M/P Helicity Switching and Chiral Amplification in Double-Helical Monometallofoldamers

Short-stranded double-helical monometallofoldamers capable of M/P-switching were constructed by the complexation of two strands, each with two L-shaped units linked by a 2,2′-bipyridine, with a Zn(II) cation. The helix terminals of the “double-helical form” folded by π–π interactions can unfold in solution to equilibrate with the “open forms” that are favored at higher temperatures. Interestingly, the helical chirality of the monometallofoldamers with chiral side chains induced a single-handed helix sense and controlled M/P-switching depending on achiral solvent stimuli. For instance, the (M)-helicity was favored in nonpolarized solvents (toluene, hexane, Et2O), whereas the (P)-helicity was favored in Lewis basic solvents (acetone, DMSO). Circular dichroism (CD) and rotating-frame overhauser enhancement spectroscopy (ROESY) measurements revealed that the conformational change of the chiral side chains due to interaction of Lewis basic solvents with the double helices induced helicity bias. These novel double-helical monometallofoldamers possessed a stable helical structure and exhibited switchable chiroptical properties (gabs ∼ 10–3–10–2). In addition, the chiral strand exhibited chiral transfer and amplification abilities through the formation of chiral heteroleptic double-helical monometallofoldamers when mixed with an achiral strand.


■ INTRODUCTION
Helical foldamers 1−16 have attracted attention as stimuliresponsive switchable molecules, 3−8 tunable chiral materials, 9,10 guest-selective receptors, 11−14 and cooperative supramolecular systems 15,16 due to their chiral and conformational switching properties.In particular, double-helical foldamers are kinetically stable and exhibit stronger chiral properties compared to single helices. 2 Furthermore, double helices can exhibit distinctive properties, 17,18 such as the transfer and transcription of chiral information from one chiral strand to the other achiral strand, 18 and are expected to be applied to higher-order structural control related to replication, similar to nucleic acids.
For switching and output chiral information, the development of chiral reversal systems (− → + or + → −) that exhibit larger output changes compared with just chiral induction (0 → ±) and the establishment of design guidelines for smaller molecules are very important.−34 For example, some helical polymers and oligomers containing single-stranded foldamers (Scheme 1a), 20−25 supramolecular gels, 26 complexes, 27 propeller-shaped molecules, 28,29 and macrocycles 30,31 exhibit chirality switching induced by achiral stimuli.−23 However, switching of helicity in small molecules and double-helical foldamers is difficult.In the former, the helix sense stabilized by chiral auxiliaries must be destabilized without the assistance of cooperative effects, which are defined by the sum of small energy differences between side chains as in polymers.−34 Therefore, the compatibility of helicity inversion and amplification in double helices is still unexplored.For example, double-helical structures bridged by covalent bonds or coordination bonds to restrict dissociation into single helices have been developed to stabilize the double helix 35−38 (Scheme 1b), 39−44 while the switching properties are restricted in these more stable multibridged double helices. 45,46n this study, we designed the attractive mechanical motif, double-helical monometallofoldamers bridged with a single metal cation in the center of the helices, to balance both the stability and dynamic properties (Scheme 2).These monometallofoldamers would adopt a "double-helical form" bridged with a single cation at the central coordination site.The folded helix terminals could unfold in solution to equilibrate with the "open forms" (Scheme 2a) and refold to a double-helical form with opposite helicity, allowing M/P-switching control.Herein, we synthesized double-helical monometallofoldamers by bridging two strands 1a−1c consisting of two L-shaped units and a 2,2′-bipyridine moiety with a single Zn(II) cation (Scheme 3).The monometallofoldamers [(1c) 2 Zn][OTf] 2 with chiral side chains not only induced a single-handed helix sense in the double helix but also showed controllable M/ P-switching in response to achiral solvent stimuli (Scheme 2b).In addition, the chiral strand exhibited chiral transfer and amplification abilities through the formation of chiral heteroleptic double-helical monometallofoldamers when mixed with achiral strands (Scheme 2c).

