Conformational Features of Thioamide-Containing Dipeptoids and

Article Cite This: J. Phys. Chem. A XXXX, XXX, XXX−XXX

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Conformational Features of Thioamide-Containing Dipeptoids and Peptoid−Peptide HybridsComputational and Experimental Approaches Magdalena M. Zimnicka* Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland

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S Supporting Information *

ABSTRACT: The effects of thioamide incorporation into N,N-dimethyl-2-(N-methylacetamido)acetamide and N-methyl-2-(N-methylacetamido)acetamide as the simplest models of a dipeptoid structure and a peptoid−peptide hybrid are discussed. The solvent-modulated conformational features of model compounds were examined by computations enhanced by natural bond orbital (NBO) analysis and experimentally by kinetic and equilibrium measurements using NMR spectroscopy. The computations supported by NBO analysis showed that intrinsic stability of the predominant trans isomer (αD and C7β forms) of the dipeptoid model results from an indirect n → π* interaction, occurring between the carbonyl oxygen lone pair (n) and the π* orbital of the adjacent amide carbonyl through the C−H antibond (σ*). The direct n → π* interaction constitutes a negligible contribution to trans stabilization. The N-terminal thioxo substitution increases this indirect electron delocalization, making the αD isomer prevalent. The nX → σN′C−H* interaction is an additional source of stability of the transC7β form relevant for the underivatized dipeptoid model and its C-terminal thioamide counterpart. In the peptoid−peptide hybrid, the trans preference is perturbed by subtle differences in the H-bond donor−acceptor abilities between the thioxo and oxo groups. The cis isomer becomes more populated with an increase in the strength of polarity and the hydrogen bonding acceptor ability of the solvent molecules. While thioxo substitution slightly shifts the trans−cis equilibrium in polar solvents, it effectively allows for increasing or decreasing the barrier to trans−cis rotation with respect to underivatized model compounds depending on N- vs C-terminal thioamide backbone substitution.

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INTRODUCTION Peptoids (N-substituted glycine oligomers) belong to the distinctive family of peptidomimetics in which the amino acid side chains are shifted from the chiral α-carbon atoms in peptides to the adjacent amide nitrogen.1 This structural modification in peptoid molecules, i.e., the replacement of the amide secondary group with a tertiary amide bond, affects their physical and chemical properties and consequently leads to several interesting biological features. The main advantages of these peptidomimetics compared to peptides are their higher stability toward proteases2−4 and improved cellular-uptake behavior.5 The above-mentioned peptoid features as well as their ease of synthesis6 and access to a wide range of molecular diversity accomplished by introduction of various functionalities within the peptoid moiety7 have made peptoids attractive building blocks in the design of bioactive ligands.8 Peptoids have been employed as drug and gene delivery agents due to their high cell-penetrating properties,9 as antimicrobial10 and lung surfactant agents,11 and as neutralizers of bacterial endotoxins.12 The main disadvantage of using peptoids as bioactive ligands is their high conformational flexibility, resulting from the side chains being located on the backbone nitrogens. Thus, © XXXX American Chemical Society

extensive efforts toward controlling peptoid backbone isomerism and introducing partially constrained isomers to reduce the conformational diversity of peptoids have been undertaken to improve their overall biomolecular activity and selectivity. Various strategies explored in peptoid studies have included: introduction of sterically bulky tert-butyl side chains,13 α-chiral side chains,14,15 side chain to side chain cyclization,16 macrocyclization,17 introduction of N-aryl side chains capable of hydrogen bonding with the peptoid backbone,18 and inducing n → πAr* interactions between a backbone carbonyl and a proximal side chain aromatic group.19 In this manuscript, the conformational changes induced by replacement of the carbonyl oxygen with a sulfur atom in model compounds, which represent alanine-containing dipeptoid (Scheme 1, structures 1, 2, and 3) and hybrids containing peptoid and peptide units (Scheme 1, structures 4, 5, and 6), are reported. The effect of amide substitution with the thioamide group has been extensively studied in simple thioamides20−22 and in more complex systems, including in Received: June 7, 2018 Revised: August 10, 2018 Published: September 5, 2018 A

DOI: 10.1021/acs.jpca.8b05456 J. Phys. Chem. A XXXX, XXX, XXX−XXX

Article

The Journal of Physical Chemistry A

enhancement of the n → π* interaction by introducing a thioamide backbone in peptoids, which takes part in trans conformer stabilization, may evoke an isomer distribution that is more similar to that of the native peptide. In this research, detailed theoretical and experimental (NMR) studies concerning the equilibrium and kinetics of cis−trans isomerization in thioxo-containing peptoids are reported. Simple model compounds that are counterparts to naturally occurring alanine-containing dipeptides were chosen to serve as examples of thioxo-substituted peptoids and thioxosubstituted peptoid−peptide hybrids. According to earlier reports regarding peptide conformations, the alanine-containing peptides adequately represent the conformational preferences of other amino acids, excluding those containing polar side chains, which evoke additional conformational perturbations. The model compounds were selected to carefully study the influence of the environment on the n → π* interaction, which has been assumed to stabilize the trans conformation in peptoids, and on hydrogen bonding interactions. The theoretical calculations performed for the gas-phase environment and for DMSO, experimental NMR studies of the cis− trans equilibrium in various solvents, and kinetic studies of the amide isomer interconversion in DMSO elucidated a clear picture of the intrinsic and solvent-induced conformational preferences of thiopeptoids.

