

9.05(7) 15.15(14)

Hbispa1ad

Hbispa1bd

log KCuL log KCuLH pM valueh

18.88(10) 21.07(6) 19.3

19.44(18) 21.77(21) 18.7

equilibrium reactiona Cu + L ⇌ CuL Cu + L + H ⇌ CuLH

ligand 1a

Hbispa Hbispa1b N2py4 N2py4diol TETA TE1PA

a

L denotes the respective ligand with completely deprotonated basic centers; the charges of the species are omitted for clarity. bβ[LHx]· [L]−·[H]x−. cValues in parentheses are standard deviations calculated ⎡ (x − x )2 ⎤1/2 according to σ = ⎢⎣∑ i n − 1 ⎥⎦ , with ⟨x⟩ being the mean value of n measurements. dMeasurements at 25 °C in water (μ = 0.1 M KNO3). f K = [MmLlHh]·[M]−m·[L]−l·[H]−h. gFormation of CuL determined by ligand/ligand competition titrations. hCalculated for 10 μM total ligand and 1 μM total metal at pH 7.4 and 25 °C.72

DOTA DO1PA NOTA NO1PA2PY H2dedpa

pKa

log KCuL

pCua

7.73(3), 3.95(5), 1.82(12) 9.05(7), 6.10(14) 6.68, 11.40 >12, 10.6(6), 4.5(1), 2.0(2), 0.82 (1), < 0.82 10.82(1), 10.10(2), 4.15(1), 3.21(1) 11.55(1), 10.11(1), 2.71(1), 1.7(1) 11.14(1), 9.69(2), 4.85(2), 3.95(1) 10.46(1), 9.26(1), 3.23(1) 11.73(2), 5.74(1), 3.16 10.61(2), 5.25(5), 3.69(5), 1.61(9) 9.00(3), 6.31(5), 3.04(6), 2.59(6)

18.88(10) 19.44(18) 16.28 19.2(2)

19.3 18.7 17.6 17.0

57 8

21.87(6)

16.7

82

25.5(1)

19.6

23

22.72(4)

17.6

82

24.01(1) 21.63(2) 20.96(5)

20.0 18.2 18.7

23 20 24

19.16(5)

18.5

30 and 83

ref

Calculated for 10 μM total ligand and 1 μM total metal at pH 7.4 and 25 °C. a

Back-titrations were carried out in order to check for complete equilibration of the system. During titration of the metal/ligand sample solutions up to a pH of 11, a shift between the titration curve and the back-titration was observed. When the final pH value was lowered to 10, both curves became congruent, which indicates decomposition processes in basic media (pH > 10). Therefore, only data points in the pH range of 2−10 were considered in the fitting procedures. The main species formed in solution are CuL and CuLH (see the Supporting Information for species distribution plots). Only 1:1 complexation was modeled, which is in agreement with the spectroscopic and structural data. Logarithmic complex stability constants of 18.9 for [Cu(bispa1a)]+ and 19.4 for [Cu(bispa1b)]+ were obtained; i.e., the CuII(bispa1b) complex is slightly more stable than its isomer, and this agrees well with the structural, spectroscopic, and electrochemical analyses. Both ligands lead to significantly larger CuII complex stabilities than the known hexadentate ligand N2py4 by around 3 orders of magnitude (16.3). Also given in Table 5 are the pM values at pH 7.4 (pM = −log [Mn+]). These define the complex stabilities at a particular pH value, and for PET chelators, the pM values at physiological pH are of particular relevance. Interestingly, while based on the log K values (and spectroscopic as well as electrochemical data) Hbispa1b is a slightly better ligand than Hbispa1a (19.4 vs 18.9), at pH 7.4 this is reversed based on the pM values (18.7 vs 19.3). The species distributions (see the Supporting Information) indicate that this is related to the relevant pKa values of the metal-free ligands, and this therefore is an excellent example for the importance of pM values to directly assess different ligands for a given metal ion.72 The preliminary results of serum stability studies, which will be reported elsewhere, show high stability of the CuII(bispa) complexes but only poor stability of the corresponding GaIII complexes. Because the presence of only one oxygen donor seems to be insufficient for stable complexation of GaIII, we are currently working on improved bispidine ligands for this specific metal ion. In the case of the bispa ligands presented here, we therefore focused the investigation of the complex stability on the CuII systems (see Table 6 for a comparison of different CuII chelators). To avoid the release of the

radioisotope, the metal complex has to be stable in the presence of competing metal ions. In this context, stability studies of similar bispidine systems have already shown high stability of the corresponding CuII complexes and good selectivity of the ligands for CuII in comparison to CoII, NiII, and ZnII.8,57

