The first Cu(I)-peptoid complex is presented here. This complex is based on a helical peptoid incorporating 2,2’-bipyridine (Bipy) ligands pre-organized on the same side of the helix. Interplay between the first and second coordination spheres is demonstrated, where the first coordination sphere is provided by the two Bipy ligands and the second by the helical structure, enabling the high stability of Cu(I).

Abstract

Stabilization of Cu(I) is ubiquitous within native copper proteins. Understanding how to stabilize Cu(I) within synthetic biomimetic systems is therefore desired towards biological applications. Peptoids are an important class of peptodomimetics, that can bind metal ions and stabilize them in their high oxidation state. Thus, to date, they were not used for Cu(I) binding. Here we show how the helical peptoid hexamer, having two 2,2’-bipyridine (Bipy) groups that face the same side of the helix, forms the intramolecular air stable Cu(I) complex. Further study of the binding site by rigorous spectroscopic techniques suggests that Cu(I) is tetracoordinated, binding to only three N atoms from the Bipy ligands and to the N-terminus of the peptoid's backbone. A set of control peptoids and experiments indicates that the Cu(I) stability and selectivity are dictated by the intramolecular binding, forced by the helicity of the peptoid, which can be defined as the second coordination sphere of the metal center.

Introduction

The majority of proteins involved in copper (Cu) homeostasis stabilizes Cu(I).¹ Indeed, +1 is the physiologically relevant oxidation state of Cu in reducing environments, for example, cells, due to the presence of glutathione or ascorbic acid in millimolar concentrations.² Mimicking the ability to stabilize Cu(I) in synthetic complexes is therefore desired for their applications in biology, medicine, and catalysis. In nature, proteins stabilize Cu(I) by protecting the Cu center from the naturally occurring “oxidation window” in which Cu(I) is oxidized back to Cu(II) by O₂ or H₂O₂ to generate hydroxyl radical and restarting the redox cycle.³ Avoiding the oxidation window is enabled via the second coordination sphere about the metal center that can shift the Cu²⁺/Cu⁺ reduction potential towards more positive values thus stabilizing Cu(I).³ In synthetic systems, Cu(I) is thermodynamically instable as it can easily undergo oxidation to Cu(II)⁴ and/or disproportionation⁵ to Cu(0) and Cu(II). Therefore, synthesis of Cu(I) complexes typically requires the use of “soft” ligands similar to the amino acids that coordinate to Cu(I) within the relevant proteins, hence ligands such as thiols and nitriles.⁵ In addition, anaerobic conditions including inert atmospheres and anhydrous solvents are typically required as well.

Although numerous studies demonstrated successful stabilization of Cu(I) by small molecules-based ligands,⁶ these do not properly represent biological systems, that is, proteins, as they only mimic the proteins’ active site and do not mimic the proteins’ structure and second coordination sphere about the metal center. Thus, the stabilization of Cu(I) and control over the Cu²⁺/Cu⁺ redox process by small molecules-based ligands can be limited. One option for overcoming this limitation is to use peptides-based ligands, which can serve as simple models for mimicking the second coordination sphere of proteins about the metal centers. Indeed, it was previously demonstrated that the secondary structure of peptides can have a key role in stabilizing Cu(I) centers coordinated by binding ligands pre-organized within these structured peptides.⁷ Specifically, the helical conformation of α-synuclein was shown to be crucial for stabilizing its Cu(I) complex when the binding methionine groups were placed at i and i+4 positions of the helix.⁸ Nevertheless, the use of peptides as ligands for metal ions towards various applications is not ideal due to the low stability of peptides in different pH and temperature conditions and their susceptibility for proteases degradation. Moreover, although several reports on peptides as ligands for Cu(I) have been published,^{8, 9} the stability of formed Cu(I)-peptide complexes is limited and typically not even reported, and their redox properties not studied. It is therefore desirable to use peptidomimetics-based ligands, which are both stable and can mimic a second coordination sphere about the metal ion(s), for the stabilization of Cu(I).^{9d, 9f, 9g}

Peptoids,¹⁰ oligo-N-substituted glycines, are a well-studied class of peptidomimetics,¹¹ having the following advantages: first, their efficient synthesis on solid support via the submonomer approach¹² utilizes primary amines instead of amino acids and therefore not only avoids protection/deprotection steps, but also allows to introduce numerous functional groups within the peptoid sequence. Second, although peptoids are incapable of forming hydrogen-bonding because the amide nitrogen is substituted, they can fold into stable secondary structures, and specifically helices, by incorporating bulky chiral side chains within their sequence.¹³ In recent years, extensive research yielded numerous peptoids for various applications, including protein-protein interactions,¹⁴ metal binding and recognition,¹⁵ and catalysis.¹⁶ However, no studies of Cu(I) binding to peptoids were reported to date. The reason for this might be that peptoids were shown to preferably stabilize metal ions in their high oxidation states, such as (Cu(II),^{15e, 15f, 16g, 16i} Fe(III),^15c Ru(III),¹⁷ and Co(III),^16h thus stabilizing low oxidation states of metal ions by peptoids is still a challenge.

Results and Discussion

Rational design, synthesis, and characterization of Cu(I)- helical peptoid complex

It was already established that peptoids can fold into PPI type helices when the majority of the side-chains along the peptoid scaffold are chiral and bulky groups,^{15a, 15b, 18} and that the (R)-(−)-3,3-dimethyl-2-butylamine (Nr1tbe) groups can lead to a highly stable PPI helical structure.^13e In addition, our group previously showed in a variety of examples that the binding of a metal ion to two ligands is much stronger if these ligands are pre-organized in the i and i+3 positions of the helical peptoid, such that they face the same side of the helix.¹⁹ In addition, it was shown that 2,2’-bipyridine (Bipy) ligand can act as a π-acceptor through the vacant π* orbitals on the pyridine rings, thus stabilizing low oxidation states metal ions such as Cu(I)²⁰ and that the steric bulk of the 6,6’ substituents is a basic structural requirement to enhance the stability of Cu(I).²¹ Finally, we have previously showed that the linear helical peptoid hexamer P1, bearing two Bipy derivatives (2-(2,2’-Bipyridine-6-yloxy) ethyl (Nbp) groups) at the 2nd and 5th positions, thus facing the same side of the helix (Figure 1A), can bind Cu(II), however, the helical structure was interrupted by the Cu(II) coordination.²² This result indicates that the helical structure of P1 can neither stabilize Cu(II) nor enable a stable penta-coordination geometry for Cu(II) (For more details on Cu(II)P1 coordination see Supporting Information, Figure S15 and Ref. [22]).

