Pt(II) and Pd(II) Complexes with β-Alanine

A sequence of stages in the syntheses of isomeric bisamino acid complexes of Pt(II) with β-aminopropionic acid (β-alanine = β-AlaH) has been studied by the 195Pt NMR spectroscopy. The techniques have been developed of the synthesis of the cis- and trans-bischelates of Pt(II) and Pd(II) with β-alanine as well as of the halide complexes of trans-[M(β-AlaH)2Cl2] (M = Pt, Pd) and trans-K2[Pt(β-Ala)2I2] types. The NMR spectroscopy and IR spectroscopy (in the nuclei of 195Pt,13C,1H) and X-ray diffraction analysis have been used to examine the structures of the synthesized compounds.


Synthesis of the trans-[Pd(β-AlaH) 2 Cl 2 ] complex
0.887 g (5 mmol) of PdCl 2 and 0.585 g (10 mmol) of NaCl were dissolved in 20 mL of water and heated in the water bath until the dilution of PdCl 2 . A solution containing 1.78 g (20 mmol) of β-AlaH and 0.800 g (20 mmol) of NaOH in 20 mL of H 2 O was added to the solution of K 2 [PdCl 4 ]. After cooling the solution as low as 0 • C, 10 mL of concentrated HCl was added to the reaction mixture. The orange precipitate fell out, which was filtered off in an hour, washed with cold water, and dried at room temperature. The yield was up to 85%.

Synthesis of the trans-[Pd(β-Ala) 2 ] complex
1.0 g of the trans-[Pd(β-AlaH) 2 Cl 2 ] was dissolved in 10 mL of water then the reaction mixture was treated with 1 M of NaOH till it became neutral to phenolphthaleine. A light yellow precipitate fell out, which was filtered off and washed with cold water. At first it was dried at room temperature and then at 110 • C. The yield was up to 76%.

Synthesis of the cis-[Pd(β-Ala) 2 ] complex
0.5 g of the trans-[Pd(β-Ala) 2 ] was dissolved in 20 mL of water. The reaction mixture was heated with stirring at 80 • C for 3 hours. After cooling the reaction mixture as low as 0 • C, a small amount of the starting trans-bischelate was filtered off. Then the cis-[Pd(β-Ala) 2 ] was settled with acetone from the filtrate solution (water : acetone ∼ 1 : 4) and was filtered off. The solid cis-[Pd(β-Ala) 2 ] was dried at room temperature at first and then at 110 • C. The yield was up to 60%.

Synthesis of the cis-[Pt(β-Ala) 2 ] complex
3.32 g (20 mmol) of KI in 25 mL of water was added to 2.08 g (5 mmol) of K 2 [PtCl 4 ] in 25 mL of water. The reaction mixture was heated in the water bath for 10 minutes. A solution of β-AlaH (0.89 g, 10 mmol) in water (25 mL) was added to the reaction mixture, which was heated in the water bath for 2 hours. While heating the reaction mixture, 10 mL of 0.5 M of KOH was added by small portions. Then a small amount of black precipitate was filtered off. The solution of AgNO 3 (3.40 g, 20 mmol) in water (25 mL) was added to the orange solution of the filtrate obtained, and the mixture was heated for ∼5 minutes. The coagulated AgI precipitate was filtered off. The reaction product was precipitated with acetone (∼100 mL) from the filtrate (V ∼50 mL). The yield was up to 20%.

