Synthesis and Characterization of Acyclic and Cyclic Aza-bridged Ligands Incorporating 2,2'-Bipyridine Subunits and Their Complexes With Copper(II), Cobalt(II), and Nickel(II)

The synthesis of a series of N,N'-disubstituted acyclic (AL) and cyclic (CL) aza-bridged ligands incorporating 2,2-pipryidine subunits is described. 1H-NMR and IR spectral data support the proposed ligand structures. Dynamic 1H-NMR studies on diurea and diamide derivatives point to the presence of slowly interconverting conformers on the 1H-NMR time-scale, owing to N−H···N hydrogen bonding and/or a restricted rotation around the amide bonds. The ligands synthesized form 1:1 complexes with divalent transition metal ions. Upon complexation, bis-ester derivatives AL5 and CL5 undergo a metal-induced hydrolysis of the ester groups to carboxyl functions, which act as additional binding sites for the metal ion, as well as hydrogen-bonding donor-acceptor binding site to produce dimeric complexes.


Introduction
Although 2,2'-bipyridine has been used as a classic bidentate ligand for over a century, only in the last two decades has this subunit been widely employed in the design of photoactive cryptands [1], polyfunctionalized ligands [2], dendrimers and star-like macromolecules [3]. In view of the potential offered by polymer-bound bipyridines and their transition-metal complexes in analytical chemistry [4] and in photochemical processes [5], we became interested in the synthesis of a variety of rigid and flexible polyamides and polyurethanes incorporating acyclic (AL 1 , Acyclic Ligand) and cyclic (CL 1 , Cyclic Ligand) bipyridinediyl diamino subunits (complexing building blocks) within the polymeric backbone [6,7]. These materials were shown to form polynuclear complexes with the first-row transition metals [6].
Current interest in macromolecular complexes bearing bipyridine chelating units [8] prompted us to design a number of acyclic and cyclic polypyridine ligands, to be exploited as model ligands for a better understanding of the coordination properties of related macromolecular systems. In this paper we wish to report the synthesis, structural characterization and fluxional properties of the ligands AL 2-5 and CL 2-5 shown in Scheme 1, as well as the preparation and characterization of their complexes with divalent transition metals Cu(II), Co(II), and Ni(II).

Results and Discussion
Ligands AL 1, 3 and CL 1, 3 were synthetized by literature procedures [2,6,9]. N,N'-Diacetyl and bisurea derivatives AL 2 , CL 2 and AL 4 , CL 4 were prepared by reaction of the appropriate acyclic or cyclic bis-amine with Ac 2 O/Et 3 N or phenyl isocyanate, respectively, in anhydrous CHCl 3 at room temperature (r.t.). Bis-esters AL 5 and CL 5 were produced in good yield by N-alkylation of the parent diamines with t-butyl bromoacetate/K 2 CO 3 in dry CH 3 CN. The structural characterization of all new compounds was accomplished by elemental analysis, FAB (+) MS measurements, and 1 H-NMR spectroscopy. The 1 H-NMR spectral data for acyclic and cyclic ligands are reported in Tables I and II, respectively. The 1 H-NMR spectra of acyclic bis-amide ligands AL 2,3 (not shown) are quite complex, and can be interpreted in terms of two overlapping sets of signals, arising from a mixture of rotamers in slow equilibrium on the 1 H-NMR time-scale, due to the restricted rotation around the amide bonds. In both compounds the ratio between the two rotamers at 293 K in chlorinated solvents is about 3:2, as it can be deduced by integration of the pair of methyl singlets in AL 2 and of the pair of H 6 doublets in AL 