Chiral Nickel(II) Binuclear Complexes: Targeted Diastereoselective

Article pubs.acs.org/Organometallics

Chiral Nickel(II) Binuclear Complexes: Targeted Diastereoselective Electrosynthesis Tatiana V. Magdesieva,*,† Oleg A. Levitskiy,† Yuri K. Grishin,† Asmik A. Ambartsumyan,‡ Ksenia A. Paseshnichenko,† Natalia G. Kolotyrkina,§ and Konstantin A. Kochetkov‡ †

Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russia Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str., 28, Moscow, Russia § Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp., 47, Moscow, Russia ‡

S Supporting Information *

ABSTRACT: Ni(II) complexes containing (S)-o-[N-(Nbenzylprolyl)amino]benzophenone as an auxiliary chiral moiety in the form of a Schiff base with α-amino acids (αamino acid = glycine, alanine, dehydroalanine; Gly-Ni, Ala-Ni, and Δ-Ala-Ni) were subjected to various types of electrochemical activation (oxidation, reduction, and a treatment with electrogenerated base), affording regio- and diastereoselective synthesis of novel types of binuclear Ni(II) complexes via C− C coupling. New compounds were fully characterized by HRMS, MALDI-TOF, CD, and 1H and 13C NMR (including two-dimensional techniques) spectroscopy; two complexes were characterized by X-ray diffraction analysis. The structures of the novel complexes obtained via electrosynthesis completely match the predictions (made from preliminary voltammetric investigations of the starting complexes as well as from DFT estimations of the energy and symmetry of their frontier molecular orbitals) about the nature of chemical transformations which may follow the electron transfer steps. Electrochemical oxidation of Gly-Ni and Ala-Ni allows access to new dimeric complexes linked via benzophenone moieties in the Ni(II) coordination environment. These new binuclear Ni(II) complexes are of interest as chiral redox mediators for both oxidative and reductive transformations, since they exhibit quasi-reversible electrochemical behavior (their reduced and oxidized forms are stable, at least on the time scale of cyclic voltammetry). Three other binuclear Ni(II) complexes which were obtained via reductive dimerization of the Δ-Ala-Ni complex, via nucleophilic addition of electrochemically deprotonated Gly-Ni to Δ-Ala-Ni, and via oxidative electrochemical dimerization of deprotonated Gly-Ni are of interest as convenient precursors for the stereoselective preparation of diamino dicarboxylic acids HO(O)CCH(NH2)(CH2)n(NH2)CHC(O)OH (n = 2−0), since the obtained binuclear Ni(II)− Schiff base complexes can be easily disassembled using aqueous HCl in methanol.

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INTRODUCTION

An electrochemical reaction has its own specialty. It is a unique oxidation−reduction process that takes place in a specific heterogeneous interface between an electrode and an electrolytic solution. It includes transport of the reactants, adsorption on the electrode surface, electron transfer step, etc. Therefore, the manner of stereocontrol of the electrochemical reaction is very complicated in general. Furthermore, due to an interplay of opposite effects, the stereoselectivity of the majority of electrochemical reactions is low. Several common approaches to induce chirality in electrosynthesis have been proposed.6 Among the most widely used are the application of an electrode supplied with enantiomeric coatings and the use of a chiral solvent or chiral conducting salt (such as quaternized ephedrine, etc.) as a supporting electrolyte. Often, however, there is the problem that low

A multitude of reactions of organometallic and coordination compounds include a key electron transfer step that results in a change in the metal oxidation state. Thus, reducing or oxidizing agents are required to perform the targeted transformations. Organic electrosynthesis has a great potential as an environmentally friendly process because it employs electrons as reagents and thereby maximizes electrochemical process efficiency. The possibility of controlling the electrode potential allows large functional group compatibility; a wide range of accessible potentials makes potentiostatic electrolysis ideal for forcing or uptake of one or more electrons from a substrate. The scope of tasks in organic and organometallic chemistry which can be solved using electrochemical approaches is not limited by electrosynthesis; it also includes electrochemical activation of reactants,1 electrocatalysis,1−3 investigation of the reaction mechanism,4 electrochemical modeling of active sites of metal enzymes,5 etc. © XXXX American Chemical Society

Special Issue: Organometallic Electrochemistry Received: January 22, 2014

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dx.doi.org/10.1021/om500034x | Organometallics XXXX, XXX, XXX−XXX

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asymmetric yields are obtained using much larger amounts of asymmetry inducers. From this point of view, a combination of the benefits of electrochemical activation with the common methods of chirality induction in homogeneous reactions seems rather promising. This approach can be realized when performing electrochemically induced reactions in metal complexes with chiral ligands, creating an efficient asymmetric environment around the metal center. Metal complexes with an asymmetric coordination environment are widely used for various types of stereoselective synthesis (see, e.g., ref 7). The rational design of a metal coordination environment based on noncovalent secondary interactions between a metal center and chiral ligand affords a high level of stereoinduction. A similar approach is also widely used in nature; the active sites of enzymes which are constructed to provide excellent chemo- and stereoselectivity of the reactions should be mentioned in this context.8−12 Though the idea of inserting a substrate in the chiral coordination environment of a stable metal complex to perform stereoselective transformations is not new, its combination with electrochemical activation of the metal complex thus modified has not yet been probed. Meanwhile, this approach might allow broadening the scope of reactions available. To be more precise, several examples of asymmetric induction in electrochemical reactions using chiral metal complexes as catalyst precursors have been reported. However, reactive complexes containing a substrate under modification in the ligand sphere have not been isolated and their formation has only been suggested. Reductive intramolecular cyclizations in which Co(II) or Ni(I) complexes with a chiral salen derivative were applied as the catalyst precursors to yield substituted dihydrobenzofurans with an enantiomeric excess of 13−16% should be mentioned13,14 in this context. The detailed reaction mechanism has not been investigated; the authors only suggested that the reaction is performed in the reduced form of a chiral complex. One more example created electrochemical asymmetric dihydrosilylation of alkenes using a I 2 − K2OsO2(OH)4−K2CO3 system in which an iodine plays the role of a mediator of anodic regeneration of an active Os(VIII) species.15−20 A Scharpless ligand added to the reaction mixture was used as a chiral reagent, and a chiral complex of Os(VIII) was suggested as an in situ hydrosilylating agent.17 Electrocatalytic oxidation of diols in the presence of Cu(OTf)2 and a chiral ligand was also described.21 The acidity of the diol is increased when it is coordinated to the copper center, and the thus formed deprotonated Cu complex is oxidized in situ, yielding the corresponding carbonyl derivative. In the present work three stable square-planar Ni(II) αamino acid/Schiff-base complexes (α-amino acid = glycine, alanine, dehydroalanine; Gly-Ni, Ala-Ni, and Δ-Ala-Ni, Scheme 1) containing (S)-o-[N-(N-benzylprolyl)amino]benzophenone ((S)-BPB) as an auxiliary chiral moiety were chosen as the objects for the investigation of stereoselective electrochemical transformations of amino acids performed in the Ni coordination environment. These complexes were synthesized in the 1980s22−24 and turned out to be very convenient and operationally simple for performing stereoselective reactions with amino acids coordinated to a Ni(II) center. A great deal of research has been already performed with these complexes. Enantiopure amino acid derivatives were synthesized via aldol,24−28 Mannich,25,29,30 and C-alkylation31−34 reactions, as well as Michael addition.35−38 It was shown that the involvement of a Schiff base of an amino acid in

Scheme 1

the Ni(II) coordination environment results in a substantial increase in the acidity of an α-C−H bond,39 giving rise to the aforementioned reactions; the presence of a chiral ligand creates a precondition for stereoselective pathways. One could expect that an application of electrochemical techniques might allow selective activation of different sites of the coordination environment of the Ni(II) complexes, giving rise to their further modification. Here we report the electrochemical diasteroselective synthesis of novel types of chiral binuclear Ni(II) complexes from the starting Gly-Ni, Ala-Ni, and Δ-Ala-Ni precursors via C−C coupling of different activated parts of the molecule. Various types of electrochemical activation will be applied, including oxidation, reduction, and treatment with electrogenerated base. It turned out that the electrochemical approach to chiral Ni(II) complexes allowed the synthesis of compounds which were not available using common chemical protocols. Since the electrochemically induced transformations occur in the coordination environment of chiral Ni(II) complexes, a targeted formation of certain diastereomers is possible. The obtained novel binuclear Ni(II) complexes are of interest as precursors for new types of practically important optically pure diastereomeric diamino dicarboxylic acids as well as chiral redox mediators for both oxidative and reductive transformations.