Scheme 1

peptides23−25 and azapeptides.26 Several structural changes upon going from amides to thioamides have been observed. The thioamide rotational barrier about the CSNH bond is approximately 8−12 kJ mol−1 larger than that for the amide (CONH) bond due to the more pronounced double bond character of the thiopeptide CN bond.27,28 The longer CS double bond (1.64 Å) in comparison with the CO bond (1.24 Å),29,30 as well as the larger covalent and van der Waals radii of sulfur,31 and modified hydrogen-bond-accepting abilities of thioamides32 affect the overall changes in the conformational behavior of thioamide-containing molecules. Some very recent studies have investigated the thioamide backbone in peptoids containing aromatic side chains.33,34 These studies outlined earlier reported findings of the importance of n → π* interactions, characterized by the donation of electron density from the thiocarbonyl sulfur lone pair to the π* orbital of an adjacent amide carbonyl, in stabilization of the trans-amide conformation in a peptide chain.35 Due to the backbone nitrogens present in peptoids, the trans−cis equilibrium is shifted to the more populated cis conformation of the amide bonds linking the monomer residues in comparison to their peptide counterparts. Thus,

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COMPUTATIONAL AND EXPERIMENTAL SECTION Calculations. All ab initio, density functional theory (DFT) and natural bond orbital (NBO) calculations were performed with the Gaussian 09 suite of programs.36 Twodimensional potential energy surface (PES) calculations along the rotation through the two selected dihedral angels (ϕ, ψ), using Becke’s hybrid functional (B3LYP)37,38 and the 631+G(2d,p) basis set, were performed for model compounds

Scheme 2a

(a) 4 equiv 2 M of 2 in THF, 0 °C - 30 min, r.t. - 3 h; (b) 4 equiv of 3, CH3CN, 0 °C; (c) 4 equiv of 4, CH2Cl2, (i-Pr)2Et3 - 2.1 equiv, r.t. - 1.5 h; (d) 1 equiv of 6, 1 equiv of Et3N, THF, 0 °C - 30 min, r.t. - 12 h; (e) 1.15 equiv of 5, benzene, 40 °C, 12 h. a

B



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Article

RESULTS AND DISCUSSION Computational Studies. Conformational potential energy surface maps of model compounds were obtained via rotation along dihedral angles ϕ and ψ from the cis (ω1 = 0°) and trans (ω1 = 180°) isomers as starting points (Scheme 3). The ϕ and

in order to determine the structures for global and local minima. The dihedral angles were rotated by 30° increments (closely spaced), while the remaining internal degrees of freedom were fully optimized. From (ϕ, ψ) conformational energy maps, the global minima were selected and were reoptimized at the B3LYP/6-31++G(2d,p) level. One-dimensional PESs (rotation by 10° increments of the selected angle) for optimized minima were additionally performed to obtain transition state structures connecting minima located on separated potential energy surface maps. Harmonic frequency analysis was applied to confirm the nature of stationary points as local minima or first-order saddle points. Harmonic frequencies were calculated with B3LYP/6-31++G(2d,p), scaled by 0.963, and used to calculate zero-point vibrational energies (ZPVE). Single-point energies were calculated for reoptimized structures with B3LYP/6-311++G(2d,p) and Møller−Plesset theory,39 MP2(frozen core)/6-311++G(2d,p), to include electron correlation and to calculate average B3LYPMP2 energy in order to cancel known errors in each method.40 The structures (atomic coordinates) of all minima and transition states connecting trans and cis isomers are presented in the Supporting Information. Other transition state structures not included in the Supporting Information are available upon request. Additionally, a sequence of calculations (reoptimization of gas-phase minima and transition states followed by frequency calculations) was run in a DMSO environment using the selfconsistent reaction field (SCRF) with the SMD solvation model,41 at the B3LYP/6-311++g(2d,p) level. The geometries of in-DMSO structures are available upon request. Synthesis and Characterization of Model Compounds. Selected model compounds were synthesized and subjected to NMR studies in order to estimate the influence of solvation on trans−cis isomerism. The general scheme for the synthesis of the model compounds is shown in Scheme 2. It comprises steps that are typical of short peptoid synthesis in solution42 combined with the steps of conversion of the amide to the thioamide group using Lawesson’s reagent.43,44 A detailed description of the synthetic procedures and NMR spectra (1H NMR, CD2Cl2) of the synthesized products are presented in the Supporting Information. NMR Spectroscopic Analysis. The NMR spectra were acquired either on a Varian VNMRS 600 MHz spectrometer (600 and 150 MHz for 1H and 13C, respectively) or a Varian VNMRS 500 MHz spectrometer (500 and 125 MHz for 1H and 13C, respectively) for solutions containing 5−10 mg of the desired compound. Two-dimensional NMR spectroscopic experiments (gHMBC and gHSQC) and 1D NOESY were carried out using the standard pulse sequences and parameter sets. Chemical shifts δ are reported on the ppm scale using the operating solvent as the internal standard. The coupling constants are given in Hertz (Hz). Variable temperature dynamic nuclear magnetic resonance (VT-DNMR) experiments were recorded on a Bruker 500 MHz spectrometer. The 1H NMR spectra were recorded at several temperature intervals of 10 and 5° in the temperature region around coalescence. The DNMR line shape simulations were performed with the WinDNMR-Pro program according to the described guidelines.45 The activation parameters from VT-DNMR measurements were calculated from the Eyring and Arrhenius plots displayed in the Supporting Information.

Scheme 3

ψ dihedral angles are generally accepted and often used as the flexible backbone dihedral angles to describe the complete dipeptide conformational space.23,46,47 All energy maps are shown in the Supporting Information (Figure 1Sa−f). Relative free energies calculated at the B3LYP-MP2 level are used in the discussion to present the results clearly. The conformational energy maps determined for 1−3 were very similar in the location of the global minimum regions on the PES maps, thus providing evidence for the small effect of sulfur substitution on the conformational diversity of the peptoid models. These results are in contrast to studies on thioxo substitution in glycine- and L-alanine-containing dipeptides, which showed significant differences in PESs between the dipeptides and their thioxo-substituted analogues.23 The appropriate minima obtained from trans- and cis-PESs were subjected to full geometry optimization. Unique stationary points with corresponding torsion angles and the energetic relations between the conformers are summarized in Table 1. The energy maps starting from the trans conformations of 1, 2, and 3 exhibited three unique minima, which were designated a, b, and f (the minima were assigned in ascending alphabetical order of energy). The structures of 1b, 2a, and 3b represent the C7β form with ϕ ≈ −120° and ψ ≈ 70°. The C7β conformation displays intermediate dihedral angle values between the C7 and β forms characteristic for peptide conformations.48 The second group of stable structures (1a, 2b, 3a) was attributed to the αD form (ϕ ≈ −90° and ψ ≈ 170°).46 The αD form represents the conformation in which the (thio)carbonyl groups are in close proximity to each other, and thus may interact with each other by well characterized n → π* orbital interactions, i.e., interactions occurring between the carbonyl oxygen lone pair (n) and the π* orbital of the adjacent amide carbonyl.49 A charge−charge interaction and a dipole−dipole interaction were discarded in a similar system.35 Two main geometric conformational requirements must be fulfilled to make the n → π* orbital interaction relevant. The first is the distance (d) between the (thio)carbonyl donor atom (oxygen or sulfur in this case) and the acceptor carbon atom of the adjacent amide carbonyl, which should be less than the sum of their van der Waals radii (rS + rC < 3.5 Å or rO + rC < 3.22 Å) to satisfy electronic delocalization requirements. The second refers to the donor atom (oxygen or sulfur)−carbonyl acceptor angle (O···CO) which is θ = 109 ± 10°. This interaction is expected to be enhanced by the presence of sulfur as a better electron-pair donor than an oxygen atom. For 1a, 2b, and 3a, the distance (d) was 3.359, 3.617, and 3.700 Å and the θ angle was 97.1, 96.2, and 99.6°, respectively. Excluding the θ value for the 3a conformation, the distance in each case is too large and the θ angle is too small to satisfy the C