3 . Dynamic NMR studies on AL 3 have shown that, upon heating a TCE solution of the ligand, broadening of most signals occurred, with a coalescence temperature at about 340 K, followed by sharpening at more elevated temperatures, corresponding to the free rotation of the benzoyl groups. Well resolved spectra were obtained at temperatures as high as 373 K, showing the characteristic three-spin system for the bipyridyl unit, and four-spin system for a 2-substituted pyridyl ring. From the dynamic parameters a ∆G = 17.2 Kcal/mol was ascertained for the torsional energy of the amide bond. "" In spite of the presence of two ureido moieties, the r.t. 1 H-NMR spectrum of acyclic diurea AL 4 in TCE displays sharp resonances for both aromatic and methylene protons, due to the locking of rotamers by the formation of intramolecular hydrogen bonding between the N-H proton and the juxtaposed pyridine ring nitrogen (Scheme 2), as suggested by the broad downfield resonance of the N-H groups at δ 9.97 ppm. As expected, N-alkylated diester AL 5 is a flexible molecule and, due to partial overlapping of the heteroaromatic protons, decoupling experiments were used for proton assignments. Noteworthy, the H 3 bipyridyl protons of AL 2-5 resonate in the range 8.45−8.25 ppm, a region considered of diagnostic value for an anti orientation of the bipyridyl unit [10]. The 293 K 1 H-NMR spectrum (CDCl 3 ) of CL 2 ( Figure 1) shows two singlets for the methyl groups, one broad and two sharp singlets for the bridging methylenes, and two sets of well-resolved resonances for the bipyridyl protons, spread out in the 6.5-7.7 ppm region. These spectral data may be suggestive of the presence of two slowly interconverting diastereomeric forms of CL 2 (in a ratio of ca. 3:2). Each of the two conformers features two pairs of pyridyl subunits in different magnetic environments, resulting in a total of four double doublets for H 3 and H 5 protons, and four triplets for H 4 protons (Table II and Figure 1).
Interconversion between the two forms may be realized by rotation of the acetyl group(s) around the amide bond(s). In order to measure the energy barrier associated with this process, a VT NMR study of CL 2 was undertaken, using deuterated TCE as a solvent, with the results shown in Figure 1. On raising the temperature, broadening of the signals was observed above 340 K, and coalescence occurred at about 373 K. At 403 K the signals of methylene and H 3 protons show up as a sharp singlet and a doublet, respectively, while H 4 protons appear as a broad triplet and H 5 protons are still broad.
Higher temperatures were precluded by the solvent used. From the dynamic parameters a ∆G = 19.0 kcal/mol was ascertained for conformational transitions.

* Residual solvent peaks
The room temperature 1 H-NMR spectrum of CL 3 is very broad in every region, again suggesting the presence of at least two conformers slowly interconverting on the 1 H-NMR scale. The methylene protons show up as two humps, which upon heating coalesce to a singlet at temperatures above 333 K, with simultaneous sharpening of the signals in the aromatic region. At 403 K (Table II) average signals are obtained, and the spectrum consists of a singlet at δ 4.96 ppm for the α and γ bridging methylenes, a broad doublet at δ 7.13 ppm for H 5 , a triplet at δ 7.39 for H 4 , a double doublet at δ 7.65 for H 3 , and two complex multiplets in a 3:2 ratio for the benzoyl protons, centered at δ 7.46 and 7.80 ppm, respectively. Unfortunately, the sparing solubility of the compound did not allow us to explore its behaviour at low temperatures.