Details are in the caption following the image — **Figure 1**
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(A) Chemical structure of peptoid oligomer P1 (B) UV-Vis spectra and a metal-to-peptoid ratio plot (inset) for the titration of P1 with Cu(I) (33 μM) (C) Job-plot of P1 with Cu(I) (33 μM total concentration). Experiments were performed in dry methanol under anaerobic conditions (Total amount of ACN in the titration and Job plot experiments is ∼7 uL (0.27 %).

Taking all of the above into consideration, we can assume that the helix of P1 will be able to stabilize Cu(I) in a tetra-coordination geometry, similar to the helical structure of peptides. Thus, we set to use P1 in this work, aiming to bind and stabilize Cu(I) ions in a tetra-coordination geometry via an intramolecular binding to two Nbp side chains, where the metal center is bound to four nitrogen atoms from the two Bipy ligands.

Peptoid P1 was synthesized via the sub-monomer approach on solid support, purified by preparative HPLC (>95 %) and characterized by analytical HPLC and ESI-MS (Figure S1 and S8). The molecular weight measured by ESI-MS was consistent with the expected mass. Metal-free peptoid P1 exhibits absorption band near λ=299 nm in methanol, arising from the π-π* transitions of two Nbp ligands, respectively. Upon titration with Cu(I) ions, this band diminished and a new absorption band at λ_max=308 nm was produced together with a MLCT broad band at λ_MLCT=428 nm, due to the interactions between the d_π orbital of the 3d¹⁰ Cu(I) center and the unoccupied π* orbital of the Bipy ligand (π-back bonding from Nbp to Cu(I)).²³ This spectrum indicates the formation of a copper-peptoid complex (Figure 1B). From the UV-Vis titration we constructed a metal-to-peptoid ratio plot where a plateau was obtained at the molar ratio of 1 (Figure 1B, inset), which suggests formation of an intramolecular complex, with a ratio of 1 : 1 Cu(I):P1. Keeping the total molar concentration of a mixture solution, which contains both Cu(I) and P1, constant at 33 μM and varying their mole fraction, a Job plot experiment was also conducted (Figure 1C). The absorbance proportional to complex formation was plotted against the mole fraction and from the intersection point at χ=0.473 a stoichiometry ratio was determined to be 0.90,²² supporting the metal-to-peptoid ratio obtained from the UV titrations. HR-MS analysis resulted in exclusively a mass of 1154.6165, which matched the calculated mass of the Cu(I)P1 complex (m/z=1154.6192). Notably, HR-MS analysis didn't show any other masses that could be assigned to full or half-masses of species with a ratio Cu(I):P1 1 : 2 or 2 : 2 (Figure S16–S17). Overall, the results from both UV-Vis titration, Job plot and HR-MS confirmed the formation of the intramolecular complex Cu(I)P1. All measurements were performed in anaerobic conditions in water-free dry solvents in order to prevent Cu(I) disproportionation/oxidation to Cu(II). For comparison, binding of P1 with other metal ions, that is, Cu(II), Co(II), Mn(II), Ni(II) and Zn(II), was studied by UV-Vis titration experiments under the same reaction conditions as with Cu(I) (Figure S30). The results demonstrated that only Cu(I) binding have an MLCT absorption band at λ_MLCT=428 nm, and thus we can follow the changes in the range of this band in further selectivity and stability study.

To determine the affinity of P1 to Cu(I), the association constant of Cu(I)P1 was calculated by a non-linear regression curve fitting of the plot constructed from the UV-Vis titration experiments at lower concentrations in methanol^{15b, 19} (Figure S31). The value for the formation of Cu(I)P1 was found to be K_A(Cu(I)P1)=1.746±0.39 ⋅ 10⁸ M⁻¹.

The selectivity of P1 to Cu(I) was initially estimated by UV-Vis mixture experiments: a mixture containing 1 equiv. of each Cu(I), Cu(II), Co(II), Mn(II), Ni(II) and Zn(II) in methanol was treated with 1 equiv. of P1, and the UV-Vis spectrum of this solution was measured. Interestingly, the obtained UV-Vis spectrum was identical to the UV-Vis spectrum of Cu(I)P1, suggesting that P1 is selective to Cu(I) with regard to the examined metal ions (Figure S32A). To further evaluate the selectivity of P1 to Cu(I), we tested its binding in mixtures containing higher concentrations of the different metal ions relatively to 1 equiv. of Cu(I) (i. e., up to 10 equiv. of each Cu(II), Co(II), Mn(II), Ni(II) and Zn(II)), and again the measured UV-Vis spectrum of this mixture was identical to the UV-Vis spectrum of Cu(I)P1 only (Figure S32B), illustrating that P1 is highly selective to Cu(I) and can extract it from a mixture solution containing excess of up to 10 equiv. of the above metal ions. The selective binding and extraction of Cu(I) by P1 was further estimated by inductively coupled plasma (ICP-OES) measurements. Thus, a mixture of 1 equiv. of P1, 1 equiv. of Cu(I) and 10 equiv. of Co(II), Mn(II) and Zn(II)²⁴ was stirred rigorously for 30 min in dry methanol under nitrogen atmosphere before the solvent was lyophilized, and the solid residue washed with water. The ICP analysis of the precipitated metallopeptoid revealed the exclusive presence of Cu with negligible amounts of the other metals (Figure 2A). ICP analysis of the filtrate showed high concentrations of Co, Mn and Zn, but insignificant amounts of Cu (Figure 2B). Furthermore, the HR-MS analysis of the precipitated metallopeptoid showed the mass of exclusively Cu(I)P1 complex (m/z=1154.5056, and isotopic distribution of this complex matched the predicted pattern of Cu(I)P1 complex, Figure S34–35). Finally, the UV-Vis spectrum of the precipitated metallopeptoid in methanol was identical to Cu(I)P1 complex with characteristic λ_max=308 nm and λ_MLCT=428 nm (Figure S33). Overall, UV-Vis experiments together with ICP-OES and HR-MS confirmed P1 ability to selectively bind Cu(I) in the presence of excess of 10 equiv. of similar and biologically relevant metal ions.