Complexation and X-ray Structures of [(1) 2 Zn]
[OTf] 2 .Foldamers 1a−c themselves did not form helical structures in solution or in the solid state due to the preference for the transoid conformation of the bipyridine spacer (Figure S5).Addition of zinc triflate [Zn(OTf) 2 ] to foldamers 1a−c promoted the formation of the double-helical complexes (Scheme 5).The zinc complex of 1a was difficult to characterize in solution due to its poor solubility.However, single crystals of complex [(1a) 2 Zn][OTf] 2 were obtained by the diffusion method from solutions, in which 1a and a Zn(II) cation source were combined and sonicated for several hours.The structures of the complex [(1a) 2 Zn][OTf] 2 was revealed by X-ray crystallography (Figure 1).[(1a) 2 Zn][OTf] 2 adopted a double-helical mononuclear structure with two bipyridines coordinated to the zinc cation skewed tetrahedrally (Figure 1a,e,f).The two strands completely enclosed the Zn(II) cation (Figure 1c).The bipyridine spacer was stacked between the two L-shaped units with a stacking distance of 3.2−3.4Å (Figure 1b).Furthermore, the crystals contained (M)-and (P)-double helices, and those M/P-forms were stacked alternately (Figure 1d).better solubility than [(1a) 2 Zn][OTf] 2 , were measured upon the addition of Zn(OTf) 2 (0.5 equiv) to 1b in CDCl 3 .The complex [(1b) 2 Zn][OTf] 2 adopted both double-helical and open form conformations, which were in equilibrium (Figure 2a).The bipyridine protons H a ' and H b ' of the complex shifted significantly upfield (5.6−6.2ppm)compared to 1b, despite coordination to a zinc cation, suggesting the stacking of the Lshaped unit and two bipyridine units (shown in blue in Figure 2b).We assigned the species with these peaks to the doublehelical form of [(1b) 2 Zn][OTf] 2 comparable to that observed in the X-ray structure of [(1a) 2 Zn][OTf] 2 .Interestingly, NMR studies revealed additional conformations of [(1b) 2 Zn][OTf] 2 .In CDCl 3 , the chemical species exhibited broad peaks (shown in orange in Figure 2c−e) that intensified with increasing temperature, suggesting the formation of another complex.
DOSY analyses revealed that the hydrodynamic radius of this complex was approximately equivalent to the doublehelical form (D = 5.55 × 10 −10 m 2 •s −1 obtained from peak E″, D = 5.61 × 10 −10 m 2 •s −1 obtained from peak E′ of the doublehelical form), suggesting this complex could have the same composition as the double-helical form of [(1b) 2 Zn][OTf] 2 (Figure S15).EXSY analyses suggested a chemical exchange between the double-helical form of [(1b) 2 Zn][OTf] 2 and this complex (Figure S14), suggesting that this complex is a conformational isomer of the double-helical form.As a candidate for this conformational isomer, the existence of an "open form" with four L-shaped units facing outward was suggested from the preliminary X-ray structure of [(1a) 2 Ag]-[PF 6 ] (Figure S7).The remarkably broad peaks of the open forms suggested that multiple conformations were in equilibrium on the NMR time scale, making them indistinguishable at 258−323 K, at least in CDCl 3 (Figure S18).Therefore, all conformers with one or more L-shaped units facing outward, except the double-helical form, were defined as open forms (Figure S16).
We expected that the two forms were in equilibrium and interconvertible by rotation of the L-shaped units.Therefore, we investigated the equilibrium behavior and thermodynamic parameters of [(1b) 2 Zn][OTf] 2 .Variable-temperature 1 H NMR revealed that the double-helical form with dense πstacking was enthalpically favored, while the open forms with a high mobility of the L-shaped units were entropically favored (Figure S18).The van't Hoff plots revealed that ΔH open→helix and ΔS open→helix for the conversion of open forms to the   S19).
The equilibrium between the double-helical form and the open forms in various solvents was investigated, revealing that the effect of the solvents was not simple (Table 1 and Figure S17).In CD 3 OD/CDCl 3 or CD 3 CN/CDCl 3 , the enthalpy difference ΔH increased negatively, suggesting that the doublehelical form was favored due to solvation of polar solvents to the double-helical form.The entropy difference ΔS open→helix also increased due to the decreasing degrees of freedom of the solvated double-helical form and solvating solvents.Interestingly, in bulky THF-d 8 and nonpolar toluene-d 8 , ΔH open→helix and ΔS open→helix decreased, suggesting that bulky solvents provided less solvation.