The 1 H-NMR spectra of cyclic diurea CL 4 are also temperature dependent, and the results of its dynamic behaviour are shown in Figure 2. At 253 K the methylene protons show a pattern of three doublets at δ 4.12, 5.21 and 5.74 ppm (ratio 2:1:1), while the aromatic protons are ill-defined, owing to a considerable overlapping. Upon raising the temperature, the two downfield methylene doublets broaden and coalesce at about 313 K, with contemporary sharpening of a set of aromatic protons (assignable to the two phenyl groups) and broadening of the remaining bipyridyl protons (multiplets centered at δ 6.62 and 7.6 ppm in the low temperature spectrum). At higher temperatures further broadening of the upfield methylene doublet and, concomitantly, of bipyridyl protons is observed. The two methylene humps coalesce to a broad singlet at temperatures above 373 K, and at 403 K the proton spectrum appears averaged by a fast motion of the molecule giving the complete equivalence of pertinent aromatic and methylene protons. The VT 1 H-NMR studies of CL 4 showed therefore two coalescence temperatures at 313 and 373 K, corresponding to conformational transitions with free energy barriers of 11.9 and 13.5 Kcal/mol, respectively. The first transition is likely associated with the breaking of intramolecular N-H!!!N hydrogen bondings, while the second one is related to the torsional barrier around PhNHC(O)−N bonds.
Owing to the low solubility of AL 3 and CL 3 , the very similar AL 2 and CL 2 ligands were synthesized only in order to better understand the influence of the amido moiety on the conformational aspects.
As a general feature, the IR spectra of all acyclic or cyclic ligands show a 1600-1395 cm -1 region dominated by strong or medium-strong absorption bands associated with the stretching vibrational modes of heterocyclic rings [10,11]. In addition, bis-amide ligands AL 2 , 3 and CL 2 , 3 display prominent carbonyl bands at 1650-1630 cm -1 , a frequency considered of diagnostic value for tertiary amides [12], while bis-urea derivatives AL 4 and CL 4 exhibit N-H stretching bands at 3280-3320 cm -1 , a carbonyl absorption band, known as the Amide I band [6], at 1640-1670 cm -1 , and a N-H band, known as Amide II band [6], at 1525-1540 cm -1 . On the other hand, bis-ester ligands AL 5 and CL 5 show a C=O stretching band at 1740-1700 cm -1 along with CC(=O)−O stretching vibration and O−C−C asymmetric stretching bands at 1270 and 1163 cm -1 , respectively. Well resolved absorption bands are also present at lower frequencies, which can be ascribed to the in-plane and out-of-plane ring deformations [11,12].
The Cu(II), Co(II), and Ni(II) complexes with the new acyclic and cyclic ligands were prepared by reacting each ligand with the appropriate metal nitrate salt (1 equiv) in aqueous MeOH at room temperature. It is noteworthy that the synthesis of complex CL 4 a was carried out at reflux. Table III shows the physicochemical characteristics of the synthesized complexes. Complexes AL 3 a-c and CL 3 a were prepared according to literature data [5] (the lettering a, b, and c refers to Cu(II), Co(II), and Ni(II) complexes, respectively).  The acyclic ligands AL 3-5 generally give stable 1:1 complexes with all the transition metals examined. Conversely, cyclic ligands CL 3,4 exhibit the unique property to specifically complex Cu(II) in the 1:1 ratio even in presence of sizeable amounts of Co(II) and Ni(II). The stoichiometry of the complexes was ascertained by microanalytical data [elemental analysis (EA) and atomic absorption (AA)] and confirmed by FAB MS spectrometry.
The IR spectra of the complexes are quite different from those of the free ligands, and give useful information on the possible binding sites involved in the coordination, according to the shift of the signals with respect to those of the free ligands, the most dramatic changes being observed in the 1600-1350 cm -1 region . As a common feature, all the complexes examined display a very strong frequency band at 1385 cm -1 , indicating the participation of the nitrogens of at least one bipyridyl moiety in the complex formation. For the complexes of AL 3 , AL 4 , and AL 5 , the carbonyl groups are undoubtedly involved in the complexation, as evidenced by a large shift (∆ν= 55-60 cm -1 ) of the carbonyl absorption to lower frequencies [13]. In the case of complexes CL 3 a and CL 4 a, the C=O stretching (Amide I band at 1631 and 1665 cm -1 , respectively) does not seem to be shifted as compared to the free ligands, indicating that it is not a binding site. On the other hand, for CL 4 a we observe a ∆ν = 11 cm -1 for the -NH stretching and a ∆ν = 22 cm -1 for the -NH bending of the urea nitrogens, suggesting that they act as binding sites.
