Cation-Induced Molecular Switching Based on Reversible Modulation

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Cite This: J. Org. Chem. 2018, 83, 12648−12663

Cation-Induced Molecular Switching Based on Reversible Modulation of Peptoid Conformational States Rosaria Schettini, Chiara Costabile, Giorgio Della Sala, Veronica Iuliano, Consiglia Tedesco, Irene Izzo,* and Francesco De Riccardis* Department of Chemistry and Biology “A. Zambelli”, University of Salerno, Via Giovanni Paolo II, 132, Fisciano, Salerno 84084, Italy

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S Supporting Information *

ABSTRACT: Peptoids are oligomers of N-substituted glycines with predictable folding and strong potentials as guest-binding receptor molecules. In this contribution, we investigate the structural features of a series of designed symmetric cyclic octamer peptoids (with methoxyethyl/propargyl side chains) as free hosts and reveal their morphologic changes in the presence of sodium and alkylammonium guests as tetrakis[3,5-bis(trifluoromethyl)phenyl]borate salts, reporting the first case of reversible adaptive switching between defined conformational states induced by cationic guests (Na+ and benzylammonium ion) in the peptoid field. The reported results are based on 1H NMR data, theoretical models, and single-crystal X-ray diffraction analysis. They represent initial steps toward deciphering the unique conformational states of cyclic octamer peptoids as supramolecular hosts with the aim to fully disclose their functional and dynamic properties.

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angular C−CH2−C moieties and trans-peptide bonds are depicted as linear C−C units (Figure 1a), exemplify their structures and connote stabilities. Rigid C3-symmetric all-cis cyclic tripeptoids, such as cyclotrisarcosyl 1,14 and conformationally stable S2-symmetric cis,trans,cis,trans (ctct)-cyclotetrapeptoids, such as cyclo-(Nbe4) 2,15 can be both represented by formal cyclohexanes in the stable chair conformation (Figure 1b,c, respectively). S2symmetric cyclic hexamers (in the common cctcct conformation4b,16 found in the X-ray structure of cyclohexasarcosyl 3)3a can be described as decalines arranged in the unstable doubleboat conformation (Figure 1d). Conformationally homogeneous C2-symmetric cyclo-octapeptoids4b (such as cyclooctasarcosyl 4)17 can be drawn as elongated trans-decalines with the two ideal fused cycles in the stable chair conformation (Figure 1e).18 Of the many macrocyclic peptoids synthesized,2e,4b,7 cyclooctamer peptoids appear as the most interesting supramolecular species for two main reasons. First, the concurrent intramolecular interactions3b−d,18b,19,20 and steric strain force the C2-symmetric oligoamide framework of most of the synthesized cyclo-octapeptoids21 in two conformationally stable enantiomorphous helical spirals (ΔG⧧ for conformational inversion: ∼15/16 kcal mol−1).21h,n Second, their excellent complexing abilities21b,j,n make them ideal platforms to study morphological modifications modulated by ions. Trimeric3a,14,15,18,22 and tetrameric3a,15,18,22b cyclic peptoids

INTRODUCTION The control of structural transformations triggered by external stimuli is the ultimate goal of research on the development of miniaturized devices. 1 Peptoids (N-substituted glycine oligomers),2 for their flexible structure,3 cis/trans-amide bond isomerization (on the order of milliseconds),4 and easy modulation of their conformation5 (by bulky/chiral residues,6 macrocyclization,7 and metalation8), are ideally suited to perform functions.2a However, in the last 26 years of intense scrutiny on these smart peptidomimetics, no contribution on the reversible modulation between defined conformational states induced by external stimuli (light, reactants, pH, cations/ anions, neutral molecules, or electron transfer) has been reported.9 Dynamic structural changes by addition, or subtraction, of components can define functional devices with mechanical-like actions or characterize switchable catalysts/receptors useful in nanotechnology and sensing.1e,f The discovery of guestresponsive hosts equates supramolecular systems to the highly adaptive natural systems1a and peptoid macrocycles, for their intrinsic structural properties,7 seem perfectly suited to respond to the presence of ions changing their conformational states.4b In cyclic peptoids, cis/trans-amide bond interconversion (involving energy barriers of the order of 18−20 kcal mol−1)10 and ring inversion4b (governed by the free energy of activation of the order of 5−15 kcal mol−1)11 vary depending on the ring size and have a crucial impact on the overall conformational properties. The Dunitz/Waser representations12 (adapted by Kessler13), where cis-peptide bonds are formally substituted by © 2018 American Chemical Society

Received: August 2, 2018 Published: September 18, 2018 12648

DOI: 10.1021/acs.joc.8b01990 J. Org. Chem. 2018, 83, 12648−12663

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The Journal of Organic Chemistry