Measurements
NMR spectra were recorded using a Bruker DPX-250 spectrometer at the frequencies of 250 ( 1 H), 62.9 ( 13 C), and 53.6 ( 195 Pt) MHz. Two solvents, D 2 O and acetone-d 6 , were used for the 1 H NMR spectrum: (a) in the D 2 O solution, the chemical shifts were determined with reference to the signal of the CH 3 -group protons of the DMSO, which was added as an internal standard (δ = 2.660 ppm); (b) in the acetone-d 6 solution, the chemical shifts were determined with reference to the central signal of the acetone residual protons (δ = 2.070 ppm). For the 13 C NMR spectrum the same solvents, D 2 O and acetone-d 6 , were used: (a) in the D 2 O solution the chemical shifts were determined with reference to the 13 C signal of the DMSO, which was added as an internal standard (δ = 40.2 ppm); (b) in the acetone-d 6 solution the chemical shifts were determined with reference to the signal of the methyl carbon atom of acetone-d 6 (δ = 29.2 ppm). The chemical shift of the 195 Pt NMR signals was recorded with regard to the external standard, that is, 1 M of the Na 2 [PtCl 6 ] water solution. All measurements were performed at room temperature. The 195 Pt and 13 C NMR spectra were recorded using proton decoupling.
The IR spectra of crystalline samples packed in the KBr pellets were measured using a Bruker Vector-22 one-beam FT spectrophotometer.
X-ray diffraction analysis. Single-crystal data were collected on a SMART APEX CCD (Bruker AXS) diffractometer (Mo Kα, λ = 0.71073Å, T = 298 K, an absorption correction applied using the Bruker SADABS program, version 2.10). The structures were solved by the direct methods and refined by the full-matrix least squares in an anisotropic approximation for all nonhydrogen atoms. The H atoms were located in difference electron density syntheses and refined together with nonhydrogen atoms in an isotropic approximation. All calculations on the structure solution and refinement were carried out with the Bruker Shelxtl Version 6.14 software.

Synthesis of the Pt(II) trans-isomers (Scheme 1)
The solutions of β-AlaH neutralized with an alkali and K 2 [PtCl 4 ] were used as the reagents for the synthesis of transisomers. The molar ratio of the reagents K 2 [PtCl 4 ] : β-AlaH : KOH was as follows 1 : 4.5 : 2. The structures of complexes were detected by the 195 Pt NMR spectroscopy at each stage of the synthesis.
According to the data of [9], the first stage of the synthesis is heating of the reaction mixture for 5 hours. We have shown that after heating the aqueous solution of K 2 [PtCl 4 ] with the neutralized β-AlaH for 2 hours, the reaction mixture does not contain the starting reagents. Instead, it contains three forms (I, II, and III) of the Pt(II) complexes (Scheme 1), complex II being predominant (∼80%). The signal assignment in the 195 Pt NMR spectra was carried out using the data of [12].

Bioinorganic Chemistry and Applications
The second stage comprises the interaction of complexes with HCl. Just after the addition of HCl to the reaction mixture, it is detected that the solution contains complexes IV, V, and VI, complex V prevailing (∼75%).
Complex IV is formed from complex I as a result of the ring opening and the insertion of Cl − ions at the site of cleavage of the Pt-OCO bond. Complex V is formed from complex II via the ring opening and the insertion of the Cl − ion. Complex VI is formed from complex III via the protonation of the β-alaninate ions of complex III. The subsequent heating of the reaction mixture in the water bath for ∼20 minutes only results in one complex (complex IV) in the solution. During this period, complex VI converts into complex V, while complex V transforms into the trans-dichloride IV due to the replacement of β-AlaH with the Cl − ion on the coordinate Cl-Pt-β-AlaH. The given replacement takes place in accordance with the kinetic effect of the trans-influence of ligands. That is, the transeffect of Cl exceeds that of the NH 2 , the group of β-alanine [13].
At the next stage, the yellow precipitate of the trans-[Pt(β-AlaH) 2 Cl 2 ](IV) gradually settles from the solution. The titration of complex IV with the KOH solution leads to the formation of yellow K 2 [Pt(β-Ala) 2 Cl 2 ] solution, which is then heated to form a white precipitate of trans-[Pt(β-Ala) 2 ](I).

