Journal of Inorganic and General Chemistry DOI: 10.1002/zaac.202000320 ARTICLE Zeitschrift für anorganische und allgemeine Chemie Synthesis and characterization of copper complexes with tripodal ligands bearing amino acid groups Christopher Gawlig,[a] Jannis Jung,[b, c] Doreen Mollenhauer,[b, c] and Siegfried Schindler*[a] Dedicated to Professor Dr. Peter Klüfers on the Occasion of his 70th Birthday The tripodal ligand (2-aminoethyl)bis(2-pyridylmethyl)amine penp]OTf. [Cu{L-His(BPh3)uns-penp}] could be structurally char- (uns-penp), known for its Cu/O2 intermediates, was modified at acterized and represents the first example of a copper(I) one side arm by a selection of amino acids. With L-Tyrosine complex with a coordinated imidazole ring of the histidine (Tyr), L-Histidine (His) and L-Lysine (Lys) it was possible to ligand. Furthermore, these complexes demonstrated catalytic introduce chirality into the tripodal ligand system and to activity for the oxygenation of thioanisole with hydrogen investigate the corresponding copper(I) complexes [Cu{L-His peroxide as an oxidant. (BPh3)uns-penp}], [Cu(L-Lys)uns-penp]OTf and [Cu(L-Tyr)uns- Introduction Copper/dioxygen intermediates play a significant role in oxy- genation reactions in nature and in industrial applications.[1,2] Complexes of this type are observed for example in the active site of the oxygen carrier copper protein hemocyanin (Hc) in arthropods and mollusks. Copper enzymes such as tyrosinase or superoxide dismutase, are responsible for the ortho hydroxyla- Figure 1. Tripodal ligands tmpa (left), tren (middle) and uns-penp tion of phenol or the reduction of superoxide and are common (right). in almost every lifeform.[1] Copper complexes with tripodal ligands based on tris(2-pyridylmethyl)-amine (tmpa), tris(2- aminoethyl)amine (tren) and (2-aminoethyl)bis(2-pyridylmethyl) metric/electronic structures of the active species of the catalytic amine (uns-penp) proved to be quite useful in the study of metal centers. Especially the ligand uns-penp is interesting reversible dioxygen binding (Figure 1).[3–8] because of the increased stability towards copper(I) ions. Examining these compact model systems and their spectral Furthermore, it obtains a primary amino group that allows easy features makes it possible to gain information about the geo- modifications of the ligand itself. Those modifications can include the attachment of a side arm that introduces stereo chemical information to the ligand system, which in turn is of great [a] C. Gawlig, Prof. Dr. S. Schindler importance in the catalytic synthesis of products with an Justus-Liebig-Universität Gießen enantiomeric excess in pharmaceutical industry.[9] For this purpose, Institut für Anorganische und Analytische Chemie the use of amino acids is a promising approach to create chirality Heinrich-Buff-Ring 17 35392 Gießen, Germany and at the same time to obtain realistic models close to the E-mail: Siegfried.Schindler@anorg.chemie.uni-giessen.de natural copper complexes in proteins. This furthermore can [b] J. Jung, Prof. Dr. D. Mollenhauer provide an opportunity to connect oxygen sensitive copper Justus-Liebig-Universität Gießen complexes to peptide chains. Related Approaches have been Institut für Physikalische Chemie reported in the past where amino acids have been attached to the Heinrich-Buff-Ring 17 original ligand by amide bonds.[10–14] However, the complexes 35392 Gießen, Germany [c] J. Jung, Prof. Dr. D. Mollenhauer described therein showed coordination of the amide oxygen to Center for Materials Research (ZfM/LaMa) the respective metal centers of Cu(II), Zn(II) or Ni(II), which is not Justus-Liebig University Giessen representative of the framework of metal-containing proteins in Heinrich-Buff-Ring 16, 35392 Giessen (Germany) nature. We wanted to avoid this type of coordination and instead Supporting information for this article is available on the WWW create a direct bond between the metal center and the chiral side under https://doi.org/10.1002/zaac.202000320 arm of the attached amino acid of the chelate ligand. In recent © 2020 The Authors. Zeitschrift für anorganische und allgemeine research, the group of Shinobu Itoh et al. developed a model for Chemie published by Wiley-VCH GmbH. This is an open access the active-site of the lytic polysaccharide monooxygenase. In this article under the terms of the Creative Commons Attribution Non- Commercial License, which permits use, distribution and example imidazole rings of the used ligand could form a direct [15] reproduction in any medium, provided the original work is coordination with the central copper ion. We wanted to pursue properly cited and is not used for commercial purposes. this approach but through the direct use of amino acids. Z. Anorg. Allg. Chem. 2021, 647, 951–959 951 © 2020 The Authors. Zeitschrift für anorganische und allgemeine Chemie published by Wiley-VCH GmbH Wiley VCH Donnerstag, 22.04.2021 2108 / 195514 [S. 951/959] 1 Journal of Inorganic and General Chemistry ARTICLE Zeitschrift für anorganische und allgemeine Chemie Scheme 1. Synthesis of acetyl uns-penp and uns-penp (1). Figure 2. Simplified drawing of uns-penp with attached amino acid groups forming corresponding copper(I) complexes. peptides via LPPC with 1 and Boc-L-His-OH. As coupling reagents, 1-hydroxybenzotriazol (HOBt) and 1-Ethyl-3-(3- dimethylaminopropyl)carbodiimid (EDC) were replaced by a combined reagent O-(Benzotriazoyl)tetramethyluronium-tetra- For