Chiral Thiophene SulfonamideâA Challenge for VOA Calculations

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A Chiral Thiophene Sulfonamide – a Challenge for VOA Calculations Joanna E. Rode, Jan Cz. Dobrowolski, Krzysztof Lyczko, Aleksandra Wasiewicz, Dorota Kaczorek, Robert Kaw#cki, Grzegorz Zajac, and Malgorzata Baranska J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.6b11015 • Publication Date (Web): 04 Aug 2017 Downloaded from http://pubs.acs.org on August 5, 2017

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The Journal of Physical Chemistry

A Chiral Thiophene Sulfonamide – a Challenge for VOA Calculations Joanna E. Rode, *† Jan Cz. Dobrowolski,† Krzysztof Lyczko,† Aleksandra Wasiewicz, ‡ Dorota Kaczorek, ‡ Robert Kawęcki, ‡ Grzegorz Zając, ¶,§ Małgorzta Baranska¶,§ †

Institute of Nuclear Chemistry and Technology, 16 Dorodna Street, 03-195 Warsaw, Poland ‡ Siedlce University, 3 Maja Street No 54, 80-110 Siedlce, Poland ¶ Faculty of Chemistry, Jagiellonian University, 3 Ingardena Street, 30-060 Krakow, Poland § Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, 14 Bobrzynskiego Street, 30-348 Krakow, Poland Email: [email protected]

Abstract Two enantiomers of 2-methyl-N-(1-thien-2-ylethyl)propane-2-sulfonamide (TSA), were synthesized and their VCD, ROA, IR, and Raman spectra were registered. The solved (S)-TSA X-ray structure shows a disorder connected to the presence of two TSA conformers differing by a slight rotation of the thiophene ring. Two molecules in the units cell of monoclinic P21 crystal form a net of NH∙∙∙OS and C*H∙∙∙OS hydrogen bonds. Out of a series of computational levels tested to interpret the spectra, the B3LYP functional combined with the def2TZVP basis set satisfactorily reproduces the experimental VCD and ROA spectra. To simulate the VCD spectra of TSA enantiomers in KBr pellets dimers and tetramers, with two different positions of the thiophene ring, were considered. The VCD spectra measured in CDCl3 are completely different from those taken in KBr due to conformational freedom of TSA in chloroform. Seven TSA conformers fall into two groups of opposite configurations at the pyramidal N-atom forming the additional stereogenic center. However, the barriers between conformers in each group are lower than the energy of thermal motions at 300 K. Thus, all conformers, but the most stable in each group, are likely to be metastable states. The calculated IR, VCD, Raman, and ROA spectra of the conformers depend not only on type of the stereogenic N-atom but also on the thiophene ring rotation. Yet, they are likely to coexist because of low barriers between them. Four approaches were tested to reproduce the chiroptical spectra in solution using PCM and hybrid solvation models. In consequence, it was found that a model in which all conformers contribute to the spectra with equal population factors seems to best reproduce the experimental data. Such a result suggests that in a dissolved state in 300 K, TSA occurs in very shallow potential well and all its conformers coexist. Key words: chiral thiophene, Vibrational Circular Dichroism, Raman Optical Activity, calculations, conformation, solvation. 1.

Introduction

Tailoring new materials requires a deep insight into their molecular and phase structure. Chiroptical vibrational spectroscopy was intensively developed since the early 1970s, but only over the last decade it has reached a level of sophistication which allows for chiral structure monitoring and control.1-8 Vibrational Optical Activity (VOA) encompasses two main forms of chiroptical spectroscopy: (1) vibrational circular dichroism (VCD) and (2) vibrational Raman optical activity (ROA). For the two methods, the common medium is the liquid or solution phase. They are powerful in determining the absolute configurations (AC),4,5,9-13 conformation of molecules14-17 and intermolecular interactions in solutions.18-22 The complexity of VCD and ROA transition moments, which are composite products of IR or Raman electric, magnetic and quadrupole transition moments, implies the necessity of running parallel calculations to interpret the experimental VOA spectra.3,5 Indeed, so far, there 1 ACS Paragon Plus Environment