Synthesis of trans-isomers of the Pd(II) complexes
The problems of isolation of the individual geometrical isomers of the Pd(II) bisaminoacid complexes with α-amino acids are related to the trans-cis isomerization processes. For the first time we described these processes for Pd(II) bischelates with glycine and α-alanine in [5,14].
The decrease of temperature from 100 • C to 0 • C at the appropriate stages of the synthesis rules out the isomerization processes and allows us to use the same approaches to the synthesis of the Pd(II) complexes as is the case with the Pt(II) complexes.
The interaction of Na 2 [PdCl 4 ] with the neutralized β-AlaH in an aqueous solution is likely to result in the formation of complexes similar to the complexes I, II, and III (Scheme 1). The treatment with HCl conc leads to the trans-[Pd(β-AlaH) 2 Cl 2 ] as the only product. The formation of a trans-isomer as the only product is possible due to the kinetic effect of the trans-influence of ligands as is the case with the Pt complexes [13].
The titration of the trans-[Pd(β-AlaH) 2 Cl 2 ] with an alkaline solution leads to the ring closure and the formation of the trans-[Pd(β-Ala) 2 ]. The ring closure reaction was conducted at room temperature because the trans-bischelate product precipitated immediately. As the cis-bischelate readily dissolves in water, it cannot be present in the solid precipitate of the trans-[Pd(β-Ala) 2 ] as an impurity.
The treatment of the trans-[Pd(β-Ala) 2 ] with HCl at ∼0 • C leads to the opening of amino acid cycles and the formation of the trans-[Pd(β-AlaH) 2 Cl 2 ].

Synthesis of the cis-[Pd(β-Ala) 2 ] complex
Due to its high solubility in water, the cis-[Pd(β-Ala) 2 ] complex can hardly be isolated as a solid. That is why the procedures that we have developed for the synthesis of the Pd(II) cis-bischelates with valine [15] are not applicable for the preparation of the solid cis-[Pd(β-Ala) 2 ] phase. The kinetic and thermodynamic data for the trans-cis isomerization of the Pd(II) bischelates with valine are reported in [15]. It can be supposed that the equilibrium and rate constants of the isomerization reaction are almost similar for the bischelates where amino acids are bonded to Pd(II) via the NH 2 or OCO groups. Thus for the synthesis of the cis-[Pd(β-Ala) 2 ], we have used the kinetic and thermodynamic data of [15].
The trans-[Pd(β-Ala) 2 ] was heated with water at 80 • C until the starting precipitate was completely diluted. The trans-isomer isomerized, and the cis-isomer stayed in solution. At 80 • C the equilibrium constant of the trans-cis process was lower than at low temperatures because the reaction is exothermal (see [15]). So the reaction mixture was abruptly cooled to ∼0 • C in order to increase the concentration of the cis-bischelate. Moreover after cooling, the starting trans-bischelate, which did not isomerize, precipitated and was filtered off. The solid cis-[Pd(β-Ala) 2 ] was settled with acetone from the aqueous filtrate solution.
The treatment of the cis-[Pd(β-Ala) 2 ] with HCl did not allow us to form the cis-[Pd(β-AlaH) 2 Cl 2 ] as is the case with the trans-isomers. Even a highly diluted solution of HCl resulted not only in the opening of the amino acid cycles, but also in completing the substitution of the amino acid ligands and the formation of PdCI 4 2− . Similar processes were observed for the Pd(II) complexes with valine [15] and for the Pd(II) complexes with aminobutyric acid [16].