■

CONCLUSIONS The two isomeric ligands Hbispa1a and Hbispa1b are well preorganized for transition-metal ions with octahedral coordination geometry and are complementary, in particular, for Jahn−Teller-active metal ions such as CuII. The substitution of the picolinic acid pendant arm to the adamantane-derived bispidine scaffold leads to a very rigid planar aminopicolinate subunit that only has one possibility to rotate away for accepting metal ions to the very rigid bispidine cavity. This leads to fast complexation, high complex stability, and, because of the ligand shape that specifically fits Jahn−Teller-distorted tetragonal geometries,59 a high metal-ion selectivity with complexes of CuII strongly preferred; for 64CuII PET applications, one may therefore expect high specific activities. These conclusions are based on the observed solid-state structures, the solution spectroscopy that indicates that the structures are preserved in solution, the electrochemical data, and the stability constants. It appears that these ligands may lead to BFCs for 64CuII PET sensors, which outperform those of other bispidine-based ligands. This, together with the fact that we now have bispidine-based 64CuII PET compounds with various charges (neutral, 1+, and 2+), makes biological studies of the complexes and their derivatives particularly interesting.

■

EXPERIMENTAL SECTION

Materials and Methods. Chemicals and solvents were purchased from Sigma-Aldrich Chemie GmbH, Fisher Scientific GmbH, and Tokyo Chemical Industry Co. Ltd., were of the highest available purity, and were used as purchased. Reactions with air-sensitive compounds were carried out under an inert gas atmosphere by means of standard Schlenk or glovebox techniques. Dry solvents were used without further purification. H


Article

Inorganic Chemistry

structures shown in this publication were performed using the programs ORTEP and POV-Ray.79,80 Syntheses. The standard piperidones 348 and 7,49 the bispidones 50 4 and 8,51 and the bispidols 5 and 952 were prepared according to slightly modified literature-known procedures.28 The tert-butyl ester protected picolinic acid derivative 2 was prepared in a two-step synthesis,46 whereby AIBN was used as the radical initiator for bromination of 1 instead of benzoyl peroxide. Bispidol (C22H26N4O5, 426.47 g/mol) 6. To a solution of 5 (1.71 g, 3.31 mmol, 1.0 equiv) in 150 mL of ethyl acetate was added palladium on activated charcoal (171 mg, 10 wt %), and the suspension was stirred at 90 °C and 1 atm of hydrogen overnight. Then the reaction mixture was concentrated in vacuo, the residue taken up in methylene chloride, and the catalyst removed by filtration over a Celite pad. After evaporation of the solvent, the crude product was recrystallized from MeOH to obtain the product as a white powder in a yield of 56% (790 mg, 1.85 mmol). 1H NMR (200.13 MHz, 27 °C, MeOH-d4): δ 1.80 (s, 3 H, N3CH3), 3.04−3.07 (m, 4 H, N7CH2ax,eq), 3.59 (s, 6 H, COOCH3), 4.12 (s, 2 H, N3CH), 4.81 (s, 1 H, CHOH), 7.36 (dd, 3 JH,H = 7.8 Hz, 4JH,H = 5.0 Hz, 2 H, Hpy), 7.57−7.88 (m, 4 H, Hpy), 8.57 (bs, 2 H, Hpy). 