Figure 1. Top: Illustration of the Dunitz−Waser concept applied to amide bonds, as suggested by Kessler (a). Left: Molecular structures of cyclic peptoids 1−4 (b−e). Center: Schematic representation for cyclic peptoids 1−4 according the Dunitz−Waser concept. Right: Single-crystal X-ray structures of 1−4. Hydrogen atoms and side chains (in 2) have been omitted for clarity. 1 and 4 are reported as one of the two possible conformational enantiomeric forms.4b Atom type: C, gray; N, blue; O, red.

are too rigid as conformationally adaptable hosts (ΔG⧧ > 19.0 kcal mol−1)4a and generally unable to complex ions,23 whereas cyclohexameric peptoids3a,7,11,15,16,18,21a,k,23−26 give complex mixtures of rotamers in slow equilibrium on the NMR time scale (ΔG⧧ ≤ 14.4 kcal mol−1).16 With the aim to demonstrate the potential of cyclic octamer peptoids as reversible switching systems, we embarked in the synthesis of symmetrically substituted N-propargyl/methoxyethyl peptoids 6, 7, and 9 (Figure 2) and carried out comparative spectroscopic studies including the known cyclooligomers 521c,k and 8.21h The methoxyethyl residue was chosen to maximize the solubility in organic solvents, and the N-propargyl side chain was selected for its ability to stabilize cis-peptoid bonds6e (reducing the number of possible statistical conformational isomers formed by cyclization). In this contribution, we studied the binding abilities of 5−9 in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB) salt16 and, in the case of homooligomer 6, with various alkylammonium6e TFPB salts, demostrating the reversible conformational switching abilities of octamer cyclic peptoids in response to complexation/ decomplexation events and the potential of this class of foldamers as transductors between ionic and structural signals.

Figure 2. Structures of the cyclic octamer peptoids 5−9 studied in the present contribution.

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RESULTS AND DISCUSSION Octamer cyclopeptoids are the largest family of cyclic peptoids displaying conformational stability on the NMR time scale:4b,18 for rings with more than eight residues, “no conformational evidence is obtainable from NMR spectroscopy”.27 The study of their properties as free hosts and host−guest ad-

ducts4b,15,16,21b,j,n,28 is crucial to assess their potential as switchable foldamers. Most of the cyclic octamer α-peptoids reported in the literature display conformationally homogeneous structures on the NMR time scale (examples are cyclo-(Sar8),18 cyclo-(Nph12649


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The Journal of Organic Chemistry Nph-Npa-Nme)4,21e 5,21c,k a cyclic propylazido octamer,21d and congeners of cyclodepsipeptides).21n The remaining cyclooctamers exhibit conformational heterogeneity (such as cyclo(Nbe8),21b cyclo-(Pro-Sar)4,21j 8,21h and cyclo-(Pro-Npm)421i) or were not sufficiently spectroscopically characterized (i.e., cyclo-(Npm-Nme)421a and cyclo-(Nap-Nnm)4).21f Linear precursors of new cyclopeptoids 6, 7, and 9 were synthesized using the solid-phase “submonomer” approach2b (see the Experimental Section) and cyclized in high dilution conditions in the presence of HATU. The corresponding macrocycles were isolated in high purity (>95%, HPLC analysis; see Supporting Information) and decent yields (27− 32%) through reverse-phase chromatographic purification (6) or precipitation (from acetonitrile or ethyl acetate solutions; 7 and 9, respectively). Known oligoamides 5 and 8 were synthesized according literature procedures21c,h and fully spectroscopically characterized in this contribution. The conformational properties of the cyclic octamer species were inspected starting from homo-oligomers 5 and 6. Structural Studies of 5 and 6. The presence of a two-fold symmetry in conformationally stable homo-oligomers 5 and 6 was given by their 1H NMR spectra, showing half of the expected signals (Figure 3). Inspection of the side chains’ N-

Figure 4. Minimum energy structures of ccttcctt-5 and ccttcctt-6 (reported as one of the two possible conformational enantiomer forms).4 Hydrogen atoms have been omitted for clarity. Atom type: C, light gray; N, blue; O, red.