the selection of the amino acids, histidine, lysine and fluoroborat (TBTU), as a higher yield could be obtained with tyrosine were chosen for the attachment to the ligand uns- these. The mixture was stirred at room temperature in DCM for penp with regard to their natural occurrence of the complexing 24 hours. However, analysis via mass spectrometry showed that amino acid ligands in copper-containing proteins. A simplified most of the conversion had caused the formation of unidenti- view of the model complexes described herein is presented in fied side products while only a very small amount of the desired Figure 2. The coupling of the chiral side arm with uns-penp was product was obtained. This is mainly caused by the participa- performed via Liquid Phase Peptide Coupling (LPPC), which relies tion of the imidazole ring of histidine in the coupling process, on the protection of the amine function of the amino acid with forming polymeric side products with the carboxylic groups of a tert-butyloxycarbonyl (Boc) group to prevent the coupling of other histidine molecules. To prevent this, it is necessary to two equal substrates or the formation of polymer side products. introduce a protection group for the NIm of histidine. It turned Common coupling reagents are the combination of a carbodii- out that a trityl group ( CPh3) was best suited for its protection, mide (e.g. DCC, DIC, EDC) and 1-hydroxybenzotriazol because it is stable in neutral and alkaline media and (HOBt).[16,17] furthermore, towards nucleophiles, which is required for the conditions of a LPPC. This approach allowed obtaining com- pound 2 in a good yield (Scheme 2). Results and Discussion The trityl protective group, like the Boc group, is labile in acidic conditions and therefore, a selective cleavage is neces- Synthesis and characterization of the ligands sary to remove the trityl group while leaving the Boc group intact. By applying a common method for the cleavage,[20] The tripodal ligand uns-penp (1) was first synthesized and stirring 2 in a 90% acidic acid solution at 60 °C for two hours, characterized in 1987 by Mandel et al.[18] Copper(I) and copper Boc-L-His-uns-penp (3, Scheme 2) was obtained in excellent (II) complexes of this ligand as well as of the methyl derivative yields and no cleavage of the Boc protection group was (Me2-uns-penp) have been described previously. [19] There are observed. different synthetic approaches to obtain this ligand, however, so far we obtained the best yields by the reaction of 2- pyridinecarboxaldehyde and 1-acetylethlyene diamine followed by a reduction of the tertiary amine with Na(AcO)3BH. In the last step, the acetyl protection group was cleaved under acetic conditions with 5 M HCl solution (Scheme 1). Boc-L-His-uns-penp Histidine is one of the most common amino acids found in the active sit of Type I, II and III copper enzymes such as e.g. tyrosinase. This natural occurrence as a ligand offers a promising candidate for a successful complexation of copper combined with uns-penp (1). The synthesis was carried out Scheme 2. Synthesis of Boc-L-His(trt)-uns-penp (2) and Boc-His-uns- according to a general procedure for the preparation of penp (3). Z. Anorg. Allg. Chem. 2021, 951–959 www.zaac.wiley-vch.de 952 © 2020 The Authors. Zeitschrift für anorganische und allgemeine Chemie published by Wiley-VCH GmbH Wiley VCH Donnerstag, 22.04.2021 2108 / 195514 [S. 952/959] 1 Journal of Inorganic and General Chemistry ARTICLE Zeitschrift für anorganische und allgemeine Chemie Boc-L-Lys-uns-penp avoid this disproportionation reaction failed. However, by using [Cu(MeCN)4]PF6 followed by an anion exchange with NaBPh4, it The coupling of 1 with L–Lysine was performed under the same was possible to isolate a stable copper(I)-complex (Scheme 5). reaction conditions as with L-Histidine (Scheme 3) In contrast to our expectations, analytics via mass spectrom- As with Histidine, it is necessary to use an additional etry and infrared spectroscopy revealed that our ligand under- protection group with Lysine, which has an additional primary went a chemical transformation during the anion exchange. amino group at its side arm that can interfere in the coupling Cleavage of one of the phenyl rings of the BPh4 anion and the process with 1. The benzyl carbamate group (Cbz) is providing formation of a bond with the imidazole nitrogen Nδ was a good option for a selective cleavage via hydrogenation, while observed leading to the new ligand 6. This was furthermore leaving the Boc group intact. By using 5 mol% Pd/C with confirmed by obtaining crystals of the corresponding copper(I) hydrogen gas at room temperature successful cleavage was complex, [Cu(6)] (Scheme 5) that were suitable for crystallo- achieved and 4 could be obtained in good yields (74%). graphic characterization. The molecular structure of [Cu(6)] is presented in Figure 3, crystallographic data are reported in the Supporting Information. The copper(I) ion is coordinated in a Boc-L-Tyr-uns-penp distorted tetrahedral manner. Besides coordination of the two pyridyl nitrogen atoms and the amine nitrogen atom of the The synthesis of Boc-L-Tyr-uns-penp (5) with 1 and L-Tyrosine uns-penp molecule the copper(I) ion is furthermore bonded to was also performed with TBTU as a coupling reagent in DCM. the nitrogen atom of the imidazole ring. Due to the fact that An additional protective group for the hydroxyl group is not histidine-with coordination through the