FTIR analysis of P1 and of Cu(I)P1 complex was performed in the solid state under aerobic conditions (see Experimental Section and Supporting Information for the synthesis of Cu(I)-peptoid complexes for FTIR analysis). The FTIR spectrum of P1 shows two bands near 1657 cm⁻¹ and 1594 cm⁻¹ for the two different stretching modes of C=O within the peptoid's backbone, one broad band of lower intensity near 1529 cm⁻¹, that corresponds to the amides bonds at C- and N-terminal of the peptoid and a broad band near 3389 cm⁻¹, assigned to the −NH stretching of the amide at the N-terminal of P1 (Figure S36).²⁵ Upon binding to Cu(I), the bands at 1657 cm⁻¹ and 1594 cm⁻¹ remains intact, suggesting that C=O doesn't participate in metal binding. However, the band at 1529 cm⁻¹ completely diminished and a new band at higher frequency near 1576 cm⁻¹ has appeared, and the band at 3389 cm⁻¹ shifted to higher frequency near 3447 cm⁻¹ while its intensity significantly decreased (Figure S37). These changes could result from an interaction between Cu(I) and the N-terminal amide that affects the stretching modes of these functional groups, as was seen previously in few cases for protein-metal interactions.²⁶ Overall, the FTIR analysis imply that the N-terminal amine participates in the coordination to the metal center.²² As Cu(I) typically adopts a tetra-coordination geometry, we suggest that only three of the four nitrogen atoms of the two Bipy ligands bind Cu(I) and that the binding of the terminal −NH provides the forth coordination site. As Bipy is known to act as a bidentate chelating ligand that binds metal ions while it is in the cis conformation,^{20, 27} binding to the metal ion in a monodentate fashion, most probably while in the trans conformation, is rare.^{27b, 28} Therefore, to further support this assumption, we performed a detailed NMR analysis.

In contrast to peptides, in which the amide bond is mostly in the trans conformation, the amide bond of peptoids goes through rapid isomerization between the cis and trans conformations leading to a significant conformational heterogeneity in solution.²⁹ As a result, rather than a single set of resonances, the NMR spectra of the peptoids will exhibit multiple sets of resonance signals in characteristic spectral regions.³⁰ In addition, due to the dual frustration that arises from the inefficient dipole-dipole magnetization transfer in the absence of dominant structural species, COSY experiment is the most suitable 2D NMR technique for peptoid characterisation in solution,³¹ while NOESY or DOSY experiments are less preferable.³² Overall, the conformational heterogeneity of peptoids in solution significantly complicates their structure determination by NMR techniques, and currently there are only 9 structures of peptoids solved by NMR.³³ P1 has several similar side chains and thus its structure cannot be solved by NMR techniques.³³ Nevertheless, we anticipated that an analysis of the NMR spectra in the aromatic region of both P1 and Cu(I)P1 will provide sufficient information on the binding mode because in this region only signals from the Bipy ligands resonate and despite co-presence of several conformers, the general trend of the chemical shift (δ) upon Cu(I) binding to P1 could be distinguished.

Peptoid P1 and its Cu(I) complex was characterized by ¹H NMR, ¹H-¹H NOESY and ¹H-¹H COSY 2D NMR methods. For the simplicity, in the text below the given number corresponds to a group of resonances from all conformers of the particular proton, that is, 6’ describes all signals of the proton 6’ in all conformers. In the COSY 2D NMR correlation map, all resonances assigned to the same proton from different conformers form the cluster of cross-peaks. As the pyridine rings within P1 are not equivalent both structurally and magnetically, the resonances stem from each pyridine ring slightly differs in their chemical shifts and are therefore marked in different letters (see Figure 1A). When the pyridine ring is mentioned in the text, it refers to the signals of the protons from all co-present conformers of the mentioned ring.

Within the ¹H NMR spectrum of P1, the broad peak at 14.64 ppm could be assigned to the N-terminal −NH (Figure 3A, black line).³⁴ The cluster of peaks in the region between 9.15–6.89 ppm is assigned to the protons of the two Nbp moieties of P1. From the COSY correlation map (Figure S46, black), the overall pattern of the chemical shifts for protons resonances³⁵ is as follows: 6’>3’>4’>3>4>5’>5. Hence, (i) the most low-field cluster of peaks appearing between 9.15–8.99 ppm can be assigned to protons 6’ due to its direct neighboring with the N- atom of the pyridine ring of the Nbp ligand,³⁶ and (ii) the most up-field cluster of peaks appearing between 7.10–6.89 ppm can be assigned to protons 5. In addition, the clusters of peaks appearing at lower field (right after protons 6’) between 8.6–8.3 ppm and 8.0–7.7 ppm are assigned to protons 3’ and 3, respectively. This is because these protons are facing the N- atom of the neighboring pyridine ring in Nbp allowing close contact to the lone-pair electrons of this nitrogen, indicating that both Nbp moieties are in trans conformation.³⁶ This is in agreement with a trans-coplanar conformation of the Nbp side-chains, the most stable form of Bipy moieties both in the solid state and in solution.³⁷

Upon metal-binding to Cu(I), several changes occur within the NMR spectra. First, the methyl protons of acetonitrile (present within the Cu(I) salt used for complexation) resonate at 2.02 ppm, suggesting the acetonitrile is not coordinated to metal (Figure S44, red).²³ Next, all the peaks in the ¹H NMR spectra are shifted; specifically, a downfield shift of the N-terminal −NH proton's signal from 14.64 ppm to 15.14 ppm (Figure 3A, red and black lines, respectively), suggests the coordination of this amine to the metal center, supporting the results from the FTIR analysis. In addition, there is an overall shift and broadening of the proton resonances in the cluster of peaks representing the ‘aromatic’ region in the ¹H NMR spectrum (Figure S44, red line), which is indicative of metal binding to the Nbp side-chains, as was observed previously for Cu(I)-(Bipy)₂ complex at rt.²³ The changes in this region shown in the COSY correlation map for Cu(I)P1 display the coordination of the Nbp moieties to the metal center (Figure S46, red). Generally, due to the electron-withdrawing effect of the metal ion, an overall downfield shift for all protons of Bipy-based ligands participating in the binding is expected.³⁵ However, for Cu(I)P1, different observations were recorded (for more details see Tables S3–6). The cluster of peaks assigned to protons 6’ exhibits an up-field shift of 0.677–0.814 ppm. This can be explained by a shielding of these protons resulting from the interaction between the paired metal d-electrons and the diamagnetic pyridine ring current (anisotropic diamagnetic shielding effect). Such shift is typically observed when the conformation of the Bipy ligand is changed from trans to cis upon metal binding,^{36, 38} suggesting that both the a and d pyridine moieties from the Nbp ligands (see Figure 1A) flipped in order to bind Cu(I). In addition, the clusters of peaks assigned to protons 3’,4’ and 5’ from both a and d pyridine rings exhibit slight up-field shift. This could be explained by increased π-back bonding in Cu(I)-Nbp,²³ or alternatively, by the through-space anisotropic shielding effect of the neighboring a and d rings with each other, similar to the aryl interactions observed for M(II)-Bipy complexes having octahedral or square-planar geometry,^{35, 39} and even for (Bipy)₂-based Cu(I) complexes, having tetrahedral geometry.²³ Notably, there is a difference between the up-field shifts of the two protons marked as 3’ such that the peaks assigned to 3’ of pyridine d exhibit the biggest up-field shift, relative to all these sets of peaks (protons 3’-5’). We suggest that this is because in the cis conformation the de-shielding effect of proton 3’ from the d ring (via proton 3 from c pyridine ring of the same Nbp moiety) is smaller than the equivalent effect in the trans conformation of metal-free P1, where protons 3 and 3’ are de-shielded by interactions with the neighboring N atom.^27c This observation supports the binding of Cu(I) to both N atoms of pyridines c and d, while this Bipy ligand is in the cis conformation.