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RESULTS AND DISCUSSION To develop an efficient electrochemically induced reaction, the possible sites of cathodic and anodic activation should be known. To obtain this information, the investigation of the electrochemical behavior of the starting Ni(II) complexes was performed, along with quantum chemical DFT calculations of the energy and symmetry of their frontier orbitals. Electrochemical and DFT Investigation of Gly-Ni, AlaNi, and Δ-Ala-Ni. The electrochemical behavior of Gly-Ni, Ala-Ni, and Δ-Ala-Ni has not yet been investigated. Only one publication appeared40 recently in which an oxidation of Gly-Ni at a glassy-carbon electrode in a mixture of 0.1 M NaOH and acetonitrile (50/50 v/v) was investigated. However, the experimental conditions are rather specific, and it is not evident that the measurements were performed exactly for GlyNi and not for its derivative. The authors40 postulate that they are dealing with “adsorbed/electropolymerized” Gly-Ni complex but “the mechanism of adsorption/electropolymerization is not clear”. Actually, the voltammogram presented in ref 40 refers to the oxidation of an unknown compound of polymeric type and not to Gly-Ni. The redox properties of Gly-Ni, Ala-Ni, and Δ-Ala-Ni were investigated using cyclic voltammetry at a Pt working electrode in acetonitrile solution. The peak potential values for the observed electron transfers for the complexes under investigation as well as for the (S)-BPB ligand are given in Table 1. B


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reasonable to assume that anodic activation of the complexes may result in some chemical transformation involving this aromatic part of the Ni coordination environment. To obtain an additional reasoning for this assumption, a DFT estimation of the SOMOs of Gly-Ni and Ala-Ni radical cations were also performed (see Figure 2). It indicates that the maximum orbital coefficient in the SOMOs for both complexes is located on the carbon atom in the para position of the benzene ring in the benzophenone moiety. The electrochemical behavior of Δ-Ala-Ni is substantially different (Figure 1). Its reduction is anodically shifted in comparison to Ala-Ni (probably due to the enhancement of the π system) and is irreversible (see Table 1). The number of electrons consumed in the reduction of Δ-Ala-Ni estimated from the peak current value in comparison to the current observed in the reduction of a equimolar amount of the GlyNi0/− couple taken as a standard gave a value of ∼0.46. Evidently, the radical anion formed after the reduction is involved in a chemical follow-up step (see below). The DFT estimated LUMO is given in Figure 2. It is formed as an overlap of π antibonding orbitals of dehydroalanine and imine fragments, with much smaller impacts of Ni orbitals and π orbitals of the aromatic moiety. Thus, electron transfer to the dehydroalanine complex can be considered as mainly ligandcentered and the radical anion formed may be expected to behave like a C-nucleophile, in contrast to the case for Gly-Ni and Ala-Ni complexes. According to the DFT data, the LUMO of Δ-Ala-Ni has lower energy in comparison to the LUMO of Ala-Ni for 0.27 eV; this facilitates the reduction of Δ-Ala-Ni in comparison to Ala-Ni and is in agreement with the experimentally obtained peak potential values (Table 1). The oxidation of Δ-Ala-Ni is more or less similar to the oxidation of Gly-Ni and Ala-Ni complexes (Figure 1). It is a one-electron process with a poorly pronounced reverse peak, indicating a further transformation of the radical cation. the DFT estimated HOMO and SOMO (Figure 2) resemble those obtained for Gly-Ni and Ala-Ni. The predictions about the nature and location of chemical transformations which follow the electron transfer steps made from voltammetry and computation data were completely supported by bulk electrolysis. Oxidative Dimerization of Gly-Ni and Ala-Ni. Preparative galvanostatic electrolysis of Gly-Ni and Ala-Ni was performed in acetonitrile in a one-compartment cell. The working electrode was a Pt plate, and graphite fibers were used as a counter electrode. The constant current value was 5 mA, and a charge of 9 C (2.3 equiv vs the amount of complex) was passed through the solution. A small amount of acetic acid (0.08 mmol) was added to the solution to provide a cathodic reaction. The reaction mixture was intensely agitated with a magnetic stirrer. The reaction products were isolated by column chromatography and investigated using a wide set of spectral methods. It turned out that anodic preparative-scale oxidation of GlyNi and Ala-Ni complexes allowed new chiral binuclear Ni(II) complexes of dimeric nature to be obtained (1 and 2; see Scheme 2). This was proved by HRMS and MALDI-TOF data. The presence of an intense peak of the molecular ion and the isotopic distribution observed in the spectra clearly indicated the formation of the dimeric product. The structure of the dimer was revealed by 1H and 13C NMR spectra (including two-dimensional techniques).

Table 1. Peak Potential Values and Peak Current Ratios for the Oxidation and Reduction of (S)-BPB, Gly-Ni, Ala-Ni, ΔAla-Ni, and Dimers 1 and 2a reduction Ecp/Eap, (S)-BPB Gly-Ni (S)-Ala-Ni Δ-Ala-Ni 1 2

V

−1.66/−1.58 −1.57/−1.44 −1.58/−1.48 −1.30 −1.55/−1.44 −1.59/−1.45

oxidation Ia/Ic

Ecp/Eap,

V

Ic/Ia

0.89 0.94 0.90

1.23 1.32/1.16 1.37/1.17 1.34/1.17 1.23/1.12 1.24/1.11

0.80b 0.83

0.81b 1.0

a

Conditions: Pt, CH3CN, 0.05 M Bu4NBF4, 100 mV/s, vs Ag/AgCl/ KCl. bThe peak current ratio approaches unity with an increase in a potential scan rate (e.g., Ia/Ic = 0.9 at 300 mV/s).

The electrochemical behavior of both glycine and alanine complexes is similar (Figure 1). The reduction of Gly-Ni and

Figure 1. CV curves for Gly-Ni (blue), Ala-Ni (red), Δ-Ala-Ni (black), and complex 1 (green). Conditions: Pt, CH3CN, 0.05 M Bu4NBF4, 100 mV/s, vs Ag/AgCl/KCl.

Ala-Ni is one electron, diffusion controlled (as follows from a linear Ip/v1/2 dependence), and quasi-reversible; the direct and reverse peak separation values are ∼100 mV, and Ia/Ic peak current ratios are close to unity. This means that Gly-Ni and Ala-Ni radical anions are stable, at least on the cyclic voltammetry time scale. The reduction potential values are typical for square-planar Ni complexes.41 Thus, we can assume the reduction of complexes to be metal-centered. This assumption was completely confirmed by DFT calculations: LUMO orbitals have similar energies for both complexes and are formed as an antibonding combination of the dx2−y2 orbital of Ni atom with the group orbitals of the ligands (Figure 2). The oxidation of Gly-Ni and Ala-Ni complexes is irreversible; the reverse and direct peak current ratio is far from unity (Figure 1). Hence, the electron transfer step is accompanied by a subsequent chemical transformation. According to DFT calculations, the HOMO of both complexes is a combination of the orbitals of the Ni center with a significant contribution of π orbitals of the aromatic benzophenone moiety in the ligand (Figure 2). Hence, it is C


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Figure 2. DFT estimated HOMOs, LUMOs, and SOMOs of Gly-Ni, Ala-Ni, and Δ-Ala-Ni.