for the minimum energy conformations, the expected ϕ (∼±90°) and ψ (∼180°) dihedral angles clustering3a,b,20,21a due to the orthogonal COi−1···C′iO (i.e., n → π*)3b,c,19,20 and COi+1···C′iO29 (typical of polyproline I and II helix foldings18b and ribbon conformation of peptoids)3d interactions (Figures S34 and S35 in the Supporting Information). Variable-temperature experiments30 (VT-NMR, DMSO-d6 solution, 400 MHz, see Figures S2 and S4 of the Supporting Information) indicated coalescence temperatures31 (Tc) equal to 323 and 343 K (ΔG⧧ = 15.0 ± 0.2 and 15.4 ± 0.4 kcal mol−1) for 5 and 6, respectively. The relatively low-energy barriers between the two conformational enantiomers4b hampered resolution on HPLC with chiral stationary phase.32 Splitting of selected 1H NMR resonances21n was observed by gradual addition of Pirkle’s alcohol33 ((R)-1-(9anthryl)-2,2,2-trifluoroethanol) as chiral shift reagent (Figure 5 and Figure S28 in Supporting Information) to a CDCl3 solution of 6. Enantiomorphous species 6a/6b crystallized in a racemic crystal by slow evaporation from a diethyl ether solution. Relevant crystallographic data and structure refinement details are listed in Table S1 (Supporting Information). Single-crystal X-ray diffraction analysis showed the expected ccttcctt peptoid bond sequence similar to those reported in the theoretical studies (Figure 4) and to those of known compounds 5,21k 8,21h plus congeners.21a,d−g Overall the macrocycle does not possess a crystallographic C2 symmetry; in particular, distal methoxyethyl side chains show remarkably different conformations (Table S2 and Figure S36 in the Supporting Information). Backbone torsion angles and side chain torsion angles are defined according to Butterfoss et al.20 and reported in Table S2. Notably, cis ω values show remarkable deviations from the ideal value. Noteworthy, for the enantiomer 6a reported in Figure 6, the two trans-amide ring portions (from C11 to C17 and from C31 to C37) form part of a left-handed poly-L-proline II (PPII) helix, as evidenced by negative φ values in Table S2. The two cis-amide ring portions (from C1 to C7 and from C21 to C27) form part of a left-handed poly-L-proline I (PPI) helix, as evidenced by positive φ values in Table S2. Of course, in the

Figure 3. 1H NMR spectra of cyclic peptoids 5 and 6. Water impurity is labeled with *; 5.0−10.0 mM solutions in DMSO-d6 for 5 and in C6D6 for 6 (600 MHz, 5.5−2.6 ppm expansion).

CH2 Δδ (small 1H NMR Δδ implied trans-amide junctions, larger Δδ indicated cis-peptoid bonds;16 see Figures S1 and S3 in the Supporting Information), literature data,3a,18b,21 and density functional theory (DFT) calculations (Figure 4; see Supporting Information for computational details of all the theoretically calculated structures) inferred a C2-symmetric structure for the ccttcctt peptoid bond sequence in both the oligomers 5 and 6. Molecular geometry optimization revealed, 12650


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Figure 5. 1H NMR spectra of quantitative stepwise Pirkle’s alcohol addition to (a) 6 (600 MHz, CDCl3, 298 K, 5.0 mM solution, 5.0−3.6 ppm expansion). In spectra (b,c) 0.5 and 1.0 equiv of Pirkle’s alcohol was added, respectively. Red asterisks denote split signals.