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are almost no empirical rules relating the sign and magnitude of the observed VOA intensities with molecular structure, conformation, H-bonding, solvent or substituent effects.4,5,23,24 Therefore, interpretation of the spectra relies strongly on the quality of quantum chemical simulations. However, several problems arise when VOA spectra are modeled. First, reproducing the VOA spectra of a non-rigid molecule requires the proper evaluation of its conformational space, which is a general problem in the study of flexible molecules.14-17 The VCD and ROA spectra are even more conformation-dependent than parent IR and Raman ones. In fact, in classical vibrational spectroscopy similar modes of different conformers may differ in band intensity and position, yet, they can form a common contour. In contrast, the VCD or ROA bands are bisignated and, in different conformers, the bands of similar modes may differ in their signs. As a result, two neighboring bands may exhibit (+,-) or (-,+) pattern but may also vanish because of mutual compensation or be enhanced when the bands of the same sign are overlapped. Moreover, there are known compounds which slightly different conformations exhibit computed spectra of almost mirror image.25,26 Hence, the proper estimation of the conformer population is crucial for the correct interpretation of the chiroptical spectra. Second, reproducing a solvent environment is especially important for molecules hydrogen-bonding with the surrounding.27 Then, usually at least the first solvation sphere needs to be taken into account by an explicit consideration of a few solvent molecules supported by a continuous solvent model which mimics the next solvation spheres and the influence of the bulk solvent.20,28 Thirdly, the use of a proper DFT functional and an adequate basis set is also important.29,30 However, carrying out modern DFT functionals is still insufficiently addressed in current literature. The role of a proper basis set is strikingly important when molecules with 3rd or higher row elements are studied. For thiophene derivatives, there are only a few papers devoted to the chiroptical spectroscopy that suggest the use of anharmonic corrections and the aug-cc-pVTZ basis set which is unrealistic even for systems of a medium size.31-33 The solid-state measurements could overcome the conformational and solute-solvent interactions problems as the molecular conformation is fixed and univocal (unless polymorphs occur). However, the solid-state technique is more difficult than the solution one because of presence of artifacts which arise from scattering from particles comparable in size to the incident light wavelength, linear birefringence form solid state medium and light polarization on crystals surfaces.3,34 They can be reduced by grinding the solid to small particle sizes and dispersing in pressed KBr, KCl or CsI discs, dual polarization modulation, and sample cell rotation.35,36 On the other hand, such a medium is advantageous for insoluble compounds and moreover the solid-state measurements require only minute amounts of sample. There are well-established protocols for measuring and interpreting the solid-state electronic circular dichroism (ECD) spectra by calculations.34,36 To exclude the presence of spectral artifacts it is recommended to measure also the solution spectra in various solvents and thus this method provides series of the spectra registered in different media.34 Unlike ECD, VCD does not require chromophores in the structure and the molecules which do not absorb in the UV-Vis range may have strong VCD signals. However, measurements of the solid-state VCD spectra is relatively rare,37-49 but parallel recording of the spectra in solution is really rare.46-49 The later show that the VCD response from the solid and solution states can be significantly different.47-49 Nevertheless, the solid-state VCD seems to have a significant potential in the AC assignment,38 studies of polymorphism (of medicines),43-45 support in crystal state studies,39 solid polymers structure,37,46 etc. Finally, let us add that, so fare, there is no reports on the solid-state ROA measurements. The reproduction of the experimental solid-state VCD spectra is a challenge even if the X-ray structure is known. The most often, the molecule from crystal is fully optimized and for it the VCD spectrum is simulated. If the agreement between the experimental and calculated 2 ACS Paragon Plus Environment

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data is unsatisfactory, taking a few molecules, bound as they are in the crystal, can be a proper solution. In such a case, optimization of only hydrogen atoms can be sufficient.50 For the largesized systems, the fragment-base quantum chemical calculations can be performed.51 The VCD and ROA methods have their specific advantages and limitations. The commercially available spectral range for ROA is 2000-100 cm-1, whereas for VCD the lower limit is usually at 850 cm-1, and a lot of bands important for characterization of biological systems cannot be registered. On the other hand, recording of the ROA spectra may be not possible if the sample fluorescence is strong which is not a problem for VCD. Furthermore, the most natural environment for ROA is water, hence, the method is recommended for studies of biosystems. For biomolecules it can be also important, that ROA can be additionally enhanced by resonance effects (RROA), however, the rules governing the RROA intensities are changed.26,52-55 On the other hand, because strong intermolecular solute-solvent interactions occur in water, for the AC assignment of natural products and chiral drugs the VCD technique performed in inert solvents is recommended. The aim of this study was to obtain a thiophene sulfonamide derivative, 2-methyl-N-(1thien-2-ylethyl)propane-2-sulfonamide (TSA, Scheme 1), to register the VCD and ROA spectra of TSA and to interpret them by means of DFT calculations.