Article

The Journal of Physical Chemistry A Table 1. Summary of Stable Conformations of 1, 2, 3, and 1SS and Their Relative Energies relative energyb structure

population % (298 K)

ϕ

ψ

1a (trans) 1b (trans) 1c (cis) 1d (cis) 1e (cis) 1f (trans) 2a (trans) 2b (trans) 2c (cis) 2d (cis) 2e (cis) 2f (trans) 3a (trans) 3b (trans) 3c (cis) 3d (cis) 3e (cis) 3f (trans) 1SSa (trans) 1SSb (trans) 1SSc (cis) 1SSd (cis) 1SSe (cis) 1SSf (trans)

46.60 39.63 12.84 0.84 0.08 0.01 64.74 31.03 3.30 0.85 0.07 0.002 82.19 8.48 8.54 0.69 0.09 0.005 51.08 43.77 2.75 2.32 0.07 0.002

−91.2 −119.5 −85.6 −147.5 −61.9 −56.79 −126.4 −89 −92.8 −143.8 −65 −58.73 −91.9 −132.6 −93.4 −140.2 −63.3 −69.7 −133.91 −84.96 −97.10 −137.61 −65.51 69.25

176.7 91.7 −174.1 63.5 −49.5 −43.62 70.4 172.8 −170.8 58.1 −44 −40.76 169.2 44.6 −176.8 62.8 −45.9 −28.5 64.88 145.71 −175.07 55.55 −39.74 28.39

a

a

B3LYP

B3LYP-MP2

B3LYP-MP2c

0.0 1.2 6.3 14.4 18.8 24.6 0.0 6.7 12.4 15.2 20.9 28.2 0.0 3.6 7.7 13.7 19.1 27.1 0.0 3.2 11.3 11.5 18.9 29.7

0.0 0.4 5.7 11.7 14.9 21.1 0.0 7.4 12.4 13.8 18.7 27.0 0.0 2.3 7.5 10.6 14.6 22.6 0.0 3.0 10.8 9.5 16.0 26.7

0.0 0.4 3.2 9.9 15.7 22.1 0.0 1.8 7.4 10.7 17.0 26.3 0.0 5.6 5.6 11.9 17.0 24.1 0.0 0.4 7.2 7.7 16.3 25.5

a The ϕ and ψ dihedral angles in degrees. bIn units of kJ mol−1, and including zero-point vibrational energies and 298 K enthalpies. cRelative free energies at 298 K.

n → π* orbital overlap requirements. The lack of n → π* interactions in the αD was further confirmed by natural bond orbital calculations. To determine the origin of the interactions, which stabilize the trans isomers, in particular to explain the significant contribution of the αD structure in the case of 3 (i.e., 3a), diminishing in the order 1 > 2, calculations were supplemented by natural bond orbital (NBO) analysis. 50 First, the interactions of the X atom lone pair as a donor (Scheme 3) were verified, as the type of the donor atom effectively influences the population of the αD form. In particular, the presence of the sulfur donor induces the highest contribution of αD in the population of 3 (82.19%, Table 1). Analysis of the NBO second-order perturbation stabilization energies associated with the interactions between the X lone pair as a donor and different acceptors allowed the proposal of an indirect n → π* interaction through the C−H antibond (σ*) as a source of αD stabilization. The stabilization due to intermediate nX → σCH* delocalization is the highest for 3a (ESOP = 8 kJ mol−1), followed by 1a (ESOP = 2.5 kJ mol−1), and in the case of 2b, this interaction is negligible at a threshold energy of 2.1 kJ mol−1. The stabilization order is in accordance with the contribution of the αD form in the population of models 1−3. In turn, according to NBO calculations, the σCH interacts with π* to make the indirect n → π* interaction fully operative. The C7β form of 1−3 is stabilized by indirect n → π* interactions to a much lesser extent according to the NBO second-order perturbation stabilization energies, excluding the 2a conformation. The nX → σN′C−H* interaction is an additional source of stability of the C7β form, which is more relevant for 1b and 2a than for 3b. Similarly, indirect “bridged” n → πAr* interactions, mediated by the N−α-C−H σ* orbital, were

