C–I···π Halogen Bonding Driven Supramolecular ... - ACS Publications

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C−I···π Halogen Bonding Driven Supramolecular Helix of Bilateral N‑Amidothioureas Bearing β‑Turns Jinlian Cao,† Xiaosheng Yan,† Wenbin He,† Xiaorui Li,† Zhao Li,† Yirong Mo,‡,§ Maili Liu,∥ and Yun-Bao Jiang*,† †

Department of Chemistry, College of Chemistry and Chemical Engineering, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, Collaborative Innovation Center of Chemistry for Energy Materials (iChEM), Xiamen University, Xiamen 361005, China ‡ Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China § Department of Chemistry, Western Michigan University, Kalamazoo, Michigan 49008, United States ∥ Wuhan Institute of Physics and Mathematics, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Chinese Academy of Sciences, Wuhan 430071, China S Supporting Information *

ABSTRACT: We report the first example of C−I···π halogen bonding driven supramolecular helix in highly dilute solution of micromolar concentration, using alanine based bilateral Isubstituted N-amidothioureas that contain helical fragments, the β-turn structures. The halogen bonding interactions afford head-to-tail linkages that help to propagate the helicity of the helical fragments. In support of this action of the halogen bonding, chiral amplification was observed in the supramolecular helix formed in acetonitrile solution. The present finding provides alternative tools in the design of selfassembling macromolecules.

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INTRODUCTION DNA double helix and protein α-helix represent two major helical structures in Nature.1 Inter- and intrahelix hydrogen bonding plays a key role in affording helical structures constituted of chiral components. In the DNA double helix π···π stacking between the base-pairs helps to form helical structures. Despite several reports in the solid state of the supramolecular helix driven by halogen bonding,2 mimicking the natural helix in the solution phase remains highly challenging since the supporting backup from the threedimensional solid matrix that accommodates the supramolecular helix does not exist in solutions, while the head-totail linked interactions that lead to supramolecular helix have to be strong enough to compete with other interactions that may lead to the assembly of the formed helices. Pioneering work of Moore et al. of Pd2+ coordination of foldable oligomers of mphenylene ethynylene bearing one or two meta-pyridine terminal groups successfully led to supramolecular helices in acetonitrile, when the oligomer was long enough for a positive cooperativity to occur to promote the formation of the helix in which intrahelix π···π stacking may have facilitated the folding of the oligomeric ligand.3 Very recently Schmuck et al.4 reported a supramolecular β-helix in pure water from moderately hydrophobic, β-sheet forming alanine octamers consisting of alternative D- and L-amino acids, which were linked via triple hydrogen bonding and electrostatic interactions © 2017 American Chemical Society

between the guanidiniocarbonylpyrrole group equipped at its N-terminus and the carboxylate anion of another octapeptide. The helix formed at the peptide concentration of 0.1 mM underwent self-assembly into fibers upon aging. Inspired by those highly instructive works and the recent progress on halogen bonding in solution phase,5 in particular the halogen bonding promoted formation of helical foldamers of foldable oligomers,6 we set out to build a supramolecular helix in solution phase by choosing helical fragments that are expected to be held together by halogen bonds. We proposed to design a helical fragment that exhibits fewer other interactions between fragments, such as hydrogen bonding and π···π stacking, in particular the latter, to prevent the formation of staircase supramolecular polymers.7 Iodophenyl groups are equipped at the two terminals of the helical fragment, since the possible noncoplanar C−I···I−C or C−I···π halogen bonding8 is expected to help propagate the helicity of the constitutional helical fragments. As our first attempt, we chose alanine based bilateral Namidothioureas with halogen atoms (F, Cl, Br, I) substituted at para-position of the terminal phenyl rings (AXs, Scheme 1), since we recently identified a β-turn structure in the dipeptide based N-amidothioureas (Scheme 1).9 The β-turn is one of the Received: December 29, 2016 Published: January 30, 2017 6605