Scheme 1. 2-methyl-N-(1-thien-2-ylethyl)propane-2-sulfonamide (TSA) Since the last decades of the XX century, the significance of thiophene derivatives has primarily been connected with their use in conductive polymers, a discovery which was awarded the Nobel Prize in Chemistry in 2000.56,57 The electrical conductivity of polythiophenes is a result of the presence of a conjugated π-electron system which permits the migration of a charge (either electrons or holes). Among conductive polymers, a class of chiral conductive polymers can be distinguished.58-61 The importance of chiral compounds in material and polymer chemistry has been steadily increasing.58,60 Indeed, the chiral polymers, including chiral polythiophenes, are used as organic electronics,61 adsorbents, membranes, phases,62 catalysts of asymmetric synthesis,63 or chiral electro-optic materials.59,64,65 On the other hand, sulfonamides are known to have an affinity to biomolecules and exhibit a broad spectrum of pharmacological profiles. Therefore, often, they are used as active pharmaceutical ingredients for treatment of bacterial and viral infections, hyperglycemia and hypertension.66,67 Here, we synthesized two enantiomers of TSA via condensation of 2thiophenecarboxaldehyde with (R)- or (S)-tert-butanesulfinamide. TSA is chiral, stable, and has good donor-acceptor properties important for interactions with a potential guest molecules in its sensor. The chiroptical studies of TSA were composed from registration of the VCD spectra of both enantiomers in KBr pellets and in CDCl3 solution, and registration of the ROA spectra only in solution. Next, the X-ray measurements were performed to establish the crystal structure. Then, using the geometry of crystal dimer and tetramer catemers, the solid-state IR and VCD spectra were simulated. To interpret the VCD and ROA spectra of TSA in chloroform, full conformational analysis took into account different computational levels and two solvation models (implicit and hybrid: implicit plus explicit). Then, different Boltzmann 3 ACS Paragon Plus Environment


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population factors were tested to best model the conformer equilibria in chloroform. Juxtaposition of the results of the above sub-aims leaded us to the conclusion that the chiroptical spectra of TSA depend on the two C- and N-atom stereogenic centers and on the thiophene ring twist. 2.

Experimental and calculations

Materials and synthesis Optically active sulfonamide TSA was obtained using Ellman methodology.68 Condensation of 2-thiophenecarboxaldehyde 1 with (R) or (S) tert-butanesulfinamide in the presence of potassium bisulphate gave N-sulfinylimine 2 (reaction a, Scheme 2).69 Enantiomers of sulfonamide TSA were obtained by the stereoselective addition of methylmagnesium bromide to sulfinimine 2 (reaction b, Scheme 2) followed by the oxidation of the sulfur atom with MCPBA (reaction c, Scheme 2). Six-membered ring transition state for the addition of Grignard reagents to (S)-sulfinimine 2, as proposed by Ellman,68 results in formation of (R,SS)-3. (R)-TSA and (S)-TSA were prepared with enantiomeric excess 84% and 90% respectively. For details see the Supplementary Information file.

Scheme 2. Synthesis of (R)-TSA enantiomer. Conditions of reaction a: (S)-t-BuS(O)NH2, KHSO4, toluene, 45oC; reaction b: MeMgBr, CH2Cl2, 0oC-rt; reaction c: MCPBA, CH2Cl2. VCD measurements The VCD and IR spectra of TSA enantiomers were measured in KBr pellets and dissolved in CDCl3. The FVS-6000 Jasco VCD spectrometer employing a 28° interferometer to reduce polarization effects and reflective optics to eliminate artifacts caused by sample birefringence was used. The KBr pellets were prepared by grinding of ca. 1.6 mg of TSA with 100 mg of KBr. The pellets were then placed in a rotating holder and the spectra were measured in the 2000– 850 cm−1 range with a 4 cm−1 resolution. To improve the signal-to-noise ratio 3000 scans were accumulated for 30 minutes. The VCD and IR spectra of TSA enantiomers in CDCl3 (0.2 M) were registered in a 0.1 mm BaF2 cell, in the 2000–1000 cm−1 range, 4 cm−1 resolution, and 10000 scans were accumulated. The baseline was corrected against the racemic mixture dissolved in the same solvent and recorded under the same conditions. Raman and ROA measurements Raman spectra of the (S)-TSA solid state were recorded using a Bruker MultiRAM FTRaman spectrometer equipped with the Raman scope III microscope module. The instrument is appointed with a Nd:YAG laser emitting at 1064 nm and a germanium detector cooled with liquid nitrogen. The Raman spectra (256 scans) were collected using macro TLC xyz stage in a 50 – 4000 cm–1 range with 4 cm–1 resolution and laser power of 500 mW. The Raman and ROA spectra of TSA enantiomers in chloroform were measured using a ChiralRAMAN-2X spectrometer (BioTools Inc.) at a resolution of 7 cm−1 in the range of 1600– 200 cm−1 using an excitation wavelength of 532 nm. The ca. 2 M solutions was measured in a ROA quartz optical cells with anti-reflective coating and a path length of 3 mm. To reduce 4 ACS Paragon Plus Environment