proposed to stabilize cis rotamers of N-α-chiral aromatic acetamides.33 The energy barriers between trans C7β and αD conformations (Table 2) were in the range of 5.8−20.2 kJ mol−1 and increase in the following order: 1 < 2 < 3 < 1SS (1SS represents the structure in which two amide bonds are replaced by a thioamide group). The least energetically favorable conformation, which meets the requirements for n → π* orbital interactions (1f, 2f, 3f), corresponded to the peptide αL structure with ϕ ≈ −60° and ψ ≈ −35°. Very similar conformational forms were found on the cis-1, 2, 3 PES maps. The most stable cis conformation of 1c, 2c, 3c reflects the αD form, while less stable 1, 2, 3-d structures and 1, 2, 3-e structures correspond to the C7β and αL forms, respectively. The energy barriers connecting the cis isomers of thiopeptoids 2, 3, and 1SS are higher than that obtained for the peptoid model (1), as well as higher than those between the two trans conformers (Table 2). Figure 1 shows representative conformations of the trans and cis C7β, αD, and αL forms. The minima obtained for 1 are in accordance with those previously reported by Moehle and Hofmann.48 Despite the remarkable similarity of the conformations of the minima between the peptoid model (1) and its thioxoanalogues (2, 3), the replacement of the carbonyl oxygen with sulfur leads to an increase in the energy difference between conformers (Table 1). Previous studies concerning the conformational behavior of peptoids indicated a larger population of the cis conformation of the amide bonds in peptoids than in peptides.14,51,52 Thioxo substitution in peptoids induces a slight trans preference in comparison to the cis−trans isomerism of 1 (Table 1). Double substitution of the carbonyl oxygens with sulfur atoms (structure 1SS) D


Article

The Journal of Physical Chemistry A Table 2. Relative Energy Barriers between Isomers Characterized for 1, 2, 3, and 1SS relative energya structure/transition

B3LYP

B3LYP-MP2

Energy Barriers between trans Isomers 0.7 0.0 5.3 6.1 2.1 2.9 5.7 8.6 Energy Barriers between cis Isomers 1c−1d 20.7 25.0 1d−1e 22.6 27.4 1c−1e 19.7 26.3 2c−2d 29.1 29.2 2d−2e 27.4 27.9 2c−2e 24.8 24.9 3c−3d 20.0 20.0 3d−3e 21.8 19.6 3c−3e 20.9 19.9 1SSc−1SSd 27.3 27.9 1SSd−1SSe 25.7 24.6 Energy Barriers between trans and cis Isomer 1a−1c (TS1) 73.0 72.0 1a−1c (TS2) 89.7 89.1 1b−1d (TS1) 72.6 68.7 1b−1d (TS2) 78.1 75.0 2b−2c (TS1) 80.7 81.0 2b−2c (TS2) 99.5 100.1 2a−2d (TS1) 72.0 69.8 2a−2d (TS2) 76.1 74.7 3a −3c (TS1) 83.3 82.3 3a−3c (TS2) 100.6 100.3 3b−3d (TS1) 83.3 78.8 3b−3d (TS2) 88.8 85.4 1SSb−1SSc (TS1) 89.9 90.2 1SSb−1SSc (TS2) 84.5 83.0 1SSa−1SSd (TS1) 80.6 77.9 1SSa−1SSd (TS2) 84.4 82.9 1a−1b 2a−2b 3a−3b 1SSa−1SSb

B3LYP-MP2b 5.8 9.4 14.3 20.2 20.1 21.1 17.7 35.5 30.9 33.1 28.2 25.2 30.6 34.5 28.5 83.1 99.5 80.8 86.6 88.3 107.7 79.0 83.7 94.6 112.1 92.9 98.4 98.2 91.8 86.9 91.6

Figure 1. Structures of the trans (3a, 3b, 3f) and cis (3c, 3d, 3e) conformers of thiopeptoid 3. The appropriate conformational forms are indicated in parentheses.

cis isomerization corresponds to the syn/exo configuration, adopting a prolyl nomenclature.53 In general, the energy barriers between trans and cis isomers were slightly higher for the αD forms than those obtained for the C7β. The presence of the thioamide at the C-terminal part of the molecule (2) does not affect, and even slightly lowers, the trans−cis rotation barrier, whereas the N-terminated thioxo derivative (3) exhibits an increase in the energy barrier of this transition by 12.1 kJ mol−1. Interestingly, double substitution of the carbonyl oxygens with sulfur is not as effective as N-terminal substitution, increasing the energy barrier for the isomerization by only 6.1 kJ mol−1. Fully relaxed energy maps obtained for peptoid−peptide hybrid 4 and its thioxo derivatives 5 and 6 (Supporting Information, Figure 1Sd−f) exhibited comparatively fewer stationary points than those for dipeptoid models. All stationary points were summarized in Table 3. The PES maps of 4, 5, and 6 displayed similar patterns, providing evidence of the small effect of thioxo substitution on the conformational changes in the model system. On the trans PES maps of 4, 5, and 6, one stable conformational form was found (4a, 5a, 6a), which corresponds to the C7 form (ϕ ≈ −90° and ψ ≈ 80°). The second type of minimum on the trans PES maps at ϕ ≈ −100° and ψ ≈ −180° was unstable during reoptimization and coincided with the C7 global minimum. Two other minima were defined on the cis PES maps as the β (4b, 5b, and 6b) and αD (4c, 5c, and 6c) forms. The energy barriers between the cis conformers of 4, 5, 6, and 4SS model

a Relative energies (relative to the most stable isomer, i.e., 1a, 2a, 3a, and 1SSa) in units of kJ mol−1, and including zero-point vibrational energies and 298 K enthalpies. bRelative free energies at 298 K.

induces similar behavior to that reported for the singly substituted thioxo analogues (Table 1). The difference between the trans−cis population was more pronounced for compound 2, in which the thioamide is located at the Cterminus, and for the 1SS model than in 3, where the thioamide is incorporated into the N-terminus. It is worth emphasizing that a trans conformational preference occurs for the C7β and αL forms, while the cis conformation dominates for the αD structure. In a simple amide structure, exchanging the amide oxygen to sulfur increases the rotational barrier between the cis and trans isomers by 8−12 kJ mol−1, i.e., due to the more pronounced double bond character of the thioamide C−N bond.22 Thus, a similar increase in the rotational barrier was expected in thiopeptoids. Additional rotation along ω1 dihedral angles was therefore performed, and the individual transition states were found to reveal the rotational barrier between the trans and cis isomers. For each model compound, two transition states were defined as the trans−cis rotational barriers between the C7β and αD forms (Table 2). In each case, the lowest TS of the trans− E


Article

The Journal of Physical Chemistry A Table 3. Summary of Stable Conformations of 4, 5, 6, and 4SS and Their Relative Energies relative energyb structure

population % (298 K)