DOI: 10.1021/jacs.6b13171 J. Am. Chem. Soc. 2017, 139, 6605−6610

Article

Journal of the American Chemical Society Scheme 1. Molecular Structures of the Bilateral NAmidothioureas (L,L- and D,D-AH, AF, ACl, ABr, and AI) and a peptide counterpart (L,L-AGI) and β-turn structure in the dipeptide based N-amidothioureasa

from those of AH, AF, ACl, and ABr, showing red-shifted absorption and sign-reversed and dramatically enhanced CD signals (g factor of −3 × 10−3 at 272 nm, Figure S1). Dynamic light scattering (DLS, Figure S2) showed the existence of species of diameters of ca. 102 nm in the CH3CN solution of AI, likely the supramolecular polymeric species15 since the Isubstituent in AI could afford halogen bonding to link the AI molecules.8 CD spectra of AI in CH3CN underwent a nonlinear enhancement upon raising its concentration (Figure S3), while the CD signal dropped dramatically when the solution was heated (Figure S4), both in line with the formation of supramolecular polymeric species15 that may form beyond a critical aggregation concentration of ca. 6 μM (Figure S3). In contrast, CD signals of AH, AF, ACl, or ABr vary linearly with their concentrations (Figures S5 and S6) and are insensitive to the change in solution temperature (Figure S7), implying their existence in monomer form in CH3CN. To better understand these intriguing observations made with AI in solutions, crystals of L,L-AI were grown in CH3CN/ DMSO (4:1, v/v) at room temperature and subject to X-ray crystallography. β-Turn structures were identified at two sides of the L,L-AI molecule (Figure 2a).9 L,L-AI molecules in the crystal were found to exist in two forms according to the parameters of the β-turns, labeled as P (with β1 and β2) and Q (with β3 and β4) (Figure S8 and Table S2), respectively. Meanwhile, β-turns at two sides of the same L,L-AI molecule differ too, despite the same L-configuration of the alanine

a

The asterisks in the structures indicate the chiral carbons. Dashed pink line highlights the intramolecular hydrogen bond (IHB).

secondary structural elements of proteins and peptides10 and can serve as a fragment of helical structures, exampled by the 310-helix.11 We chose thiourea derivatives also because of the weak intermolecular interactions such as hydrogen bonding between thiourea moieties.12 Indeed, we found that the interfragment head-to-tail type C−I···π interaction8 between the two terminal iodophenyl groups, a halogen bond with π system analogous to the C−H···π interaction,13 acts to support the supramolecular helix of AI in the highly dilute solution of acetonitrile above 6 μM and in the solid state as well. To the best of our knowledge, this is the first observation of the halogen-bonding triggered supramolecular helix in solution.

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RESULTS AND DISCUSSION Alanine based bilateral N-amidothioureas (L,L- and D,D-AX, X = H, F, Cl, Br, and I, Scheme 1) were synthesized via procedures given in Scheme S1. AH, AF, ACl, and ABr exhibited similar absorption and CD spectra in CH3CN (Figure 1), in which the Cotton effect at 228 nm is assigned to the alanine residues and amide bonds,14 while that beyond 253 nm is attributed to the achiral phenylthiourea chromophore embraced within the βturn.9 AI differs very much in its absorption and CD spectra

Figure 2. (a) X-ray crystal structure of L,L-AI with β-turn at each side. Dashed green lines highlight the IHBs while the β-turn structures are labeled as β1 and β2. (b) The C−I2···π interaction, in which Cg is the centroid of benzene ring. (c) Intermolecular C−I···π interactions linking alternative P and Q molecules of L,L-AI. Dashed black lines indicate C−I···π interactions. (d) Single-stranded left-handed helix in the crystal packing of L,L-AI.

