Copper Complexes in the Promotion of Aldol Addition to Pyridine-2-carboxaldehyde: Synthesis of Homo- and Heteroleptic Complexes and Stereoselective Double Aldol Addition

1 Copper complexes in the promotion of aldol addition to pyridine-2-carboxaldehyde: synthesis of homo and heteroleptic complexes and stereoselective double aldol addition Lucía Álvarez-Miguel,† Héctor Barbero,† Adriana Sacristán-Martín, † José M. Martín Álvarez,† Alfonso Pérez-Encabo,‡ Celedonio M. Álvarez, † Raúl García-Rodríguez,†* Daniel Miguel.†* †GIR MIOMeT/IU CINQUIMA/Química Inorgánica, Facultad de Ciencias Universidad de Valladolid, Paseo de Belén 7, E-47011 Valladolid Spain. ‡ IU CINQUIMA/Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7, E-47011 Valladolid, Spain. 2 ABSTRACT CuCl2·2H2O and Cu(ClO4)2·6H2O are able to promote aldol addition of pyridine-2- carboxaldehyde (pyca) with acetone, acetophenone or cyclohexenone under neutral and mild conditions. The general and simple one pot procedure for the aldol addition to Cu(II) complexes accesses novel Cu complexes with a large variety of different structural motifs, from which the aldol-addition ligand can be liberated by treatment with NH3. Neutral heteroleptic complexes in which the ligand acts as bidentate, or homoleptic cationic complexes in which the ligand acts as tridentate can be obtained depending on the copper salt used. The key step in these reactions is the coordination of pyca to copper, which increases the electrophilic character of the aldehyde, with Cu(ClO4)2 leading to a higher degree of activation than CuCl2, as predicted by DFT calculations. A regio- and stereoselective double aldol addition of pyca in the reaction of Cu(ClO4)2·6H2O with acetone leads to the formation of a dimer copper complex in which the novel double aldol addition product acts as a pentadentate ligand. A possible mechanism is discussed. The work is supported by extensive crystallographic studies. KEYWORDS: copper complexes, aldol addition, pyridyl ligands, metal activation, double aldol addition. INTRODUCTION Copper is a cheap and ubiquitous metal and one of the most abundant transition metals present in living systems. It is very active in promoting a large number of catalytic and stoichiometric transformations due to its Lewis acid character and its redox activity, which makes the use of copper complexes very attractive in modern organic chemistry. 1 In particular, copper is able to promote C-C and C-heteroatom bond formation through aldol addition and related processes, and 3 it has been extensively used, together with chiral ligands, in the catalytic enantioselective synthesis of chiral molecules. 2 Aldol reactions are among the most powerful tools for the creation of C-C bonds. 3 , 4 The popularity of this reaction stems from the large library of protocols available, which allows the chemist great control and selectivity over the final product. In these reactions, an enolizable carbonyl compound with acidic hydrogens in the alpha position acts as a nucleophile towards an electrophilic carbonyl, typically an aldehyde or ketone (see Scheme 1a). The control in aldol addition relies on the choice of the enolizable carbonyl and the carbonyl electrophile precursor. Depending on the strategy chosen, it is possible to obtain different chemoselective, regioselective, diastereoselective, and enantioselective aldol products.3, 5 Despite providing a great level of control, existing methods rely on the use of additives, usually accompanied by strongly basic or acidic conditions. For instance, strong bases such as LDA are normally used to generate the lithium enolate. For the formation of silicon and boron enolates, additional reagents, such as TMSCl or expensive dialkylboron triflate, are required. The ‘preformed’ enolate subsequently reacts with the carbonyl electrophile, usually in the presence of a Lewis base or a Lewis acid (typically TiCl4) that enhances its electrophilic character (see Scheme 1b). 5b, 6 4 Scheme 1. a) General aldol addition under strongly basic conditions. b) Aldol reaction via preformed enolates. Considerable efforts have gone into developing methods for the “direct” aldol reaction, in which the compounds undergoing reaction are activated ‘in situ’ to avoid the preparation of a ‘preformed’ enolate in a separate step, as well as into finding more tolerant Lewis acids capable of activating the carbonyl in milder conditions. 