Synthesis of the cis-isomers of the Pt(II) complexes (Scheme 2)
For the synthesis of the cis-bischelate, we have used K 2 [PtI 4 ], which is formed by the reaction of K 2 [PtCl 4 ] with KI. We supposed that the heating of K 2 [PtI 4 ] with β-AlaH at pH ∼6-7 (pH was kept at this level by adding KOH) led to the formation of cis-K 2 [Pt(β-Ala) 2 I 2 ]. The formation of the cis-isomer was expected to be in agreement with the kinetic effect of the trans-influence (TI) of the ligands (TI (I − ) TI(NH 2 )).
Further heating of the cis-K 2 [Pt(β-Ala) 2 I 2 ] does not lead to the ring closure as is the case with the trans-dichlorides. Instead, it leads to the isomerization of the cis-K 2 [Pt(β-Ala) 2 I 2 ] and the formation of the trans-K 2 [Pt(β-Ala) 2 I 2 ]. After heating for 10 hours, the solution only contains one form of δ( 195 Pt) = −3408 ppm. This new form was isolated as a single crystal and identified by the X-ray diffraction analysis, which confirmed that it was the trans-K 2 [Pt(β-Ala) 2   In addition to the main product, the cis-[Pt(β-Ala) 2 ], the solution contained KCl and KNO 3 . We added acetone to the reaction mixture (water : acetone ∼ 1 : 2) to separate the desired product from inorganic salts. Cis-[Pt(β-Ala) 2 ] was the only substrate that precipitated under such conditions. PMR spectra (Table 1) The PMR spectrum of β-AlaH (Figure 1(a)) in D 2 O contains two triplets of two CH 2 groups. The spectrum corresponds to an A 2 X 2 four-spin system with magnetically equivalent protons in each CH 2 group [17, page 54]. Figure 1 shows that the coordinate β-alanine (spectra b, c, and d) has a more complex spectrum than the incoordinate β-alanine (spectrum a) in the region of CH 2 protons. The spectrum contains more lines, and their intensities are distorted. This indicates that the protons of both CH 2 groups are magnetically nonequivalent. Therefore, these spectra cannot be interpreted using first order rules [17, page 57].
It should be noted that the spectrum of the trans-[Pd(β-AlaH) 2 Cl 2 ] is similar to that of the trans-[Pt(β-AlaH) 2 Cl 2 ]. For both spectra (Figure 1(b)), it is impossible to evaluate the chemical shifts of the individual CH 2 groups from the spectra. In order to do that we should employ a sixspin system of AA BB X 2 type, where AA and BB are magnetically nonequivalent protons of the two CH 2 groups, and X 2 are magnetically equivalent NH 2 protons. In this system, the protons of the CH 2 group, which is related to NH 2 group, are additionally split at the NH 2 protons. After the suppression of interaction with the NH 2 protons, the PMR spectrum (Figure 1(c)) corresponds to an AA BB fourspin system, is symmetric, and allows us to estimate the chemical shifts of the CH 2 groups on the center of each multiplet [   The spectrum of the cis-[Pt(β-Ala) 2 ] also shows that the weak-field signal of the CH 2 group combined with the NH 2 group is split at 195 Pt (broadened doublet).
It should be noted that for the Pt and Pd cis-bischelates we succeeded in recording the signals of the NH 2 protons in D 2 O because the NH 2 protons are deuterated in the transbischelates faster than in the cis-bischelates. 195 Pt NMR spectra (Table 1) The 195 Pt signal in the spectrum of the trans-[Pt(β-AlaH) 2 Cl 2 ] is found in the region of δ ∼ −2200 ppm, as is the case with the other similar compounds with α-amino acids. The difference between the chemical shifts of the cis-and trans-bischelate complexes is up to 200 ppm, the signals of the trans-bischelates lying in a weaker field. Such differences are also observed for the bischelates with α-amino acids [18].   (15) 1.249 (7) 1.255 (7) 1.308 (13) 1.186(14) 1.281(10) 1.221 (11) 1.259 (14) 1.252 (14) 1.317 (13) (14) It should be noted that the signals of cis-and transbischelates with β-alanine lie in a stronger field compared to the signals of similar α-amino acid complexes, the difference being up to 60-70 ppm. 13 C NMR spectra (Table 1) The spectrum of the trans-[Pt(β-Ala) 2 ] could not be recorded because of the very low solubility of this compound in water. Table 1 shows that the 13 C signals of the protonated COOH group in the trans-[M(β-AlaH) 2 Cl 2 ] (M = Pt, Pd) lie in a stronger field than the signals of the coordinate COO groups in the cis-and trans-bischelate complexes of Pt(II) and Pd(II).