imidazole unit-is quite necessary. No major side products could be observed by ESI-MS common in copper proteins it could be expected that a large (Scheme 4). Synthesis and characterization of copper(I) complexes The copper(I) complexes of all ligands were prepared under inert conditions in an argon atmosphere. Copper(I) salts [Cu- (MeCN4)]X (X=OTf, ClO4) were used for complexation. By using 3 it was not possible to synthesize a stable copper(I)-complex. After an initial formation of the complex, indicated by a color change of the solution to yellow, a green/brown color developed after about 20–30 minutes and furthermore, a reddish precipitate (elemental copper) formed. All attempts to Scheme 5. Formation of Boc-L-His(BPh3)-uns-penp (6) and copper complex [Cu{Boc-L-His(BPh3)-uns-penp}]. Scheme 3. Synthesis of Boc-L-Lys-uns-penp (4). Figure 3. Molecular structure of [Cu{Boc-L-His(BPh3)-uns-penp}] ([Cu(6)]) with a distorted tetrahedral coordination geometry and coordinated imidazole ring of L-histidine. Ellipsoids are set to 50% Scheme 4. Synthesis of Boc-L-Tyr-uns-penp (5). probability level. Z. Anorg. Allg. Chem. 2021, 951–959 www.zaac.wiley-vch.de 953 © 2020 The Authors. Zeitschrift für anorganische und allgemeine Chemie published by Wiley-VCH GmbH Wiley VCH Donnerstag, 22.04.2021 2108 / 195514 [S. 953/959] 1 Journal of Inorganic and General Chemistry ARTICLE Zeitschrift für anorganische und allgemeine Chemie number of structurally characterized copper complexes with this amino acid should be known. However, the opposite is true and with only a few exceptions of copper(II) histidine complexes[13,14,21–23] most of the few crystal structures reported (according to a search in the Cambridge Crystallographic Data Base) show no coordination to the imidazole ring. To the best of our knowledge, complex [Cu{Boc-L-His(BPh3)-uns-penp}] is the first example of a structurally characterized copper(I) complex with a coordinated imidazole ring of L-histidine. The presence of the BPh3 group seems to have favored the crystallization process, because this compound was the only copper(I) complex of our ligand series of amino acids for which it was possible to obtain a crystalline sample suitable for crystallographic characterization. Another positive side effect of the triphenyl boron group attached to the ligand is the increased stability of the copper(I)-complex itself. In contrast to our attempts (that failed as described above) to obtain a complex with ligand 3, [Cu(6)] did not show signs of decomposition for a longer period of time. Most likely, this is caused by the substituted proton of the imidazole ring in 3. Trials to remove protons by adding triethylamine or diisopropy- Figure 4. Molecular structures obtained by CREST//DFT calculations lethylamine prior to adding the copper salt were not successful for the cations of [Cu(4)(MeCN)]OTf and [Cu(5)(MeCN)]OTf based on either and again only enforced disproportionation/decomposi- the analytical data. For clarity, the hydrogen atoms have been tion. Our hypothesis is also supported by a test that showed removed. CPK coloring scheme: black-carbon, red-oxygen, blue- nitrogen, orange-copper. when using ligand 2 with [Cu(MeCN)4]OTf, a stable copper(I) complex could be obtained. Due to the trityl group on the imidazole ring, analogous to the BPh3 group from compound 6, Table 1. Bond length of the coordination complex of the cations there is no longer a proton that can impair the stability of the of [Cu(4)(MeCN)]OTf and [Cu(5)(MeCN)]OTf. complex. + + Syntheses of the copper(I)-complexes with ligands 4 and 5 Bond length [Å] [Cu(4)(MeCN)] [Cu(5)(MeCN)] were carried out under similar conditions as described above. Cu-N (Amine) 2.533 2.644 For the preparation of the copper(I) complex of 5 a stoichio- Cu-N (Pyridine-1) 1.996 2.031 metric amount of triethylamine was added additionally due to Cu-N (Pyridine-2) 1.984 2.039 Cu-N (Nitrile) 2.091 1.941 the acidic nature of the phenol side arm. It was possible to Cu-O 2.214 2.267 obtain yellow solids of both complexes. No crystals were obtained for structural analysis via SC-XRD. A conformational search applying the Conformer-Rotamer Ensemble Sampling Tool (CREST) at an extended tight-binding semiempirical level Cyclic voltammetry of theory based on the analytical data and subsequent DFT (PBE, cc-pVDZ) calculations allow to suggest structural models The electrochemical properties of [Cu(Me2-uns-penp)]OTf, [Cu- for both complexes, [Cu(4)(MeCN)]OTf and [Cu(5)(MeCN)]OTf (acetyl-uns-penp]OTf, [Cu(4)MeCN]OTf, [Cu(5)(MeCN)]OTf, [Cu- (Figure 4). The calculated bond lengths of the atoms of the (6)] were examined by cyclic voltammetry in acetonitrile. With ligands to the metal centre are presented in Table 1. The the exception of [Cu(6)] all complexes showed a reversible calculations within this study serve to obtain a structural guess redox reaction. As an example, the cyclic voltammogram of of the complexes, rather than representing a full theoretical [Cu(4)(MeCN)]OTf is presented in Figure 5 (ferrocene has been consideration. used as an internal standard). The E1/2 values do not differ too It is interesting to note that in both cases calculations much for all complexes (except for [Cu(6)]) investigated and all suggest the amide oxygen is coordinated to the copper(I) ion. electrochemical data are reported in the Supporting Informa- We are not aware that this has been reported previously for tion. copper(I) complexes, however, the amide oxygen atom coordi- nation has been observed for a very similar copper(II) complex.