7 Since the seminal work by Evans, 8 in which the enantioselective addition of silyl enolates to (benzyloxy)acetaldehydes, which act as chelating electrophiles, was achieved using a chiral Cu(II) catalyst, a large number of copper (II) complexes have emerged as convenient catalysts for the aldol reaction. 9 Despite the large number of examples of Cu(II) complexes employed in the aldol addition, most methodologies are based on preactivated silyl enolates; comparatively few examples of the use of Cu(II) complexes in the direct aldol2a,2e, 10 or nitro-aldol 11 reaction are known. For instance, Cu(II) complexes derived from ortho substituted pyridine ligands have been shown to be highly efficient catalysts in the direct asymmetric aldol reactions of ketones while keeping very good stereoselectivity10e,10f. In light of the wide use of Cu(II) in catalysis, the formation of copper complexes with molecules derived from aldol addition has been relatively less explored, and there is still a lack of general protocols available to access such compounds. 12 Given the great structural diversity of Cu(II) complexes, the study of the structures of Cu(II)-aldol ligand complexes could also be beneficial to the understanding of the exact catalytic mechanisms. Recently, a few examples of self-aldol type reactions in which the product remains coordinated to copper as a ligand in the 5 coordination sphere of copper (II) have been published; however, these required strongly basic conditions. 13 In the course of our previous studies of the Schiff condensation reactions of pyridine-2- carboxaldehyde (pyca) with peptides and other molecules 14 we found some very interesting examples of the addition of acetone to pyca in manganese(I) and rhenium(I) carbonyl systems. 15 These reactions required the previous coordination of pyca to the metal complex (by thermally induced carbonyl substitutions) and the use of an appropriate halogen extractor reagent in order to create a coordination vacancy. Cu(II) complexes such as CuCl2 and Cu(ClO4)2 are harder Lewis acids that have several available coordination sites and flexible coordination geometries as a result of the d9 configuration. We anticipated that the ability of copper (II) to promote aldol addition could be exploited to design simple methods for the preparation of complexes containing mixed N,O donors derived from the aldol additions of ketones to pyca. Our approach, although a simple one, echoes the way that class II aldolases are used in nature, which has inspired the development of several small molecule catalysts. 16 Class II aldolases use as a cofactor a transition metal that acts as a Lewis acid (typically Zn2+ although other divalent transition metals such as Fe2+ or Co2+ are known). 17 Bidentate coordination of the carbonyl substrate acidifies the -protons, so that the resulting metal enolate can subsequently attack a hydrogen-bonding activated carbonyl to give the aldol product upon decomplexation. We envisioned that the use of pyca as chelate ligand would promote the activation of the electrophile through strong bidentate coordination to Cu(II), while the presence of additional binding sites would be used to simultaneously acidify the -protons of the ketone, thus facilitating the formation of the enolate (see Fig 1). 6 Figure 1. Scheme of the synthetic approach for the in situ aldol addition promoted by Cu(II). Our aim herein is to explore the possibility of using cheap and easily available Cu(II) sources under aerobic and neutral conditions to promote aldol reaction with several objectives in mind: i) To devise facile and simple procedures for the preparation of complexes containing mixed N,O ligands via in situ aldol addition to Cu(II) complexes, including the subsequent liberation of the aldol product from the complex. ii) To study the dependence of the reactivity patterns on the Cu(II) source employed. Additionally, we report a novel and stereoselective double aldol addition of acetone to pyca. The work is supported by extensive crystallographic