Figure 6. X-ray molecular structure of the two conformational enantiomers 6a/6b related by a crystallographic inversion center (black dot). Hydrogen atoms have been omitted for clarity. Short intramolecular CO···CO contacts (95%; conditions: 5−100% A in 30 min (A, 0.1% TFA in acetonitrile, B, 0.1% TFA in water); flow = 1 mL min−1, 220 nm. Cyclo-[(cis)Npa2-(trans)Npa2]2 (5): synthesized according to literature procedure;21c 1H NMR (600 MHz, DMSO-d6) δ 4.78 (2H, d, J 18.1 Hz, OCCHHN), 4.71 (2H, m, NCHHCCH and 2H, m, OCCHHN, overlapping), 4.63 (2H, bd, J = 17.4 Hz, NCHHCCH), 4.52 (2H, m, NCHHCCH and 2H, m, O CCHHN, overlapping), 4.39 (2H, d, J = 18.1 Hz, OCCHHN), 4.36 (2H, d, J = 17.9 Hz, NCHHCCH), 4.27 (2H, d, J = 18.7 Hz, OCCHHN), 4.12−4.00 (2H, m, NCHHCCH and 4H, m, O CCHHN, overlapping), 3.76 (2H, d, J = 17.9 Hz, NCHHCCH), 3.65 (2H, d, J = 17.9 Hz, NCHHCCH), 3.58 (2H, d, J = 17.4 Hz, NCHHCCH), 3.43 (2H, t, J = 2.4 Hz, CCH), 3.27 (4H, overlapping, m, CCH), 3.20 (2H, t, J = 2.4 Hz, CCH), 3.14 (2H, d, J = 17.2 Hz, OCCHHN); 13C NMR (150 MHz, DMSO) δ 168.8 (CO), 168.6 (CO), 168.0 (CO), 166.8 (CO), 79.1 (−C), 79.0 (−C), 78.6 (−C), 77.8 (−C), 76.4 (CH), 76.3 (CH), 75.3 (CH), 75.1 (CH), 49.1 (OCCH2N), 47.0 (OCCH2N), 46.9 (OCCH2N), 46.8 (OCCH2N), 38.0 (NCH2CCH), 37.1 (NCH2CCH), 36.4 (NCH2CCH), 35.6 (NCH2CCH); HRMS (ESI/FTICR) m/z [M + Na]+ calcd for C40H40N8O8Na+ 783.2861; found 783.2877. Cyclo-[(cis)Nme2-(trans)Nme2]2 (6): white amorphous solid, 0.100 g, 27%; tR = 13.0 min; 1H NMR (600 MHz, C6D6) δ 5.24 (2H, d, J = 17.2 Hz, OCCHHN), 4.92 (2H, d, J = 16.3 Hz, OCCHHN), 4.69 (2H, d, J = 18.1 Hz, OCCHHN), 4.35 (2H, d, J = 18.1 Hz, OCCHHN), 4.17 (2H, m, NCHHCH2OCH3), 4.03 (2H, m, NCHHCH2OCH3), 3.95 (4H, OCCHHN, overlapping), 3.58 (2H, d, J = 17.2 Hz, OCCHHN), 3.53−3.48 (2H, m, NCHHCH2OCH3 and 2H, m, OCCHHN, overlapping), 3.44−3.41 (4H, m, NCH2CHHOCH3), 3.38−3.33 (6H, m, NCH2CHHOCH3), 3.31− 3.28 (2H, m, NCHHCH2OCH3 and 2H, m, NCH2CHHOCH3, overlapping), 3.23−3.18 (6H, s, OCH3; 2H, m, NCHHCH2OCH3 and 2H, m, NCH2CHHOCH3, overlapping), 3.14 (6H, s, OCH3), 3.11−3.07 (2H, m, NCHHCH2OCH3 and 2H, m, NCH2CHHOCH3, overlapping), 3.03 (6H, s, OCH3), 2.98−2.95 (6H, m, OCH3 and 2H, m, NCHHCH2OCH3, overlapping), 2.78 (2H, m, NCHHCH2OCH3); 13C NMR (150 MHz, C6D6) δ 170.9 (CO), 170.2 (CO), 169.9 (CO), 168.0 (CO), 72.1 × 2 (NCH2CH2OCH3), 70.6 (NCH2CH2OCH3), 70.2 (NCH 2CH 2OCH3), 59.0 (OCH 3), 58.8 (OCH 3), 58.4 × 2 (OCH3), 50.9 (OCCH2N), 50.5 (OCCH2N), 50.1 (O CCH2N), 49.4 (OCCH2N), 49.2 (NCH2CH2OCH3), 48.8 (NCH2CH2OCH3), 48.6 (NCH2CH2OCH3), 48.3 (NCH2CH2OCH3); ESI-MS m/z [M + Na]+ 943.5; HRMS (ESI/ FTICR) m/z [M + Na]+ calcd for C40H72N8O16Na+ 943.4958; found 943.4899. Cyclo-[(trans)Nme2-(cis)Npa2]2 (7a, 91% of the Conformational Isomers): white amorphous solid, 0.095 g, 28%; tR = 9.8 min; 1H NMR (600 MHz, DMSO) δ 4.77 (2H, d, J = 17.9 Hz, OCCHHN), 4.70−4.65 (2H, m, OCCHHN and 4H, m, NCHHCCH, overlapping), 4.46 (2H, d, J = 17.3 Hz, OCCHHN), 4.36 (2H, d, J = 17.9 Hz, OCCHHN), 4.20 (2H, d, J = 18.4 Hz, OCCHHN), 4.07 (2H, d, J = 18.4 Hz, OCCHHN), 3.93 (2H, d, J = 16.7 Hz, OCCHHN), 3.69 (2H, m, NCHHCH2OCH3), 3.58−3.51 (4H, m, NCHHCCH, overlapping), 3.49−3.31 (4H, m, NCHHCH2OCH3 and 8H, m, NCH2CHHOCH3, overlapping), 3.29 (6H, s, OCH3), 3.26 (2H, t, J = 2.6 Hz, CCH), 3.22 (6H, s, OCH3), 3.19 (2H, t, J = 2.6 Hz, CCH), 3.06 (2H, d, J = 17.3 Hz, OCCHHN), 2.92 (2H, dt, J = 14.8, 2.6 Hz NCHHCH2OCH3); 13C NMR (150 MHz, DMSO) δ 169.4 (CO), 168.8 (CO), 168.7 (CO), 167.5 (C 12658