Scheme 2

A detailed analysis of the spectral data is given below; however, to anticipate, we can say that coupling of two Gly-Ni or two Ala-Ni occurs at the para position of benzene ring in the benzophenone moiety, exactly as has been predicted by DFT estimations of the HOMOs and SOMOs of the starting complexes (see Scheme 2). The 1H NMR spectrum of dimer 1 has only one set of signals for both monomeric units. This can be explained by the presence in 1 of the C2 axis which is perpendicular to the Ar− Ar′ bond. A comparison of 1H NMR spectra for Gly-Ni and 1 indicates that the glycine fragment is not altered. However, the aromatic four-spin system observed in the spectrum of Gly-Ni is converted into an AMX system in 1 (see Figure 3). Instead of the doublet of doublets at 8.3 ppm corresponding to H8 of Gly-Ni (for the numeration of the atoms see Figure 4), a doublet at 8.21 ppm appears in the spectrum of 1. This means that spin−spin coupling of H8 through four bonds is eliminated; hence, a new C6−C6′ bond at the para positions of benzene rings is formed in 1. As an alternative, a coupling via C7 carbons can also be suggested. However, it seems unlikely,

Figure 3. Low-field region of the 400 MHz 1H NMR spectrum of dimer 1.

since in this case too large a difference in the chemical shifts of H5 (8.21), H6 (7.04) and H8 (6.71) should be observed in D


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Figure 4. NOE data attributed to through-space interactions observed for H5 in complex 1. The blue curve corresponds to a monoresonance 1H spectrum; the brown curve shows an NOE1D spectrum.

comparison to the starting mononuclear Gly-Ni complex,42 and this is not the case. For the complete assignment of the signals in the 1H (Figure S1) and 13C NMR spectra (Figure S2) of 1, two-dimensional homo- and heteronuclear correlated techniques (Figures S3− S5) were used (Supporting Information). The characteristic group of signals corresponding to the AB spin system of the methylene group of the Gly fragment (two doublets at 3.74 and 3.63 ppm) can be observed in the 1H NMR of 1. These protons give in the HMBC spectrum (Figure S3) two intense cross-peaks with 13C signals at 171.71 and 177.28 ppm, along with two less intense cross peaks (with 13C at 125.53 and 134.46 ppm). These four carbon atoms have no correlation peaks in the HMQC spectrum (Figure S4); hence, they should be of a quaternary type. Two low-field signals at 177.28 and 171.71 ppm are attributed to the carbonyl C1 and imine C3 atoms. The signal at 177.28 ppm in HMBC has only one cross-peak with the methylene protons of glycine; hence, it corresponds to the C1 carbonyl center. Consequently, the signal of the C3 carbon of the imine fragment appears at 171.71 ppm. The aromatic carbon atom at 134.46 ppm has no cross peaks in HMBC with any of the protons H5−H8, but it is correlated with the H24 and H27 meta protons of the phenyl ring. This means that the signal at 134.46 ppm corresponds to the C22 atom. Hence, the remaining carbon atom which is correlated with the methylene protons of the Gly moiety in the HMBC spectrum corresponds to C4 (125.53 ppm). The HMBC data allow rejecting the possibility of the dimerization via a C7−C7′ bond. The H8 proton exhibits two intense cross peaks with quaternary carbons, namely with C4 and with an atom creating the Ar−Ar′ bond (at 132.18 ppm). In accordance with the rule that 3JCH ≫ 2JCH for aromatic rings, these cross peaks correspond to correlations through three bonds. Consequently, the monomeric units in 1 are linked through the C6−C6′ bond. The interpretation of the HMBC spectrum presented above (see Figure S3) is in agreement with the NOE data, which allow unequivocal confirmation of C6− C6 coupling in 1 (see Figure 4). The NOE spectrum testifies to the presence of the strong through-space interactions between the H5 and H7′ protons (which correspond to the different

mononuclear units in the dimeric structure) and between H5 and H23/H27 (within the same mononuclear unit). Additionally, there are some other related problems: whether the rotation around C6−C6′ bond is free or not, how many rotamers can be found on the potential energy surface (PES), and which is the most stable one. To solve these questions, quantum chemical DFT calculations were performed. The PES scan with the constrained C7−C6−C6′−C7′ torsion angle ranging from 0 to 360° revealed the existence of four rotamers of similar energy (Figure 5). The optimization of the transition

Figure 5. PES scan with the constrained C7−C6−C6′−C7′ torsion angle in 1.

states between the local minima revealed that the rotation is free at room temperature (the highest barrier is ∼3 kcal/mol). In the most stable conformation the protons H5 and H7′ are in the closest proximity (2.27 Å). The distances between H5 and the other two proximal protons H23 and H27 are 3.33 and 3.05 Å, respectively. This range of distances is sufficient for NOE observations; moreover, the NOE values observed for these three interactions correlate with the distances between H5 and H7′, H23, and H27. All other protons are more distant from H5 (>4.25 Å). Consequently, the signals in the NOE spectrum are attributed to the H5−H7′, H5−H23, and H5−H27 interactions. An analysis of the NMR spectral data obtained for 2 indicated that its structure is similar to that of 1. An AMX spin E


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Scheme 3

system is also present in the aromatic region of the 1H NMR spectrum of 2 (Figure S6 (Supporting Information)), indicating the coupling of two monomeric units via para positions of the benzene rings of the benzophenone fragments. Chemical shifts of the corresponding signals are shifted upfield in comparison to their counterparts in the AMX system in dimer 1. This effect is the most noticeable for H5 (the numeration is the same as given in Figure 4) and H8 signals (the differences in the chemical shifts are 0.16 and 0.18 ppm, respectively). The position of these two signals is influenced by a shielding effect of the phenyl ring and a deshielding effect of the amide carbonyl group, respectively. Thus, they are very sensitive to any changes in the mutual spatial arrangement of different groups in the complex. An introduction of a methyl substituent to the α-C atom provides some conformational changes. Steric repulsion between the methyl group and the phenyl ring decreases the distance between H5 and the phenyl group, thus resulting in the enhancement of a shielding effect. The methyl group at the α-C atom also influences the mutual arrangement of H8 and amide carbonyl group. The change in the chemical shift of H8 indicates that the Ni coordination plane is distorted in comparison to the Gly-containing complex 1. The remainder of the spectrum of 2 contains the same set of signals as the initial Ala-Ni. The NMR spectra of 2 are given in the Supporting Information (Figures S6−S9). The complete assignment of all signals was based on a detailed analysis of 1H (Figure S6) and 13C (Figure S7) spectra as well as 2D NMR experiments (COSY and HSQC, see Figures S8 and S9), supporting the structure of the dimer given in Scheme 2. The isolated yields of Gly-Ni and Ala-Ni dimers were 50% and 43%, respectively. In both cases, in addition to the dimers, the initial Gly-Ni and Ala-Ni complexes were isolated. The yields of the dimers recalculated to the converted complexes were 98% for 1 and 96% for 2. Various attempts to improve the conversion were performed. The variation of the amount of charge passed through the solution indicated that 9 C is the optimal value. Though the current efficiency is only 19%, a decrease in the electrolysis duration results in a significant decrease in the yield of the dimers, whereas a further increase in the amount of charge passed does not influence the yield significantly. The agitation of the solution during the electrolysis is also important: if only an argon flow is used, the yield of the dimer decreases substantially and a precipitate appears which might be an