[24] The structural assignment was furthermore sup- Copper(II) complexes ported by IR measurements and elemental analysis. Unfortu- nately, we did not succeed to record decent NMR spectra for Efforts to prepare copper(II) complexes were carried out with 3 the complexes with ligands 4, 5 and 6 due to the instability of and 4. Cu(ClO4)2 · 6 H2O as well as Cu(OTf)2 were used as copper the complexes (paramagnetic Cu(II) formed in the samples). salts for the complexation. Unfortunately, it was not possible to obtain crystalline samples for molecular structure determina- Z. Anorg. Allg. Chem. 2021, 951–959 www.zaac.wiley-vch.de 954 © 2020 The Authors. Zeitschrift für anorganische und allgemeine Chemie published by Wiley-VCH GmbH Wiley VCH Donnerstag, 22.04.2021 2108 / 195514 [S. 954/959] 1 Journal of Inorganic and General Chemistry ARTICLE Zeitschrift für anorganische und allgemeine Chemie Catalytic oxygenation of thioanisole Despite the fact that no “dioxygen adduct” complexes were formed as intermediates it seemed worthwhile to test their properties with regard to catalytic oxidations. As a substrate thioanisole was used and its oxygenation to sulfoxide and/or sulfone was investigated using the copper complexes with the ligands 4, 5, 6 and [Cu(Boc-L-His(trt)uns-penp}] in comparison with uns-penp, [Cu{acetyl-uns-penp]OTf, [Cu(Me -uns-penp)]OTf Figure 5. Cyclic voltammogram of [Cu(4)(MeCN)]OTf, left without 2 and right with ferrocene added (298 K, scan rate: 100 mVs 1, in combination with dioxygen or hydrogen peroxide according c[Cu(4)(MeCN)]OTf=1 mM, electrolyte (NBu4)BF : 0.1 M). to Scheme 6.4 Especially the sulfoxide as a product is of interest, because of its widespread application in pharmaceutical chemistry. This and the simple analysis of the two oxidation products methyl phenyl sulfoxide and methyl phenyl sulfone make thioanisole a popular substrate for catalytic oxygenation of sulfides.[26,27] Another interesting property of the sulfoxide is its chirality. By examining the reaction with a chiral gas chromatography column, it is possible to determine if a catalyst can form an enantiomeric excess of a specific enantiomer. The reaction shown in Scheme 6 was carried out at room temperature with a reaction time of 2 hours. After several attempts applying molecular oxygen as the sole oxidant in a temperature range between 80 °C and room temperature, it became clear that no conversion had taken place. For that reason, hydrogen peroxide was used for further experiments. All reactions were analyzed and quantified via GC/MS. The results are presented in Table 2. Figure 6. UV/Vis spectrum of [Cu(4)](OTf) with a λ =690 nm. Using just hydrogen peroxide without adding a copper2 max complex no oxidation was observed (Table 2, entry a). Further- more, applying only CuCl as a copper source negligible conversion was observed (Table 2, entry b). Furthermore, [Cu- tion. Solid samples furthermore showed impurities that ham- (uns-penp)]OTf showed nearly no reactivity at all. In contrast, pered further characterization. However, mixing stoichiometric using [Cu(Me2-uns-penp)]OTf conversion to 40% sulfoxide and amounts of Cu(ClO4)2 · 6 H2O with ligands 3 and 5 allowed UV- 8% sulfone was observed (entry d). However, when [Cu(acetyl- vis measurements in methanol. Maxima of λmax=690 nm for uns-penp]OTf was applied conversion went down to only 12% both complexes support a complexation of copper(II) in a for the sulfoxide and 3% sulfone (entry e). All copper(I) distorted square planar geometry in solution (Figure 6).[25] complexes with the ligands 4, 5, 6 and [Cu{Boc-L-His(trt)uns- penp}]OTf applied as suspensions did lead to the oxygenation of thioanisole (Table 2, entries f, g, h and i). However, it was not Reactivity of copper(I) complexes towards dioxygen and possible to gain an enantiomeric excess by any of the three hydrogen peroxide catalysts. In all cases, the sulfoxide is the main product, with the highest conversion of 84% with catalyst [Cu(Boc-L–Lys-uns- As described in the introduction it is well known that a large penp)(MeCN)]OTf (4) (entry f). A further oxidation to the sulfone number of copper(I) complexes with tripodal ligands including distinguishes between the reactions, with the highest conver- as [Cu(Me2-uns-penp]X react with dioxygen to form dinuclear sion of 13% with [Cu{Boc-L-His(BPh3)-uns-penp}] (6). Compared end-on-peroxido complexes. However, reacting all our copper(I) to CuCl (entry b) with only 2% of the sulfoxide and traces of the complexes [Cu(4)(MeCN)]OTf, [Cu(5)(MeCN)]OTf and [Cu(6)] as sulfone and, the amino acid uns-penp catalysts show a well as [Cu(acetyl-uns-penp]OTf and [Cu{L-His(trt)uns-penp}]OTf significant higher catalytic activity with maximum conversions in a benchtop test with dioxygen in solution at low temper- of 97% (entry f). Besides, in case of the oxygenation with atures ( 80 °C) only showed a slow color change to a green colored solutions indicating oxidation to copper(II) without a detectable intermediate. This was furthermore confirmed by low temperature stopped-flow measurements as described previously.