analyses of the complexes. RESULTS AND DISCUSSION We started our studies with the one pot reaction of CuCl2·2H2O with 1 equivalent of pyridine- 2-carboxaldehyde (pyca) in acetone, in order to assess whether the copper complex could promote the aldol addition under mild conditions. After 10 h at room temperature, green microcrystals of 1a were obtained in virtually quantitative yield (92%). The structure of 1a was studied by X-ray crystallography, revealing that complex 1a contains a 2(N,O) hydroxyketone ligand (HL1a) that results from the aldol addition of acetone to the aldehyde carbon of pyca (see Fig 2 and Scheme 2). The coordination around copper is completed by two chloride ligands, 7 forming a nearly planar arrangement around the copper atom. In solid state, the molecules are arranged in the lattice to form centrosymmetric dimers through longer Cu-Cl interactions of 2.756(2) Å, as shown in Fig 2, and therefore the copper atom can be considered to lie in a nearly square pyramidal pentacoordinated environment, in which the Addison parameter (τ) is 0.18. 18 The quantitative formation of 1a from CuCl2 is quite remarkable since it shows the ability of the copper complex to promote the aldol addition of acetone to the pyca aldehyde in the absence of a base and under mild conditions. Although the high thermodynamic stability of the resulting complex is usually the driving force for the formation of the ligand in the coordination sphere of the metal, it may make the liberation of the ligand difficult.13,15 Therefore we moved next to test whether the hydroxyketone ligand derived from the aldol addition of acetone to pyca (HL1a) could be liberated from complex 1a. To our delight we found that this task can be easily accomplished by simple treatment of the complexes with NH3/CH2Cl2 (see experimental part) which resulted in the easy liberation and isolation of the pyridyl ligand HL1a from the complex 1a. Figure 2. Structure of 1a showing the association into dimers in solid state through Cu-Cl interactions. Selected bond lengths (Å) and angles (º): Cu(1)-Cl(1) 2.216(2), Cu(1)-Cl(2) 2.254(1), Cu(1)-Cl(2A) 2.757(2), Cu(1)-N(1) 2.008(4), Cu(1)-O(1) 1.996(3), N(1)-Cu(1)-O(1) 8 78.40(0), Cl(1)-Cu(1)-Cl(2) 96.45(6), Cl(2)-Cu(1)-Cl(2A) 91.72 (5). H-Bonding: O(1)-H(1) 0.938(0), O(1)…O(2) 2.679(4), H(1)…O(2) 1.945(4), O(1)-H(1)…O(2) 133.5(3). A possible reaction pathway for the formation of complex 1a would involve initial coordination of one molecule of pyca as a chelate 2(N,O) to CuCl2 to give an intermediate complex I in which the electrophilic character of the aldehyde is increased, favoring the attack of the acetone enolate to give 1a (Scheme 2). The coordination sphere of I is not saturated, so a molecule of acetone could additionally interact with the complex, increasing the acidity of the - hydrogen atoms of the ketone.17a This further facilitates the attack to the activated pyca aldehyde so that the aldol reaction occurs under mild and neutral conditions to give complex 1a. All attempts to produce a second aldol addition by reacting 1a with 1 equivalent of pyca and acetone did not work; unreacted 1a was recovered in all cases. This is perhaps not surprising since the coordination and activation of a second molecule of pyca and acetone are compromised due to the presence of the pyridyl hydroxyketone ligand HL1a and the two chloride ligands. 9 Scheme 2. Reaction of CuCl2·2H2O with pyridine-2-carboxaldehyde (pyca) to give complex 1a, featuring the 2(N,O) hydroxyketone ligand (HL1a) that results from the in situ aldol addition of acetone to pyca. The reaction involves the intermediacy of a complex in which pyca coordinates to CuCl2 in a chelate fashion (I). Although this complex could not be isolated, addition of an excess of pyca resulted in the precipitation of complex 2, thus demonstrating the coordination of pyca as a chelate to Cu. Although attempts to isolate any intermediate from the reaction mixture have failed so far, the reaction of CuCl2·2H2O in acetone with an excess of pyridine-2-carboxaldehyde (3 equivalents) results in the clean precipitation of complex 2 after 15 min, which can be isolated in virtually quantitative yield (95%). Fig 3 shows the structure of