While all clusters of peaks assigned to the protons from a and d rings are up-field shifted, for b and c rings we can see a different trend. The clusters of peaks assigned to the protons of the c moiety, exhibit slight downfield shifts (Figure3B, red), and the effect decreases with the increase of the distance to the metal ion (Δδ 3>4>5); the protons that are located further from the metal center experience the least overall effect on their chemical shift. On the contrary, the clusters of peaks assigned to the protons of the b ring exhibit negligible downfield shifts (less than 0.1 ppm). Such phenomena shouldn't be observed if both Nbp ligands bind Cu(I) equally in a cis chelating mode. Therefore, we suggest that the Bipy moiety of only one Nbp ligand is in cis, while the second one is in the trans conformation with only one pyridine ring binding to Cu(I). We already saw that the downfield shift of the N-terminal amine suggests that the −NH is coordinated to metal center, therefore, it is possible that the Nr1tbe sidechain appended to this N atom provides steric de-stabilization of the planar chelating mode of the neighboring Nbp ligand (having the a and b rings). As a result of the steric disturbance, this ligand might be enforced into a hypo-dentate mode,^28e leading to a flip of the b ring and to the overall trans conformation of this Nbp ligand. Hence, the b ring does not bind Cu(I), and this is also explained by the neglectable downfield shift of the clusters of peaks assigned to the protons of this ring. An additional support for this proposed binding mode comes from the difference between the chemical shift of the clusters of peaks assigned to the protons of 3’ (see above). Proton 3’ in the d ring is more shielded after binding to Cu(I) due to the Nbp ligand being in the cis conformation, while proton 3’ from the a ring is less shielded after Cu(I) coordination, suggesting that the Nbp ligand with the a and b moieties might not be in the cis conformation. Assuming that after Cu(I) binding the Bipy ligand associated with rings a and b is in the trans conformation and the Bipy ligand associated with rings c and d is in the cis conformation, the steric hindrance that arises from Nr1tbe moiety, which presumably prevents interactions between b and c rings but not between a and d rings, further prevents the anisotropic effect on the chemical shifts of the protons associated with the b and c rings, thus leading to the shifts observed in the NMR spectra of Cu(I)P1.

Taken together, the results from the FTIR and NMR experiments provide strong evidence for a tetra-coordination about the Cu(I) center, involving the terminal −NH and three out of four nitrogen atoms from the Bipy ligands (Figure 4).

Next, several observations from the NMR analysis suggest that peptoid P1 is folded. First, the ¹H-¹H NOESY 2D NMR spectra of the metal-free peptoid P1 showed the NOE signal between the geminal protons of the −NH₂ group at C-terminal end of the peptoid (5.64 ppm) and the proton of the −NH group at N-terminal end of the peptoid (14.64 ppm) (Figure S47), suggesting that these two are in-space neighbors. In addition, these protons produced cross-peaks with the protons of the aromatic region of the peptoid. Overall, these cross peaks indicate interactions between the neighboring in-space groups of protons and imply an overall folding of the peptoid. Second, an indication for the folding of P1 was also observed in ¹H-¹H COSY 2D NMR method, which is the more suitable technique for peptoid characterization in solution.³¹ The COSY correlation map for peptoid P1 has two clusters of peaks that can indicate peptoid folding: (i) the ‘side-chain’ cluster, for the correlations between the methyl groups of the side-chains and various vicinal protons (1–1.4 ppm to 2.5–4.7 ppm, respectively) and (ii) the ‘backbone’ cluster, displaying correlations between the prochiral geminal protons in glycine-like backbone (near the diagonal, 3.5 to 4.7 ppm) (Figure S45, black). Similar to what was shown in previous studies,^{13e, 27, 29, 30} the “side-chain” cluster of the free peptoid P1 spectrum has three sub-clusters, where the downfield subcluster corresponds to the cis conformation of the peptoid amide bond, and the up-field sub-cluster corresponds to the trans conformation. The third sub-cluster represents the N-terminal Nr1tbe sidechain, which resonates further up-field, as expected for the secondary amine (Figure S45, black). The cluster representing the backbone protons of the free peptoid P1 exhibits many well-resolved off-diagonal cross-peaks, those indicating structured and relatively rigid backbone^13e (Figure S45, black). Upon addition of Cu(I) only slight changes in these regions could be observed; both in the cluster of the backbone protons, as well as in the cluster of the side-chain protons (Figure S45, red), there is only a small overall shift of the signals associated with the prochiral geminal protons of the glycine-like backbone, and neglectable changes in the peak positions of cis and N-terminal Nr1tbe side-chain, respectively, implying that Cu(I) binding does not disturb the folding of P1.

The secondary structure of P1 was further studied by circular dichroism (CD) spectroscopy in the presence and absence of Cu(I) and under aerobic conditions (in air). The CD spectrum of metal-free P1 in methanol (Figure S48A, black) exhibits a relatively weak signal with a minimum at 205 nm and maximum at 221 nm, and resembles the mirror like image of a spectrum of helical Ns1tbe-bearing homohexamer reported recently by our group^{13e, 22} (exhibiting a minimum near 225 nm and a maximum near 209 nm). These observations imply that the overall helical structure is not disturbed when the initial sequence (a homohexamer) is modified by replacing two Nr1tbe side chains with two Nbp side chains, and that P1 is folded into a left-handed helix in solution. Addition of Cu(I) to P1 showed a significant increase in the CD signal intensity of the helical minima and maxima near 205 and 221 nm (Figure S48A, red). These bands are associated with peptoid's helical structure, and the observed changes could suggest increase of conformational order of peptoid and stabilization of the helical structure upon binding to Cu(I), as it was previously shown for the binding of P1 to Co(II) or to Ni(II).²² Binding to Cu(I) led to additional CD band with λ_max=317 nm, supporting the formation of metal-peptoid complex. The helical structure of P1 can be considered a second coordination sphere, which, in addition to the first coordination sphere, might have a role in selective binding and stabilizing of Cu(I).