[19] Reactions of all complexes including [Cu(Me2-uns- penp)]OTf with hydrogen peroxide only led to green solutions with more or less gas bubbles (dioxygen from decomposition of hydrogen peroxide). Scheme 6. Oxygenation of thioanisole with hydrogen peroxide. Z. Anorg. Allg. Chem. 2021, 951–959 www.zaac.wiley-vch.de 955 © 2020 The Authors. Zeitschrift für anorganische und allgemeine Chemie published by Wiley-VCH GmbH Wiley VCH Donnerstag, 22.04.2021 2108 / 195514 [S. 955/959] 1 Journal of Inorganic and General Chemistry ARTICLE Zeitschrift für anorganische und allgemeine Chemie Table 2. Oxygenation of thioanisole with copper(I) catalysts and H2O2. # Catalyst Sulfoxide [%] Sulfone [%] Total conversion [%] TON a – 0 0 0 0 b CuCl 2 traces 3 0.6 c [Cu(uns-penp)]OTf 4 traces 5 1 d [Cu(Me2-uns-penp)]OTf 40 8 48 3 e [Cu(Ac-uns-penp)]OTf 12 3 15 11 f [Cu(4)MeCN)]OTf 84 13 97 19 g [Cu(5)(MeCN)]OTf 6 2 8 2 h [Cu(6)] 23 10 34 13 i [Cu{Boc-LHis(trt)uns-penp}]OTf 8 2 10 3 0.5 mol% catalyst, 2 h, 1 eq. H2O2, MeCN, room temperature. compounds were performed in a glovebox or under standard catalyst [Cu(4)(MeCN)]OTf, the sulfoxide was synthesized and Schlenk techniques. Electrospray-ionization MS (ESI-MS) measure- isolated. After purification by column chromatography a yield ments were performed on a Bruker microTOF mass spectrometer. of 69% was determined. From the results it is obvious that we The conversions of the catalytic reactions were determined with a do not see an effect of redox potential or the ability to form a Hewlett Packard 5890 gas chromatograph (GC) and an Agilent Technologies 7820 A GC-System coupled with an Agilent Technolo- peroxido complex as an intermediate species. We suspect a gies 5977B MSD EI mass spectrometer (GC/MS). For NMR measure- Fenton-like mechanism due to the gas development that occurs ments a Bruker Avance II 400 MHz (AV II 400) was used for all after adding hydrogen peroxide to the reaction solution.[28] samples. IR spectroscopy was performed on a Jasco FT/IR 4100 and all samples were measured as KBR-pellets. UV-vis spectra were obtained using an Agilent 8453 spectrophotometer. Diffraction Conclusions data were collected on a BRUKER D8 Venture system. Synthesis of N-acetyl-uns-penp.[19] Under Schlenk conditions, 2- Our results showed that it is possible to synthesize amino acid pyridinecarbaldehyde (4.3 g, 40 mmol) and N-acetylethylenedi- derivatives based on the tripodal ligand uns-penp. These amine (2.0 g, 20 mmol) were dissolved in 100 mL 1,2-dichoro- ethane. Na(AcO)3BH (12.1 g, 57.1 mmol) was added and the solutionmodified flexible ligand frameworks are able to adapt to the was stirred for 4 hours at room temperature. After that, 100 mL of coordination sphere geometry of copper(I) metal ions. Further- 2 M aqueous NaOH solution were added and the organic layer was more, they provide an opportunity to connect these complex extracted with 2×50 mL DCM. Furthermore, the combined organic units to peptide chains. In the case of L-Lysine, L-Histidine and solution was washed with brine (2×50 mL), dried over anhydrous L-Tyrosine, copper(I) complexes were isolated, however, it was Na2SO4, and the solvent evaporated in vacuo. The crude product is a yellowish oil (4.11 g, 14.4 mmol, 85%) and was used without not possible to obtain the corresponding copper(II) complexes. further purification in the next step to remove the acetyl protecting We could determine the molecular structure of [Cu{L-His(BPh3) group. uns-penp}] by using single crystal X-ray diffraction. This is the first example of a structurally characterized copper(I) complex Synthesis of uns-penp (1). [19] The crude N-Acetyl-uns-penp (4.11 g, 14.4 mmol) was dissolved in 40 mL of a 5 M hydrochloric acid with coordination to the nitrogen atom of the imidazole ring of solution and refluxed for 24 hours. The pH of the cooled solution histidine. However, in contrast to our previous findings was increased to 10 by the addition of NaOH. The crude product (applying copper(I) complexes with related ligands) it was not was extracted with 3x50 mL DCM, dried over Na2SO4 and the possible to detect a “dioxygen adduct” intermediate in bench- solvent was evaporated. The obtained oil was purified by Kugelrohr top experiments (or stopped-flow measurements) when dioxy- distillation in vacuo (0.2 mbar) and at 150 °C. The yellowish-colorless oil (2.7 g, 11 mmol, 77%) was stored under argon. 1H-NMR gen was reacted with the described copper(I) complexes herein. (400 MHz, CDCl3): δ=8.53 (ddd, 2H), 7.65 (td, 2H), 7.50 (dt, 2H), 7.14 In addition, the influence of the chirality introduced with the (dd, 2H), 3.85 (s, 4H), 2.85–2.72 (m, 2H), 2.66 (t, 2H). 13C-NMR amino acid groups in the uns-penp ligand system was (101 MHz, CDCl3): δ=159.6, 149.0, 136.3, 122.9, 122.8, 121.9, 77.5, investigated for the catalytic oxygenation of thioanisole to 1- 77.1, 76.8, 60.7, 57.4, 39.6. methyl phenyl sulfoxide, which bears a stereo center at its Synthesis of Boc-L-His(trt)-uns-penp (2). In a 100 mL Schlenk flask sulfur atom. While no enantiomeric excess could be detected all and under inert conditions, uns-penp (0.24 g, 1.0 mmol), Boc-L-His the catalysts could oxidize thioanisole to the sulfoxide, with the (trt)-OH (0.50 g, 1.0 mmol), TBTU (0.35 g, 1.1 mmol) and TEA (0.12 g, highest conversion of 97%. 