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fluorescence, TSA solutions were purified in use of activated charcoal, filtered with a syringe filters with PTFE membrane (pore size 0.2 μm), and exposed to the incident laser radiation (1000 mW) for 30 minutes. Spectral acquisition time was 4 days (194 820 scans). The laser power was set to 60-120 mW at the source. The curve of the ROA spectrum was slightly smoothed with the eleven-point Savitzky–Golay procedure. The baseline was corrected by subtracting the spectrum obtained for the solvent recorded under the same conditions, and corrected by the polynomial function. X-ray crystallography The single-crystal X-ray diffraction measurement for the studied compound was performed at 100 K using a Rigaku SuperNova (dual source) four circle diffractometer equipped with an Eos CCD detector. A suitable crystal was mounted on a nylon loop by means of cryoprotectant oil (paratone-N). A mirror-monochromated Cu K radiation ( = 1.54184 Å) from a microfocused Nova X-ray source was applied for the data collection. CrysAlis PRO software was used for all operations with using a diffractometer. The structure was solved by direct methods and refined by full-matrix least squares technique on F2 data using SHELXTL programs.70 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms bonded to carbon atoms were inserted in calculated positions and refined isotropically as riding model. The H atom of the NH pair was located in a difference map and its position was freely refined. The thiophene ring was disordered over two positions sharing one carbon atom (C1) with the occupancy ratio refined to 0.60:0.40. The crystallographic data and structural refinement parameters are presented in Table S1. The crystal structure presented in this paper was deposited at the Cambridge Crystallographic Data Center (CCDC 1542893). Calculations The conformational analysis of the (S)-TSA enantiomer was performed using two independent Conflex71 and ComputeVOA72 programs in which two different MM force fields were implemented. The conformational space was explored through systematic rotation about the single bonds by changing the following four dihedrals: χ1(S1-C2-C6-N7), χ2(C2-C6-N7S8), χ3(C6-N7-S8-C9), and χ4(N7-S8-C9-H) (Scheme 1). Geometry optimizations and spectra calculations were performed using different methods: B3LYP73,74 and B3PW9175 DFT functionals supplemented for the Grimme’s D3 dispersion correction;76 the B2PLYP77 doublehybrid functional including nonlocal correlation effects explicitly by an MP2 orbital dependent term and the MP278 approximations including a second-order perturbative approach. The computational methods were combined with the 6-311++G**,79 TZVP,80 def2TZVP,81 augcc-pVDZ,82 and aug-cc-pVTZ83 basis sets, the implicit PCM84,85 as well as the hybrid solvation model.27,86 The latter is a combination of the implicit and the explicit supermolecular approaches. The stationary structures were found by ascertaining that all the harmonic frequencies were real and the relative abundances were calculated based on the ΔG values referred to the value of the most stable conformer. In all calculations the Ultrafine grid was applied. In some cases, such as energy profile calculations, the Fine grid default in Gaussian09 program, was also tested, but the convergence was slower and the energy fluctuations occurred. Seven TSA conformers were located and, for some basis sets, one of them was split into two forms (4, Table S2). The difference in number of calculated conformers with different basis sets size is probably connected with presence of the sulfur atom belonging to the 3rd row of periodic table, for which the triple zeta type of basis sets are more adequate to properly describe the system.31 Different basis sets were examined to find the computational level the best reproducing the experimental IR and Raman spectra (Figs. S5 and S6). Often, this can be the first step to check the correctness of the computational level used further to reproduce the VCD and ROA 5 ACS Paragon Plus Environment