indication of the further oxidation of the dimeric species formed in the electrode vicinity (see below). Thus, the DFT and spectral data confirm the reaction scheme of the oxidative dimerization of Gly-Ni and Ala-Ni complexes presented above (Scheme 2). Coupling of two Nicontaining radical cations occurs at the para positions of the aromatic rings of the benzophenone moiety, yielding dicationic species which undergo fast deprotonation to restore the aromatic system. Though no new chiral centers are created in this reaction, the chiral coordination environment of the Ni centers is preserved. Electrochemical investigations of the isolated dimeric complexes 1 and 2 were performed in acetonitrile using cyclic voltammetry (Figure 1They showed that both reduction and oxidation of 1 and 2 are two-electron and reversible, in contrast to the monomeric precursors, whose oxidation is accompanied by a follow-up chemical step. The reversibility of the dimer’s oxidation seems quite natural, taking into account that the para position in the dimers is blocked by a stable C−C bond between two mononuclear units. The reversible electrochemical behavior of the dimers means that they can form cationic and anionic species which are stable, at least on the CV time scale. Consequently, dimers 1 and 2 can be used as chiral mediators of oxidative and reductive processes. This research is in progress now. The peak potential values observed for 1 and 2 are similar to those for Gly-Ni and Ala-Ni (see Table 1). A small cathodic shift in the oxidation potential values (∼90 mV; see Table 1) might be an explanation of why the preparative yields of 1 and 2 are dependent on the agitation of the solution. It is important to remove the dimeric species formed in the electrode vicinity from the electrode surface to prevent their further oxidation, which may possibly result in some subsequent transformations (though they should be rather slow since they cannot be detected in the CV curve). Reductive Dimerization of Δ-Ala-Ni. As follows from the voltammetric and DFT investigation of the Δ-Ala-Ni complex, its reduced form may be expected to behave like a Cnucleophile. This conclusion was completely proved by preparative cathodic reduction of the dehydroalanine complex. Potentiostatic electrolysis was performed at the potential slightly more cathodic than the Epc of the Δ-Ala-Ni complex (−1.4 V) in a two-compartment cell in acetonitrile using carbon felt as a working electrode. The current dropped to 0 after half of the electricity required for one-electron reduction F


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in the region 440−480 nm and a positive sign in the region 480−640 nm. The same type of Cotton effect has been observed for similar complexes containing (S,S)-diaminoglutaric and (S,S)-diaminosuccinic acids,43 allowing us to conclude that the symmetrical diastereomer of 3 contains an (S,S)diaminoadipic acid fragment. Hence, the other diastereomer (39% yield, 39% of current efficiency) corresponds to the unsymmetrical S,R,S,S structure. A total of 24 aliphatic and 28 aromatic protons can be found, indicating the presence of two monomeric units which are not interrelated with symmetry transformations. The assignment of signals in 1H (Figure S14) and 13C (Figure S15) spectra of 3-(S,R,S,S) was based on HSQC, HMBC, and COSY 2D NMR spectral analysis (Figures S16− S18). The signals of α-H protons from two monomeric units (complex multiplets at 3.86−3.81 ppm) have almost identical chemical shifts (the difference is about 0.01 ppm). The signals of α-H protons have two couples of cross peaks in COSY spectrum with the protons, which should be assigned to two bridging methylene groups. This was unambiguously confirmed by HSQC data. Each couple of cross peaks is attributed to one of the bridging carbon atoms (exhibiting the signals in 13C NMR at δ 31.41 ppm for the one CH2 group and at 32.59 ppm for the other). The protons of these two methylene groups are interrelated in the COSY spectrum, confirming the formation of a CH2−CH2 bond. The complete assignments of all signals in 1H and 13C spectra are given in the Supporting Information and in the Experimental Section. The CD spectrum obtained for 3-(S,R,S,S) (Figure 7) was completely different from the spectrum obtained for 3-(S,S,S,S)

of the complex passed through the solution. This result is in agreement with the preliminary CV estimation (see above) and it allows suggesting that electrochemically generated radical anions enter into nucleophilic addition to the activated double bond of the starting neutral complex. Thus, the formation of a binuclear Ni complex should be expected. The isolation of products using column chromatography revealed the formation of two new Ni complexes. Their investigation using a complete set of spectral methods showed that the novel binuclear complex 3 (Scheme 3) is formed in two diastereomeric forms (it should be mentioned that theoretically the formation of three diastereomers is possible). Both complexes exhibit the same peak of the molecular ion and the isotope distribution in MALDI-TOF and HRMS spectra corresponding to the dimer of the starting Δ-Ala-Ni. Though the m/z ratios for the molecular ions in MS spectra of the diastereomers are identical, their 1H NMR patterns are substantially different. For one of the fractions (obtained with an isolated yield of 51% and current efficiency of 51%) a doublet of doublets can be observed at 4.02 ppm (Figure S10). This area corresponds to α-protons of the amino acid in the coordination environment of the complexes under investigation (e.g., for (S)-Ala-Ni the signal appears at 3.85 ppm). In the 2D COSY spectrum (Figure S12) the signal at 4.02 ppm has two cross peaks at 3.05 and 2.01 ppm, which are also interrelated. According to the HMQC spectrum (Figure S13) these two protons are bound to the same carbon atom (δ 30.31 ppm) (Figure S11). The proton with the chemical shift of 4.02 ppm belongs to another carbon atom (δ 69.74 ppm) which has no extra correlations in the HMQC spectrum. Thus, three nonequivalent protons (one methyne and one methylene group) are formed, supporting the structure given in Scheme 3. These data can be expected to correspond to one of two possible symmetrical structures which differ in the absolute configurations of the α-amino acid fragment (either S,S,S,S or S,R,R,S; see Scheme 3). The absolute configuration of the α-amino acid moiety was determined from CD spectra, by comparison with literature analogues (Figure 6). Circular dichroism, which

Figure 7. CD spectra for 5-(S,R,S,S) (solid line) and 3-(S,R,S,S) (dotted line).

and was less informative, due to the mutual compensation of the Cotton effects, which have the opposite signs for R and S stereocenters. On the basis of voltammetric, DFT, and spectral data, the following reaction scheme for reductive dimerization of Δ-AlaNi can be suggested (Scheme 3). Radical anions formed in electrochemical reduction react with the CC double bond of the starting Δ-Ala-Ni complex, which is activated toward nucleophilic addition, yielding dimeric species. The DFTestimated enthalpy of this process is negative (−18 kcal/mol), indicating that it is thermodynamically favorable. The dimeric radical anionic species after consecutive H atom abstraction and protonation steps allow binuclear complex 3 to be obtained. The control experiments with the addition of triphenylmethane (as an H atom donor) in the solution before the electrolysis showed that the yield of 3 is increased, thus supporting the involvement of an H atom abstraction step in the reaction course.

Figure 6. CD spectra for 5-(S,S,S,S) (solid line), 3-(S,S,S,S) (dotted line), and 4-(S,S,S,S) (bold line).

creates an example of chiroptical phenomena, is related to electronic transitions in chiral molecules, providing information about their absolute configuration. It is known22 that Ni(II) complexes of this type exhibit two maxima in the region of d−d transitions; the sign of the Cotton effect is dependent upon the configuration of the α-amino acid (pseudoaxial or pseudoequatorial orientation of the substituent), and it is not influenced by the structure of the substituents. For the S configuration (pseudoaxial orientation) the Cotton effect has a negative sign G