1.2 mmol) was mixed with 30 mL of dry DCM. The mixture was stirred for 24 hours at room temperature. After that, the reaction was quenched with 250 mL of EtOAc and washed with 3×50 mL 0.5 M citric acid, 3×50 mL sat. NaHCO3 solution and 3×50 mL brine.Experimental Section The combined organic layers again were acidified to pH 2 with Materials and Methods. All chemicals used were of p.a. quality and conc. HCl. The aqueous phase was separated and NaOH was added were purchased from either Acros Organics, ACS or Sigma Aldrich. till pH 12 was reached, followed by an extraction with DCM. The Dry purchased solvents for air sensitive synthesis were redistilled solution was dried with MgSO4 and the solvent was evaporated. A under argon. The preparation and handling of air sensitive Z. Anorg. Allg. Chem. 2021, 951–959 www.zaac.wiley-vch.de 956 © 2020 The Authors. Zeitschrift für anorganische und allgemeine Chemie published by Wiley-VCH GmbH Wiley VCH Donnerstag, 22.04.2021 2108 / 195514 [S. 956/959] 1 Journal of Inorganic and General Chemistry ARTICLE Zeitschrift für anorganische und allgemeine Chemie greenish colored product (0.58 g, 0.80 mmol, 80%) was obtained chromatography. The yield was 32% (0,291 g, 0.576 mmol). ESI-MS: (ESI-MS: [M+H]+ =722.36, [M+Na]+ =744.36) [M+H]+ =506.27, [M+Na]+ =528.25 1H-NMR (400 MHz, CDCl3): δ 8.58 8.43 (m, 2H), 7.76 (s, 1H), 7.63 (d, 1H-NMR (400 MHz, CDCl3): δ 8.50 – 8.43 (m, 2H), 7.62 (s, 1H), 7.55 2H), 7.40 (d, 2H), 7.37 7.21 (m, 11H), 7.14 7.00 (m, 9H), 6.60 (d, (td, 2H), 7.22 (d, 3H), 7.09 (dd, 2H), 6.96–6.89 (m, 2H), 6.64 – 6.55 (m, 1H), 4.48 (s, 1H), 4.12 (q, 1H), 3.85 (d, 2H), 3.77 (d, 2H), 3.34 (dt, 1H), 2H), 5.34 (d, 1H), 4.33 (d, 1H), 3.67 (s, 4H), 3.19 (q, 2H), 2.58 – 2.53 3.26 3.03 (m, 2H), 2.92 (dd, 1H), 2.74 2.58 (m, 2H), 1.41 (s, 9H). (m, 2H), 1.39 (d, 12H), 1.20 (d, 1H). 13C-NMR (101 MHz, CDCl3): δ 13C-NMR (101 MHz, CDCl3) δ 171.1, 159.2, 155.7, 149.1, 142.4, 138.3, 170.2, 157.8, 154.5, 154.3, 148.0, 135.8, 129.4, 127.1, 122.4, 121.4, 137.0, 136.7, 129.7, 128.0, 123.0, 122.1, 119.6, 79.5, 75.2, 60.1, 53.4, 114.9, 76.3, 76.0, 75.7, 58.6, 55.1, 52.4, 51.6, 37.7, 36.4, 27.3. 52.4, 38.6, 28.4, 21.1. Synthesis of [Cu{Boc-L-His(trt)-uns-penp}] (6). Under inert con- Synthesis of Boc-L-His-uns-penp (3). Boc-L-His(trt)-uns-penp ditions, 100 mg (0.139 mmol) Boc-L-His(trt)-uns-penp were dis- (0.58 g, 0.80 mmol) was mixed with 90% acetic acid and stirred for solved in 4 mL acetone. In another vial, 51.8 mg (0.139 mmol) of two hours at 60 °C. After the reaction was allowed to cool, the [Cu(MeCN)4]PF6 was dissolved in 2 mL acetone and was added acetic acid / water was evaporated. The oily remains were solved in dropwise to the stirred solution of Boc-L-His(BPh3)-uns-penp. A 40 mL DCM and washed with 3×40 mL sat. NaHCO3 solution and yellow suspension forms. For anion exchange, 47.6 mg NaBPh4 brine. The combined organic layers were acidified to pH 2 with (0.139 mmol) were added and the suspension became a clear conc. HCl. The aqueous phase was separated and again basified to yellow solution. For precipitation, the solution was added dropwise pH 12 with NaOH, followed by an extraction with DCM. The solution to an excess of diethyl ether and the resulting yellow solid complex was dried with MgSO4 and the solvent was evaporated. The (132 mg, 86%) was filtered and washed again with ether. IR-(KBr- yellowish-colorless oil was obtained in a yield of 90% (0.35 g, disc)/cm 1: 3411 (w), 3057 (m), 2988 (m), 1708 (m), 1588 (m), 1478 0.72 mmol). ESI-MS: [M+H]+ =480.26, [M+Na]+ =502.25; 1H-NMR (m),1427 (m), 1153 (m), 1031 (m), 853 (s), 745 (s), 711 (s), 605 (m), (400 MHz, CDCl3): δ 8.43 (dt, 2H), 7.77 (s, 1H), 7.56 (td, 2H), 7.31 (d, 561 (w), 510 (w). 1H), 7.29–7.23 (m, 5H), 7.08 (dd, 2H), 6.72 (s, 1H), 5.81 (d, 1H), 3.71 (s, 4H), 3.24 (s, 1H), 3.07 (d, 1H), 2.94 (dd, 1H), 2.64–2.55 (m, 2H), Synthesis of [Cu{Boc-L-His(BPh3)-uns-penp}] (6). Under inert con- 1.35 (s, 9H). 13C-NMR (101 MHz, CDCl ): δ 170.6, 157.8, 148.1, 145.9, ditions, 200 mg (0.417 mmol) Boc-L-His-uns-penp was dissolved in3 135.7, 133.9, 126.9, 126.2, 122.3, 121.3, 81.0, 76.3, 76.0, 75.7, 58.8, 4 mL acetone. In another vial, 155 mg (0.417 mmol) of [Cu(MeCN)4] 52.4, 51.5, 37.6, 36.4, 27.3. PF6 was dissolved in 2 mL acetone and was added dropwise to the stirred solution of Boc-L-His(BPh3)-uns-penp. A yellow suspension Synthesis of Boc-L–Lys(Z)-uns-penp. In an 100 mL flask, uns-penp forms. For anion exchange, 143 mg NaBPh4 (0.417 mmol) was (0.50 g, 1.9 mmol), Boc-L-Lys(Z)-OH (0.72 g, 1.9 mmol), TBTU (0.67 g, added and the suspension became a clear yellow solution. For 2.1 mmol) and TEA (0.12 g, 2.1 mmol) was mixed with 30 mL of dry precipitation, the solution was added dropwise to an excess of DCM. The mixture was stirred for 24 hours at room temperature. diethyl ether and the resulting yellow solid complex (130 mg, 40%) 250 mL of EtOAc was added. The solution was washed with (3× was filtered and washed again with ether. Crystals were obtained 50 mL) 0.5 M citric acid, (3×50 mL) sat. NaHCO3 and (3×50 mL) by evaporation of the complex solution in acetone. (CCDC brine. After that, the organic layer was dried over MgSO4 and the deposition number 2025303) IR-(KBr disc)/cm 1: 3401 (m), 3311 (m), solvent evaporated. A reddish oil (73%, 0.84 g, 1.4 mmol) was 3060 (m), 1715 (m), 1570 (m), 1361 (s), 1321 (m), 1277 (s), 1153 (s), obtained. The following cleavage of the cbz protective group was 1029 (s), 1134 (s), 1088 (m), 1005 (m), 704 (m), 636 (m), 570 (w), 514 carried out without further purification. (m). Synthesis of Boc-L-Lys-uns-penp (4). 