Stability of Cu(I) within Cu(I)P1

To evaluate the ability of P1 to stabilize Cu(I) we conducted two independent experiments: (i) cyclic voltammetry (CV) of Cu(I)P1 and (ii) UV-Vis measurements of Cu(I)P1 with respect to time. The electrochemical behavior of Cu(I)P1 and of the control complex Cu(I)(Bipy)₂ (for details see Experimental Section) was explored by CV under aerobic conditions in dichloromethane, using tetrabutylammonium hexafluorophosphate as supporting electrolyte, Ag/AgNO₃ as reference electrode and ferrocene as an internal standard. Both Cu(I)P1 and Cu(I)(Bipy)₂ complexes exhibit irreversible redox behavior, with E_pa=+0.200 V (vs Ag/AgNO₃) for Cu(I)P1 and E_pa=−0.030 V (vs Ag/AgNO₃) for Cu(I)(Bipy)₂ which could be assigned to Cu²⁺/Cu⁺ couple (Table 1 and Figure S49C–D). We note that the reduction potential of Cu²⁺/Cu⁺ for Cu(I)P1 is 230 mV more positive than that of Cu(I)(Bipy)₂ at the same experimental conditions. In addition, the CV of the mixture of Cu(I) and P1 with increased ratio of Cu(I):P1 to 1 : 2 did not show changes in the current intensity or in the E_pa value, and the CV spectra of Cu(I):P1(1 : 1) and Cu(I):P1(1 : 2) overall appear similar to each other (Figure S49D). This observation suggests that the complex Cu(I)(P1)₂ is not formed, which further confirms the exclusive formation of intramolecular 1 : 1 Cu(I)P1 complex, as was demonstrated from UV-Vis and HR-MS experiments. Furthermore, when converted to SHE and compared to the potentials reported for previously published Cu(II)-peptoid complexes,^{16i, 16g} E(Cu²⁺/Cu⁺) of Cu(I)P1 is 640–840 mV more positive (Table 1). The more reduction potential of the Cu²⁺/Cu⁺ couple for Cu(I)P1 relative to Bipy and to other peptoids clearly indicates the stabilizing effect of P1 on the Cu(I) oxidation state.

Table 1. Comparison of redox potential for Cu²⁺/Cu⁺ couple of Cu(I)P1 to these of other reported Cu(II) complexes.

Peptoid sequence	E(Cu²⁺/Cu⁺) vs Ag/AgNO₃	E(Cu²⁺/Cu⁺) vs SHE	δE (Cu²⁺/Cu⁺) compared to P1	[Ref.]
Nr1tbe-Nbp-(Nr1tbe)₂-Nbp-Nr1tbe (P1)	+0.200 V	+0.887 V	0 mV	This work
2, 2’-bipyridine (Bipy)	−0.030 V	+0.657 V	+230 mV	This work
2, 2’-bipyridine (Bipy)		+0.437 V^[c]	+450 mV	[41]
Nbp-Nhe^[a]->Nhe (Dinuclear-copper-complex)		+0.050 V	+837 mV	[16i]
Nbp-Nhe^[a]->Nhe (Dinuclear-copper-complex)		+0.240 V	+647 mV	[16i]
Nbp-Nhe-Npm^[b]		+0.200 V	+687 mV	[16g]

[a] Nhe – ethanolamine [b] Npm – benzylamine [c] converted from the reported value of E(Cu²⁺/Cu⁺) vs SCE in Ref. [41].

In the second experiment, a cuvette open to air containing 1 equiv. of P1 was treated with 1 equiv. of Cu(I) and it's UV-Vis spectra were measured. Changes of this solution with time were further monitored by measuring the UV-Vis spectra of this solution during five hours with time intervals of 1 h and additional measurements after 8 h and after 24 h (one day). These spectra revealed no shifts in the absorption bands of Cu(I)P1 complex, and overall, the spectra remained the same with only slight decrease in the intensity of MLCT broad band at λ_MLCT=428 nm with time, suggesting that Cu(I)P1 species are present up to 1 day (Figure S50A). Furthermore, even after four days Cu(I)P1 species were still present and the intensity of the MLCT band did not change (Figure S51A). For comparison, we have conducted the same experiment with Cu(I)-(Bipy)₂; it was previously reported that Cu(I)-(Bipy)₂ complex is air stable⁴⁰ but its stability over time was not specified. Our results showed that Cu(I) within this complex completely oxidized to Cu(II) after only 1 h, emphasizing the advantage of P1 in stabilizing Cu(I) (Figure S50B). At this point we assumed that this high stability, together with the high selectivity of P1 to Cu(I), could be related to the relatively stable helical structure of P1, the intramolecular binding mode, the unique coordination that involves the backbone terminal amine or a combination of at least two of these factors.

The role of the secondary structure of the peptoid in Cu(I) binding and stability

To investigate the role of the peptoid's helicity in the stability of Cu(I) we designed a set of the Bipy modified peptoids which are expected to have less stable helical structures than P1 (Figure 5A). Thus, we have prepared the hexamers P2 and P3 bearing Nbp at the same positions as P1 and (S)-(+)-1-phenylethylamine (Nspe) or S-(+)-methoxy-propylamine (Nsmp) groups, respectively, instead of Nr1tbe groups at the other positions. In contrast to Nr1tbe side chains that promote prevalence of all cis conformations, the Nspe side-chain cannot provide such preference, which results in greater conformational heterogeneity (K_cis/trans for (Ns1tbe)₅=7.96^13e vs. K_cis/trans for (Nspe)₅=1.5³⁰ in CD₃CN) and the Nsmp side-chain groups lead to unstructured peptoid oligomers.⁴² Therefore, P2 has a less stable helical structure than P1, while P3 does not have a helical structure, as also reflected by the CD spectra of these three peptoids (Figure S48C,D). We also synthesized the peptoid dimer P4, bearing two Nbp side chains, in order to probe, when compared to the peptoid hexamers, whether the peptoid backbone has any role in Cu(I) stability.