Chirality Switching of Monometallofoldamers.The monometallofoldamers were kinetically stable and not in intercomplex equilibrium (or were in very slow intercomplex equilibrium), as revealed in the ligand exchange experiment (see Supporting Information, Section 5).This suggested that the switching property between the double-helical form and the open forms could be applied to M/P helicity switching via open forms as intermediate structures (Figure 3).Therefore, the control of the chirality of the monometallofoldamer was investigated by using [(1c) 2 Zn][OTf] 2 with chiral auxiliaries    The diastereomeric bias was investigated by CD measurements (Figure 4 and Table 2).In the 250−600 nm region, the strand (R)-1c showed a marginal Cotton effect (Figures S30− S33), whereas [(R)-(1c) 2 Zn][OTf] 2 exhibited a large Cotton effect, attributed to the double-helical structure (Figure 4a).In the 400−530 nm region, a negative Cotton effect was observed in toluene, whereas a positive Cotton effect was observed in acetone.In CHCl 3 , only a small negative Cotton effect was observed.These results were consistent with the reversed diastereomeric bias observed in the 1 H NMR spectra. 51TD-DFT calculations for model complexes [(M)-(1d) 2 Zn] 2+ and [(P)-(1d) 2 Zn] 2+ (with R = OMe and methyl groups instead of pentyl groups) attributed the negative Cotton effect to the (M)-double helix and the positive Cotton effect to the (P)double helix (Figure S65).Therefore, the preference for (M)helicity in toluene and (P)-helicity in acetone was suggested.There was no significant difference in the conformational preference of [(1c) 2 Zn][OTf] 2 in the concentration range of 100 μM to 1 mM by 1 H NMR spectroscopy (Figures S70 and  S71) and 5 μM to 100 μM by CD spectroscopy (Figure S61).The temperature dependence of [(1c) 2 Zn][OTf] 2 was investigated by CD spectroscopy and revealed that the Cotton effect decreases at higher temperatures, probably due to an increase in the ratio of the open forms (Figure S60).The diastereomeric M/P-helix pair was expected to invert the apparent equilibrium via the open forms depending on the solvation to the double-helical form.In fact, (M)-helicity was favored in nonpolar solvents [e.g., hexane, cyclohexane, benzene, toluene, Et 2 O, MTBE (t-BuOMe)], and (P)-helicity was favored in Lewis basic solvents (e.g., acetone, DMSO) (Figure 4b, Table 2, and Figures S34 and S35).Acetone and DMSO exhibited a large positive Cotton effect, suggesting that carbonyl and sulfoxide (C�O, S�O) groups were biased toward (P)-helicity.Alcohols (R−OH) were also biased toward (P)-helicity (Figure 4b, Table 2, and Figure S36).
Interestingly, halogenated solvents exhibited remarkable differences in the M/P preferences.(M)-helicity was favored in CCl 4 and CHCl 3 , but (P)-helicity was increasingly favored in 1,1,2,2-C 2 H 2 Cl 4 , CH 2 Cl 2 and 1,2-C 2 H 4 Cl 2 in that order (Figure 4b, Table 2, and Figure S37).These results indicate that the (P)-helicity was stabilized depending on Lewis basicity, which was consistent with the trend in cation solvation capacity reported by Swain et  : n/a). 52In contrast to acetone and DMSO, CH 3 CN and DMF exhibited limited effects on the preference for (P)helicity, affording a relatively equal diastereomeric ratio (M/P) (Figure 4b and Table 2).These results demonstrated that the helicity of the double-helical complex [(R)-(1c) 2 Zn][OTf] 2 with a chiral side chain can be controlled based on the Lewis basicity of achiral solvents.In fact, reversible switching of the chiral properties by solvents was demonstrated in acetone/ toluene (Figures 4c and S59).The plot of Δε against the ratio of acetone/toluene showed an S-shaped nonlinear curve, suggesting that acetone molecules are solvating cooperatively. 50,53,54xamples of chirality switching induced by achiral solvents in small molecules are limited. 28,29,32In terms of chiral   S76 and 77).The enthalpic preference of the (P)-helicity in acetone-d 6 showed that stabilization by solvation was more effective for the (P)-helicity than for the (M)-helicity, probably due to the additional CH−π interactions between L-shaped units and chiral side chains.S72 and S73).On the other hand, in acetone, the chiral side chains were directed outward, and the (P)-helicity was enthalpically favored.The conformational change of the chiral side chains by interaction with acetone could cause a reversal of both the polarity and the interaction with the double helix of the side chain, resulting in stabilization of the (P)-helicity.