0.84 g (1.4 mmol) Boc-L-Lys Synthesis of [Cu(Boc-L-Lys-uns-penp)(MeCN)]OTf. Under inert (Z)-uns-penp was dissolved in methanol in a 100 mL flask. One conditions, 50 mg (0.10 mmol) of 4 was dissolved in 2 mL of spate tip of the Pd/C was added to the solution and a balloon filled acetone with the addition of 15 μL (0.11 mmol) triethylamine. In a with hydrogen gas was attached to the flask. The suspension was second vial, 37 mg (0.10 mmol) of [Cu(MeCN)4]OTf was dissolved in vigorously stirred at room temperature for 24 hours. The solution 1 mL acetone which was added dropwise to the Boc-L-Tyr-uns- was filtered and the solvent evaporated. The remaining oil was penp solution. The solvent of the solution was evaporated and a dissolved in 100 mL EtOAc and extracted three times with 2 M HCl yellow solid was obtained in a quantitative yield. IR-(KBr disc)/cm 1: solution. The pH of the aqueous phase then was adjusted to 12 by 3325 (m), 3073 (m), 2939 (m), 2864 (m), 1711 (s), 1668 (s), 1516 (m), a slow addition of NaOH solution. After that, the solution was again 1366 (m), 1268 (s), 1160 (s), 1036 (s), 762 (m), 638 (s), 570 (m), 518 extracted with (3×50 mL) EtOAc. The combined organic phases (m). Elemental analysis: found: C, 48.4%; H, 6.4%; N, 11.4%; were dried over MgSO4 and the solvent was evaporated. The yield C28H41CuF3N7O8S x 2 acetone requires: C, 48.0%; H, 6.2%; N, 11.9%. of the grass green solid is 78% (0.514 g, 1.5 mmol). ESI-MS: [M+ H]+ 471.29, [M Na]+ 493.30; Synthesis of [Cu(Boc-L-Tyr-uns-penp)(MeCN)]OTf. Under inert= + = conditions, 50 mg (0.10 mmol) of 5 was dissolved in 2 mL of 1H-NMR (400 MHz, CDCl3): δ 8.58 (dd, 2H), 7.33 (dt, 2H), 7.17 (dd, acetone with the addition of 15 μL (0.11 mmol) triethylamine. In a 2H), 5.47 (d, 1H), 4.25 (d, 1H), 3.87 (s, 4H), 3.38 (d, 1H), 3.01 (s, 1H), second vial, 37 mg (0.10 mmol) of [Cu(MeCN)4]OTf was dissolved in 2.77 (t, 2H), 2.71 (t, 2H), 1.44 (m, 13H). 13C-NMR (101 MHz, CDCl3): δ 1 mL acetone which was added dropwise to the Boc-L-Tyr-uns- 171.8, 159.0, 155.6, 149.1, 136.6, 123.2, 122.2, 79.5, 77.3, 77.0, 76.7, penp solution. The solvent of the solution was evaporated and a 59.9, 54.3, 52.5, 41.6, 38.6, 33.4, 32.6, 28.4, 22.6. yellow solid was obtained in a quantitative yield. IR-(KBr disc)/cm 1: 3340 (m), 2977 (m), 2928 (m), 2851 (w), 1712 (s), 1602 (m), 1518 (s), Synthesis of Boc-L-Tyr-uns-penp (5). 0.464 g (1.64 mmol) Boc-L- 1442 (m), 1367 (m), 1253 (s), 1159 (s), 1029 (s), 827 (w), 760 (m), 637 Tyrosine, 0.436 g uns-penp, 0.372 g (1.80 mmol) DCC, 0.276 g (s), 570 (w), 515 (w). Elemental analysis: found: C, 51.0%; H, 5.9%; N, (1.80 mmol) HOBt and 0.250 mL (1.80 mmol) TEA were dissolved in 9.8%; C31H38CuF3N O S x 2 acetone requires: C, 50.8%; H, 5.8%; N,50 mL DCM. The reaction was stirred for 24 hours at room temper- 6 89.6%. ature. 200 mL EtOAc was added and the solution washed with 3× 50 mL sat. NaHCO3, 3×50 mL 0.05 M citric acid solution and Synthesis of [Cu(uns-penp)]OTf, [Cu(Me2-uns-penp)]OTf [Cu(Ac- 3x50 mL brine. The solution was dried over Na SO and the solvent uns-penp)]OTf and complexes.[19]2 4 Under inert conditions, 1 eq. of evaporated. The light-yellow solid was cleaned via column the ligand was dissolved in 2 mL of acetone with the addition of 1.1 eq. of triethylamine. In a second vial, 1 eq. of [Cu(MeCN)4]OTf Z. Anorg. Allg. Chem. 2021, 951–959 www.zaac.wiley-vch.de 957 © 2020 The Authors. Zeitschrift für anorganische und allgemeine Chemie published by Wiley-VCH GmbH Wiley VCH Donnerstag, 22.04.2021 2108 / 195514 [S. 957/959] 1 Journal of Inorganic and General Chemistry ARTICLE Zeitschrift für anorganische und allgemeine Chemie was dissolved in 1 mL acetone which was added dropwise to the [1] E. I. Solomon, D. E. Heppner, E. M. Johnston, J. W. Ginsbach, J. ligand solution. The complexes were precipitated in n-pentane and Cirera, M. Qayyum, M. T. Kieber-Emmons, C. H. Kjaergaard, R. G. yellow solids were obtained in a quantitative yield. Hadt, L. Tian, Chem. Rev. 2014, 114, 3659–3853. [2] S. E. Allen, R. R. Walvoord, R. Padilla-Salinas, M. C. Kozlowski, Catalytic oxygenation of thioanisole. 1.1 mL thioanisole (1.24 g, Chem. Rev. 2013, 113, 6234–6458. 10 mmol) and 5 mol% of catalyst [Cu(4)(MeCN)]OTf, [Cu(5)(MeCN)] [3] D. Maiti, D.-H. Lee, K. Gaoutchenova, C. Würtele, M. C. OTf or [Cu(6)] were suspended in 10 mL acetonitrile. After that, a Holthausen, A. A. Narducci Sarjeant, J. Sundermeyer, S. Schin- hydrogen peroxide solution (50%, 560 μL, 10 mmol) was added dropwise in the stirred solution. To prevent the evaporation of the dler, K. D. Karlin, Angew. Chem. 2008, 120, 88–91; Angew. substrate the flask was sealed and the cap was equipped with a Chem. Int. Ed. 2008, 47, 82–85. cannula which was plugged through a septum for pressure [4] D. Das, Y. M. Lee, K. Ohkubo, W. Nam, K. D. Karlin, S. Fukuzumi, equalizing. The solution was stirred until the gas formation J. Am. Chem. Soc. 2013, 135, 2825–2834. subsided and was then examined via GC/MS. [5] H. R. Lucas, L. Li, A. A. N. Sarjeant, M. A. Vance, E. I. Solomon, K. D. Karlin, J. Am. Chem. Soc. 2009, 131, 3230–3245. Isolation of 1-Methylphenylsulfoxide. The reaction solution was [6] S. Schindler, Eur. J. Inorg. Chem. 2000, 2311–2326. filtered and the solvent evaporated in vacuo. The resulting [7] C. Würtele, O. Sander, V. Lutz, T. Waitz, F. Tuczek, S. Schindler, brownish crude solid was purified via column chromatography (1 : 1 J. Am. Chem. Soc. 2009, 131, 7544–7545. EtOAc/n-Hex, Rf: 0.32). A pure white solid was obtained with a yield [8] C. E. Elwell, N. L. Gagnon, B. D. Neisen, D. Dhar, A. D. Spaeth, of 950 mg (69%). G. M. Yee, W. B. Tolman, Chem. Rev. 2017, 117, 2059–2107. 1 [9] K. Singh, P. Shakya, A. Kumar, S. Alok, M. Kamal, S. P. Singh, Int.H-NMR (400 MHz, Chloroform-d): δ 7.71–7.60 (m, 2H), 7.60 – 7.46 J. Pharm. Sci. Res. 2014, 5, 4644. (m, 3H), 2.73 (s, 3H). [10] N. Niklas, F. W. Heinemann, F. Hampel, R. Alsfasser, Angew. 