ϕ

4a (trans) 4b (cis) 4c (cis) 5a (trans) 5b (cis) 5c (cis) 6a (trans) 6b (cis) 6c (cis) 4Ssa (trans) 4Ssb (cis) 4Ssc (cis)

91.98 7.66 0.37 97.49 2.48 0.03 85.97 13.72 0.31 94.31 5.67 0.02

−87.60 −101.50 −89.80 −86.74 −102.70 −101.70 −97.81 −96.02 −95.39 −97.19 −98.08 −107.74

a

ψ

B3LYP

B3LYP-MP2

B3LYP-MP2c

76.00 8.60 −152.00 73.15 7.80 −145.06 86.93 8.19 −153.27 76.89 10.27 −147.53

0.0 8.5 16.0 0.0 12.4 24.4 0.0 8.9 18.3 0.0 12.4 25.8

0.0 8.1 16.7 0.0 11.9 24.0 0.0 7.7 19.1 0.0 11.1 25.0

0.0 6.2 13.7 0.0 9.1 20.5 0.0 4.5 14.0 0.0 7.0 21.2

a

a The ϕ and ψ dihedral angles in degrees. bIn units of kJ mol−1, and including zero-point vibrational energies and 298 K enthalpies. cRelative free energies at 298 K.

compounds vary in the range 20.8−26.6 kJ mol−1 (Table 4), and in contrast to the energy barriers obtained for dipeptoid Table 4. Relative Energy Barriers between the Isomers Characterized for 4, 5, 6, and 4SS relative energya structure/transition

B3LYP

B3LYP-MP2

B3LYP-MP2b

Energy Barriers between cis Isomers 4b−4c (TS1) 19.65 20.08 4b−4c (TS2) 20.97 21.75 5b−5c (TS1) 26.08 26.15 5b−5c (TS2) 30.96 30.77 6b−6c (TS1) 20.58 20.89 6b−6c (TS2) 20.80 21.32 4SSb−4SSc (TS1) 27.34 27.43 4SSb−4SSc (TS2) 29.73 29.49 Energy Barriers between the trans and cis Isomers 4a−4b (TS1) 67.40 65.90 4a−4b (TS2) 74.36 73.53 5a−5b (TS1) 69.97 68.74 5a−5b (TS2) 75.72 75.26 6a−6b (TS1) 78.54 76.08 6a−6b (TS2) 85.49 84.18 4SSa−4SSb (TS1) 79.86 77.85 4SSa−4SSb (TS2) 85.10 84.38

29.39 31.30 34.28 34.88 30.25 25.27 35.89 33.64 75.58 83.03 75.22 82.24 85.25 93.27 84.14 90.38

Figure 2. Structures of the trans (6a) and cis (6b, 6c) conformers of thiopeptoid−peptide hybrid model compound 6. The appropriate conformational forms are indicated in parentheses.

peptoid−peptide hybrid model (compound 4), the participation of the trans form is slightly more pronounced for 5, in which the thioxo group is located at the C-terminus, due to the better H donor ability of the thioamide compared to the amide group. In 6, the intramolecular hydrogen-bonding interactions stabilizing the trans form are diminished because the thioxo group is a weaker H-bond acceptor than the amido group; thus, there is a decreased trans isomer population in comparison to other model compounds. The trans−cis rotational energy barriers follow similar trends as the dipeptide models. The presence of the thioamide group at the N-terminus (compound 6) and in the doubly substituted thioxo analogue 4SS increases the trans−cis barrier by 9.7 and 8.5 kJ mol−1, respectively, considering the lowest barrier represented by the transition state 1 (TS1, Table 4), while the C-terminated thioamide 5 shows the same energy barrier as unsubstituted 4. Additional rotations along ω2 dihedral angles of peptoid− peptide hybrid model compounds were performed and analyzed to obtain transition states for the second (thio)amide

a Relative energies (relative to the most stable isomer, i.e., 4a, 5a, 6a, and 4SSa) in units of kJ mol−1, and including zero-point vibrational energies and 298 K enthalpies. bRelative free energies at 298 K.

models, the thioamide substitution does not significantly increase this barrier. All minima obtained for 6 are shown in Figure 2. Double substitution of carbonyl oxygens with sulfur in 4 (referring to 4SS structure) does not introduce any significant conformational changes, and minima obtained for 4SS exhibit similar values of ϕ and ψ dihedral angles compared to unsubstituted (4) and singly thioxo-substituted (5 and 6) model compounds. The energy differences between the trans and cis isomers of peptoid−peptide hybrid model compounds (Table 3) show that not only the presence of the thioamide group but also its position affects the trans−cis population. The trans conformation is significantly more favored in all model compounds. However, in comparison to the unsubstituted F


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populated cis isomer of 1, the selective inversion of the peak at 1.9 ppm (corresponding to the protons of CH3CO−, Figure NMR1c, Supporting Information) induced a peak presence at 4.04 ppm (CH2). Likewise, the assignment of NMR signals to the cis and trans isomers of each compound was accomplished on the basis of NOE observations. NMR integration of the proton signal intensities in the 1H NMR spectra allowed the populations of the cis and trans isomers to be determined in each of the examined solvents. Moreover, the populations of each species were used to calculate the trans−cis equilibrium constants and Gibbs free energies (ΔG°) (Table 5).