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spectra. Indeed, if a level fails in reproducing IR or Raman characteristics there is no chance that it will properly reproduce computationally much more requiring VCD or ROA ones. For most basis sets tested, the harmonic spectra were red-shifted with respect to the experimental ones (Table S3). The anharmonicity correction taken into account for the TZVP and aug-ccpVDZ basis sets showed that the bands with such a correction are even more red-shifted making the agreement even worse. Next, the influence of Grimme's D3 correction combined with the B3LYP functional and different basis sets was examined (Figs. S7 and S8). Further, change of the B3LYP into the B3PW91 functional (Figs. S9 and S10) was tested and the influence of dimer formation on the simulated spectra was checked (Figs. S11-S13). The def2TZVP basis set yielded the best agreement with the experimental IR and Raman spectra (Figs. S5 and S6) and thus only spectra simulated with these basis sets are presented hereafter unless otherwise stated. The bands in simulated VOA spectra with unscaled frequencies were multiplied by the appropriate conformer population factors and were assumed to have Lorentzian shapes with 6 cm-1 or 7 cm-1 half-width at half-peak height. All calculations were performed using the Gaussian 09 package of programs.87 3. Results and discussion 3.1 Experimental spectra The experimental IR and VCD spectra of two TSA enantiomers were measured in KBr pellets (Fig. 1a ) and in CDCl3 (Fig. 1b), and the ROA spectrum in CHCl3 (Fig. 1c).

(a)

(b)

(c)

Figure 1. The (R)- and (S)-TSA IR and VCD spectra measured in (a) KBr and (b) CDCl3, respectively, and (c) the Raman and ROA spectra measured in CHCl3. The solution VCD and ROA spectra were corrected against the spectra of racemic mixture of TSA and pure chloroform followed by the polynomial baseline correction, respectively. The low limit of the spectra in CDCl3 is set to 1000 cm-1 because of strong absorption of CDCl3 while the VCD spectra in KBr pellet are registered up to 850 cm -1. Notice that, roughly, the VCD band intensities in KBr are ca. 30-times larger than in solvent. In this moment we see no good explanation for the VCD band intensity enhancement in the solid-state. The concentrations of TSA in solutions and pellets are about the same. So, an increase of the intensity can be possibly connected with the solid state intermolecular interactions in the crystal. 6 ACS Paragon Plus Environment

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Nevertheless, according to our calculations neither electric nor magnetic transition moments increase sufficiently with H-bond multimers formation in the solid phase. In solution, the VCD and ROA spectra of (R)- and (S)-TSA are mirror images of each other. However, the VCD spectra in pellets are imperfectly mirrored. This is probably due to the disorder connected to thiophene moiety twist (see next section). 3.2. The VCD spectra in KBr In the X-ray structure of (S)-TSA, one can observe a disorder connected to presence of two TSA conformers (Fig. 2a, Table S1). They are present in the 3:2 ratio and differ by a slight rotation of the thiophene ring, i.e., by the χ1 torsion angle (Scheme 1) equal to 301.5° and 141.9° for thiophene ring atoms labelled by "A" and "B" (Fig. 2a), respectively.

(a) (b) Figure 2. (a) The molecular structure of (S)-TSA in crystal determined by the X-ray diffraction and (b) H-bond chains between TSA molecules in crystal. The X-ray analysis revealed that (S)-TSA crystallized in the monoclinic P21 space group, with two molecules in the unit cell (Table S1). In the net of hydrogen bond chains, one TSA molecule is simultaneously an NH group proton donor to one of the SO groups of neighboring molecule and a proton acceptor of the C*H group of the same neighboring molecule to its own SO group (Fig. 2b). The intermolecular NH∙∙∙OS distance is 2.19 Å and the (S)O∙∙∙HN angle is 150°. The intermolecular C*H∙∙∙OS distance is 2.57 Å and the (S)O∙∙∙HC* angle is 127°. The hydrogen atom of the NH group is deviated from the C*SN plane by 163°. To simulate the VCD spectrum of the TSA in the solid-state, the monomers and H-bonded dimers and tetramers were considered at the B3LYP/def2TZVP/PCM level. In the spectra simulations two positions of the thiophene ring were considered and the solid-state population factors were taken into account. The simulated IR and VCD spectra of dimers and tetramers are very similar to each other and they are in good agreement with the experimental ones (Figs. 3a and 3b). Notice, that the calculated spectra of tetramers build from the of A and B conformer found in crystals, yield similar IR (Fig. 3a) but significantly different VCD spectra (Fig. 3b). Therefore, use of the solid-state population factors has been important. Based on the calculated VCD spectra of A and B tetramers (Figs. 3c and 3d) it is possible to assign the experimental bands: The most intense bands at ca. 1300 cm-1 and 1100 cm-1 have the (-,+) pattern and can be assigned to the νas(SO2) and νs(SO2) modes coupled with the ν(CN) mode, respectively. In the 1550-1450 cm-1 range, the β(CH3) vibrations occur. In the 1450-1400 cm-1 range there are β(C*H) bending modes coupled with the β(NH) ones. Also the band of negative intensity at ca. 1330 cm-1 can be assigned to the coupled β(C*H) and β(NH) vibrations. Finally, the positive band at ca. 1025 cm-1 is the ν(CN) bond stretching coupled with the ν(CS) one.