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NCH2CH2OCH3, overlapping), 3.29 (6H, s, OCH3 and 2H, NCH2CH2OCH3, overlapping), 3.25 (6H, s, OCH3), 2.39 (4H, overlapping, t, J = 2.4 Hz, CCH); 13C NMR (150 MHz, CDCl3) δ 170.1 (CO), 169.7 (CO), 169.4 (CO), 168.7 (CO), 161.7 (q, J = 50 Hz, C-1), 134.8 (C-2), 128.9 (q, J = 30 Hz, C-3), 124.6 (q, J = 270 Hz, C-5), 117.5 (C-4), 75.4 (CCH), 75.3 (CCH), 75.2 (CCH), 74.9(CCH), 69.6 (2 X NCH2CHHOCH3), 69.3 (2 X NCH2CHHOCH3), 59.0 (OCH3), 58.9 (OCH3), 49.1 (NCH2CHH OCH3), 48.9 (NCH2CHHOCH3), 48.8 (OCCHHN), 47.9 (O CCHHN), 38.2 (NCH2CCH), 37.9 (NCH2CCH), the C-1/C-5 numbering refers to the TFPB anion; see the Supporting Information for the structure. [All-trans-8·2Na]2+2TFPB−: 1H NMR (600 MHz, CDCl3) δ 7.69 (16H, s, TFPB-o-H), 7.54 (8H, s, TFPB-p-H), 4.88−4.80 (8H, m, OCCHHN), 4.17−4.09 (6H, NCHHCCH and 2H, O CCHHN, overlapping), 4.02−4.00 (2H, d, J = 17.6 Hz, O CCHHN), 3.97 (2H, d, J = 17.5 Hz, OCCHHN), 3.86 (4H, bd, J = 17.5 Hz, NCHHCCH overlapping), 3.82 (2H, bd, J = 17.2 Hz, NCHHCCH), 3.76 (2H, d, J = 17.1 Hz, OCCHHN), 3.47−3.42 (4H, m, NCH2CH2OCH3), 3.37−3.34 (4H, m, NCH2CH2OCH3), 3.27 (6H, s, OCH3), 2.42 (2H, t, J = 2.5 Hz, CCH), 2.40 (2H, t, J = 2.5 Hz, CCH), 2.39 (2H, t, J = 2.5 Hz, CCH); 13C NMR (150 MHz, CDCl3) δ 169.8 (CO), 169.4 (CO), 168.9 (CO), 168.7 (CO), 161.7 (q, J = 50 Hz, C-1), 134.8 (C-2), 128.8 (q, J = 30 Hz, C-3), 124.6 (q, J = 270 Hz, C-5), 117.5 (C-4), 75.7 (CCH), 75.5 (CCH), 75.2 (CCH), 75.1 (CCH), 74.9 (CCH), 74.8 (C CH), 69.4 (NCH2CH2OCH3), 58.9 (OCH3), 49.1 (NCH2CH2OCH3), 48.9 (OCCHHN), 48.9 (OCCHHN), 48.2 (OCCHHN), 47.8 (OCCHHN), 38.4 (NCH2CCH), 38.2 (NCH2CCH), 38.1 (NCH2CCH), the C-1/C-5 numbering refers to the TFPB anion; see the Supporting Information for the structure. [All-trans-9·3Na]3+3TFPB−: 1H NMR (600 MHz, CDCl3) δ 7.68 (24H, s, TFPB-o-H), 7.53 (12H, s, TFPB-p-H), 4.85−4.78 (8H, m, OCCHHN), 4.15 (2H, d, J = 17.1 Hz, OCCHHN), 4.12 (2H, bd, J = 17.9 Hz, NCHHCCH), 3.92 (2H, d, J = 16.8 Hz, O CCHHN), 3.88 (2H, d, J = 16.8 Hz, OCCHHN), 3.78 (2H, O CCHHN and 2H, NCHHCCH, overlapping), 3.49−3.42 (12H, m, NCH2CHHOCH3 and NCHHCH2OCH3), 3.38−3.33 (8H, m, NCH2CHHOCH3 and NCHHCH2OCH3), 3.29 (6H, s, OCH3), 3.26−3.25 (12H, m, OCH3 and 4H, NCH2CHHOCH3, overlapping), 2.35 (2H, t, J = 2.3 Hz, CCH); 13C NMR (150 MHz, CDCl3) δ 170.2 (CO), 170.1 (CO), 169.8 (CO), 169.3 (CO), 161.7 (q, J = 50 Hz, C-1), 134.8 (C-2), 128.9 (q, J = 30 Hz, C-3), 124.6 (q, J = 270 Hz, C-5), 117.5 (C-4), 75.6 (CCH), 74.7 (CCH), 69.8 (NCH2CH2OCH3), 69.5 (NCH2CH2OCH3), 69.4 (NCH 2 CH 2 OCH 3 ), 59.0 (2 x OCH 3 ), 58.9 (OCH 3 ), 48.9 (NCH2CH2OCH3), 48.8 (NCH2CH2OCH3), 48.7 (NCH2CH2OCH3), 48.5 (OCCHHN), 48.0 (OCCHHN), 38.0 (NCH2 CCH), the C-1/C-5 numbering refers to the TFPB anion; see the Supporting Information for the structure. General Procedure for the Ammonium Complexes Formation. To 5.0 mM solutions of 6 (2.3 mg, 2.5 μmol) in CDCl3 (0.5 mL) were added increasing amounts of benzylammonium TFPB, bisbenzylammonium TFPB, and N-butyl,N-benzylammonium TFPB (2.0, 2.0, and 1.0 equiv, respectively, depending on the titration; see also Supporting Information). After any addition, the mixtures were sonicated for 1 min, and the NMR spectra were recorded. The 13C NMR spectra of the ammonium complexes gave broad signals and were not reported. The mass spectra gave [6·Na]+ (the ammonium complexes are labile) and are not reported. [6·2BnNH3]2+2TFPB−: 1H NMR (600 MHz, CDCl3) δ 7.69 (16H, s, TFPB-o-H), 7.52 (8H, s, TFPB-p-H), 7.36−7.32 (10H, m, ArH), 4.61 (8H, d, J = 16.7 Hz, OCCHHN), 4.07 (4H, s, NCH2Ph), 3.91 (8H, d, J = 16.7 Hz, OCCHHN), 3.36 (24H, m, NCHHCH2OCH3 and NCH2CHHOCH3, overlapping), 3.23 (24H, s, OCH3), 3.03 (8H, bd, J = 14.6 Hz, NCHHCH2OCH3). [6·2(Bn)2NH2]2+2TFPB−: 1H NMR (600 MHz, CDCl3) δ 7.69 (16H, s, TFPB-o-H), 7.51 (8H, s, TFPB-p-H), 7.40−7.35 (20H, m, ArH), 4.71 (8H, d, J = 17.1 Hz, OCCHHN), 4.05 (8H, s,