group. The energies of stationary points resulting from those rotations were 20−35 kJ mol−1 higher than those of the lowest energy conformers. The energies of the transition states varied depending on the model compound and were substantially higher (by 17−40 kJ mol−1) than the trans−cis transition states for 4, 5, and 4SS, while the TS energy of 6 increased by only 1 kJ mol−1. The thioamide substitution exerts a slight effect on the general conformation of both the dipeptoid and peptoid− peptide hybrid model compounds. The observed changes in the ϕ and ψ dihedral angles were in the range 3−30% depending on the model system (detailed values of the ϕ and ψ dihedral angles are shown in Tables 1 and 3). If one ignores the less populated conformations (less than 1%), dipeptide analogues have three minima, two trans and one cis, while peptoid−peptide hybrid models present two minima, one trans and one cis. The lack of the second trans minimum in the last case is due to privileged stabilization resulting from the amide hydrogen being intramolecularly hydrogen-bonded to the amide oxygen or sulfur. Although conformational similarities between minima obtained for unsubstituted and thioxo-substituted model compounds were observed, significant changes in their energetics and the energy barriers between stable conformers were identified. The trans arrangement of both dipeptoid and peptoid−peptide hybrid model compounds dominates. The participation of the trans conformers is more favored in all thioxo-substituted dipeptoids in comparison to the underivatized models. In the case of peptoid−peptide models, the Hbond acceptor ability of thioamide54 and increased size of the sulfur atom in a thiocarbonyl compared to a carbonyl group modulates the trans preference. NMR Studies. The conformational changes induced by the replacement of the carbonyl oxygen with a sulfur atom in the model compounds, which represent alanine-containing dipeptoids (Scheme 1, structures 1, 2, and 3) and hybrids containing peptoid and peptide units (Scheme 1, structures 4, 5, and 6) in solution were examined using NMR spectroscopy. Due to earlier reports of significant solvent effects on the cis−trans equilibria of (thio)amide conformations,55,56 the effect of chemical environment, i.e., the polarity of the solvent, was considered regarding the conformational preferences of the examined compounds. The examined compounds exist in solution as an equilibrium mixture of two isomers. The unambiguous assignment of the NMR signals to each isomer was realized on the basis of the nuclear Overhauser effect (NOE) interactions between the protons belonging to CH3CX− and N−CH3− or CH2− groups (Scheme 4). For example, in the case of 1, a selective inversion of the peak at 2.1 ppm (Figure NMR1d) corresponding to the protons in the CH3CO− group of the major isomer in CD2Cl2 led to an NOE peak appearance at 3.03 ppm (N−CH3), suggesting through-space connectivity between the CH3CO− and N−CH3 groups. This observation indicates that the trans isomer is the major form. In the less

Table 5. Populations of the cis and trans Isomers, Estimated Equilibrium Constants (K), and Gibbs Free Energies (ΔG°, in kJ mol−1) for the trans-to-cis Interchange of 1−6 at 298 K in Different Solventsa compound

solvent

% cis

% trans

1

CD2Cl2 CD3CN DMSO-d6 CD2Cl2 CD3CN DMSO-d6 CD2Cl2 CD3CN DMSO-d6 CD2Cl2 CD3CN DMSO-d6 CD2Cl2 CD3CN DMSO-d6 CD2Cl2 CD3CN DMSO-d6

23 39 43 22 41 51 27 38 48 26 34 41 19 30 40 16 30 39

77 61 57 78 59 49 73 62 52 74 66 59 81 70 60 84 70 61

2

3

4

5

6

K (trans → cis)b

ΔG° (trans → cis)

± ± ± ± ± ± ± ± ± ± ± ±

0.02 0.01 0.03 0.02 0.02 0.01 0.03 0.02 0.03 0.03 0.03 0.03

± ± ± ± ±

0.01 0.01 0.01 0.03 0.02

3.0 1.1 0.7 (2.5) 3.1 0.9 −0.1 (−1.6) 2.5 1.2 0.2 (1) 2.6 1.6 0.9 (−1.8) 3.6 2.1 1.0 (−4.3) 4.1 2.1 1.1 (−0.6)

0.30 0.64 0.75 0.28 0.69 1.04 0.37 0.61 0.92 0.35 0.52 0.69 0.23 0.43 0.67 0.19 0.43 0.64

In parentheses is the ΔG° calculated in DMSO (SMD). bThe equilibrium constants (K) are reported with errors associated with the population estimation from proton signal integration based on the 1H NMR spectra (for details, please see the Supporting Information Characterization of model compounds). a

Several conclusions concerning the molecular conformation−chemical environment relationship can be drawn from the data shown in Table 5. A general observation for all of the examined compounds is that the trans isomer is dominant in all of the analyzed solvents, with one exception of compound 2 in DMSO, in which the cis conformation is slightly privileged. The contribution of the trans conformation in the overall isomer distributions of 1−6 decreases with increasing polarity and hydrogen bond acceptor ability of the solvent molecules, i.e., in the following order: CH2Cl2 < CH3CN < DMSO.57 The cis conformation has a markedly higher population in the dipeptoid model group (1−3) than in peptoid−peptide hybrid models (4−6). The hydrogen-bonding interactions between CX···HNC(Y) (Figure 2, 6a) stabilize the trans configuration of peptoid−peptide hybrids (4−6). The lack of this type of stabilization in 1−3 results in higher contributions of the cis isomer in all solvents. On the other hand, the trans-amide conformation of (thio)peptoids 1−3 may be stabilized by the indirect n → π* interaction through