13C NMR (150.92 MHz, 22 °C, MeOH-d4): δ 42.5, 43.9, 52.6, 52.9, 74.4, 76.9, 124.8, 138.7, 150.5, 159.3, 173.6. HRDART MS (pos, CH2Cl2): [M + H]+, calcd 427.19760, obsd 427.19785; [2M + H]+, calcd 853.38792, obsd 853.38866. Elem anal. (report no. 37780). Calcd for [M·H2O]: C, 59.45; H, 6.51; N, 12.61. Obsd: C, 59.31; H, 6.51; N, 12.34. (tBu)bispa1a (C33H39N5O7, 617.69 g/mol). 6 (1.62 g, 3.80 mmol, 1.0 equiv) was dissolved in 80 mL of MeCN. To this solution were added tert-butyl 6-(bromomethyl)picolinate 2 (1.03 g, 3.80 mmol, 1.0 equiv) and Na2CO3 (2.42 g, 22.8 mmol, 6.0 equiv). The suspension was heated to reflux for 24 h, and then the excess of Na2CO3 was removed by filtration. The filtrate was concentrated in vacuo and the yellow residue partitioned between equal volumes (100 mL) of water and methylene chloride. Then the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was recrystallized from MeCN to obtain (tBu)bispa1a as colorless needles in a yield of 69% (1.61 g, 2.61 mmol). 1H NMR (600.13 MHz, 22 °C, MeCN-d3): δ 1.57 (s, 9 H, COOC(CH3)3), 1.80 (s, 3 H, N3CH3), 2.38 (s, 4 H, N7CH2ax,eq), 3.47 (s, 2 H, N7CH2), 3.60 (s, 6 H, COOCH3), 3.74 (bs, 1 H, CHOH), 4.04 (s, 2 H, N3CH), 4.61 (bs, 1 H, CHOH), 7.13 (dd, 3JH,H = 7.1 Hz, 3JH,H = 5.1 Hz, 2 H, Hpy), 7.48 (t, 3JH,H = 7.1 Hz, 2 H, Hpy), 7.62 (d, 3JH,H = 7.7 Hz, 1 H, Hpy), 7.90− 7.94 (m, 3 H, Hpy), 8.01 (d, 3JH,H = 7.7 Hz, 1 H, Hpy), 8.34 (d, 3JH,H = 5.1 Hz, 2 H, Hpy). 13C NMR (150.92 MHz, 22 °C, MeCN-d3): δ 28.4, 44.3, 49.9, 52.4, 53.8, 65.8, 72.9, 75.6, 82.6, 123.5, 124.3, 124.4, 128.6, 137.0, 138.4, 149.2, 150.5, 159.3, 161.1, 165.7, 173.0. HR-DART MS (pos, MeCN): [M + H]+, calcd 618.29223, obsd 618.29391. Elem anal (report no. 34944). Calcd for [M]: C, 64.17; H, 6.36; N, 11.34. Obsd: C, 63.74; H, 6.43; N, 11.40. Hbispa1a·TFA (C31H32F3N5O9, 675.62 g/mol). To (tBu)bispa1a (2.66 g, 4.31 mmol) in 50 mL of methylene chloride was added 50 mL of trifluoroacetic acid, and the solution was stirred for 24 h at rt. Then the solvent was evaporated and the crude product recrystallized from MeOH to obtain Hbispa1a·TFA as colorless crystals in a yield of 42% (1.23 g, 1.82 mmol). 1H NMR (600.13 MHz, 22 °C, MeCN-d3): δ 1.71 (s, 3 H, N3CH3), 3.63 (s, 6 H, COOCH3), 3.66 (d, 2JH,H = 11.9 Hz, 2 H, N7CH2ax,eq), 3.82 (d, 2JH,H = 11.9 Hz, 2 H, N7CH2ax,eq), 4.39 (s, 2 H, N3CH), 4.55 (s, 2 H, N7CH2), 4.83 (s, 1 H, CHOH), 7.24 (bd, 3JH,H = 7.5 Hz, 2 H, Hpy), 7.29 (ddd, 3JH,H = 7.5 Hz, 3JH,H = 4.5 Hz, 4JH,H = 0.8 Hz, 2 H, Hpy), 7.76 (td, 3JH,H = 7.5 Hz, 4JH,H = 1.5 Hz, 2 H, Hpy), 7.91 (d, 3JH,H = 7.7 Hz, 1 H, Hpy), 8.15 (d, 3JH,H = 4.5 Hz, 2 H, Hpy), 8.25 (t, 3JH,H = 7.7 Hz, 1 H, Hpy), 8.35 (d, 3JH,H = 7.7 Hz, 1 H, Hpy). 13C NMR (150.92 MHz, 22 °C, MeCN-d3): δ 42.1, 50.9, 53.5, 53.7, 62.4, 71.5, 73.1, 125.0, 125.1, 125.8, 129.4, 139.0, 141.2, 147.9, 150.9, 151.1, 156.1, 160.6, 165.3, 170.1. HR-ESI MS (pos, MeCN): [M + H]+, calcd 562.22962, obsd 562.22913; [M + Na]+, calcd 584.21157, obsd 584.21128. Elem anal. (report no. 36729). Calcd for [M·TFA]: C, 55.11; H, 4.77; N, 10.37. Obsd: C, 55.10; H, 4.84; N, 10.39.