CCH2N; rot a), 50.5 (OCCH2N; rot b), 50.3 (OCCH2N; rot b), 50.1 (OCCH2N; rot a), 49.4 (NCH2CH2OCH3; rot b), 49.2 (NCH2CH2OCH3; rot a), 49.2 (OCCH2N; rot a), 49.1 (O CCH 2 N; rot b), 48.8 (NCH 2 CH 2 OCH 3 ; rot a), 48.7 (NCH2CH2OCH3; rot b), 48.5 (NCH2CH2OCH3; rot b), 48.3 (NCH2CH2OCH3; rot a), 47.6 (OCCH2N; rot b), 47.2 (O CCH2N; rot a), 36.8 (NCH2CCH; rot a), 36.3 (NCH2CCH; rot b); ESI-MS m/z [M + Na]+ 903.7; HRMS (ESI/FTICR) m/z [M + Na]+ calcd for C40H64N8O14Na+ 903.4434; found 903.4431. General Procedure for the Evaluation of the Coalescence Temperatures (Tc) and the Energy Barrier of Conformational Interconversion (ΔG⧧). The chosen oligomer was dissolved in the proper deuterated solvent (DMSO-d6 or TCDE; see Supporting Information), and 1H NMR spectra were acquired at increasing temperatures. The coalescence temperature (Tc, reported in K) was recorded observing an AX doublet related to a specific OC−CH2− N moiety (and reported in the Supporting Information). Subsequently, the ΔGc⧧ was calculated considering the chemical shift difference of the observed diastereotopic OC−CH2−N protons (Δν) and their coupling constants (J) in Hz, according the following relation: É ÅÄÅ ij yzÑÑÑÑ ÅÅ Tc j zÑÑ Å ⧧ j z Å zzÑÑ ΔGc = aTcÅÅÅ9.972 + logjjj j Δν 2 + 6J 2 zzÑÑÑ ÅÅÅÅ k {ÑÑÖ Ç where a = 4.575 × 10−3 kcal/mol.30 Individual data (Tc, Δν, and J) for free hosts and host/guest complexes are given in the Supporting Information for every compound analyzed (5DMSO, Figure S2; 6TCDE, Figure S4; 7DMSO, Figure S6; 8DMSO, Figure S8; 9TCDE, Figure S10; [5−9·nNa]+n TFPB−TCDE complexes, Figures S17−21). General Procedure for the Metal Complexes Formation [5−9· nNa]n+ nTFPB−. To 1.0−5.0 mM (depending on the host solubility) solutions of 5−9 in CDCl3 (0.5 mL) were added increasing amounts of NaTFPB until 3.0 equiv (depending on the titration; see Supporting Information). After any addition, the mixtures were sonicated for 5 min, and the NMR spectra were recorded. The mass spectra gave monosodium complexes (the bis- and tris-sodium complexes are labile) and are not reported. The only exception was the [6·3Na]3+, which showed the presence of the [6·2Na]2+ complex. [All-trans-5·3Na]3+3TFPB−: 1H NMR (600 MHz, CDCl3) δ 7.69 (24H, s, TFPB-o-H), 7.53 (12H, s, TFPB-p-H), 4.85 (8H, d, J = 16.4 Hz, OCCHHN), 4.17 (8H, d, J = 18.7 Hz, NCHHCCH), 4.01 (8H, d, J = 16.4 Hz, OCCHHN), 3.88 (8H, d, J = 18.7 Hz, NCHHCCH), 2.45 (8H, t, J = 2.4 Hz, CCH); 13C NMR (150 MHz, CDCl3) δ 168.9 (CO), 161.7 (q, J = 50 Hz, C-1), 134.8 (C2), 128.8 (q, J = 30 Hz, C-3), 124.7 (q, J = 270 Hz, C-5), 117.6 (C-4), 75.8 (CCH), 74.6 (CCH), 48.1 (OCCH2N), 38.3 (NCH2C CH), the C-1/C-5 numbering refers to the TFPB anion; see the Supporting Information for the structure. [All-trans-6·3Na]3+3TFPB−: 1H NMR (600 MHz, CDCl3) δ 7.69 (24H, s, TFPB-o-H), 7.53 (12H, s, TFPB-p-H), 4.81 (8H, d, J = 16.6 Hz, OCCHHN), 3.93 (8H, d, J = 16.6 Hz, OCCHHN), 3.49 (8H, m, NCH2CH2OCH3), 3.43 (8H, m, NCH2CHHOCH3), 3.36 (8H, m, NCH2CHHOCH3), 3.28 (24H, s, OCH3), 3.20 (8H, m, NCHHCH2OCH3); 13C NMR (150 MHz, CDCl3) δ 170.0 (CO), 161.7 (q, J = 50 Hz, C-1), 134.8 (C-2), 128.8 (q, J = 30 Hz, C-3), 124.6 (q, J = 270 Hz, C-5), 117.5 (C-4), 69.5 (NCH2CH2OCH3), 58.9 (OCH3), 48.6 (NCH2CH2OCH3), 48.3 (OCCH2N), the C-1/ C-5 numbering refers to the TFPB anion; see the Supporting Information for the structure; ESI-MS m/z 483.8 (100 [M + 2Na]2+); 942.9 (20 [M + Na]+). [All-trans-7·2Na]2+2TFPB−: 1H NMR (600 MHz, CDCl3) δ 7.68 (16H, s, TFPB-o-H), 7.53 (8H, s, TFPB-p-H), 4.86−4.79 (8H, m, OCCHHN), 4.16 (2H, NCHHCCH and 2H, OCCHHN, overlapping), 4.12 (2H, bd, J = 18.7 Hz, NCHHCCH), 3.99 (2H, d, J = 17.2 Hz, OCCHHN), 3.88 (2H, d, J = 17.2 Hz, O CCHHN), 3.84 (2H, bd, J = 18.3 Hz, NCHHCCH), 3.80 (2H, bd, J = 18.7 Hz, NCHHCCH), 3.76 (2H, d, J = 16.8 Hz, O CCHHN), 3.48−3.42 (8H, m, NCH2CH2OCH3 + NCH2CH2OCH3, ov erlap ping), 3 .37−3.33 (6H, m, NCH 2 CH 2 OCH 3 + 12659