compound 2, which contains two molecules of pyca coordinated in a chelating fashion to copper through the nitrogen atom of the pyridine ring and the oxygen atom of the aldehyde group as 2-(N,O) chelate. The structure of 2 16 It is worth mentioning that the deprotonation of the complex 1a can also occur after prolonged storage in solution and in the absence of a base. Storage of compound 1a in methanol at room temperature yielded the formation of a few crystals of 3a after 48 h. This result not only illustrates the increased acidity of the hydroxyl groups as a result of the coordination to copper, but the also the ability of the alkoxo/OH ligand to form bridges.As described above, the success of the aldol reaction promoted by CuCl2 seems to involve several factors. Firstly, coordination of pyca to copper enhances the electrophilic character of the aldehyde, and secondly, the Cu(II) atom increases the acidity of the -hydrogen atoms of the ketone in such a way that aldol addition occurs under mild conditions. Scheme 5. Aldol addition of acetone to pyca in cationic Cu(II) complexes With this background in mind, we decided to explore the use of Cu(ClO4)2·6H2O in the aldol addition. Replacing Clwith ClO4- results in an increase of the Lewis acidity of Cu, which in turn leads to a higher degree of activation for the pyca aldehyde, as shown by DFT calculations (see above, Fig 4). In addition to this, the choice of a much less coordinating ligand (ClO4- instead of Cl-) not only opens up more coordination sites but should also enhance the activation of the ketone by interacting with Cu, which is now more available for coordination. To test these ideas, we reacted Cu(ClO4)2·6H2O and pyca with acetone or acetophenone at room temperature in THF 17 (Scheme 5). The reaction resulted in the fast (cf 10 h for 1a vs 4 h for 4a) formation of cationic homoleptic complexes 4a and 4b that are now formed by the coordination of two ligands (HL1a and HL1b for 4a and 4b, respectively) from the aldol reaction to the pyca aldehyde. In these structures, the ketone from the ligand HL1a or HL1b is now strongly bound to Cu (Cu(1)-O(1) 2.038(3)) in contrast with previous neutral complexes derived from CuCl2 (see for instance 1a-c and 3a) so that ligands HL1a and HL1b now act as a tridentate chelating ligands  3(N, O, O’) as shown in Fig 7 for complexes 4a and 4b. Both structures are similar, having in both cases a distorted octahedral geometry around the Cu that arises from the coordination of two ligands in a tridentate fashion, reflecting the poor coordinating ability of ClO4- compared to Cl-. Figure 7. a) Structure of the dication in 4a, showing the atom numbering. The two ClO4 anions have been omitted for clarity. Selected bond lengths (Å) and angles (º): Cu(1)-N(1) 1.945(4), Cu(1)-O(1) 2.038(3), Cu(1)-O(2) 2.283(4), O(1)-Cu(1)-N(1) 82.18(2), O(2)-Cu(1)-N(1) 86.47 (2), O(1)-Cu(1)-O(2) 79.54(2). b) Structure of the dication in 4b, showing the atom numbering. The two ClO4 anions have been omitted for clarity. Selected bond lengths (Å) and angles (º): Cu(1)-N(1) 1.966(5), Cu(1)-O(1) 1.904(4), Cu(1)-N(2A) 1.978(5), Cu(1)-O(1A) 1.948(4), Cu(1)- O(2A) 2.336 (4), Cu(1)-Cu(1A) 2.948(2), N(1)-Cu(1)-N(2A) 106.4(2), N(1)-Cu(1)-O(1) 82.21(2), O(1)-Cu(1)-O(1A) 80.14(2). a) b) 18 We noticed that the synthesis of 4a led to very small amounts of additional species (as observed by 1H NMR analysis of the reaction crude). After several tries to optimize the reaction conditions to study these new species, we found that the optimal conditions were to carry out the reaction in a CH2Cl2/acetone mixture (see experimental part). In this way, it was possible to isolate a small fraction of pale blue crystals of the binuclear complex 5 from the synthesis of complex 4a (15 % crystalline yield) (Fig 8a). The X-ray structure reveals that the dimer contains a novel anionic ligand (HL5-) which results from the double aldol addition of pyca to one of the carbons of acetone (see Fig 8b and 8c). Therefore, the dimer 5 is formed by two H2L5 ligands in which one of the OH groups of each ligand is deprotonated and the resulting alkoxo group Figure 8. (a) Diagram of complex 5 showing that it consists of 2 anionic HL5- ligands. (b) X