NMR spectra were recorded on Bruker Avance II 400 and Bruker Avance III 600 spectrometers, equipped with a direct-detection cryoprobe for maximum sensitivity in the detection of 13C. 1H and 13C NMR chemical shifts are referenced to the signals of the solvent (MeOH-d4, MeCN-d3, and D2O). Two-dimensional correlation spectra were used to assign the signals. Mass spectra were recorded on a Bruker ApexQe FT-ICR instrument. Elemental analyses were performed on a CHN-O Vario EL by the “Mikroanalytisches Labor”, Department of Chemistry, University of Heidelberg, Heidelberg, Germany. UV−vis−NIR spectra were recorded on a Jasco V-570 or an Agilent 8453 spectrophotometer at ambient temperature. In the spectra, device-related noise was smoothed using Origin 2016. EPR measurements were performed on a Bruker ELEX-SYS-E-500 instrument at 8 K, using MeOH as the solvent. The spin-Hamiltonian parameters were obtained by simulation of the experimental data with the Xsophe software package.73,74 Fourier (Hamming function) and Savitzky−Golay filtering were undertaken to increase the spectral resolution. The cutoff of the Hamming function was adjusted so that the high-frequency noise was minimized without distorting the spectrum. Electrochemical measurements were performed on a CH Instruments CHI660D electrochemical workstation, equipped with a CH Instruments Picoamp Booster and Faraday Cage. A three-electrode setup consisting of a glassy carbon working electrode, a platinum wire auxiliary electrode, and an Ag/AgCl reference electrode (3 M NaCl) was used. The solutions [0.1 M (Bu4N)(ClO4) in dry DMF] were thoroughly degassed, and a slight argon stream was set above the solution during the measurement (scan rate of 0.1 V/s). The values are referenced against the potential of ferrocene as an external standard [E1/2(fc/fc+) = 0.55 V]. Potentiometric measurements were carried out using a Metrohm Titrando 905 instrument equipped with a BlueLine 17 pH electrode (Schott instruments) and dosing systems (Dosino 800, Metrohm) containing 0.1 M KOH and 0.1 M HNO3 as titrants. The titration procedure and data collection were automatically performed by the software package tiamo 2.3 (Metrohm). The potentiometric setup consisted of a water-jacketed glass vessel maintained at 25 °C using a Lauda ecoline E300 thermostat. To exclude atmospheric CO2 from the titration cell, a slight argon stream was passed over the sample solution during the measurement. All pH titrations were carried out at a constant ionic strength of μ = 0.1 M KNO3. Prior to and after each measurement, the standard potential of the electrode (E0) was determined by titration of a HNO3 solution and subsequent analysis of the titration curve using the computer program TITKURVE.75 Aqueous stock solutions of the ligands were prepared at a concentration of 2 mM. The samples (20 mL, 0.04 mmol ligand) were placed in the glass vessel, and 0.1 M HNO3 was used to adjust the initial pH value. Measurements were carried out in the absence of metal ions and with a metal-to-ligand ratio of 1:1. Each titration curve consisted of 50−65 titration points at the pH 2−11 range, and three replicate titrations were performed for each system. Backtitrations were always carried out in order to ensure that equilibrium was attained at each point. Measuring times of 120 s (determination of the protonation constants) and 300 s [determination of the copper(II) stability constants] per titration point proved to be sufficient to avoid hysteresis. For determination of the stability constants with Cu2+, 1:1 ligand/ligand competition titrations were performed. K2H2EDTA was used as the competing ligand with known pKa values and complex stability constants.76 The protonation constants and stability constants were calculated from the potentiometric data with the computer program HYPERQUAD (version hq2008).77 The total concentrations of the compounds and the pKw value (13.77) were not refined. The errors given in parentheses are the standard deviations of three measurements. Species distributions were plotted from the obtained constants using the HySS program (version 4.0.31).78 X-ray Crystallography. See the Supporting Information for the details of the crystal structure determinations. The plots of the crystal I