All three peptoids were synthesized on rink amide resin via the solid phase submonomer approach, cleaved, and purified by HPLC (>95 % purity) and their identity was confirmed by ESI-MS (Figure S2–4, S9–11). UV-Vis titration experiments of P2-P4 with Cu(I) were conducted in the same concentrations and reaction conditions as were conducted with P1. The UV-Vis spectrum of P2 was similar to that of P1: upon titration with Cu(I), the bands corresponding to P2 disappeared and new bands at λ_max=308 nm and λ_MLCT=428 nm appeared indicating the formation of a Cu(I)-P2 complex (Figure S52A). However, molar to ratio plot, that was constructed from the UV-Vis titrations of the peptoid P2 with Cu(I) resulted in a Cu:P2 ratio of 0.5 : 1 (Figure S52A, inset), suggesting an intermolecular binding mode and the formation of the complex Cu(I)(P2)₂. The UV-Vis spectra of P3 and P4 and their corresponding Cu(I) complexes were similar to these of P2 and it's Cu(I) complex. Addition of Cu(I) to P3 produced absorption bands at λ_max=309 nm and λ_MLCT=419 nm (the slightly blue-shifted MLCT band might be an indication of less effective Cu(I)-Nbp π-back bonding interaction,²³ Figure S53A). Addition of Cu(I) to P4 led to absorption bands at λ_max=306 nm and λ_MLCT=450 nm, however the MLCT-related absorbance band decreased with the addition of excess Cu(I) ions, suggesting disturbance in Cu(I) binding by P4, which might arise from a partial oxidation of Cu(I) to Cu(II) during UV-Vis titration experiment (Figure S54A). The molar-to-ratio plot, constructed from the UV-Vis titrations for P3, also resulted in a Cu:Peptoid ratio of 0.5 : 1, suggesting an intermolecular binding mode, as was seen for the binding of Cu(I) to P2 (Figure S53A, inset). Furthermore, solid state FTIR suggested that the binding mode of peptoids P2, P3 and P4 to Cu(I) involves the secondary amine of the N-terminal of these peptoids; the intensity of the stretching bands of this −NH group together with C−N stretching (coupled with −NH bending) in the FTIR spectra of the metal-free peptoids decreased and they slightly shifted upon binding to Cu(I), similarly to the FTIR spectra of Cu(I)P1 described above (Figure S40–43). Interestingly, peptoids P2-P4 did not show the same selectivity for Cu(I) as P1: although P2 was able to selectively bind Cu(I) from a mixture containing 1 equiv. of each Cu(I), Cu(II), Co(II), Mn(II), Ni(II) and Zn(II) in methanol (the UV-Vis spectrum of the mixture solution was identical to the UV-Vis spectrum of Cu(I)-peptoid complex, Figure S56A), when the excess of other metal ions was raised to only 1.5 equiv., the UV-Vis spectrum of the mixture solution was different from the corresponding spectrum of Cu(I) complex; the intensity of the MLCT band at 417 nm decreased and λ_max shifted to 311 nm (Figure S56B). In contrast, P3 and P4 was unable to selectively bind Cu(I) even from the mixture of 1 equiv. of each Cu(I) and other metal ions (Figure S56-D). Based on these results we can propose that the less stable helical structure of P2, as well as the non-helical peptoids P3 and P4, do not enable pre-organization of the two Nbp side chains and thus intramolecular binding is not preferred, and this has effect on the selectivity of the peptoids to Cu(I).

Next, we wished to check the stability of Cu(I) within the complexes of peptoids P2, P3 and P4 at the same conditions as we've done for P1. To this aim, we prepared a set of cuvettes containing 1 equiv. of either P2, P3 or P4, and these were added separately to 1 equiv. of Cu(I). We then followed the changes in the UV-Vis spectra as a function of time, as we previously did with P1. The results, presented in Figure 5B, revealed that in contrary to P1, which could stabilize Cu(I) over time, P2-P4 could not stabilize Cu(I) ions. Instead, Cu(I) is oxidized to Cu(II) within 1–4 h as seen from the decrease in the intensity of the MLCT band, from the shift of the initial λ_max from 301–309 nm to >310-312 nm and the increase in the intensity of the new λ_max (For Cu(II)-peptoids UV-Vis spectra see Figure S52–54,B). Within P4, Cu(I) is oxidized completely to Cu(II) after only 1 h, and within P2 and P3 full oxidation occurs in 4 h. From these results we can suggest that the helical structure of P1 has a key role in the stabilization of Cu(I) ions, as neither Bipy nor the dimer P4 were able to stabilize Cu(I) for more than an hour. Moreover, P2, which has a less stable helical structure than P1, and P3, which is a non-helical peptoid, could stabilize Cu(I) for just a few hours, compared to P1, having a stable helical structure, which could stabilize Cu(I) for at least four days.

The role of the coordination mode in Cu(I) binding and stability

To understand whether the unique coordination of P1 to Cu(I), that is, via the terminal amine and only three out of four nitrogen atoms of Nbp, has a role in the high stability of Cu(I), we decided to acetylate the terminal −NH group such that it cannot bind to Cu. Thus, the peptoid P1Ac (Figure 6A) was synthesized on solid support, cleaved from resin, purified by HPLC (>95 % purity) and its identity was confirmed by ESI-MS analysis (Figure S5, S12). P1Ac was titrated with Cu(I) in the same reaction conditions that were performed with P1, followed by UV-Vis measurements. Metal free P1Ac exhibits a band at λ=300 nm with shoulder at λ=328 nm. Upon addition of Cu(I) two new bands were obtained with λ_max=309 nm and MLCT band at λ_MLCT=428 nm (Figure S55A). The UV-Vis spectra of the P1Ac titration with Cu(I) was similar to these of P1, indicating the formation of a 1 : 1 Cu(I):peptoid complex with an intramolecular binding mode (Figure S55A, inset). This solution was further analyzed by HR-MS techniques and the obtained mass of 1196.6287 matched the calculated mass of the intramolecular 1 : 1 Cu(I)P1Ac complex (m/z=1196.6298, (Figure S20-21). The binding of P1Ac to Cu(I) was further characterized by FTIR (Figure S39). As the N-terminal of P1Ac is acetylated, there is no stretching of the −NH bond in the corresponding FTIR spectrum before or after addition of Cu(I). Finally, addition of Cu(I) to P1Ac was monitored by CD spectroscopy (Figure S48B). The spectrum of free P1Ac is identical to that of free P1 with minima and maxima near 205 and 221 nm, an indicative of the peptoid P1Ac folding into helical structure in solution. Binding to Cu(I) did not lead to changes in the intensity of these two bands, as was seen for Cu(I)P1, but a CD band near λ_max=320 nm was obtained, indicating the formation of Cu(I)P1Ac complex. A UV-Vis stability test, performed in the same reaction conditions as was previously done with P1 showed that Cu(I) within Cu(I)P1Ac is stable for 5 h (Figure 6B) and even for four days in solution, similar to Cu(I) within Cu(I)P1 (Figure S51B). A comparison between the CD spectra of P1Ac and its Cu(I) complex, as well as between Cu(I)P1Ac, Cu(II)P1Ac, Cu(I)P1 and Cu(II)P1 (Figure S48A,B) suggests that the absence of −NH in P1Ac does not disrupt its helical structure for both the metal-free and the Cu(I)-bound peptoid. Thus, we can conclude that the unique binding of P1 to Cu(I) via the terminal −NH, is not a factor in the ability of P1 to stabilize Cu(I), and it is more likely that the main factor in this ability is the helical structure of both P1 and P1Ac, which enables coordination of Cu(I) in a stable geometry.