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Reductive dimerization of Δ-Ala-Ni yielded the formation of two diastereomers of 3 in almost equimolar S,S,S,S:S,R,S,S ratio; no traces of the S,R,R,S diastereomer were detected in the reaction mixture. This result is in line with the literature data44 indicating that the R configuration of the alanine α-carbon atom is less favorable than S, since the S absolute configuration of the N-benzylproline moiety in the Ni(II) coordination environment induces the S stereochemistry of the newly formed stereocenter at the α-carbon atom of the amino acid. As concerns the absolute configuration of the second stereocenter which is formed in the protonation step, both S and R configurations are created with equal probability, since the protonation is fast and is kinetically controlled. The obtained novel binuclear complex 3 is of special interest as a convenient precursor for the asymmetric synthesis of different stereomers of diaminoadipic acid, which can be isolated after the treatment of 3 with HCl/MeOH solution. Treatment of Gly-Ni and Ala-Ni with Electrochemically Generated Base. It was very intriguing to obtain one more type of dimeric complex linked via α-carbon atoms of an amino acid fragment, since previous attempts via common chemical routes failed.43 As follows from the DFT estimation, it is impossible to activate this site of the coordination environment using direct electrochemical oxidation or reduction and we had to use an alternative approachthe application of an electrogenerated base. The acidity of α-H in the Ni complex is sufficient (pKa 18.8 in DMSO39) for the complex to be deprotonated using a strong base.22,23,26,45,46 The stereochemical result of further transformations of the deprotonated complex might be dependent on the type of base applied and the reaction conditions.23,26 Electrochemically generated base is of special interest, since electrochemical techniques allow precise control of the concentration of a base and its in situ reaction with the complex47,48 (a detailed discussion of the reaction of the electrochemically deprotonated Gly-Ni with various electrophiles is the subject of our subsequent publication49). In the present work, azobenzene radical anion was used as an electrogenerated base. It is formed at the potential of −1.32 V vs Ag/AgCl/KCl and can be applied to the deprotonation of substrates with pKa ≤ 20.48 The radical species formed after protonation of azobenzene radical anion are immediately reduced to the corresponding hydrazobenzene anions which are even stronger bases than the starting radical anion (see Scheme 4). Consequently, the possibility of deprotonation of substrates with pKa ≤ 26 by azobenzene is determined by the rate of electron transfer to Ph2N2•−. First of all, the possibility of electrochemical deprotonation of Gly-Ni and Ala-Ni using azobenzene was estimated using cyclic voltammetry. A consecutive addition of the Gly-Ni complex to azobenzene solution results in a gradual decrease in the current corresponding to azobenzene radical anion reoxidation (Figure 8). This means that the radical anions are consumed for deprotonation of the starting Gly-Ni complex. A new peak corresponding to the oxidation of hydrazobenzene formed appears in the voltammogram at a potential of 0.46 V,48 along with a peak corresponding to the oxidation of deprotonated Gly-Ni (−0.44 V). The latter peak is increased with an increase in the amount of Gly-Ni in solution. The reduction peak of the starting Gly-Ni is not observed, indicating that it is completely deprotonated by azobenzene radical anions. Thus, CV estimation indicated that an efficient deprotonation of the Gly-Ni complex can be performed at the potential of

Scheme 4

Figure 8. CV curves observed for azobenzene: black curve, no Gly-Ni added; red curve, 0.5 mM of Gly-Ni; blue curve, 1 mM of Gly-Ni. Conditions: 2 mM Ph2N2, 0.05 M Bu4NBF4, MeCN, 300 mV/s, Pt.

azobenzene reduction, encouraging us to perform the bulk electrolysis. It was carried out in a two-compartment cell at a potential of −1.40 V using carbon felt as the working electrode and Al wire as the counter electrode. The orange solution of the starting complex became almost black after passing the charge necessary for complete deprotonation of Gly-Ni (∼1.2 mol equiv). Afterward, the potential of the working electrode was changed to −0.1 V. This value is optimal for selective oxidation of the deprotonated complex, whereas Ph2N2H2 remains intact. The Gly-Ni anions were oxidized to the corresponding radicals, which undergo fast dimerization, yielding dimeric species. The color of the solution during the potentiostatic oxidation gradually changed from black to intense red. The solution was electrolyzed until the current dropped to 3% of its initial value. The reaction products were isolated using column chromatography and investigated using spectral and X-ray methods. H


Organometallics

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A certain amount of the starting Gly-Ni was isolated (2%), along with the new dimeric complex 4 (60%) in two diastereomeric forms in an almost equimolar ratio (33% and 27%). This was proved by ESI MS and HRMS spectra: both forms of the dimeric complex 4 exhibit intense peaks corresponding to M + H+ and M + Na+ ions. However, the 1 H NMR spectra of 4 registered at room temperature were not informative: the signals were not completely resolved, and they exhibit strong temperature dependence (Figure 10), indicating that rotation around the C−C bond is restricted. This seems quite natural for the dimer linked via α-carbon atoms of the glycine moiety due to the presence of bulky neighboring groups. Formation of complex 4 in two diastereomeric forms was unambiguously confirmed by X-ray diffraction analysis as well as by dynamic NMR experiments (see below). Thus, the reaction scheme of the electrochemical oxidative dimerization of the deprotonated Gly-Ni can be presented as shown in Scheme 4. It should be remarked here that previous attempts to obtain dimer 4 using deprotonation of Gly-Ni with subsequent oxidation of the anions have been described in the literature.43,50 Various chemical bases (BuLi, t-BuOK) and oxidants (MnO2, O2) were applied, but without any success. The application of the electrochemical approach allowed 4 to be obtained in two enantiopure forms. This novel binuclear Ni(II) complex is of special interest as a convenient precursor for the stereoselective synthesis of enantiomerically pure forms of diaminosuccinic acid which is practically required. We tried to apply the approach described to synthesize the same type of dimer from the Ala-Ni complex. Preliminary voltammetric estimation was performed first. Surprisingly, the voltammogram obtained for the mixture of Ala-Ni and azobenzene given in Figure 9 looks like a superposition of

Scheme 5

NMR and X-ray Investigation of Dimer 4. To obtain a deeper insight into the structural features of 4, a dynamic NMR experiment was performed. 1H NMR spectra of the one of the diastereomers of 4 were recorded in a temperature interval of 100 °C. Initially broad signals became narrow upon cooling to −47 °C, indicating the presence of two forms of 4 in 6:1 ratio (Figure S19). For the major component only one set of signals common for this type of complexes is observed, indicating that we are dealing with a symmetrical dimer. Hence, this suggests that the investigated diastereomer has an S,S,S,S configuration. The assignment of the signals corresponding to the aromatic protons of the major form was performed in accordance with several decoupling experiments, revealing spin−spin interactions. The order of signals in a low-field range is similar to that of the monomeric Gly-Ni complex. The most peculiar feature of the 4-(S,S,S,S) spectrum is the signal of the proton of the glycine moiety. It appears as a singlet at 5.49 ppm: i.e., it is strongly deshielded in comparison to the corresponding signal of the parent Gly-Ni complex (by a value of 1.7 ppm). Such a strong effect shows that the α-amino acid proton of the one monomeric fragment is located exactly above the Ni coordination plane of the other monomeric unit. The signal of the α-amino acid proton in the minor form appears as a singlet at 3.98 ppm; this value is close to the chemical shift of the glycine protons in the starting Gly-Ni. This means that in the minor form this proton no longer occupies the position above the Ni coordination plane. Thus, the dynamic process observed in the spectrum should be assigned to the internal rotation around the C(α)−C(α′) single bond, as had been expected. With the temperature increase the signals are gradually broadening; coalescence and further averaging of signals are observed (Figure 10). The evolution of the α-H signals of two rotamers was studied to evaluate the kinetic parameters of the process observed. At low temperatures (a slow-exchange region), a linear relationship between the peak broadening (Δν) and the rate constant (k) was assumed:51 p kAB = π ΔνA = π B ΔνB pA

Figure 9. CV curve of the solution containing azobenzene (1 × 10−3 M) and Ala-Ni (5 × 10−4 M). Conditions: Bu4NBF4 (0.05 M), MeCN, 100 mV/s, Pt.

where pi is a population of state i. At the lowest temperatures (−47 to −25 °C) the rate constant was determined from the broadening (ΔνB) of the minor rotamer peak. This ensures the minimization of an error due to the larger value of peak broadening for the minor form in comparison to that for the major rotamer. At higher temperatures (−30 to 0 °C) the signal corresponding to the major rotamer became broad enough to provide a sufficient accuracy of the measurements, whereas the signal of the minor form almost disappears. Thus, the rate constants were calculated from ΔνA in this region. At room temperature coalescence of the signals is observed. The averaged line became narrow enough to measure the rate

two CV curves measured for Ala-Ni and Ph2N2 independently and shows no interaction between the components of the solution. At first glance, it seems strange, since the thermodynamic acidity of the Ala-Ni complex is only 0.3 pKa unit lower39 than that for Gly-Ni. However, it can be attributed to steric reasons. The deprotonation of the Gly-Ni complex is much more favorable when the attack is performed from the less sterically hindered side of the Ni coordination plane (Scheme 5). In the (S)-Ala-Ni complex this attack is impeded due to the presence of a methyl group. Probably, the deprotonation of Ala-Ni with a bulky organic base is a much slower process in comparison to its Gly counterpart and cannot be detected on the CV time scale. I


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Figure 10. 400 MHz 1H NMR spectra of α-H of the glycine moiety of 4-(S,S,S,S) at various temperatures.