13C-NMR (101 MHz, CDCl3): δ 145.7, 131.0, 129.4, 123.5, 77.4, 77.1, Chem. Int. Ed. 2002, 41, 3386–3388; Angew. Chem. 2002, 114, 76.8, 44.0. 3535–3537. [11] N. Niklas, S. Wolf, G. Liehr, C. E. Anson, A. K. Powell, R. Alsfasser, Inorg. Chim. Acta 2001, 314, 126–132. Computational Details [12] N. Niklas, F. Hampel, G. Liehr, A. Zahl, R. Alsfasser, Chem. A Eur. + J. 2001, 7, 5135–5142.The composition of the complexes [Cu(4)MeCN)] and [Cu(5) + [13] O. Yamauchi, A. Odani, M. Takani, J. Chem. Soc. Dalton Trans.MeCN)] was derived from the IR and elemental analysis. The creation and analyzation of the geometric structures have been 2002, 3411–3421. performed using the program CREST[29] with the iMTD-GC algorithm [14] O. Yamauchi, A. Odani, S. Hirota, Bull. Chem. Soc. Jpn. 2001, 74, and the semiempirical method GFN2-xTB[30] to obtain the energet- 1525–1545. ical most favourable conformation. For the five conformers with the [15] A. Fukatsu, Y. Morimoto, H. Sugimoto, S. Itoh, Chem. Commun. lowest total energy at GFN2-xTB level of theory DFT calculations 2020, 56, 5123–5126. have been conducted employing the program Turbomole,[31–33] [16] F. Albericio, Curr. Opin. Chem. Biol. 2004, 8, 211–221. version 6.6. The PBE[34] exchange-correlation functional with RI [17] C. A. G. N. Montalbetti, V. Falque, Tetrahedron 2005, 61, 10827– approximation[35–37] and D3 (BJ)[38,39] dispersion correction have been 10852. chosen for the structural optimization and the calculation of the [18] J. B. Mandel, B. E. Douglas, C. Maricondi, Inorg. Chem. 1988, 27, energies. The Dunning basis sets cc-pVDZ[40] for the elements C, H, 2990–2996. O and N has been applied. For the copper atom the pseudopoten- [19] M. Schatz, M. Leibold, S. P. Foxon, M. Weitzer, F. W. Heine- tial ECP10MDF[41] and the corresponding basis set cc-pVDZ-PP[42] mann, F. Hampel, O. Walter, S. Schindler, Dalton Trans. 2003, has been used. Unrestricted KS-DFT calculations considering a 1480–1487. singlet state have been employed for the single positively charged [20] P. Sieber, B. Riniker, Tetrahedron Lett. 1987, 28, 6031–6034. complexes. The electronic convergence criterion has been set to [21] P. Deschamps, P. P. Kulkarni, M. Gautam-Basak, B. Sarkar, 10 7 EH, the convergence of the structural relaxation to 10 6 E Coord. Chem. Rev. 2005, 249, 895–909.H. Frequency calculations confirm the calculated structures as minima. [22] H. Sigel, D. B. Mccormick, H. Sigel, D. B. Mccormick, J. Am. The complex structures with the lowest total energy according to Chem. Soc. 1971, 93, 2041–2044. the semiempirical and DFT methods are presented within this study [23] B. Graham, M. T. W. Hearn, L. Spiccia, B. W. Skelton, A. H. White, and the structural data are given in the SI. Aust. J. Chem. 2003, 56, 1259–1261. [24] P. Hirva, A. Nielsen, A. D. Bond, C. J. Mckenzie, J. Phys. Chem. B 2010, 114, 11942–11948. [25] M. Becker, F. Heinemann, F. Knoch, W. Donaubauer, G. Liehr, S. Acknowledgements Schindler, G. Golub, H. Cohen, D. Meyerstein, Eur. J. Inorg. Chem. 2000, 2000, 719–726. We would like to thank Dr. Jonathan Becker (Justus-Liebig [26] S. Yamaguchi, A. Suzuki, M. Togawa, M. Nishibori, H. Yahiro, ACS Catal. 2018, 8, 2645–2650. University, Gießen) for his help solving the molecular structure [27] P. Kelly, S. E. Lawrence, A. R. Maguire, Synlett 2007, 1501–1506. of [Cu{Boc-L-His(BPh3)-uns-penp}]. Open access funding enabled [28] A. D. Bokare, W. Choi, J. Hazard. Mater. 2014, 275, 121–135. and organized by Projekt DEAL. [29] P. Pracht, F. Bohle, S. Grimme, Phys. Chem. Chem. Phys. 2020, 22, 7169–7192. [30] C. Bannwarth, S. Ehlert, S. Grimme, J. Chem. Theory Comput. Keywords: tripodal ligands · thioanisole oxidation · amino acid 2019, 15, 1652–1671. derivatives · copper complex [31] R. Ahlrichs, M. Bär, M. Häser, H. Horn, C. Kölmel, Chem. Phys. Lett. 1989, DOI 10.1016/0009-2614(89)85118–8. [32] O. Treutler, R. Ahlrichs, J. Chem. Phys. 1995, 102, 346–354. [33] M. Von Arnim, R. Ahlrichs, J. Comput. Chem. 1998, 19, 1746– 1757. Z. Anorg. Allg. Chem. 2021, 951–959 www.zaac.wiley-vch.de 958 © 2020 The Authors. Zeitschrift für anorganische und allgemeine Chemie published by Wiley-VCH GmbH Wiley VCH Donnerstag, 22.04.2021 2108 / 195514 [S. 958/959] 1 Journal of Inorganic and General Chemistry ARTICLE Zeitschrift für anorganische und allgemeine Chemie [34] J. P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev. Lett. 1996, 77, [40] T. H. Dunning, J. Chem. Phys. 1989, 90, 1007–1023. 3865–3868. [41] D. Figgen, G. Rauhut, M. Dolg, H. Stoll, Chem. Phys. 2005, 311, [35] K. Eichkorn, O. Treutler, H. Öhm, M. Häser, R. Ahlrichs, Chem. 227–244. Phys. Lett. 1995, 240, 283–290. [42] K. Peterson, C. Puzzarini, Theor. Chem. Acc. 2005, 114, 283–296. [36] K. Eichkorn, F. Weigend, O. Treutler, R. Ahlrichs, Theor. Chem. Acc. 1997, 97, 119–124. [37] F. Weigend, Phys. Chem. Chem. Phys. 2006, 8, 1057–1065. [38] S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010, 132, 154104. Manuscript received: August 27, 2020 [39] S. Grimme, S. Ehrlich, L. Goerigk, J. Comput. Chem. 2011, 32, Revised manuscript received: November 7, 2020 1456–1465. Accepted manuscript online: November 9, 2020 Z. Anorg. Allg. Chem. 2021, 951–959 www.zaac.wiley-vch.de 959 © 2020 The Authors. Zeitschrift für anorganische und allgemeine Chemie published by Wiley-VCH GmbH Wiley VCH Donnerstag, 22.04.2021 2108 / 195514 [S. 959/959] 1