Article

Inorganic Chemistry (tBu)bispa1b (C33H39N5O7, 617.70 g/mol). 9 (620 mg, 2.28 mmol, 1.0 equiv) was dissolved in 50 mL of MeCN. To this solution were added tert-butyl 6-(bromomethyl)picolinate 2 (972 mg, 2.28 mmol, 1.0 equiv) and Na2CO3 (1.44 g, 13.67 mmol, 6.0 equiv). The suspension was heated to reflux for 24 h, and then the excess of Na2CO3 was removed by filtration. The filtrate was concentrated in vacuo and the yellow residue partitioned between equal volumes (100 mL) of water and methylene chloride. Then the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to obtain (tBu)bispa1b as an orange solid in a yield of 92% (4.58 g, 7.25 mmol). The product was used without further purification. 1H NMR (600.13 MHz, 22 °C, MeCN-d3): δ 1.65 (s, 9 H, COOC(CH3)3), 2.15 (s, 3 H, N7CH3), 2.20 (s, 2 H, N7CH2ax,eq), 2.30 (bs, 2 H, N7CH2ax,eq), 3.57 (s, 6 H, COOCH3), 3.59 (s, 2 H, N3CH2), 4.64 (d, 2JH,H = 3.2 Hz, 1 H, CHOH), 4.86 (s, 2 H, N3CH), 6.83 (d, 3JH,H = 7.7 Hz, 1 H, Hpy), 7.16 (dd, 3JH,H = 6.7 Hz, 3JH,H = 5.3 Hz, 2 H, Hpy), 7.55 (t, 3JH,H = 7.7 Hz, 1 H, Hpy), 7.69−7.72 (m, 3 H, Hpy), 8.03 (bd, 3JH,H = 5.3 Hz, 2 H, Hpy), 8.36 (d, JH,H = 4.3 Hz, 2 H, Hpy). 13C NMR (150.92 MHz, 22 °C, MeCN-d3): δ 28.5, 46.2, 52.0, 52.4, 53.9, 59.3, 72.0, 72.3, 82.4, 123.4, 123.5, 125.3 127.8, 136.8, 137.6, 149.2, 149.8, 159.0, 161.1, 165.5, 173.3. HR-ESI MS (pos, MeCN-d3/MeOH): [M + H]+, calcd 618.29223, obsd 618.29217; [M + Na]+, calcd 640.27536, obsd 640.27445. Hbispa1b·TFA (C31H32F3N5O9, 675.62 g/mol). To (tBu)bispa1b (3.57 g, 5.78 mmol) in 70 mL of methylene chloride was added 70 mL of trifluoroacetic acid, and the solution was stirred for 24 h at rt. Then the solvent was evaporated, and the crude product was washed with ethyl acetate to obtain Hbispa1b·TFA as a colorless solid in a yield of 90% (2.93 g, 5.22 mmol). Crystals suitable for X-ray diffraction were obtained by recrystallization from hot MeOH. 1H NMR (600.13 MHz, 22 °C, D2O): δ 3.09 (s, 3 H, N7CH3), 3.47 (d, 2JH,H = 13.0 Hz, 2 H, N7CH2ax,eq), 3.66 (s, 6 H, COOCH3), 3.80 (d, 2JH,H = 13.0 Hz, 2 H, N7CH2ax,eq), 3.89 (s, 2 H, N3CH2), 5.03 (s, 1 H, CHOH), 5.06 (s, 2 H, N3CH), 6.75 (d, 3JH,H = 7.9 Hz, 1 H, Hpy), 7.26 (dd, 3JH,H = 7.6 Hz, 3 JH,H = 4.9 Hz, 2 H, Hpy), 7.35 (d, 3JH,H = 7.6 Hz, 2 H, Hpy), 7.79 (td, 3 JH,H = 7.6 Hz, 4JH,H = 1.6 Hz, 2 H, Hpy), 7.97 (t, 3JH,H = 7.9 Hz, 1 H, Hpy), 8.04 (d, 3JH,H = 7.9 Hz, 1 H, Hpy), 8.31 (d, 3JH,H = 4.9 Hz, 2 H, Hpy). 13C NMR (150.92 MHz, 22 °C, D2O): δ 43.1, 50.6, 53.0, 53.5, 55.5, 69.4, 70.5, 123.9, 125.1, 125.2, 125.9, 139.1, 145.3, 146.9, 150.0, 152.6, 153.3, 163.2, 170.1. HR-ESI MS (pos, MeOH): [M + H]+, calcd 562.22962, obsd 562.22994; [M + Na]+, calcd 584.21157, obsd 584.21216. Elem anal. (report no. 37961). Calcd for [M·TFA]: C, 55.11; H, 4.77; N, 10.37. Obsd: C, 55.08; H, 4.82; N, 10.42. [CoII(bispa1a)](TFA) (C31H30F3N5CoO9, 732.54 g/mol). Under an inert gas atmosphere, Hbispa1a·TFA (150 mg, 222 μmol, 1.0 equiv) was dissolved in 10 mL of MeOH. Co(OAc)2·4H2O (55.3 mg, 222 μmol, 1.0 equiv) was added, and the red solution was stirred for 2 h at rt. After evaporation of the solvent, the residue was taken up in MeOH and subjected to diethyl ether diffusion at rt to obtain red crystals of the product (55.8 mg, 71.9 μmol, 32%). HR-ESI MS (pos, MeOH): [CoII(bispa1a)]+, calcd 619.14717, obsd 619.14725. Elem anal. (report no. 38721). Calcd for [[CoII(bispa1a)](TFA)·0.5H2O]: C, 50.54; H, 4.31; N, 9.36. Obsd: C, 50.65; H, 4.51; N, 9.64. UV−vis−NIR (DMSO, rt): λ [nm] (ε [M−1 cm−1]) = 470 (123), 557 (43), 993 (5). CV (DMF, rt): E1/2 = −0.37, −1.94 V (vs fc/fc+). [NiII(bispa1a)](TFA) (C31H30F3N5NiO9, 732.30 g/mol). Solutions of Hbispa1a·TFA (100 mg, 150 μmol, 1.0 equiv) and Ni(OAc)2·4H2O (37.3 mg, 150 μmol, 1.0 equiv) each in 5 mL of MeOH were combined, and the violet solution was stirred overnight at rt. After evaporation of the solvent, the residue was taken up in MeOH and subjected to diethyl ether diffusion at 5 °C to obtain violet crystals (110 mg, 128 μmol, 85%). Some of the crystals were redissolved in a mixture of MeOH and water (2:1), and violet plates suitable for X-ray diffraction were obtained by slow evaporation of the solvent mixture. HR-ESI MS (pos, MeOH): [NiII(bispa1a)]+, calcd 618.14932, obsd 618.14926. Elem anal. (report no. 36295). Calcd for [[NiII(bispa1a)](TFA)·2H2O]: C, 48.46; H, 4.46; N, 9.12. Obsd: C, 48.36; H, 4.51; N, 9.24. UV−vis−NIR (MeOH, rt): λ [nm] (ε [M−1 cm−1]) = 515 (12), 558 (11), 819 (20), 923 (25). CV (DMF, rt): E1/2 = 0.76 (irrev.), −2.18 V (vs fc/fc+).