IR spectra (Table 2)
As is known, for free amino acids, which exist as bipolar NH 3 + CH(R)COO − ions, there is a broad band of up to 3400 cm −1 in the region of the N = H ( ν (NH)) stretching vibrations, while the C = O ( ν (CO)) stretching vibrations display in the region of 1600 cm −1 .
For the coordinated α-amino acids in the Pt(II) and Pd(II) bischelate complexes, the ν (CO) is recorded in the region of 1650 cm −1 , while the ν (NH) is found at 3200 cm −1 . For example, for the Pt(II) trans-bischelate with glycine, the ν (CO) is equal to 1643 cm −1 , and the ν (NH) is equal to 3230 and 3090 cm −1 . For the similar Pd(II) complex, the ν (CO) equals 1642 cm −1 , and the ν (NH) equals 3230 and 3120 cm −1 [19].
For all complexes presented in this work, the split lines of NH antisymmetric stretching vibrations in the region of ∼3200 cm −1 were found as well as NH symmetric stretching vibrations at ∼3100 cm −1 , that correspond to the coordinated NH 2 group.
In the region of the C = O stretching vibrations for the Pt(II) and Pd(II) bischelates, the ν (CO) is in the range of 1617-1640 cm −1 , which shows that the OCO group is coordinate.
For the trans-K 2 [Pt(β-Ala) 2 I 2 ] complex with the incoordinate COO group, the ν (CO) is equal to 1602 cm −1 , as is the case with free amino acids.

X-ray diffraction data (Table 3)
In the trans-[Pd(β-Ala) 2 ] centrosymmetric molecule (Figure 2(a)), the Pd-O and Pd-N distances are 2.004 and 2.026Å. The deviations of atoms from the plane of the chelate ring may be as high as 0.88Å(for α-C). The chelate angle is 94.35 • , which corresponds to the transannular distance O· · · N 2.958Å. The hydrogen bonds between the NH 2 groups and the incoordinate atoms of carboxyl O groups link the molecules into a framework (Figure 2(b)).
In the structure of the trans-[Pt(β-Ala) 2 ], both of the crystallographically independent molecules are also centrosymmetric. The Pt(II) atom is surrounded by a square formed by the N donor atoms of the amino groups and the O atoms of the two alaninate anions (Figure 3(a)).
The average Pt-O and Pt-N bond lengths are 1.996 and 2.028Å, respectively. As in the trans-[Pd(β-Ala) 2 ] , the C-O distances for the coordinate O atom of the deprotonated OH group are appreciably longer than those for the incoordinate atoms (1.29 and 1.23Åon the average). The independent molecules differ in the configuration of the chelate rings. The maximal deviation of nonhydrogen atoms from the plane of the coordination square is 0.26Åin the Pt1 molecule and 1.09Åin the Pt2 molecule (Figure 3(a)). The N-Pt-O chelate angle in the Pt2 molecule, which is "more planar," is 95.7(3) • ; this is much larger than in the Pt1 molecule (94.0(3) • ). The molecules in the structure are hydrogen bonded into a framework by N-H· · · O type bonds (Figure 3(b)).
In the crystallographically independent cis-[Pt(β-Ala) 2 ] molecules the metal atom also has square planar surroundings (Figure 4(a)). The average values of the Pt-O and Pt-N bond lengths are 2.015 and 1.997Å, respectively.
The maximal deviation of nonhydrogen atoms from the coordination square plane is 0.58Åin the Pt1 molecule and 0.54Å (Figure 4(a)) in the Pt2 molecule. The hydrogen bonds link the molecules into layers (Figure 4(b)).
In the trans-K 2 [Pt(β-Ala) 2 I 2 ] • 2H 2 O complex, the coordination trans-square of Pt is formed by two I atoms and by the N atoms of the β-alaninate ions. The Pt-I distance is 2.5902(5)Å, and the Pt-N distance is 2.047(5)Å. The N· · · O distance in β-Ala is 4.197Å. The carboxylate groups of the β-alaninate ions link the [Pt(β-Ala) 2 I 2 ] fragments with K + ions, thus forming polymer layers in the structure ( Figure 5). The environment of the K ion includes three O atoms of the carboxylate groups, two O atoms of the water molecules (d K-O = 2.780(4) − 2.863(5)Å), and two I ions (d K-I = 3.797(1) and 4.285(2)Å), because of which the layers are linked into a framework.