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NCH2Ph), 3.94 (8H, d, J = 17.1 Hz, OCCHHN), 3.49 (8H, bm, NCHHCH2OCH3), 3.38 (8H, m, NCH2CHHOCH3), 3.27−3.17 (40H, m, NCHHCH2OCH3, NCH2CHHOCH3, OCH3, overlapping). [6·Bn(nBu)NH2]+TFPB−: 1H NMR (600 MHz, CDCl3) δ 7.69 (8H, s, TFPB-o-H), 7.52 (4H, s, TFPB-p-H), 7.36 (5H, m, ArH), 4.78 (8H, d, J = 16.5 Hz, OCCHHN), 4.10 (2H, s, NCH2Ph), 3.98 (8H, d, J = 16.5 Hz, OCCHHN), 3.57 (8H, m, NCHHCH2OCH3), 3.47− 3.34 (8H, m, NCHHCH2OCH3 and 8H, m, NCH2CHHOCH3, overlapping), 3.25 (24H, s, OCH3), 3.10 (8H, m, NCH2CHHOCH3), 2.83 (2H, m, N+CH2CH2CH2CH3), 1.59 (2H, m, N+CH2CH2CH2CH3), 1.27 (2H, m, N+CH2CH2CH2CH3), 0.83 (3H, t, J = 6.9 Hz, N+CH2CH2CH2CH3). General Procedure for the Na+-Induced Molecular Switching on Cyclic Peptoid 6. To a 5.0 mM solution of 6 (2.3 mg, 2.5 μmol) in CDCl3 (0.5 mL) was added 2.0 equiv of NaTFPB (4.4 mg, 5.0 μmol). The mixture was sonicated for 5 min, and the 1H NMR spectrum was recorded. To this mixture was added 4.0 equiv (respect to host 6) of tetrabutylammonium hydroxide ((Bu)NOH·12.6H2O, 4.8 mg, 10.0 μmol; see note 4 of Supporting Information). The mixture was sonicated for 5 min, and the 1H NMR spectrum was recorded. After that, 4.0 equiv of NaTFPB (8.8 mg, 10.0 μmol) was added. The mixture was sonicated for 5 min, and the 1H NMR spectrum was recorded. To the mixture was added 4.0 equiv (respect to host 6) of tetrabutylammonium hydroxide ((Bu)NOH·12.6H2O, 4.8 mg, 10.0 μmol), and the 1H NMR spectrum was recorded. General Procedure for the BnNH3+-Induced Molecular Switching on Cyclic Peptoid 6. To a 5.0 mM solution of 6 (2.3 mg, 2.5 μmol) in CDCl3 (0.5 mL) was added 2.0 equiv of BnNH3+TFPB− (4.8 mg, 5.0 μmol). The mixture was sonicated for 5 min, and the 1H NMR spectrum was recorded. To this mixture was added 2.0 equiv (respect to host 6) of commercially available tetrabutylammonium hydroxide (((Bu)NOH·30H2O; MW = 799.9, 4.0 mg, 5.0 μmol). The mixture was sonicated for 5 min, and the 1H NMR spectrum was recorded. Finally, 2.0 equiv of BnNH3+TFPB− (4.8 mg, 5.0 μmol) was added. The mixture was sonicated for 5 min, and the NMR spectrum was recorded. Computational Methodology. The DFT calculations for TFPB, NaTFPB, N-benzylammonium TFPB, ccttcctt-5, ccttcctt-6, all-trans-6, [6·Na]+, [6·2Na]2+, [6·3Na]3+, [6·BnNH3]+, and [6·(BnNH3)2]2+ were performed with the Gaussian09 set of programs,41 using the BP86 functional of Becke and Perdew.42 The electronic configuration of the molecular systems was described with the standard triple-ζ valence basis set with a polarization function of Ahlrichs and coworkers for H, B, C, N, O, F, and Na (TZVP keyword in Gaussian).43 The geometry optimizations were performed without symmetry constraints, and the characterization of the located stationary points was performed by analytical frequency calculations. Solvent effects including contributions of non-electrostatic terms have been estimated in single-point calculations on the gas-phase-optimized structures, based on the polarizable continuous solvation model using CHCl3 as a solvent.44 X-ray Crystallography. A single crystal of 6a/6b suitable for Xray analysis was glued on a glass fiber and mounted on a goniometer head. Measurements were performed with a Bruker D8 Quest diffractometer equipped using Cu Kα radiation (λ = 1.5418 Å). Data reduction was performed with the crystallographic package APEX3. Data were corrected for Lorentz, polarization, and absorption. The structures were solved by direct methods using the program SIR201444 and refined by means of full matrix least-squares based on F2 using the program SHELXL.45 OLEX2 was used as GUI and also to draw ORTEP figures.46a Crystal structures were drawn using the CCDC software Mercury.46b Non-hydrogen atoms were refined anisotropically. Hydrogen atoms were positioned geometrically and included in structure factors calculations but not refined. CCDC 1858814 contains the supplementary crystallographic data for this paper. These data are provided free of charge by The Cambridge Crystallographic Data Centre. See Tables S1 and S2 of the Supporting Information for all the relevant crystallographic data.

Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01990. 1D and 2D spectra of cyclic peptoids 5−9 and their complexes, 1H NMR at variable temperature and titration experiments, HPLC chromatograms of linear and cyclic peptoids, Pirkle’s alcohol titration of 6, minimum energy structures and Cartesian coordinates of ccttcctt-5, ccttcctt-6, all-trans-6, [6·Na]+, [6·2Na]2+, [6· 3Na]3+, [6·BnNH3]+, and [6·(BnNH3)2]2+, and X-ray data of 6 (PDF) Crystallographic data for 6 (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Rosaria Schettini: 0000-0002-0515-424X Chiara Costabile: 0000-0001-8538-7125 Giorgio Della Sala: 0000-0001-5020-8502 Consiglia Tedesco: 0000-0001-6849-798X Irene Izzo: 0000-0002-0369-0102 Francesco De Riccardis: 0000-0002-8121-9463 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the University of Salerno (FARB), the Italian Ministero dell’Università e della Ricerca (MIUR) (PRIN 20109Z2XRJ_006), Regione Campania under POR Campania “FESR 2007-2013-O.O. 2.1 (FarmaBioNet)” and from POR CAMPANIA FESR 2007/2013 O.O.2.1.-CUP B46D14002660009 “Il potenziamento e la riqualificazione del sistema delle infrastrutture nel settore dell’istruzione, della formazione e della ricerca”.

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REFERENCES

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Cation-Induced Molecular Switching Based on Reversible Modulation

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