ray structure of the dication 5. The structure contains two ClO4- anions that have been omitted for clarity. Selected bond lengths (Å) and angles (º): Cu(1)-N(1) 1.966(5), Cu(1)-O(1) 1.904(4), Cu(1)-N(2A) 1.978(5), Cu(1)-O(1A) 1.948(4), Cu(1)-O(2A) 2.336 (4), N(1)-Cu(1)-N(2A) 106.4(2), N(1)-Cu(1)-O(1) 82.21(2), O(1)-Cu(1)-O(1A) 80.14(2). (c) H2L5 ligand that results from the double addition of pyca to the same carbon of acetone. The ligand has three stereogenic centers; one of them, marked in red, is pseudo asymmetric. Note: Compound 5 is present as a mixture of stereoisomers. The X ray diffraction structure c) b) a) H2L5 19 shown in Fig 5b corresponds to only one of these stereoisomers. See Scheme 5 and later discussion. bridges together two Cu atoms in a central Cu2O2 ring analogous to the one present in complex 3a and similar to the structure of other dicopper complexes prepared in the literature by other means. 20 Although some cases of double aldol addition have been reported recently, 21 these were conducted with an excess of a strong Lewis acid such as SiCl4 or in strongly basic conditions. In these examples, the double addition product does not act as a ligand. The formation of 5, however, proceeds at room temperature and in the absence of a base, and the novel HL5- ligands act as pentadentate 5 (N,O,O’,O’’,N’’) in which each pyridine arm coordinates a Cu atom. Importantly, 1H NMR analysis of the reaction crude of several reactions showed that the second aldol reaction is regio- and stereoselective. Upon liberation of the H2L5 ligand, three species are observed, in a ratio of 47.5: 47.5: 5, all of which originate from the addition of two molecules of pyca to the same carbon of the acetone. That is, after the first aldol addition of pyca to acetone to give the simple aldol product, HL1a, the subsequent second aldol addition occurs via the attack of the methylene -carbon protons to a second molecule of pyca. This implies that the reaction is regioselective and that the H2L5 ligand is produced exclusively as the double aldol product (i.e., there are no species resulting from the CH3 enolate). The H2L5 ligand contains three chiral carbons (see Fig 8c), one of which is pseudo-asymmetric, and could be present as a mixture of 4 stereoisomers: two meso compounds, RRS and RSS, and a pair of enantiomers, RR/SS (with coincident NMR signals), see the SI for details and notation. Out of these four stereoisomers, only the pair of enantiomers (RR/SS) and one of the meso forms are produced in significant proportions, while the formation of the other meso form is negligible (< 5% of the double aldol product), thus giving rise to the two majority species observed by NMR (see SI for further 20 discussion and details). In other words, the double aldol addition of pyca to acetone promoted by Cu(ClO4)2·6H2O is regio and stereoselective. Although we do not know the exact details of this selectivity, we believe that coordination to copper plays a key role. Scheme 6 shows a tentative mechanism for the production of 5 and the observed stereoisomers. Initially, activation of pyca through coordination to Cu promotes the first aldol addition with acetone to produce a heteroleptic complex with an HL1a ligand strongly coordinated in a  tridentate fashion (compound I in Scheme 6). This complex could give the homoleptic complex 4a via a second aldol reaction. However, the formation of 5 does not seem to involve the intermediacy of the homoleptic complex 4a (see Scheme 6, path a), because reaction of 4a with pyca and Cu(ClO4)2·6H2O in the presence or absence of a base (K2CO3 or KOH) does not lead to the formation of 5. We also note that due to geometric restraints the intramolecular attack of pyca (i.e., from coordination of pyca to the same Cu complex instead of from a second Cu complex) is prevented (Scheme 6, path c). Therefore the formation of 5 appears to involve an intramolecular mechanism. We propose that the reaction involves the initial formation of a dimer between compound I and another Cu-pyca complex to give complex II (see Scheme 6 path b). The formation of such a complex is key because: i) it brings together a second molecule of pyca activated by coordination of Cu; ii) it restrains