= 11.6 ± 0.4 kcal mol−1 and the entropy of activation is ΔSAB⧧ = −6 ± 1 cal mol−1 K−1. These values seem quite reasonable for the barriers of a hindered rotation around the C(sp3)−C(sp3) bond.52 DFT calculations of the relative energy and of the structure of the possible 4-(S,S,S,S) rotamers were also performed, being in line with the predicted geometry of the most stable rotamer. A PES scan revealed the existence of four rotamers. All rotamers correspond to retarded conformations (the Newman projections along C2−C2′ bond are given in Figure 12). The existence of four conformations instead of the three commonly observed for rotation around the C(sp3)−C(sp3) bond is attributed to the alteration of the mutual arrangement of two phenyl rings of the different monomeric units when going from B to C (not shown in Figure 12). The interconversion among three rotamers (B−D; Figure 12) is fast on the NMR time scale

constant at temperatures higher than 35 °C. The fast exchange approximation was applied to calculate the rate constant:51 kAB =

4πpA pB 2 (νA − νB)2 Δνav

where νA − νB is the difference in chemical shifts. The rotamer ratio in the fast-exchange region was estimated using a Boltzmann distribution assumption: −1 ⎡ ⎛ ΔE ⎞⎤ ⎟⎥ pB = ⎢1 + exp⎜ ⎝ RT ⎠⎦ ⎣

where ΔE = 0.76 kcal mol−1 was estimated from the ratio of the rotamers at low temperatures. The ln(kAB/T) vs T−1 plot remains linear in the whole 100 °C temperature range (Figure 11). Thus, the activation parameters can be determined from the slope and the intercept of this linear relationship. The enthalpy of activation is ΔHAB⧧

Figure 12. PES scan for the possible rotamers of 4-(S,S,S,S) with a constrained C1−C2−C2′−C1′ torsion angle.

Figure 11. Eyring plot for 4-(S,S,S,S). J


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The temperature dependence of the observed chemical shifts allows estimating the ΔG‡ of the phenyl ring rotation. According to Gutowski and Holm,52 the experimentally observed signals separation value is connected with the rate constant of the dynamic process by the equation

due to the low activation barriers (−10 °C) the second dynamic process starts, resulting in a backward shift and a significant broadening of the signal of the major form. According to the assignments made in the spectrum recorded at −47 °C, the signals of two ortho protons of the phenyl ring appear at 7.50 and 6.05 ppm. Hence, the observed downfield shift of the latter signal (Figure 13) means that the two aforementioned signals are shifted toward each other and their averaging proceeds, thus indicating the beginning of the second dynamic process attributed to the rotation of the phenyl ring of the benzophenone moiety. K


Organometallics

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Figure 14. Molecular structures of 4-(S,R,S,S) (left) and 4-(S,S,S,S) (one independent molecule, right) with key atoms labeled. Thermal ellipsoids are shown at the 20% probability level. Hydrogen atoms (except those at the asymmetric centers) and solvent molecules have been omitted for clarity.

Scheme 6

The mutual position of two monomeric units of the molecule in 4-(S,R,S,S) results in a Ni1···Ni1A distance equal to 4.562 Å and a O11···O11A distance equal to 3.616 Å. In 4-(S,S,S,S) the Ni1B···Ni1C distance is 5.889 Å, 1.3 Å longer than in 4(S,R,S,S), in contrast to the O11B···O11C distance, which is shorter (3.109 Å); this indicates more compact folding of dimeric molecules. Thus, the X-ray data presented above are in complete agreement with the structural features of diastereomers 4 determined from the NMR data. Reaction of Deprotonated Gly-Ni with Δ-Ala-Ni. The deprotonated Gly-Ni complex can be considered as a Cnucleophile. An addition of Δ-Ala-Ni complex to its solution allowed one more chiral binuclear Ni complex to be obtained, 5, as a result of nucleophilic addition of deprotonated Gly-Ni to the activated CC bond of Δ-Ala-Ni (Scheme 6). In contrast to the other binuclear complexes obtained in the present work, this complex was previously described,37 and it was interesting to compare the stereochemical result of electrosynthesis with that obtained using common bases. The deprotonated Gly-Ni complex was obtained as described above, using azobenzene radical anion. Afterward, an equimolar amount of solid Δ-AlaNi was added to the reaction mixture and already in 2 min the black solution (typical of the Gly-Ni anion) became intensely red. After 5 min the reaction came to completion and the products were isolated using column chromatography and analyzed using spectral methods (MALDI-TOF, NMR). The structures of the products were determined from 1H NMR by comparison with the literature data.46 Two diastereomers of 5 were obtained (52% isolated yield): the thermodynamically stable symmetrical 5-(S,S,S,S) isomer and

In both diastereomers, the Ni atoms have a slightly distorted square planar coordination environment, and the bond lengths and angles involving the Ni atoms lie within the expected ranges. However, it is interesting to note that in 4-(S,R,S,S) both Ni1−N10 bond lengths (in two monomeric units of the molecule) exceed the corresponding bond lengths in 4(S,S,S,S): 1.956(4) and 1.940(5) Å versus 1.909(7) and 1.931(6) Å. In 4-(S,R,S,S), the six-membered metallacycle Ni1−N3−C4−C5−C6−N7 is nearly planar, while the corresponding metallacycle including the Ni1A atom adopts an “envelope” conformation with Ni1A being 0.623(1) Å out of the plane. In 4-(S,S,S,S), the conformations of both corresponding metallacycles are close to “envelopes”. In 4-(S,R,S,S), the Ni atoms of both monomeric units of the molecule make short contacts with the H atoms of the pyrrolidine and benzyl groups: Ni1···H93 = 2.977, Ni1···H11 = 2.844, Ni1···H12 = 2.851 Å, Ni1A···H22A = 2.890, Ni1A··· H94A = 3.325 Å. Such short contacts of Ni atoms with the pyrrolidine and benzyl H atoms are also present in 4-(S,S,S,S) and lie within the range 2.73−3.178 Å. The same short contacts are also characteristic of the parent Gly-Ni. In all cases it results in a downfield shift of the signals of the corresponding protons, thus supporting the assignment of signals in 1H NMR (see Figure S19). The presence of short contacts of the Ni atom with α-amino acid protons of the neighboring monomeric unit is a distinctive feature of the diastereomer 4-(S,S,S,S): these contacts lie within the range 2.91−2.99 Å and are not observed in 4-(S,R,S,S). This result is also in agreement with the NMR data (see above). Close O···H contacts (from 2.15 to 2.25 Å) between the O atom of the carboxy group and H atoms of the phenylene group are also observed in 4-(S,S,S,S). L