Figure 1. Absorption (a) and CD (b) spectra of L,L-AX (X = H, F, Cl, Br, I) in CH3CN. [L,L-AX] = 20 μM. 6606

DOI: 10.1021/jacs.6b13171 J. Am. Chem. Soc. 2017, 139, 6605−6610

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Journal of the American Chemical Society residue, that is, β1 is of type I while β2 is of type I′ (Table S2).16 In one-dimensional packing mode of L,L-AI, C−I···π halogen bonds8 constituted by the terminal iodophenyl groups were observed between two adjacent molecules P and Q (Figure 2b,c). These C−I···π interactions can be divided into two kinds, according to their structural parameters. For C− I2···π (Figure 2b), the distance of iodine atom to the centroid of benzene ring Cg, dI···π, is 3.445 Å, and the angle θ is 148.1°, while those for C−I3···π are 3.488 Å and 154.6°, respectively (Table 1), within the criteria for C−I···π interactions.8 In the

the C−I···π interaction (4.05 Å, Table S3).8 It is noteworthy that Ph−I1 in P and Ph−I3 in Q act as both donor and acceptor of the C−I···π halogen bonding at the same time, while Ph-I2 in P and Ph-I4 in Q act as donor and acceptor, respectively. Therefore, each L,L-AI in the crystal is stabilized by three halogen bonds, two intrahelix head-to-tail halogen bonds and one interhelix halogen bond, leading to supramolecular architecture constituted by infinite single-stranded helices (Figure 3). We also grew the crystals of L,L-ACl suitable for structural characterization, thus allowing a comparison with the crystal structure of L,L-AI. L,L-ACl is in general similar to L,L-AI, both containing two types of β-turn structures (Figure S8 and Table S2). However, L,L-ACl molecules in the crystal exist in only one repeating unit and the Cl-substituent does not participate in any intra- or intermolecular interaction. Two adjacent L,L-ACl molecules contact only by one CS···H−N hydrogen bond (Figure S9a). Thus, the formed structures from L,L-ACl display zigzag-like linear arrangement (Figure S9b), differing much from the helical structure of its L,L-AI counterpart (Figure 2d). It was expected that in polar solvents such as CH3CN, intermolecular hydrogen bonding between L,L-ACls might not be strong enough to hold molecules together,15 leaving ACl molecules in their monomer forms. This is indeed what was experimentally observed from the spectral behavior of L,L-AX in CH3CN (X ≠ I, Figure 1). The highest efficiency of C−X···π interaction of the I-substituent8 affords halogen bonding between AI molecules so that AI remains in its polymeric form in CH3CN. It is interesting to emphasize that DFT calculations confirmed that the C−I···π interaction occurs between two iodobenzene structural units both in gas phase and in CH3CN solutions, giving a bonding strength of ca. 15.2 kJ mol−1 (Figure S10 and Table S4). However, for other halogenated benzenes, similar C−X···π halogen bonding was not shown, agreeing with that noted in the crystal structure of L,L-ACl and the monomeric form of them in CH3CN. In addition, according to the crystal structure of L,L-AI, the calculated energies for the intrahelix C−I···π halogen bonds are 22.4 kJ mol−1 (C−I2···π) and 28.6 kJ mol−1 (C−I3···π) in CH3CN solutions (Table 1), which are stronger than the C−I···π interaction between two iodobenzene molecules (15.2 kJ mol−1, Table S4). These energies are also more significant than the C−I···π interactions in solution phase between 2-C3F7I or 1-C3F7I and toluene-d8 with strength of ca. 6.4 or 5.4 kJ mol−118 and C−H···π interactions that are weaker than 4.0 kJ mol−1.13 Because of the weak inductive effect of para-thiourea group in AI molecule,19 the stronger C−I···π interaction between AI molecules than that between iodobenzene molecules is attributed to the formation of supramolecular helix from the helical fragments in AI molecules that facilitates the halogen bonding in CH3CN, a cooperativity that could also be seen in the sigmoidal dependence of the CD signal on the concentration of AI (Figure S3). To correlate the solid and the solution phase structures, AI was subject to solid-state CD measurements. We found that the solid-state CD spectra were similar to those obtained in CH3CN solutions (Figure 4a). Therefore, similar stacking modes were assumed for AI molecules in the solid state and in the solution. For other AXs (X ≠ I), their CD spectra in the solid state and solution phase differ very much in both signs and positions (Figure S11), suggesting that the existing forms are not the same in the solid state as in the CH3CN solutions.