The synthesis of the complexes AL 5 a-c was plagued by the competitive formation of a coloured side-product, obtained as a powder sparingly soluble in the reaction medium. These powders, also insoluble in CH 2 Cl 2 , were identified as dimeric complexes (AL 6 a-c) formed by a new ligand (AL 6 , R = COOH; Scheme 1), arising from a metal-induced hydrolysis of the ester functions [14].
The IR data of these complexes show: (i) a very intense and broad O-H stretching band at 3380 cm -1 , (ii) two C-H stretching bands at 2930-2985 cm -1 , (iii) a C=O stretching band at 1680 cm -1 indicative of the presence of a free carboxylate anion, (iv) the lack of bands in the region 1750-1700 cm -1 (i.e. no resonance of the C=O group acting as binding site). These data may be consistent with a dimeric structure for these complexes composed of two monomeric subunits held together by a C(=O)O¯···HOC(=O) hydrogen bond [supported by microanalytical data, and FAB-MS measurements]. Each monomer is mononuclear, probably adopting an octahedral geometry around the complexed ion, with bipyridine nitrogens and the β bridged nitrogens forming a square plane, while the pyridine nitrogens occupy the axial positions. The general formula of these complexes can be written as [Me 2 (AL 6 ) 2 H](NO 3 ) 3 ·xH 2 O being Me = Cu(II), Co(II), Ni(II) ( Table III).
A similar behaviour was observed by reacting the ligand CL 5 with the metal nitrate salts. This cyclic ligand is not able to coordinate any metal by itself, as AL 5 do, but, also in this case, owing to the hydrolysis of the ester groups a new ligand CL 6 (R = COOH; Scheme 1) was obtained that uses its two -COOgroups in two different ways: one as binding site for the metal, the other one to link, through a hydrogen bond, another similar structure. As a matter of fact the IR data of the complexes CL 6 a-c show, inter alia, a resonance at ν = 1665 cm -1 due to C=O group indicating a dimeric form via an intermolecular hydrogen bonding between two mononuclear complexes, and a resonance at ν = 1626 cm -1 that can be attributed to the asymmetrical stretching of the carboxylate anion that acts as binding site. complexes held together by a hydrogen bond forming between the carboxylate unit of one moiety and the carboxylic functionality of the other, as depicted in Figure 3.
Splitting of the dimers produces prominent peaks at m/z 572, 568 and 567, respectively, corresponding to [CL 6 Me -H] + ions, which represent the base peak in the spectra of complexes CL 6 b,c. In the case of CL 6 a the base peak is found at m/z 573 ([CL 6 Me] + ). Of note is the fact that no multicharged ion peaks could be detected in the FAB spectra of the complexes investigated. The observed isotopic patterns of all ion peaks are in good agreement with the calculated ones. The FAB spectrum of CL 6 b is shown in Figure 4.
In Table III thermal gravimetric analysis (TGA) data of the synthesized complexes are reported. All complexes show a first degradation step, in the 40-50 °C range, corresponding to the loss of water/solvent molecules. AL 3 a-c complexes show a second degradation step in the 100-110 °C range, that can be easily attributed to the loss of bound water ligand. The complexes with the acyclic ligands show, as expected, a decomposition temperature lower than that of the cyclic ones. Comparing the IR, FAB, and TGA data of the complexes bearing cyclic units to those of acyclic ones, we observe that the binding sites are different owing to the rigidity of cyclic structures that influence the complexing properties of the correspective free ligands. It is known that the free bipyridyl moiety assumes an anti configuration that changes to syn when it works as bidentate binding site [15].