Organometallics

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subsequent anodic oxidation of the anions of deprotonated complex to the corresponding radical species results in the formation of a mixture of two diastereomers of binuclear complex 4 in which two Gly-Ni groups are linked directly via αglycine carbon atoms. Finally, nucleophilic addition of electrochemically deprotonated Gly-Ni to the activated double bond of Δ-Ala-Ni gives complex 5, in which two Gly-Ni groups are linked with one methylene unit between α-glycine carbon atoms. All diastereomers were isolated in enantiomerically pure form. The structure of the new binuclear Ni(II) complexes and the configuration of the stereocenters formed was proved by a wide set of spectral methods (1H and 13C NMR (including 2D techniques), HRMS, MALDI-TOF, CD) and X-ray data (for two diastereomers of complex 4). Complexes 1 and 2 were obtained in the S,S form, since no new chiral centers are formed in the coupling reaction. Complexes 3−5 were synthesized and isolated in two diastereomeric forms, S,S,S,S and S,S,R,S, in various molar ratios depending on the type of stereocontrol. 1 H NMR spectra recorded for complex 4-(S,S,S,S) over a temperature interval of 100 °C allowed the dynamic process to be revealed, which was assigned to internal rotation around the C(α)−C(α′) single bond. The structures of the most stable rotamers determined from NMR spectra and DFT estimation were completely confirmed by X-ray data. The activation parameters of the rotation were determined. The second dynamic process which can be observed at temperatures higher than −10 °C is attributed to the rotation of the phenyl ring of the benzophenone moiety. The estimated ΔG⧧ value of the phenyl ring rotation is 13 kcal/mol. It should be mentioned that the phenomenon of impeded rotation of an unsubstituted phenyl ring at ambient temperatures is rather rare; only a few examples are known. Novel chiral binuclear Ni(II) complexes obtained in the present work are of interest for various applications. Dimers 1 and 2 containing Gly-Ni or Ala-Ni groups linked via aromatic moieties can be used as chiral redox mediators for both oxidative and reductive transformations, since they exhibit quasi-reversible electrochemical behavior and their reduced and oxidized forms are stable enough, at least on the time scale of cyclic voltammetry. Dimers 4, 5, and 3 containing two chiral Gly-Ni moieties linked via α-Gly carbon atoms (directly or through one or two methylene unints, respectively) open the route to the stereoselective preparation of diaminodicarboxylic acids HO(O)CCH(NH2)(CH2)n-(NH2)CHC(O)OH (n = 0−2), since the obtained binuclear Ni(II)−Schiff base complexes can be easily disassembled using HCl in methanol. The simplicity of the described experimental procedure, the availability and low cost of the starting chiral amino acid/Schiff base complexes, and the appreciable chemical and stereochemical yields make the presented approach very convenient. Pure stereomers of diaminodicarboxylic acids are of great interest for practical applications as precursors for pharmaceuticals and biologically active compounds.

less stable 5-(S,R,S,S) isomer in a ratio of 1.3:1. The manner of stereocontrol can be explained as follows: one of the stereocenters is created in the first step, which is reversible and, consequently, thermodynamically controlled; hence, the S configuration is formed (see Scheme 6). The configuration of the second stereocenter is determined by the protonation step, which is kinetically controlled and nonselective. Since the electrogenerated base reacts with the complex in situ and it is produced exactly in a stoichiometric amount, further epimerization does not occur. The other reason for the formation of a significant amount of the diastereomer containing meso-diaminoglutaric acid in the electrosynthesis is the short reaction time: 5 min vs. 36 h in ref 37. It is known46 that the isomer 5-(S,R,S,S) can be converted to the more stable 5-(S,S,S,S) isomer via epimerization in the presence of a base and this process is slow (it requires 36−48 h to come to completion46). For both obtained diastereomers CD spectra were recorded. The CD spectrum for 5-(S,S,S,S) is almost identical with that for 3-(S,S,S,S) (Figure 6). However, the CD spectrum observed for 5-(S,R,S,S) is completely different (Figure 7). Since this diastereomer contains two stereocenters with opposite configurations, their vicinal contributions are also the opposite, resulting in a mutual compensation of the Cotton effects: Δε values in the maxima in CD spectrum of (S,R,S,S)-5 are ∼1/6 of that observed for (S,S,S,S)-5. The same effect was observed for the two diastereomers of 3.

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CONCLUSION The electrochemical properties of Gly-Ni, Ala-Ni, and Δ-AlaNi complexes were investigated using cyclic voltammetry. All three complexes are redox active in both anodic and cathodic potential ranges, but their electrochemical behaviors are substantially different. The oxidations of all complexes and the reduction of Δ-Ala-Ni are irreversible; this opens up the possibility to perform various chemical transformations of the starting complexes induced by electrochemical electron transfer. The possible sites of anodic and cathodic activation were determined using DFT estimations of the relative energy and symmetry of the frontier orbitals of the complexes. The predictions made from voltammetric and DFT estimations were completely supported by bulk electrolysis. When the type of electrochemical activation was varied (anodic vs cathodic vs application of electrogenerated base), it became possible to activate different redox-active sites in the coordination environment of the metal center, giving rise to various targeted regioselective coupling reactions yielding different types of binuclear Ni(II) complexes. Since electrochemically induced transformations occur in the coordination environment of chiral Ni(II) complexes, they allow targeted formation of certain diastereomers. Furthermore, the electrochemical approach allows the synthesis of compounds which were not available using common chemical protocols. Anodic activation of Gly-Ni and Ala-Ni results in the coupling of two Gly-Ni or two Ala-Ni groups via the para positions of benzene rings in the benzophenone moiety, yielding the enantiomerically pure binuclear Ni(II) complexes 1 and 2. Cathodic activation of Δ-Ala-Ni allowed the new chiral binuclear complex 3 to be obtained, containing two Gly-Ni groups linked with two methylene units between α-glycine carbon atoms. Electrochemical deprotonation of Gly-Ni using electrogenerated base (azobenzene radical anion) with

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EXPERIMENTAL SECTION

General Information. Voltammetric experiments were performed with a IPC-Win potentiostat and a one-compartment 10 mL cell with a platinum-wire counter electrode (CE) and Ag/AgCl/KCl(aq) reference electrode (RE). All potentials below refer to this reference electrode. The formal potential of the ferrocene couple (Fc/Fc+) versus our RE is about 0.48 V in AN + Bu4NBF4. The working M