[CuII(bispa1a)](TFA) (C31H30CuF3N5O9, 737.15 g/mol). Solutions of Hbispa1a·TFA·MeOH·H2O (107 mg, 147 μmol, 1.0 equiv) in 4 mL of MeOH and Cu(OAc)2·H2O (29.3 mg, 147 μmol, 1.0 equiv) in 6 mL of MeOH were combined, and the turquoise solution was stirred for 2 h at rt. After evaporation of the solvent, the residue was taken up in MeOH and subjected to diethyl ether diffusion at 5 °C to obtain turquoise crystals (100 mg, 123 μmol, 84%) suitable for X-ray diffraction. HR-ESI MS (pos, MeOH): [CuII(bispa1a)]+, calcd 623.14358, obsd 623.14326. Elem anal. (report no. 34995). Calcd for [[CuII(bispa1a)](TFA)·1.5MeOH·1.5H2O]: C, 48.06; H, 4.84; N, 8.62. Obsd: C, 47.83; H, 4.62; N, 8.77. UV−vis−NIR (MeOH, rt): λ [nm] (ε [M−1 cm−1]) = 672 (93), 1284 (34). CV (DMF, rt): E1/2 = −1.02 V (vs fc/fc+). [ZnII(bispa1a)](TFA) (C31H30F3N5O9Zn, 738.98 g/mol). Solutions of Hbispa1a·TFA (100 mg, 150 μmol, 1.0 equiv) and Zn(OAc)2·2H2O (32.9 mg, 150 μmol, 1.0 equiv) each in 5 mL of MeOH were combined, and the solution was stirred overnight at rt. After evaporation of the solvent, the residue was taken up in MeOH and subjected to diethyl ether diffusion at 5 °C to obtain colorless crystals (100 mg, 147 μmol, 98%). Some of the crystals were redissolved in a mixture of MeOH and water (2:1), and colorless plates suitable for Xray diffraction were obtained by slow evaporation of the solvent mixture. 1H NMR (600.13 MHz, 22 °C, D2O): δ 2.22 (s, 3 H, N3CH3), 2.56 (d, 2JH,H = 12.9 Hz, 2 H, N7CH2ax,eq), 2.98 (d, 2JH,H = 12.9 Hz, 2 H, N7CH2ax,eq), 3.80 (s, 6 H, COOCH3), 4.01 (s, 2 H, N7CH2), 5.03 (s, 2 H, N3CH), 5.04 (s, 1 H, CHOH), 7.37−7.38 (m, 2 H, Hpy), 7.48−7.51 (m, 2 H, Hpy), 7.64 (d, 3JH,H = 7.8 Hz, 1 H, Hpy), 8.02−8.05 (m, 4 H, Hpy), 8.26 (d, 3JH,H = 7.8 Hz, 1 H, Hpy), 8.33 (d, 3 JH,H = 7.8 Hz, 1 H, Hpy). 13C NMR (150.92 MHz, 22 °C, D2O): δ 43.5, 50.3, 53.5, 61.6, 68.7, 68.8, 123.4, 124.9, 126.2, 126.3, 141.8, 142.8, 146.5, 148.5, 152.1, 153.6, 169.3, 171.3. HR-ESI MS (pos, MeOH): [ZnII(bispa1a)]+, calcd 624.14312, obsd 624.14336. Elem anal. (report no. 36296). Calcd for [[ZnII(bispa1a)](TFA)·2H2O]: C, 48.04; H, 4.42; N, 9.04. Obsd: C, 48.06; H, 4.25; N, 9.35. [GaIII(bispa1a)](TFA)(NO3) (C31H30F3GaN6O12, 805.33 g/mol). Solutions of Hbispa1a·TFA (100 mg, 148 μmol, 1.0 equiv) in 10 mL of a MeOH/water mixture (1:2) and Ga(NO3) (37.9 mg, 148 μmol, 1.0 equiv) in 5 mL of a MeOH/water mixture (1:2) were combined, and the pH was adjusted to 5 by the addition of 0.1 M NaOH. The solution was then stirred at 60 °C for 2 h, and after evaporation of the solvent, the residue was taken up in a mixture of MeOH and water (2:1). By slow evaporation of the solvent mixture, colorless crystals (83.0 mg, 96.6 μmol, 65%) suitable for X-ray diffraction could be obtained. 1H NMR (200.13 MHz, 27 °C, D2O): δ 2.67 (s, 3 H, N3CH3), 2.89 (d, 2JH,H = 13.7 Hz, 2 H, N7CH2ax,eq), 3.57 (d, 2JH,H = 13.7 Hz, 2 H, N7CH2ax,eq), 3.86 (s, 6 H, COOCH3), 4.60 (s, 2 H, N7CH2), 5.21 (s, 1 H, CHOH), 5.70 (s, 1 H, N3CH), 7.73−7.81 (m, 4 H, Hpy), 7.99 (d, 3JH,H = 5.3 Hz, 2 H, Hpy), 8.10 (dd, 3JH,H = 7.3 Hz, 4 JH,H = 1.3 Hz, 1 H, Hpy), 8.38 (td, 3JH,H = 7.8 Hz, 4JH,H = 1.5 Hz, 2 H, Hpy), 8.66−8.78 (m, 2 H, Hpy). 13C NMR (150.92 MHz, 22 °C, D2O): δ 44.4, 52.1, 52.1, 53.2, 54.1, 62.1, 67.3, 67.6, 125.1, 125.1, 125.8, 128.3, 128.3, 128.4, 142.9, 145.8, 147.4, 147.6, 148.7, 151.5, 151.6, 164.6, 168.7. HR-ESI MS (pos, MeOH): [GaIII(bispa1a)]2+, calcd 314.56950, obsd 314.56964; [Hbispa1a + H]+, calcd 562.22941, obsd 562.22962; [GaIII(bispa1a) − H]+, calcd 628.13173, obsd 628.13167. Elem anal (report no. 36368). Calcd for [[GaIII(bispa1a)](TFA)(NO3)·3H2O]: C, 43.33; H, 4.22; N, 9.78. Obsd: C, 43.33; H, 4.40; N, 9.71. [CoII(bispa1b)](TFA) (C31H30F3N5CoO9, 732.54 g/mol). Under an inert gas atmosphere, Hbispa1b·TFA (150 mg, 222 μmol, 1.0 equiv) was dissolved in 10 mL of MeOH. Co(OAc)2·4H2O (55.3 mg, 222 μmol, 1.0 equiv) was added, and the orange solution was stirred for 2 h at rt. After evaporation of the solvent, the residue was taken up in MeOH and subjected to diethyl ether diffusion at rt to obtain brown crystals (116 mg, 150 μmol, 67%). HR-ESI MS (pos, MeOH): [CoII(bispa1b)]+, calcd 619.14717, obsd 619.14728. Elem anal. (report no. 38723). Calcd for [[CoII(bispa1b)](TFA)·0.5H2O]: C, 50.54; H, 4.47; N, 9.36. Obsd: C, 50.40; H, 4.51; N, 9.53. UV−vis−NIR (DMSO, rt): λ [nm] (ε [M−1 cm−1]) = 475 (117), 516 (9), 544 (23), J