the reaction of the HL1a ligand to the closer CH2 group (regioselectively) so that it would react with the pyca aldehyde though only one of the enolate faces (i.e the face of the enolate pointing towards the O bridge rather than the one pointing to the HL1a pyridine). Although the enolate can react through only one of its faces (stereoselectively), it is able to attack both faces of the aldehyde (path b, above and below), 21 yielding the two observed H2L5 species: a pair of Scheme 6. Tentative mechanistic pathway for the stereo and regioselective formation of 5, involving a double aldol addition of pyca to acetone. The reaction produces the novel H2L5 ligand as a mixture of a pair of enantiomers (RR/SS) and the meso compound RSS, so two sets of signals are observed by NMR. For the sake of clarity, the diagram only shows the attack starting from the R-HL1a ligand in intermediate I to give RR and the meso compound RSS. Attack from the other enantiomer, S-HL1a (not shown) leads to the formation of SS and the meso compound SSR (same molecule as RSS). Note that the very small amount of the meso compound RRS (5%) observed by NMR could suggest that the coordination of the ketone in 22 HL1a in I is not strong enough to completely restrict the reaction of the enolate to one of the faces. enantiomers (RR/SS, with coincident NMR signals) and the meso compound RSS, but preventing the formation of the meso compound RRS. The formation of complex 5 would involve another sequence of reaction between a pyca molecule and a HL1a ligand to complete the formation of the dimeric complex shown in Fig 8. This is most straightforwardly realized from the intermolecular reaction between two heteroleptic Cu(HLa)(Pyca) complexes. Repeated attempts to produce double aldol addition of pyca to acetone under similar conditions using CuCl2·2H2O failed. This points out the critical role of the choice of the appropriate metal precursor with the right balance of Lewis acidity to produce a high enough degree of activation to the pyca aldehyde to undergo a second aldol addition to acetone while retaining regio- and stereoselectivity. The success of the reaction to obtain 5 therefore requires a metal complex precursor with enough Lewis acidity to promote a second aldol addition of pyca to acetone and with a non-saturated coordination sphere so that formation of the O bridge can easily occur. The latter is also provided by weakly coordinated ClO4- ligands, which also guarantee that the product of the first aldol addition, the HL1a ligand, is strongly coordinated in a tridentate fashion, thus defining the attacking face of the enolate. The very small amount of the other meso compound could suggest, however, that the ketone coordination of HL1a is not strong enough to induce complete stereoselectivity. In principle, this reactivity could potentially be extended to other copper complexes that fulfill these requirements. In order to extend this reactivity to similar electron deficient complexes of copper, we also used Cu(BF4)2·6H2O as a metal precursor instead of Cu(ClO4)·6H2O. We found that Cu(BF4)2 can also be used in this regio- and stereoselective double aldol reaction of acetone 23 and pyca, producing 5·BF4, the complex analogous to 5 with BF4- anions instead of ClO4-. The reaction proceeds with similar yields (15%, see experimental part) and the complex 5·BF4 could also be studied crystallographically (see the SI). CONCLUSION In conclusion, we found that the ability of copper to promote aldol addition can be used advantageously to develop procedures for the preparation of complexes in which the products of the aldol addition act as ligands in neutral complexes, when starting from CuCl2·2H2O, or cationic homoleptic complexes, when starting from Cu(ClO4)2·6H2O. The copper atom in these reactions plays a twofold role: i) the coordination of the oxygen of the ketone promotes the formation of the corresponding enolate and ii) the coordination of the oxygen of the aldehyde group of pyca enhances the electrophilic character of the aldehyde carbon, as shown by the calculations. The degree of activation of the pyca aldehyde depends on the choice of the metal precursor, thus opening a way to modulate its