If this behaviour is easily hypothesized for the flexible acyclic ligand series, it may not be true for the cyclic one, because both bipyridyl units should assume the more favorable syn orientation for the complexation. This is why the CL 3 and CL 4 cyclic ligands are able to complex only the Cu(II) cation even if Co(II) or Ni(II) cations are present, due to the fact that the latter prefer an octahedral geometry that cannot be meet with the rigid cyclic ligands; on the contrary the Cu(II) can be complexed owing to its ductility to assume different geometries. It is noteworthy that the cyclic ligand CL 6 (arising from the hydrolysis of CL 5 ) does not show any particular selectivity for the cations under study, probably due to its flexibility and to the presence of the -COOH groups that, working as binding sites, meet the Co(II) and Ni(II) geometric needs, unlike the rigid amido and ureido moieties present in CL 3 and CL 4 , respectively.

Conclusions
Following our interest in macromolecular complexes bearing bipyridine chelating units, we have synthesized a series of N,N'-disubstituted acyclic (AL) and cyclic (CL) ligands, which can be viewed as model compounds for the related polymers, along with their complexes with Cu(II), Co(II), and Ni(II) transition metal ions. Dynamic 1 H-NMR studies on diurea and diamide derivatives point to the presence of slowly interconverting conformers on the 1 H-NMR time-scale. The complexing behaviour of the acyclic ligands was found to be different with respect to the cyclic ones. The former, following an easy anti to syn reorganization of the bipyridyl unit, give stable 1:1 complexes, while the latter, owing to their rigidity, show the unique property of recognising and binding copper(II) ion even in the presence of cobalt(II) and nickel(II) ions. A metal catalyzed hydrolysis of the ester groups was also observed, leading to the formation of dimeric structures linked by intermolecular hydrogen bonds.
Tables II and III. FAB (+) MS spectra were taken on a Kratos MS 50 S double-focusing mass spectrometer equipped with a standard FAB source, using 3-nitrobenzyl alcohol as a matrix. IR spectra (KBr disks) were recorded on a Perkin Elmer 684 Infrared Spectrophotometer. AA measurements were obtained on a Perkin Elmer AAnalyst 300. The appropriate amount of the considered complex was destroyed with conc. HNO 3 (50 mL) and then diluted to 1 L with distilled water. Metal concentrations of such solutions were measured with a multielement hollow cathod lamp, by an oxidizing airacetylene flame. Two standard solutions (concentrations of 0.5 and 1 ppm, respectively) were prepared for each metal by dissolving the metal compound (BDH Chemical Ltd. Laboratory Reagent Standards) in diluted HNO 3 . Thermogravimetry was performed under nitrogen employing a Mettler TA 3000 thermogravimetric analyzer coupled with a Mettler TC 10 A processor at a heating rate of 10 °C/min. A chilled solution of diamine AL 1 (59 mg, 0.15 mmol), Ac 2 O (31 mg, 0.3 mmol) and Et 3 N (0.3 mL) in dry CHCl 3 (2 mL) was stirred for 3 h. After quenching with water (1 mL), the reaction mixture was extracted with CHCl 3 , washed with water and dried (MgSO 4 ). The solvent was evaporated to give an oily residue, which was subjected to column chromatography (neutral alumina, eluent: 3:1cyclohexane-AcOEt), to afford diamide AL 2 (53 mg, 85%) as white prisms, m.p. 129-130 °C To a vigorously stirred and ice-chilled solution of diamine AL 1 (0.89 g, 2.25 mmol) in dry CHCl 3 (10 mL) was added dropwise a solution of phenyl isocyanate (0.54 g, 4.5 mmol) in dry CHCl 3 (5 mL). The mixture was allowed to stir at rt for 24 h. After evaporation of the solvent, the residue was dissolved in CH 2 Cl 2 and purified by column chromatography (neutral alumina, cyclohexane-AcOEt 1:1 as an eluent) to give AL 4 (1.07 g, 75%) as white crystals, m.p. 160-161 °C (cyclohexane-AcOEt); FAB (+) MS, m/z 635 [MH]