Scheme 4

G


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hence, in this case, a slightly higher increase in the cis conformation with respect to the peptoid group is observed. The differences in the contribution of the cis form in overall isomer distributions between unsubstituted and thioxosubstituted compounds are more pronounced for dipeptoid models than for peptoid−peptide hybrids and have a distinct nature. In the first case, the thioxo substitution induces an increase in the cis conformation with respect to the unsubstituted 1 in DMSO (in CH3CN, the cis preference is only slightly highlighted). When changing the solvent to DMSO, thioxo substitution did not increase the contribution of the cis form in peptoid−peptide hybrids (4−6), and the difference in the cis preference between the thioxo-substituted and native compounds was less apparent than that for compounds 1−3. As expected, in the presence of DMSO, in which the intramolecular hydrogen-bonding effects are minimized, the subtle differences in the H-bond donor− acceptor abilities between the thioxo and oxo groups of 4−6 become unremarkable. The NMR experiments were supplemented by theoretical calculations ran in a DMSO environment using self-consistent reaction field (SCRF) with solvation model density (SMD) of Truhlar and co-workers.41 This recently proposed solvation method has been widely used by computational chemists, due to the advantage of being parametrized in 91 solvents for an appreciable set of solvation data. Thus, the evaluation of its reliability to different molecular systems is still worthwhile. The SMD calculations were performed in a DMSO solvent due to the available experimental activation parameters obtained within this study for comparison. Moreover, this solvent allows for estimation of the effectiveness of the SMD model to describe systems in which the hydrogen bonding intra- and intermolecular interactions play an important role in conformational stability, as is the case for peptoid−peptide hybrids 4−6. The reoptimization of the gas-phase stable conformations of 1−6 using SMD introduced a rather small variation in their geometries but significant changes in their energies (Table 5, SMD results are given in parentheses). Good overall correlations of the experimental and calculated values of ΔG° were obtained for dipeptoids 1−3. In this case, the preferences for the trans and cis conformations are similar, although with slightly higher energy differences between them. For peptoid−peptide hybrids (4−6), the calculations predict a significantly higher contribution of the cis isomer compared to the experimental results. This discrepancy between experimental results and the calculations suggests that the intramolecular hydrogen bonding stabilizing interaction occurring in the trans isomer is very effective, much more effective than the intermolecular interactions with DMSO predicted by the SMD solvation model. Although the SMD solvation model was optimized over six electronic structure methods, including B3LYP, and it has been parametrized with a training set of numerous solvation data in different solvents, including DMSO,41 a recent report suggested that the SMD model is not adequate for dipolar aprotic solvents.58 In the present study, the SMD model seems to overestimate intermolecular interactions between DMSO and the NH group peptoid−peptide hybrids, significantly diminishing the contributions of intramolecular hydrogen-bonding effects between CX and HN. Exchange between the trans and cis configurational isomers of 1−6 occurs by rotation around the (thio)amide bond (ω1). The kinetics of this interconversion were studied by VT-NMR

the C−H antibond (σ*), as indicated by computations. The earlier studies on the origin of stabilization interactions and their influence on trans−cis equilibrium constants have suggested the relevance of the direct and indirect n → π*(Ar) interactions in the case of peptoids depending on the type of side chains and backbone thioamide substituent.33,34 In order to evaluate which type of interaction is operative in the analyzed systems in solution, the indirect n → π* interaction as indicated by the calculations or direct n → π* interaction effectively less significant according to the calculations, the additional measurements of the 1JCH coupling constants for the N−α-C−H bonds of the trans and cis isomers were performed Table 6. Experimentally Measured (in CD2Cl2) 1JCH Coupling Constants for the N−α-C−H Bonds of cis and trans Rotamers of 1−3 1

JCH (N−α-C−H)

compound

trans

cis

Δ 1JCH

1 2 3

137.5 139.2 138.5

136.2 136.9 138.0

1.3 2.3 0.5

(Table 6). The previous studies showed that measurements of JCH coupling constants may be helpful to estimate the role of direct vs indirect n → π* interactions on observed trans−cis equilibrium constants as an indication of N−α-C−H···O/S interactions.33 A larger 1JCH coupling constant of the trans vs cis rotamer of 1−3 was detected, and within trans rotamers, the thioxo-substitutied dipeptoid models (2 and 3) have larger 1 JCH than their oxo analogue (1). This finding suggests the enhancement of N−α-C−H···S interaction in trans conformation for 2 and 3 in comparison with 1. The values of 1JCH for 1−3 correlate well with the population of cis−trans conformations from computation studies (Table 1). Moreover, the differences in 1JCH between the trans and cis isomers of 1− 3 agree well with the observed K (trans → cis) values. The above presented results strongly support the hypothesis that the indirect n → π* interaction through the C−H antibond (σ*) mainly affects the K (trans → cis) in solution in the analyzed systems. The effect of indirect n → π* interaction between carbonyl−thiocarbonyl gropus is more pronounced for 2, i.e., for the C → N direction, than for 3, i.e., for the N → C direction. The presented hypothesis on the importance of the of indirect n → π* over direct n → π* interaction for thiopeptoids contradicts previously reported findings, giving evidence that the different nature of stabilization forces may be accounted for in the peptoid system depending on the side chain structure. The impact of the nature of the solvent on different stabilization forces responsible for the trans−cis equilibrium may be observed while comparing the increase in the contribution of the cis isomer going from CH2Cl2 to DMSO solvent, which is as follows: 20, 29, 21, 15, 21, and 23 for 1−6, respectively. The increase in the cis isomer population is higher for peptoids than for peptoid−peptide hybrids, providing evidence of the higher impact of DMSO on the mediated n → π* interaction, which is supposed to be a major stabilizing force of the trans rotamer, than that on the hydrogen bonding interaction occurring in 4−6. One exception in this trend was observed for 6, which may be explained by the fact that sulfur is a weaker H bond acceptor than the carbonyl oxygen, and 1

H


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Figure 3. Experimental (black, bottom line) and simulated (green, top line) VT-NMR spectra of the CH2 signal of 1 (left) and 2 (right). Temperatures and computed exchange rates k are also given for every trace. The simulated spectra were obtained with the WinDNMR-Pro program.45

spectroscopic experiments in DMSO. This solvent allowed a higher temperature to be reached during measurement and therefore a higher barrier to internal rotation around the (thio)amide bond to be determined, which is the case of studying thioxo-containing compounds. However, the rotation barrier depends on the solvent. The studies of the solvent effect on the (thio)amide rotational barrier showed that increasing solvent polarity induces an increase in the rotational barrier and that this effect is larger for thioamide compared to

amide bonds, as the thioamides have a larger ground-state dipole moment.22 Therefore, the rotational barriers measured in DMSO were expected to be relatively high. VT-NMR experiments carried out in DMSO produced the coalescence of five or four groups of protons. Full line-shape analysis was performed for CH2 protons (Figure 3). Upon heating during VT-NMR experiments, the CH2 proton signals of both isomers broadened and allowed for the temperature of coalescence and the activation parameters for amide trans−cis I


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Table 7. Relevant VT-NMR Data and Related Activation Parameters for Conformational Interconversions of 1, 2, 4, and 5 Peptidomimetics (for an In-Depth Description, Please See the Supporting Information) Obtained from Line-Shape Analysis of CH2 Protonsa Tc (K)

ΔGav⧧ b (kJ mol−1)

1

378

2

355

4

363

5

343

81.16 ± 0.14 (80.33) 78.16 ± 0.43 (78.00) 79.71 ± 0.23 (78.80) 77.82 ± 0.28 (76.88)

compound

Ea (kJ mol−1) 80.11 (79.99) 63.53 (65.63) 77.85 (76.09) 71.69 (69.64)

ΔH⧧ (kJ mol−1) c

ΔS⧧ (J mol−1 K−1) −11.1c/−11.1d (−9.2/−9.2) −49.5/−51.7 (−43.1/−45.1) −13.5/−12.7 (−15.8/−15.1) −26.2/−26.8 (−29.4/−30.2)

d

77.00 /77.02 (76.85/76.90) 60.58/60.71 (62.68/64.48) 74.83/74.91 (73.07/73.16) 68.83/68.99 (66.79/66.94)

a The data for both transitions trans → cis and cis → trans (in parentheses) are included. bAverage values calculated from ΔGT=i⧧. cActivation parameters determined by applying Arrhenius plots. dValues obtained from Eyring plots.