Table 1. Geometrical Parameters and Calculated Energies of C−I···π Halogen Bonding Interactions Based on Crystal Structure of L,L-AI C−I···π

dI···π (Å)a

θ (deg)

ΔEb (kJ mol−1)

ΔEc (kJ mol−1)

C-I1···π C−I2···π C−I3···π C−I4···π

3.625 3.445 3.488 4.100

152.8 148.1 154.6 155.0

−40.6 −28.8 −34.8

−32.5 −22.4 −28.6

a

Distance of iodine to the centroid of benzene ring Cg. bCalculated in gas phase. cCalculated in CH3CN solution. Method: MO62X DFT with the 6-311G** basis set for C, H, LANL2DZ for I atoms, and D3 empirical dispersion correction.

same AI molecule, the iodophenyl group at one side (i.e., Ph−I2 in P) acts as the donor of the C−I···π halogen bond (halogen atom), while that at the other side (i.e., Ph−I1 in P) is the acceptor (π system). Dihedral angles of 66.57° (Ph−I2 and Ph−I4) and 76.48° (Ph−I1 and Ph−I3) were measured between two adjacent molecules that may help to propagate the helicity of the β-turn structures. Indeed, repeating intermolecular C− I···π interactions between alternative P and Q molecules lead to a single-stranded supramolecular left-handed helix (helical pitch 17.58 Å and diameter 20.84 Å) in the crystal of L,L-AI (Figure 2d), the helicity being the same as that suggested by the negative exciton-coupled Cotton effect of L,L-AI in CH3CN (Figure 1).17 In the crystal, the single-stranded helices are connected by interhelix C−I1···π halogen bonds (3.625 Å in distance and 152.8° in angle, Table 1), forming two-dimensional supramolecular architecture (Figure 3). The C−I4···π is negligible since its distance (4.100 Å, Table 1) is out of the cutoff value of

Figure 3. (left) Two dimensional supramolecular network of L,L-AI formed by interhelix C−I1···π halogen bonds between single-stranded helices. Dashed red lines indicate the interhelix C−I1···π interactions, while dashed black lines indicate intrahelix C−I2···π and C−I3···π halogen bonds. For clarity, hydrogen atoms are omitted. (Right) Supramolecular helices constituted by single-stranded helices built from L,L-AI. 6607

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Journal of the American Chemical Society

Figure 4. (a) CD spectra of AI in CH3CN solution and in solid state. [AI] = 20 μM in CH3CN. The concentration of the solid CD sample is 1.0 mg/300 mg KCl. (b) SEM image of air-dried sample of L,L-AI in CH3CN on a platinum coated silicon wafer.