reactivity. More Lewis acidic Cu precursors such as Cu(ClO4)2 or Cu(BF4)2 result in a higher degree of activation. In these cases, in addition to the formation of the simple aldol product, a small amount of double addition of pyca to acetone through a regio- and stereoselective reaction under mild and neutral conditions is also observed. EXPERIMENTAL SECTION Materials and general methods. All reagents were purchased and used without further purification. Solvents were used as purchased. Kieselguhr (diatomaceous earth, Merck) was used for filtration. Column chromatography separations were carried out using silica gel 60 (particle size 0.040-0.063 mm; 230-400 mesh; Merck, Germany) as the stationary phase, and TLC was performed on pre-coated 24 silica gel plates (0.25 mm thick, 60 F254, Merck, Germany) and observed under UV light. NMR spectra were recorded on Agilent DD2 500 instruments. 1H and 13C NMR chemical shifts (δ) are reported in parts per million (ppm) and are referenced to TMS, using solvents as internal references. Coupling constants (J) are reported in hertz (Hz). Standard abbreviations are used to indicate multiplicity: s = singlet, d = doublet, t = triplet, m = multiplet. 1H and 13C assignments were performed by utilizing 2D NMR methods (COSY, gradient CRISIS-HSQC, and gradient CRISIS-HMBC). 22 Some quaternary carbon atoms were not detected, but they were located with the help of a 1H-13C HMBC experiment. IR spectra of solid samples were recorded with a Frontier Perkin Elmer Spectrum RX I FT-IR instrument. The magnetic moments were calculated from magnetic susceptibilities which were measured in Unidade de Magnetosusceptibilidade of Santiago de Compostela University. Elemental analyses were performed using a Perkin-Elmer 2400B microanalyzer. XRPD measurement (X-Ray Powder Diffraction) was performed in the Laboratory of Instrumental Techniques of the University of Valladolid (L.T.I., www.laboratoriotecnicasinstrumentales.es) using a Bruker Discover D8. The XRPD patterns of all isolated compounds were coincident with those predicted by the software package MERCURY from the X-ray single crystal analysis (see SI) thus confirming the identity of the bulk product. High resolution mass spectra were recorded at the mass spectrometry service of the Laboratory of Instrumental Techniques of the University of Valladolid as well. A MS-TOF (MS: Bruker Maxis Impact) by electrospray ionization (positive and negative ESI) was utilized. The HRMS spectra were analyzed using Bruker DataAnalysis 4.1© (www.bruker.com). Synthesis of complex 1a To a green solution of CuCl2·2H2O (0.170 g, 1 mmol) in acetone (15 mL) was added pyridine- 2-carboxaldehyde (pyca) (0.107 g, 1 mmol) with stirring. After 10 hours, a green precipitate 25 appeared. The solid was isolated by filtration with a fritted funnel. Yield 0.275 g, 92%. Anal. Calcd. for C9H11Cl2CuNO2: C 36.06, H 3.70, N 4.67. Found C 36.23, H 3.63, N 4.17. μeff(293K) 1.61 MB. A crystal suitable for X-ray determination was obtained by slow evaporation of a solution of CuCl2·2H2O with pyca in acetone. Synthesis of complex 1b To a green solution of CuCl2·2H2O (0.170 g, 1 mmol) in THF (15 mL) was added pyridine-2- carboxaldehyde (pyca) (0.107 g, 1 mmol) and acetophenone in excess (0.600 g, 5 mmol) with stirring for 16 hours. The resulting solution was concentrated, and hexane was added to obtain a green precipitate that was isolated by filtration and washed with hexane (3 x 10 mL). Yield 0.303 g, 84%. Anal. Calcd. for C14H13Cl2CuNO2: C 46.49, H 3.62, N 3.87. Found C 46.35, H 3.63, N 3.92. μeff(293K) 1.52 MB. A crystal suitable for X-ray determination was obtained by slow evaporation of a solution of CuCl2·2H2O (0.1 mmol) with pyca (0.1 mmol) in acetophenone (1 mL). Synthesis of complex 1c To a green solution of CuCl2·2H2O (0.170 g, 1 mmol) in THF was added pyridine-2- carboxaldehyde (pyca) (0.107 g, 1 mmol) and 2-cyclohexen-1-one in excess (0.480 g, 5 mmol), and the solution was stirred for 16 hours. After this time, an oil precipitate appeared. The crude was stirred with THF/ether 1:4 in an ultrasonic bath until a solid precipitate was obtained, which was isolated by filtration with a fritted funnel and dried under vacuum. Yield 0.290 g, 86%. Anal. Calcd. for C12H13Cl2CuNO: C 42.68, H 3.88, N 4.15. Found C 42.31, H 3.57, N 4.03. μeff(293K) 1.46 MB. A crystal suitable for X-ray determination was obtained by slow evaporation of a solution of CuCl2·2H2O (0.1 mmol) with pyca (0.1 mmol) in cyclohexenone (1 mL). 