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passed through a column with silica gel; a 9/1 ethanol/hexane mixture was used as an eluent. The first fraction contained unreacted Gly-Ni, and the second fraction was the dimeric complex. Compounds 1 and 2 were obtained as microcrystalline solids upon removal of the solvent. Yield of 1: 10 mg, 50% (98% as recalculated for the converted GlyNi), 20% of current efficiency. Yield of 2: 8,6 mg, 48% (96% as recalculated for the converted AlaNi), 22% of current efficiency. Compound 1. HRMS: m/z 992.2307 (M+, 992.2341 calculated for C54H48N6Ni2O6), 1015.2200 (M + Na+, 1015.2239 calculated for C54H48N6Ni2O6Na). 1H NMR (CDCl3; J, Hz; δ, ppm): 8.21 (d, 2H (H8), 3J = 9.0 Hz), 8.07−8.03 (m, 4H (H-17,21)), 7.54−7.39 (m, 10H (H-24,25,26,18,20)), 7.33−7.27 (m, 2H (H-19)), 7.04 (dd, 3J = 9.0 Hz, 4J = 2.3 Hz, 2H (H-7)), 7.02−6.98 (m, 2H (H-27)), 6.88 (m, 2H (H-23)), 6.71 (d, 4J = 2.3 Hz, 2H (H-5)), 4.46 (d, 2J = 12.7 Hz, 2H (Bn H-15)), 3.74 (d, 2J = 20.2 Hz, 2H (Gly H-2)), 3.73−3.67 (m, 2H (Pro H-14)), 3.64 (d, 2J = 12.7 Hz, 4H (Bn H-15)), 3.63 (d, 2J = 20.1 Hz, 2H (Gly H-2)), 3.44 (dd, 3J = 10.7, 5.5 Hz, 2H (Pro H-11)), 3.31−3.24 (m, 2H (Pro H-13)), 2.55−2.34 (m, 4H (Pro H-12)), 2.20−2.11 (m, 2H (Pro H-14)), 2.10−2.02 (m, 4H (Pro H-13)). 13 C{1H} NMR (CDCl3; δ, ppm): 181.64 (C-10), 177.28 (C-1), 171.71 (C-3), 141.84 (C-9), 134.46 (C-22), 133.39 (C-16), 132.18 (C-6), 131.92 (C-17,21), 130.69 (C-5), 130.25 (C-7), 130.03 (C-24), 129.91 (C-25), 129.60 (C-26), 129.31 (C-19), 129.08 (C-18,20), 126.09 (C27), 125.62 (C-23), 125.53 (C-4), 124.79 (C-8), 69.93 (C-11), 63.25 (C-15), 61.52 (C-2), 57.76 (C-14), 30.88 (C-12), 23.86 (C-13). Compound 2. MS (MALDI-TOF): m/z 1020 (M+). 1H NMR (CDCl3; J, Hz; δ, ppm): 8.03 (d, 3J = 8.9 Hz, 2H (H-8,17,21)), 8.03− 7.99 (m, 4H (H-24,26)), 7.55−7.50 (m, 4H (H-24,26)), 7.44−7.38 (m, 2H (H-25)), 7.37−7.33 (m, 4H (18,20)), 7.22−7.15 (m, 4H (H19,27)), 6.95 (dd, 3J = 9.0 Hz, 4J = 2.3 Hz, 2H (H-7)), 6.88−6.85 (m, 2H (H-23)), 6.55 (d, 4J = 2.3 Hz, 2H (H-5)), 4.39 (d, 2J = 12.7 Hz, 2H (Bn H-15)), 3.87 (q, 3J = 7.0 Hz, 2H (Ala H-2)), 3.74−3.64 (m, 2H (Pro H-13)), 3.58 (d, 2J = 12.7 Hz, 2H (Bn H-15)), 3.56−3.52 (m, 2H (Pro H-14)), 3.44 (dd, 3J = 11.2, 5.6 Hz, 2H (H-11)), 2.74−2.65 (m, 2H (Pro H-12)), 2.57−2.44 (m, 2H (Pro H-12)), 2.24−2.16 (m, 2H (Pro H-13)), 2.11−2.02 (m, 2H (Pro H-14)), 1.57 (d, 3J = 7.0 Hz, 6H (Ala CH3)). 13C{1H} NMR (CDCl3; δ, ppm): 180.64 (C-1), 180.47 (C-10), 170.42 (C-3), 141.44 (C-9), 133.35 (C-22), 133.23 (C-16), 132.06 (C-6), 131.74 (C-17,21), 130.60 (C-5), 130.05 (C-25), 129.96 (C-7), 129.23−129.10 (C-24, C-26, C-19), 129.06 (C-18,20), 127.48 (C-23), 127.11 (C-27), 126.85 (C-4), 124.45 (C-8), 70.24 (C11), 66.88 (C-2), 62.98 (C-15), 57.32 (C-14), 30.93 (C-12), 24.24 (C13), 22.04 (−CH3). Reductive Dimerization of Δ-Ala-Ni. A 20 mg portion (0.04 mmol) of Δ-Ala-Ni was dissolved in 10 mL of acetonitrile containing 164 mg (0.5 mmol) of Bu4NBF4. Potentiostatic electrolysis (E = −1.40 V) of the solution deaerated with an Ar flow was performed in a twocompartment cell using carbon felt as a working electrode. After a charge of 1.8 C (0.5 F/mol of Δ-Ala-Ni) was passed through the solution, its color changed from reddish orange to dark green and the current dropped to 0. After that 20 mcL (0.4 mmol) of acetic acid was added and the resulting solution was evaporated under reduced pressure. The residue was dissolved in a minimum amount of CHCl3 and the solution was passed through a column with silica gel; a 2/1 (v/ v) ethanol/hexane mixture was used as an eluent. Two fractions were eluted, and after removal of the solvent two diastereomers of 3 were obtained: 10.26 mg of 3-(S,S,S,S) (51% yield) and 7.8 mg of 3(S,S,R,S) (39%). The total current efficiency was 90%. 3-(S,S,S,S). HRMS: m/z 1021.2709 (M + H+, 1021.2733 calculated for C56H53N6Ni2O6), 1043.2534 (M + Na+, 1043.2552 calculated for C56H52N6Ni2O6Na), 1059.2273 (M + K+, 1059.2291 calculated for C56H52N6Ni2O6K). 1H NMR (CDCl3, J, Hz; δ, ppm): 8.33 (dd, 3J = 8.7 Hz, 4J = 0.9 Hz, 2H (H-8)), 8.05−8.01 (m, 4H (H-17,21)), 7.53− 7.44 (m, 4H (H-24,26)), 7.37−7.31 (m, 4H (H-18,20)), 7.25−7.12 (m, 8H (H-27,25,7,19)), 6.63 (ddd, 3J = 8.1 Hz, 6.9 Hz, 4J = 1.2 Hz, 2H (H-6)), 6.58−6.54 (m, 4H (H-23,5)), 4.41 (d, 2J = 12.7 Hz, 2H (Bn H-15)), 4.02 (dd, 3J = 7.2, 2.0 Hz, 2H (H-2)), 3.52 (d, 2J = 12.7 Hz, 2H (Bn H-15)), 3.48−3.39 (m, 4H (Pro H-11,14)), 3.24−3.12 (m, 2H (Pro H-13)), 3.10−3.00 (m, 2H (β-CH2)), 2.57−2.47 (m, 2H

electrode (WE) was a Pt-disk electrode with an active surface area of 0.049 cm2. Ohmic drop corrections were performed using the convolution approach,4 as well as an estimation of a number of electrons consumed in the electrochemical processes. The latter was referenced to the value obtained for Gly-Ni taken as a standard. All solutions were thoroughly deaerated by passing Ar through the solution prior to the CV experiments and above the solution during the measurements; the supporting electrolyte in all experiments was 0.05 M n-Bu4NBF4 (Aldrich, purity >99%), which has been dried under vacuum prior to use. Preparative electrolysis was performed with a P-5827 M potentiostat with an output voltage of 200 V in 10 mL cells of two types: one or two compartments. The WE was graphite felt (10 mm × 25 mm) with an internal surface area of 12 m2/g or a Pt plate (5 × 20 mm); the CE was a platinum plate or an aluminum wire. The solution was stirred with an argon flow or with a magnetic stirrer. Anhydrous potassium phosphate was added to the counter electrode compartment to absorb possibly forming protons. MALDI mass spectra were recorded using a Bruker Daltonics AutoFlex II reflector time-of-flight mass spectrometer equipped with a N2 laser (337 nm, 3 ns pulse) and anthracene as a matrix. Highresolution MALDI mass spectra were recorded using a Bruker micrOTOF II Transform mass spectrometer with electrospray ionization. 1 H (400.0 MHz) and 13C (100.6 MHz) NMR spectra (including COSY, HMBC, HSQC, HMQC, and NOE1D) were recorded using an Aglient 400-MR spectrometer in CDCl3. Chemical shifts were referenced to the nondeuterated aliquot of the solvent. CD spectra were recorded using a CCD-2 instrument for 2−5 M methanol solutions in a 1 cm cuvette. DFT calculations were carried out with the PRIRODA quantum chemistry program.54,55 The gradient-corrected exchange-correlation Perdew, Burke, and Ernzerhof (PBE) functional56 and basis sets L1 and L22 were used for calculations.57 The 10−5 threshold on the molecular gradient at the geometry optimization procedure was employed. Acetonitrile (AN, Aldrich spectroscopic quality,

Chiral Nickel(II) Binuclear Complexes: Targeted Diastereoselective

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