Those solution samples of AI for spectral measurements were also characterized by scanning electron microscopy (SEM). The observed left-handed helicity of the L,L-AI fibers (Figure 4b) agrees with that obtained from the crystal structure (Figures 2d and 3) and the CD spectra (Figure 1b). These helical fibers were approximately 100 nm in pitch and 40 nm in diameter and some of them were tangled together. Righthanded helices were found in the SEMs taken from samples of D,D-AI (Figure S12), confirming that the helicity of the supramolecular helix is dictated by the absolute configuration of the chiral alanine residues, which is again supported by the mirror-imaged CD spectra of L,L-AI and D,D-AI in both solid state and CH3CN solutions (Figure 4a). In contrast, SEM images of AH, AF, ACl, and ABr only show block or amorphous aggregates (Figure S13), demonstrating the critical importance of I-substituent in AI in terms of affording the C− I···π halogen bonding. NMR was next applied to investigate the structural characteristics of AXs in solution phase. Protons Hf and Hg were assigned by 2D NOESY spectra taken in DMSO-d6/ CD3CN in which AXs exist in monomer forms (Figure S14). 1 H NMR of L,L-AX in the binary solvents verified the existence of the β-turn structure featuring an IHB, since the resonance of the thioureido −NHd proton involved in this IHB does not change very much when the competitive component DMSO-d6 was loaded (Figures S15 and S16).20 To bring in direct evidence for C−I···π halogen bonding in solution, 1H NMRs of AXs (20 μM) in CD3CN were recorded on an 850 MHz NMR equipment. Under the same conditions, 1H NMR signals of AI were approximately 13 times weaker than those of ACl (Figure S17). This can be explained in terms of the formation of supramolecular helix of AI in CD3CN, which is invisible by the solution NMR technique due to signal broadening. Interestingly, two sets of sharp 1H NMR peaks are observed for AI but only one set for other AXs (X ≠ I, Figures S17 and S18). The stronger ones are those of the monomers, while the weaker ones are assigned to the small helical oligomers of AI, on the basis of the concentration-dependent 1H NMR spectra (Figures S19 and S20). The upfield shift of the proton signals on iodophenyl rings (Hf′ and Hg′) in the helical oligomers is consistent with their participation in the C−I···π halogen bonding.21 Meanwhile, the larger shifts observed in the signals of Hf′ (0.186 ppm) and Hg′ (0.046 ppm) than that of He′ (0.014 ppm) support their direct involvement in the intermolecular halogen bonding. 2D NMR experiments were next performed. For ACl, observation of obvious NOE peaks between He and Hf but not for He−Hg (Figure 5a) agrees with their distances identified in the crystal structure of L,L-ACl (3.189 Å for He−Hf and 4.348 Å for He−Hg). Despite the low

Figure 5. Expanded 2D NOESY spectra in CD3CN showing couplings between protons in phenyl rings in L,L-ACl (a) and L,L-AI (b). Crystal structures are also shown with protons and distances labeled. For clarity, one of the L,L-AI molecules in (b) only shows its iodophenyl moiety. [L,L-ACl] = [L,L-AI] = 20 μM, 850 MHz, 298 K, mixing time 900 ms.

solubility and the existence of helices of varying sizes, NOE peaks in AI were observed (Figure 5b). The obvious contact between Hg and Hg′ indicates the interconversion of monomers and the helical structures. The intramolecular distance between He and Hg (4.550 Å) is longer than that of He−Hf (3.106 Å), yet NOE signals of He−Hg were observed but not for He−Hf, opposite to those of L,L-ACl (Figure 5a). Both COSY and ROESY spectra of AI (Figures S21 and S22) confirmed these NOEs. These H e−H g couplings therefore result from intermolecular coupling because of the halogen bonding. Indeed crystal structure shows that the distance between He (He′) and Hg (Hg′) of the two adjacent L,L-AI molecules is 2.368 Å and that of He(He′)−Hf(Hf′) is 3.686 Å. Therefore, 2D NMR studies confirm the intermolecular C−I···π halogen bonding between AI molecules in CD3CN solutions. Influence of solvent of varying basicity provides further support for the halogen bonding. With increasing volume fraction of the electron-donating solvent THF, the CD spectrum of AI in CH3CN converted slowly to one similar to that of ACl, whereas it remained unchanged when CHCl3 of low basicity was added into CH3CN (Figures S23−S25), supporting the halogen bonding nature of the interactions between AI molecules in CH3CN.22 Meanwhile, the CD spectrum of ACl in CH3CN showed no response to those added solvents, implying that the added solvents do not break the intramolecular β-turn structures. It was also found that the absorption and CD spectra of AI in CH3CN responded more strongly to I− than to Cl− (Figures S26−S28), while the responses of ACl to I− and Cl− were both negligible (Figures S29−S31). The former is attributed to the stronger affinity of halogen bonding of I− than Cl− to compete with the C−I···π halogen bonding between AI molecules,8f while the latter is a reflection of the weak binding of the thiourea moiety with I− and Cl− anions.23 It was therefore concluded that the C−I···π halogen bonding between AI molecules drives the formation of the supramolecular helix of AI in solution. In order to confirm the role of β-turn structures designed in the AI molecule, we synthesized a peptide counterpart of L,L-AI, 6608