Finally, to understand whether the intramolecular binding mode enforced by the two Bipy side chains that pre-organized due to the helical structure of P1 has a role in the high stability of Cu(I), we designed and synthesized P5 and P6, bearing only one Nbp moiety on either i or i+3 position and Nr1tbe on the other positions, respectively (Figure 7A). These peptoids were synthesized on solid support, cleaved from resin, purified by HPLC (>95 % purity) and their identity was confirmed by ESI-MS analysis (Figure S6–7, S13–14). The UV-Vis titration spectra of P5 and P6, performed in the same conditions as with P1, revealed that in contrast to P1, the UV-Vis spectra of P5 and P6 upon addition of Cu(I) fail to produce an MLCT band at >400 nm and for both peptoids binding to Cu(I) resulted in only a slight red shift of the π-π* transitions of Nbp, from 300 nm in the metal-free peptoid to 304 nm or 307 nm for P5 and P6, respectively (Figure 7B–C). These results indicate that Cu(I) complexes of P5 or P6 were not formed. The CD spectra of metal-free P5 and P6 exhibit characteristic minima and maxima near 205 and 221 nm, implying their folding into helical structures (Figure S48E,F, black line). Addition of Cu(I) to these peptoids resulted in negligible decrease in the intensity of these two bands (Figure S48E−F, red line). Furthermore, addition of Cu(I) to these peptoids did not produce any bands at >300 nm (indicating the formation of a metallopeptoid), suggesting that the corresponding Cu(I)-peptoid complexes were not formed. Overall, the disability of P5 and P6 to bind Cu(I) suggests that the binding of Cu(I) by a Bipy-based peptoid requires two incorporated Nbp ligands.

Conclusions

The stabilization of Cu(I) by small molecule-based ligands, as well as by peptides and peptidomimetics, is an important task in various fields of research including biology, catalysis, and medicine. Nevertheless, the low oxidation potential of Cu(I) in aerobic environment makes this task rather challenging. Specifically, the stabilization of Cu(I) by peptoids, peptidomimetics known to stabilize a variety of metal ions, was not demonstrated to date. Herein we describe how we obtained the first Cu(I)-peptoid complex by successfully stabilizing Cu(I) in air using the helical peptoid hexamer P1 or its N-terminal acetylated version P1Ac. P1 was identified as an excellent candidate for the selective binding (in the excess of up to 10 equiv. of other metal ions, as confirmed by UV-Vis, HR-MS and ICP experiments) and stabilization of Cu(I) due to: (i) the high stability of its helical structure, that was destabilized by the binding of Cu(II), and (ii) the incorporated and pre-organized two Bipy ligands, that are known to form a Cu(I)bis Bipy complex. Capitalizing on these properties of P1, we demonstrate here for the first time, the formation of air stable Cu(I)-peptoid complexes, based on extensive spectroscopic and cyclic voltammetry studies. We further used a set of control peptoids, some not structured, some having only one Bipy ligand and one that does not have a free −NH group at its N-terminal, to probe the key factor(s) for selective binding and stabilizing Cu(I) by Bipy-based peptoids. Thus, we show that the ability of the peptoid to bind Cu(I) in an intramolecular mode by two incorporated Bipy ligands, either when the terminal −NH participates in the coordination or when it does not participate in the coordination to Cu(I), is an important factor both in the binding of Cu(I) to the peptoid and in the stabilization of Cu(I) within the peptoid. We also showed that the helical structure, which can be considered the second coordination sphere of the metal ion, has a key role in the intramolecular binding mode and thus in the overall stabilization and selective binding of Cu(I) within the peptoid.

Experimental section

Materials: Rink amide resin was purchased from Novabiochem. Trifluoroacetic acid (TFA) and (S)-(+)-1-methoxy-2-propylamine (Nsmp), zinc(II) acetate dehydrate and nickel(II) acetate were purchased from Alfa Aesar. (S)-(−)-1-phenylethylamine (Nspe) and manganese(II) acetate tetrahydrate were purchased from Acros. Bromoacetic acid, cobalt(II) acetate tetrahydrate and copper(II) chloride and tetrakis(acetonitrile)copper(I) hexafluorophosphate were purchased from MERCK. 6-bromo-2,2’-bipyridine, (R)-(−)-3,3-dimethyl-2-butylamine (Nr1tbe), N,N’-diisopropylcarbodiimide (DIC), piperidine, acetonitrile (ACN) and water and HPLC grade solvents were purchased from Sigma-Aldrich; dimethylformamide (DMF), dichloromethane (DCM) and Methanol (MeOH) solvents were purchased from Bio-Lab Ltd. All reagents and solvents except ACN and MeOH were used without additional purification. Acetonitrile (ACN) and Methanol (MeOH) were dried under molecular sieves 4 Å and degassed under pressure of N₂ before use. 2-(2,2’-Bipyridine-6-yloxy) ethylamine (Nbp) was synthesized according to previously published procedure^17a

Synthesis and purification of the peptoid oligomers: Peptoid oligomers were synthesized manually in fritted syringes on Rink amide resin at room temperature using a variation of a previously reported peptoid sub-monomer protocol.¹² See detailed procedure in Supporting Information.

UV/Visible titrations: UV measurements were performed using a sealed cuvette. In a typical experiment, 10–20 μL of a peptoid solution (5 mM in MeOH) was added (to get 17–33 μM concentration) and then sequentially titrated with 2–4 μL aliquots of a metal ion (5 mM) in multiple steps, until the binding was completed.

UV/Visible Job plot experiment: Job plot was determined using UV-Vis spectrometry by varying mole fraction of Cu(I) ion and P1 using 33 μM total molar concentration in MeOH solution.

UV/Visible stability experiments: In a typical experiment, 1 equiv. of a peptoid solution (10-20 μL, 5 mM in MeOH) was added to get 17–33 μM concentration, followed by addition of 1 equiv. of Cu(I) solution. The cuvette was left exposed to air. UV-Vis spectra were recorded immediately after addition, and then every hour. Duration of experiment - 96 h.