32 Supporting Information. The supporting information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.XXXXX. Crystallographic data (CIF), comparison of XRPD patterns of the bulk samples and the patterns predicted by XRD single crystal analysis, graphs of χM vs T for complexes 3a and 5, HRMS spectrum of ligand H2L5 and 1H NMR spectra of free ligands HL1a-c and H2L5. AUTHOR INFORMATION Corresponding Author *E-mail for D. M.: [email protected]; E-mail for R. G-R.: raul.ga[email protected] Author Contributions The manuscript was written through contributions of all authors. ACKNOWLEDGMENT This research was supported by the Spanish Ministerio de Economía y Competitividad (MINECO) (project number CTQ 2013-41067-P). R. G.-R. acknowledges the Spanish MINECO-AEI and the European Union (ESF) for a Ramon y Cajal contract (RYC-2015–19035). ABBREVIATIONS Pyca, pyridine-2-carboxaldehyde. 33 1a 1b 1c 2 Formula C18H22Cl4Cu2N2O4 C14H13Cl2CuNO2 C28H34Cl4Cu2N2O5 C12H10Cl2CuN2O2 Mf 599.25 361.69 747.45 348.66 crystal system triclinic orthorhombic monoclinic monoclinic space group P 1 Pbca P21/c P21/c a [Å] 8.5131(8) 7.8681(5) 19.0706(5) 7.2339(7) b [Å] 8.6879(8) 17.6088(18) 11.9615(3) 8.4932(11) c [Å] 9.1287(7) 20.976(3) 14.8605(4) 11.2227(10)  [º] 93.824(7) 90 90 90.00 β [º] 114.005(9) 90 107.578(3) 94.101(9) γ [º] 105.792(9) 90 90 90.00 V [Å3] 581.28(10) 2906.1(5) 3231.57(16) 687.75(13) Z 1 8 4 2  [Mgm–3] 1.712 1.653 1.536 1.684 µ(Mo K) [mm–1] 2.316 1.869 1.685 1.973 crystal size [mm] 0.2084×0.1521×0.1131 0.29×0.0827×0.0605 0.3484×0.136×0.1154 0.295× 0.128 × 0.094 F(000) 302.0 1464.0 1528.0 350.0  range [º] 4.974 to 57.186 4.626 to 57.162 4.076 to 57.218 5.64 to 57.56 reflns collected 3724 7468 13830 2743 indep. refl. [R(int)] 2577 [0.0309] 3294 [0.0814] 7192 [0.0258] 1547 [0.0324] GOF on F2 1.086 1.036 1.033 0.895 Data/restraints/parameters 2577/0/137 3294/0/181 7192/0/370 89/0 R1 (on F, I > 2 (I)) 0.0583 0.0794 0.0479 0.0574 wR2(on F2, all data) 0.1081 0.1774 0.1195 0.1693 Max/min   [eÅ-3] 0.67/-0.36 0.53/-0.47 0.61/-0.44 1.27/-0.54 CCDC number 1576053 1576054 1576055 1491834 34 3a 4a 4b 5 Formula C36H40Cl4Cu4N4O8 C18H22Cl2CuN2O12 C36H34Cl2CuN2O13 C36H46Cl2Cu2N4O18 Mf 1052.68 592.81 837.09 1020.75 crystal system orthorhombic triclinic monoclinic triclinic space group Fddd P 1 P21/n P 1 a [Å] 14.5777(7) 7.8646(5) 12.9342(3) 7.5652(7) b [Å] 21.1806(8) 8.5460(8) 10.6919(3) 11.0310(11) c [Å] 29.7098(12) 9.4424(8) 26.9101(7) 14.7049(14)  [º] 90 75.641(7) 90 104.540(9) β [º] 90 79.517(6) 94.257(2) 103.136(9) γ [º] 90 76.302(7) 90 103.882(8) V [Å3] 9173.3(7) 592.18(9) 3711.16(15) 1097.9(2) Z 8 1 4 1  [Mgm–3] 1.524 1.662 1.498 1.544 µ(Mo K) [mm–1] 2.111 1.213 0.801 2.992 crystal size [mm] 0.387×0.246×0.147 0.2631×0.1911×0.1005 0.4313×0.3083×0.2226 0.1552×0.0704×0.0552 F(000) 4256.0 303.0 1724.0 526.0  range [º] 5.332 to 59.024 4.492 to 57.176 4.1 to 59.688 6.522 to 143.61 reflns collected 7783 3773 20894 6996 indep. refl. [R(int)] 2775 [0.0366] 2655 [0.0227] 8957 [0.0255] 4168 [0.0556] GOF on F2 1.076 1.050 1.045 0.977 Data/restraints/parameters 2775/0/128 2655/68/189 8957/136/544 4168/68/314 R1 (on F, I > 2 (I)) 0.0384 0.0614 0.0624 0.0739 wR2(on F2, all data) 0.0991 0.1717 0.2078 0.2413 Max/min   [eÅ-3] 0.45/-0.47 0.50/-0.34 0.70/-0.59 0.55/-0.70 CCDC number 1576056 1576057 1576058 1576059 35 REFERENCES ( 1 ) a) Zweifel, G. S.; Nantz, M. H.; Somfai, P. Organocopper Reagents. In Modern Organic Synthesis: An Introduction, 2nd Ed., 2017. ( 2 ) For selected recent examples see a) Weidner, K.; Sun, Z.; Kumagai, N.; Shibasaki, M. Direct Catalytic Asymmetric Aldol Reaction of an α-Azido Amide. Angew. Chem., Int. Ed. 2015, 54, 6236-6240. b) Li, Z.; Li, R.; Gan, M.; Lan, J.; Li, Z. Copper-catalyzed domino reactions: conjugate alkylative aldol addition/lactonization of α,β-unsaturated diesters. Tetrahedron Lett. 2015, 56, 5541-5544. c) Shi, S.; Wei, X.; Shimizu, Y.; Kanai, M. 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