Inorganic Chemistry

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584 (7), 677 (6), 920 (6). CV (DMF, rt): E1/2 = −0.52, −2.09 V (vs fc/fc+). [NiII(bispa1b)](TFA) (C31H30F3N5NiO9, 732.30 g/mol). Solutions of Hbispa1b·TFA (100 mg, 148 μmol, 1.0 equiv) and Ni(OAc)2·4H2O (36.8 mg, 148 μmol, 1.0 equiv) each in 5 mL of MeOH were combined, and the brown solution was stirred for 2 h at rt. After evaporation of the solvent, the residue was taken up in MeOH and subjected to diethyl ether diffusion at 5 °C to obtain brown crystals (77.6 mg, 106 μmol, 72%). HR-ESI MS (pos, MeOH): [NiII(bispa1b)]+, calcd 618.14932, obsd 618.14908. Elem anal (report no. 37469). Calcd for [[NiII(bispa1b)](TFA)·0.5MeOH]: C, 50.56; H, 4.31; N, 9.36. Obsd: C, 50.43; H, 4.35; N, 9.47. UV−vis−NIR (MeOH, rt): λ [nm] (ε [M−1 cm−1]) = 512 (18), 796 (13), 877 (36). CV (DMF, rt): E1/2 = 0.71, −2.27 V irrev. (vs fc/fc+). [CuII(bispa1b)](TFA) (C31H30CuF3N5O9, 737.15 g/mol). Solutions of Hbispa1b·TFA (100 mg, 148 μmol, 1.0 equiv) and Cu(OAc)2·H2O (29.6 mg, 148 μmol, 1.0 equiv) each in 5 mL of MeOH were combined, and the blue solution was stirred for 2 h at rt. After evaporation of the solvent, the residue was taken up in MeOH and subjected to diethyl ether diffusion at 5 °C to obtain dark-blue crystals (100 mg, 123 μmol, 84%) suitable for X-ray diffraction. HR-ESI MS (pos, MeOH): [CuII(bispa1b)]+, calcd 623.14358, obsd 623.14372. Elem anal. (report no. 37467). Calcd for [[CuII(bispa1b)](TFA)· H2O]: C, 49.31; H, 4.27; N, 9.27. Obsd: C, 49.02; H, 4.43; N, 9.40. UV−vis−NIR (MeOH, rt): λ [nm] (ε [M−1 cm−1]) = 651 (78), 904 (18). CV (DMF, rt): E1/2 = −1.17 V (vs fc/fc+). [ZnII(bispa1b)](TFA) (C31H30F3N5O9Zn, 738.98 g/mol). Solutions of Hbispa1b·TFA (100 mg, 148 μmol, 1.0 equiv) and Zn(OAc)2·2H2O (32.5 mg, 148 μmol, 1.0 equiv) each in 5 mL of MeOH were combined, and the solution was stirred overnight at rt. After evaporation of the solvent, the residue was taken up in MeCN and subjected to diethyl ether diffusion at 5 °C to obtain colorless crystals (66.9 mg, 90.5 μmol, 61%). 1H NMR (600.13 MHz, 22 °C, D2O): δ 2.75 (d, 2JH,H = 13.3 Hz, 2 H, N7CH2ax,eq), 2.79 (s, 3 H, N7CH3), 3.04 (d, 2JH,H = 13.3 Hz, 2 H, N7CH2ax,eq), 3.70 (s, 6 H, COOCH3), 4.28 (s, 2 H, N3CH2), 5.08 (s, 1 H, CHOH), 5.29 (s, 2 H, N3CH), 6.98 (d, 3 JH,H = 7.8 Hz, 1 H, Hpy), 7.31 (dd, 3JH,H = 7.6 Hz, 3JH,H = 5.4 Hz, 2 H, Hpy), 7.37 (d, 3JH,H = 7.6 Hz, 2 H, Hpy), 7.65 (t, 3JH,H = 7.8 Hz, 1 H, Hpy), 7.74 (d, 3JH,H = 7.8 Hz, 1 H, Hpy), 7.81 (td, 3JH,H = 7.6 Hz, 4JH,H = 1.6 Hz, 2 H, Hpy), 8.33 (d, 3JH,H = 5.4 Hz, 2 H, Hpy). 