Chiral Transfer and Amplification in Monometallofoldamers. Cooperativity and information transfer between two strands are the most remarkable features of double helices.Therefore, the transfer of chirality from one strand to the other in the double-helical monometallofoldamers was examined.Information transfer and replication between two strands in double helices are central dogmas in nature.The exclusive formation of the chiral heteroleptic complex with achiral strands observed in toluene suggested the possibility of chiral transfer 15,18,21,55 and amplification. 56Therefore, we measured and compared the nonlinearity in CD spectra of mixtures of homoleptic and heteroleptic complexes prepared with different ratios of 1b and 1c (Figure 6).No Cotton effect was observed under conditions where only [(1b) 2 Zn][OTf] 2 was present (Figure 6, 1b/1c = 5:0), while the Cotton effect increased with the addition of 1c, due to the increase in the ratio of [(1b)(1c)Zn][OTf] 2 and [(1c) 2 Zn][OTf] 2 (Figure 6, 1b/1c = 4:1−1:4).Although the plot in acetone was nearly linear, the plot in toluene was nonlinear, indicating that both [(1c) 2 Zn]-[OTf] 2 and [(1b)(1c)Zn][OTf] 2 produced with statistical probability were biased toward (M)-helicity.This result could be regarded as the nonlinear chiral amplification, such as in the sergeants-and-soldiers principle. 15,21,57,58In other words, this allows chiral amplification of up to 2 equiv of chiral double helices from 1 equiv of chiral strands by adding excess achiral strands.We subsequently demonstrated such chiral amplification upon adding 12 equiv of 1b and Zn(OTf) 2 to 1 equiv of 1c.The CD spectra of the mixture of homoleptic and heteroleptic complexes in toluene exhibited an amplified Cotton effect compared with that of the complexes under the conditions without 1b (Figures 7b and S81−S83).The increase in Cotton effects was 1.4 times greater in toluene and 1.2 times greater in acetone, indicating a clear chiral amplification due to the formation of a heteroleptic complex.Chiral induction to an achiral strand and solvent-dependent helicity inversion in these heteroleptic complexes of [(1b)-(1c)Zn][OTf] 2 will provide important insights for more efficient and complex control of chiral information beyond that in single helices.

■ CONCLUSIONS
In conclusion, double-helical monometallofoldamers [(1) 2 Zn]-[OTf] 2 were synthesized from bipyridine-type strands 1a−c with L-shaped dibenzopyrrolo[1,2-a] [1,8]naphthyridine units by complexation with a Zn(II) cation.X-ray crystallography revealed double-helical structures with L-shaped units densely stacked by π−π interactions and enclosing a metal cation.The stimuli-responsive switchability of the monometallofoldamers was investigated, and these complexes were found to be in equilibrium between the double-helical form favored at low temperatures and the open forms favored at high temperatures.Interestingly, the helix sense of [(1c) 2 Zn][OTf] 2 with chiral side chains can be controlled in response to achiral solvent stimuli, where the M/P helicity switching is induced by conformational changes of the chiral side chains due to the interaction of Lewis basic solvents to double helices.In addition, in the chiral heteroleptic double-helical monometallofoldamer [(1b)(1c)Zn][OTf] 2 , which was produced from the achiral strand 1b and the chiral strand 1c, the switchable chiral properties of the chiral strand were transferred and amplified through the information transfer capability of the double helix.These double-helical monometallofoldamers would offer novel design guidelines for switching significant chiral properties and higher-order chiral structure controls as in nature and would facilitate the development of new chiroptical switching materials.

1 H
Scheme 1. Helicity Inversion Induced by External Stimuli a

Scheme 2 .
Scheme 2. Dynamic and Chiral Properties of Double-Helical Monometallofoldamers a