UV/Visible selectivity experiments: In a typical experiment, solutions containing mixtures of metal ions (1 equivalent of Cu(I) and 1–10 equivalents of Cu(II), Ni(II), Co(II), Mn(II) and Zn(II), which is of 10–20 μL of 5 mM and 2–40 μL of 25 mM, respectively in 3 mL of MeOH were first measured as a blank. Then, peptoid was added (10 μL, 5 mM) and the spectrum was measured again.

Synthesis of metal complexes for MS analysis: Samples for MS analysis were prepared shortly before measurements. In a typical experiment, a solution of peptoid oligomers (100–200 μL of 0.05 mM) in MeOH was treated with metal solution (5 mM in MeOH:ACN=2 : 1) and the mixture was stirred for 30 min under N₂ pressure prior to MS analysis.

Binding constants calculations: The association constant for Cu(I)P1 was calculated by non-linear regression curve fitting of a plot (absorbance intensity at λ=299 nm vs concentration of Cu(I) ions added) constructed from UV-Vis titration of 10 μL 5 mM solution of P1 by 2 μL aliquots of a Cu(I) solution (1 mM in MeOH) into a total volume of 3 mL MeOH.^{15b, 19}

Inductively coupled plasma (ICP) experiments: To a solution of 1 equiv. of Cu(I) (0.35 mM in MeOH) and 10 equivalents of Co(II), Mn(II) and Zn(II) (3.5 mM each in MeOH), ∼4 mg of peptoid P1 (weighted precisely) was added, and the mixture was allowed to shake for 30 min under N₂ pressure. The solvent was then evaporated, and the ACN/water solution was lyophilized overnight. To the lyophilized powder, 1 mL of H₂O was added; the mixture was shaken for 5 min and centrifuged 15 min to separate the solution and the precipitate. After the centrifugation, the water was removed, and this process was repeated another 9 times. From the precipitated metallopeptoid, small amount was taken, re-dissolved in MeOH, and it's UV-Vis and HR-MS spectra were taken. Next, to the precipitated metallopeptoid, 0.2 mL of 69 % nitric acid HNO₃ was added, the mixture was mixed thoroughly for 30 min, followed by the addition of water to get 10 mL final volume. All solutions were filtered by 0.2 mm filters prior to ICP analysis. Standard errors are represented by error bars, with experiments number=3.

Circular dichroism (CD) spectroscopy: CD scans were performed at 25 °C at a concentration of 100 μM in a solution of methanol. The spectra were obtained by averaging 4 scans per sample in a fused quartz cell (path length=0.1 cm). Scans were performed over the 370 to 190 nm region using 50 nm min⁻¹ scan rate.

FTIR spectroscopy: For FTIR analysis, Cu(I)-peptoid complexes were synthesized by mixing 1 equiv. of peptoid with 1 equiv. of tetrakis(acetonitrile)copper(I) hexafluorophosphate in water-dry solution of 2 : 1 methanol:acetonitrile under nitrogen atmosphere for 30 min. The solution was evaporated and the isolated complex was dried in vacuo. All measurements were performed in the solid state at rt.

Cyclic voltammetry experiments: Solutions of the compounds were placed in one-compartment three-electrode cells. Complexes Cu(I)P1 and Cu(I)(Bipy)₂ were prepared in situ prior to the experiment. Glassy Carbon (GC) was used as a working electrode, Ag/AgNO₃(0.01 M AgNO₃, 0.1 M TBAP in ACN) as a reference electrode and Pt wire as a counter electrode. Working electrode pretreatment before each measurement included polishing with 0.05 μm alumina paste following by rinsing with water and acetone and finally drying in air. Redox potentials given by Ag/AgNO₃ reference electrode was corrected by using internal standard of ferrocene couple in DCM for calibration. All redox potentials in the present work are measured in DCM and converted from E vs Ag/AgNO₃ to E vs SHE by adding +0.600 V to the measured potential⁴³ (to convert Ag/AgNO₃ to SCE) and additional +0.242 V (to convert SCE to SHE). CVs were collected at 100 mV/s.

NMR experiments: All experiments were conducted at 14.1 T and 294.4 K in dry CDCl₃. Samples were prepared prior to measurement in the inert atmosphere (glovebox) and transferred into the sealed J-Young NMR tube. Peptoid P1 and it's Cu(I)P1 complex were characterized in this study using two-dimensional homonuclear method, COSY experiment and NOESY experiment. For COSY, typical acquisition parameters were 256–512 complex points and an acquisition time of 42.6–85.2 ms in the indirect 1H dimension, and 6008 complex points and an acquisition time of 499.8 ms in the observed 1H dimension. For NOESY, typical acquisition parameters were 256 complex points and an acquisition time of 11.8 ms in the indirect 1H dimension, and 2048 complex points and an acquisition time of 94.6 ms in the observed 1H dimension.

Supporting Information

Additional references cited within the Supporting Information.⁴⁴

Acknowledgments

We thank Mrs. Larisa Panz for her assistance with the various MS measurements, Mr. Guilin Ruan for his assistance with electrochemistry experiments and Dr. Ira Ben-Shir for her assistance with NMR measurements.

Conflict of interest

There are no conflicts to declare.

Open Research

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

Supporting Information

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Volume29, Issue43

August 1, 2023

e202301118

The First Cu(I)-Peptoid Complex: Enabling Metal Ion Stability and Selectivity via Backbone Helicity

Graphical Abstract

Abstract

Introduction

Results and Discussion

Rational design, synthesis, and characterization of Cu(I)- helical peptoid complex

Stability of Cu(I) within Cu(I)P1

The role of the secondary structure of the peptoid in Cu(I) binding and stability

The role of the coordination mode in Cu(I) binding and stability

Conclusions

Experimental section

Supporting Information

Acknowledgments

Conflict of interest

Open Research

Data Availability Statement

Supporting Information

References

Figures

References

Information

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The First Cu(I)-Peptoid Complex: Enabling Metal Ion Stability and Selectivity via Backbone Helicity

Graphical Abstract

Abstract

Introduction

Results and Discussion

Rational design, synthesis, and characterization of Cu(I)- helical peptoid complex

Stability of Cu(I) within Cu(I)P1

The role of the secondary structure of the peptoid in Cu(I) binding and stability

The role of the coordination mode in Cu(I) binding and stability

Conclusions

Experimental section

Supporting Information

Acknowledgments

Conflict of interest

Open Research

Data Availability Statement

Supporting Information

References

Figures

References

Related

Information