13C NMR (150.92 MHz, 22 °C, D2O): δ 46.7, 52.5, 53.4, 53.9, 60.1, 68.9, 70.8, 122.5, 124.6, 125.2, 126.3, 140.7, 141.1, 143.3, 147.7, 149.7, 151.6, 170.1, 170.9. HR-ESI MS (pos, MeOH): [ZnII(bispa1b)]+, calcd 624.14312, obsd 624.14347. Elem anal. (report no. 3574). Calcd for [[ZnII(bispa1b)](TFA)·H2O·0.5MeCN]: C, 49.43; H, 4.34; N, 9.91. Obsd: C, 49.63; H, 4.00; N, 9.84. [GaIII(bispa1b)](NO3)2 (C29H30GaN7O13, 754.32 g/mol). Solutions of Hbispa1b·TFA (100 mg, 148 μmol, 1.0 equiv) in 5 mL of a MeOH/ water mixture (1:2) and Ga(NO3)·6H2O (37.9 mg, 148 μmol, 1.0 equiv) in 5 mL of a MeOH/water mixture (1:2) were combined, and the pH was adjusted to 5 by the addition of 0.1 M NaOH. The solution was then stirred at 60 °C for 3 h, and after evaporation of the solvent, the residue was taken up in MeOH and subjected to diethyl ether diffusion at 5 °C to obtain colorless crystals (62.6 mg, 83.0 μmol, 56%). 1H NMR (600.13 MHz, 22 °C, D2O): δ 3.05 (s, 3 H, N7CH3), 3.08 (d, 2JH,H = 14.1 Hz, 2 H, N7CH2ax,eq), 3.27 (d, 2JH,H = 14.1 Hz, 2 H, N7CH2ax,eq), 3.77 (s, 6 H, COOCH3), 4.95 (s, 2 H, N3CH2), 5.23 (s, 1 H, CHOH), 5.97 (s, 2 H, N3CH), 7.42 (d, 3JH,H = 7.9 Hz, 1 H, Hpy), 7.67−7.71 (m, 4 H, Hpy), 8.05 (t, 3JH,H = 7.9 Hz, 2 H, Hpy), 8.11 (d, 3JH,H = 7.9 Hz, 1 H, Hpy), 8.19 (td, 3JH,H = 8.0 Hz, 4JH,H = 1.2 Hz, 2 H, Hpy), 8.60 (d, 3JH,H = 5.3 Hz, 2 H, Hpy). 13C NMR (150.92 MHz, 22 °C, D2O): δ 46.7, 53.8, 53.8, 54.1, 62.1, 67.4, 70.1, 124.9, 126.3, 126.9, 128.9, 139.3, 144.9, 145.0, 146.2, 146.4, 147.9, 165.6, 168.5. Elem anal. (report no. 37566). Calcd for [[GaIII(bispa1b)](NO3)2· 2H2O]: C, 44.07; H, 4.34; N, 12.41. Obsd: C, 43.75; H, 4.23; N, 12.26.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.6b01787. CCDC 1481458−1481470 containing crystallographic data in CIF format (CIF) NMR, UV−vis−NIR, and EPR spectra (including spectra simulations), cyclic voltammograms, species distribution diagrams, details of the AOM analysis of the CuII complexes, and details of the X-ray crystal structure determinations, including structural plots of all complex cations and packing diagrams (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: +49-6221546617. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support by the Landesgraduiertenförderung, Heidelberg University, and Helmholtz Virtual Institute NanoTracking is gratefully acknowledged. C.O. sincerely thanks the Alexander von Humboldt Foundation for a Research Award and the Canada Council for the Arts for a Killam Research Fellowship (2011−2013). We also thank Miriam Knopf and Maren Haas for experimental assistance.

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REFERENCES

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Inorganic Chemistry

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