DOI: 10.1021/jacs.6b13171 J. Am. Chem. Soc. 2017, 139, 6605−6610

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Journal of the American Chemical Society (Scheme 1) that presumably bears no β-turn structure. H NMR titrations indicated no IHB and no β-turn structure in L,L-AGI (Figures S32, S33). Spectral studies suggested that L,LAGI existed in monomeric form in CH3CN (Figures S34− S36). Therefore, we conclude that the β-turn structures as helical fragments are essential for forming the supramolecular helix via collaboratively promoting the C−I···π halogen bonding that holds AI molecules together. Chiral amplification has been observed in helical polymers in solutions.24 We therefore examined if this occurred with our supramolecular helix, by taking the “majority rules” principle.24 We measured CD spectra of the mixtures of the enantiomeric pair of AI in CH3CN as a function of its enantiomeric excess (ee). The Cotton effects at 238 and 272 nm of the mixtures of L,L- and D,D-AI in CH3CN (Figure S37) were found to exhibit respectively an “S”- and “Z”-shaped profile when plotted against ee (Figure 6), confirming the occurrence of chiral amplification

exhibits substantially enhanced CD signals, with for example a high value of g-factor (−3 × 10−3) at 272 nm and a chiral amplification. These findings open a new avenue toward the rational design of building blocks to create functional supramolecular helices driven by halogen bonding.

L,L-AGI 1

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.6b13171. Detailed synthetic procedures, characterization, crystal data, spectral analysis and others (PDF) Crystallographic information for L , L -AI (CCDC 1484798) (CIF) Crystallographic information for L ,L -ACl (CCDC 1484799) (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Yun-Bao Jiang: 0000-0001-6912-8721 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the NSF of China (Grants 21275121, 21435003, 91427304, 21521004, and J1310024) and the Program for Changjiang Scholars and Innovative Research Team in University, administrated by the MOE of China (Grant IRT13036).

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Figure 6. Plots of CD signals at 238 and 272 nm of AI in CH3CN against ee. [L,L-AI] + [D,D-AI] = 20 μM. Black lines represent the situation without any chiral amplification.

REFERENCES

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in the formed supramolecular helix in CH3CN at 20 μM.24 At other two concentrations of the enantiomeric pair (15 μM and 10 μM), similar observation was made, and the normalized curves superimposed (Figures S38−S43). This means that the supramolecular helix present in solution is single-stranded. To the best of our knowledge, this is the first example of chiral amplification in supramolecular helix triggered by halogen bonding in solution phase. Propagation of the helicity of the constitutional unit along the supramolecular helix likely plays a role that leads to the chiral amplification. In contrast, the enantiomeric mixtures of AH, AF, ACl, and ABr show linear dependence of their CD signals on ee (Figures S44−S47), agreeing with their existence in monomer form in CH3CN.

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CONCLUSIONS In summary, we demonstrate for the first time the singlestranded supramolecular helix in solution phase at micromolar concentration, driven by intermolecular C−I···π halogen bonding. This was realized by designing bilateral Namidothioureas that bear two β-turn structures as the helical fragments, with two iodophenyl groups equipped at two terminals of the compound as the donor and acceptor of the C−I···π halogen bonding, while attempting to avoid other interhelix interactions except this “head-to-tail” intrahelix halogen bonding. This single-stranded supramolecular helix 6609

DOI: 10.1021/jacs.6b13171 J. Am. Chem. Soc. 2017, 139, 6605−6610

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DOI: 10.1021/jacs.6b13171 J. Am. Chem. Soc. 2017, 139, 6605−6610