Figure 4. Arrhenius (a and c) and Eyring (b and d) plots for the trans → cis (a and b) and cis → trans (c and d) isomerization of 1.

isomerization in both directions of the equilibrium to be estimated in the classical manner, from Eyring and Arrhenius plots (Table 7, plots are presented in the Supporting Information, representative plots are shown in Figure 4). The barrier to rotation around the thioamide bond was too high to be measured using VT-NMR experiments described here. Hence, only the discussion of the presence of the thioamide bond on the rotational amide bond may be undertaken. Additionally, for CH3− protons, a simplified formula to calculate ΔG⧧ from the coalescence temperature and the maximum separation Δv (Hz) of the NMR signals under conditions of slow exchange was applied (Table 8). The Gibbs free energies of activation found in this manner differ from the values obtained by full line-shape analysis by less than 1%.

Table 8. Frequency Difference (ΔνCH3−), Coalescence Temperature (Tc), and Calculated Energetic Barrier at Tc for the trans−cis Isomerization Process (CH3−) compound

Δν (Hz)

Tc (K)

ΔG⧧ (kJ mol−1) (trans → cis)

ΔG⧧ (kJ mol−1) (cis → trans)

1 2 4 5

87.3 66.3 50.8 41.8

388 373 373 358

81.6 78.7 80.1 77.5

80.7 78.8 79.0 76.3

The neighborhood effect of the thioamide group in place of an oxoamide results in a decrease of the rotational barrier, and this effect is larger for dipeptoid models than for peptoid− peptide hybrids. Similar results, although to a lesser extent, J


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for dipeptoid models. The additional interactions associated with the presence of polar side chains would further alter the trans−cis equilibrium. These studies are underway in the laboratory.

were obtained for a gas-phase environment. The entropic contribution to ΔG⧧ is significant for thioxo derivatives as a result of the higher rigidity of the thioxo derivatives due to the more pronounced double bond character of the thiopeptide C−N bond. The theoretically computed barriers to rotation around the amide bond for 1, 2, 4, and 5 in DMSO are as follows: 79.1, 70.9, 68.9, and 63.3 kJ mol−1, respectively. The good correlation between the theoretical and experimental ΔG⧧ was obtained only for 1. For other compounds, the computed barriers are substantially lower than the experimental values. The highest discrepancy between the calculated and experimental values occurs for 4 and 5. This may be another example in which the SMD solvation model underestimates the intramolecular hydrogen bonding effects in DMSO, effectively reducing the rotational barriers of compounds due to the significant contribution of intramolecular hydrogen bonds as stabilization forces.

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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/acs.jpca.8b05456. Conformational energy maps, optimized structures with energies, compound synthesis and characterization, NMR spectra, VT-NMR data, simulations, and Arrhenius and Eyring plots (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

■

ORCID

CONCLUSIONS The backbone substitution of the oxoamide with a thioamide group in N,N-dimethyl-2-(N-methylacetamido)acetamide (1) and N-methyl-2-(N-methylacetamido)acetamide (4), which serve as the simplest models of a dipeptoid structure and a peptoid−peptide hybrid, evokes conformational changes that alter the trans−cis isomer population and are related to the position of substitution, N- vs C-terminal, and chemical environment. In all analyzed model compounds, the trans isomer dominates. The intrinsic interactions stabilizing the trans arrangements (αD and C7β forms) of dipeptoid models are related to indirect n → π* interaction through a C−H antibond (σ*), as revealed by computations and orbital bond analysis. The presence of a sulfur atom as an efficient electronpair donor enhanced this interaction, significantly shifting the equilibrium to favor the trans isomer (αD) in the N-terminal thioamide dipeptoid model (3). The direct n → π* interaction constitutes a negligible contribution to trans stabilization. The nX → σN′C−H* interaction is an additional source of stability of the trans-C7β form, which is relevant for the underivatized dipeptoid model (1) and its C-terminal thioamide counterpart (2). In peptoid−peptide hybrids, the trans−cis equilibrium is perturbed by subtle differences in H-bond donor−acceptor abilities between the thioxo and oxo groups. The omnipresent contribution of the trans conformation in a solvent-free environment precipitously decreases with increasing polarity and hydrogen bond acceptor abilities of the solvent molecules, as indicated by NMR measurements. The trans preference, associated with the more effective, relevant in the analyzed systems, indirect n → π* interaction in the Nterminal thioamide dipeptoid model, declines more rapidly than that induced by hydrogen-bonding effects in peptoid− peptide hybrids. While thioxo substitution slightly shifts the trans−cis equilibrium in polar solvents, it effectively increases or decreases the barrier to trans−cis rotation with respect to underivatized model compounds depending on N- vs Cterminal thioamide backbone substitution. The attempts to include solvent effects in theoretical calculations have been done with self-consistent reaction field (SCRF) with solvation model density (SMD). The SMD solvation model failed in describing the DMSO-induced effects on hydrogen bonding in peptoid−peptide hybrids, effectively diminishing the trans contribution, while overall satisfactory results were obtained

Magdalena M. Zimnicka: 0000-0001-5078-4374 Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS Support of this research by the Polish Ministry of Science and Higher Education (Grant “Iuventus Plus” 0641/IP3/2011/71) is gratefully acknowledged.

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REFERENCES

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