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(a)

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(b)

(c) (d) Figure 3. Comparison of the experimental and calculated IR (a) and VCD (b) spectra of (R)TSA. The B3LYP/def2TZVP/PCM spectra of (R)-TSA tetramers build from A (c) and B (d) conformers present in the crystal.

3.3. The VCD spectra in CDCl3 3.2.1. PCM calculations 3.2.1.1 TSA conformation Seven TSA conformers are found to be stable at the B3LYP/def2TZVP level for which the chloroform environment was simulated by the PCM method (Fig. 4, Table 1). The conformers fall into two groups differing by configuration at the pyramidal N-atom which generates the additional stereogenic center (Fig. 4). In each group, the conformers differ by rotation of the thiophene ring (χ1 torsion angle). Interconversion of the conformers within each group is shown in Fig. 5. The (S,RN) conformers are predicted to predominate over the (S,SN) ones. The conformer population varies depend on whether the total energies, Gibbs free energies in 300 K, or presence of thermal RT factor is taken into account (Table 1, Fig. 5). In consequence, the simulated spectra also vary significantly - see next sections.


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(S,RN)

1 (38°)

2 (88°)

3 (170°)

4 (294°)

(S,SN)

5 (84°)

6 (189°)

7 (282°)

Figure 4. The (S)-TSA conformers obtained at the B3LYP/def2TZVP/PCM(CHCl3) level. Conformers 1, 2, 3 and 4 exhibit R-, whereas conformers 5, 6 and 7 exhibit S-configuration of the pyramidal N-atom. The N-C*-C-S dihedral χ1 angle defining rotation of the thiophene ring is given in parentheses. The most populated conformer A observed in the crystal can be identified with the calculated conformer 4 for which the χ1 is equal to ca. 295° (Fig. 5a). The less populated in crystal conformer B has no a direct analog in solvent. The χ1 angle of ca. 140° in conformer B is between the χ1 values for conformers 3 and 2. Notice that the crystallographically detected conformers exhibit only R configuration of the pyramidal N-atom (Fig. 2). Table 1. The TSA conformers energies (ΔE, ΔG; kcal/mol) and population factors (%) calculated at the B3LYP/def2TZVP level and PCM and hybrid models of solvation. The values are referred to the most stable conformer.

1 2 3 4 5 6 7 Σ(S,RN) Σ(S,SN)

ΔE E, % ΔG G, % B3LYP/def2TZVP/PCM 0.18 16.57 1.23 6.30 1 0.18 16.73 0.48 22.40 2 0.43 10.89 1.04 8.66 3 0.00 22.57 0.00 50.04 4 0.54 9.12 1.54 3.71 5 0.53 9.20 1.62 3.24 6 0.24 14.93 1.29 5.64 7 66.76 87.40 Σ(S,RN) 33.25 12,59 Σ(S,SN)

ΔE E, % ΔG G, % B3LYP/def2TZVP/hybrid 0.30 14.59 1.43 3.19 0.17 18.04 0.61 12.81 0.50 10.39 1.78 1.77 0.00 24.02 0.44 17.04 0.56 9.35 0.93 7.48 0.67 7.74 0.00 35.83 0.25 15.87 0.29 21.88 67.04 34.81 32.96 65.19

In the conformers with SN configuration at the N atom, the χ1 torsion angles are very close to those with the RN configuration (Fig. 5a and 5b). However, the energy of each of the SN conformers is higher than the corresponding RN one. It is important that transition from one type of conformers to the other can be realized not by a simple inversion at the N atom but 9 ACS Paragon Plus Environment


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during the rotation of the χ3 torsion angle (Scheme 1) i.e., the angle rotating the SO2(tBu) group. The barrier between the most stable conformers of each type, 4 and 7, is estimated to 6.11 kcal/mol=2134 cm-1 (QST3 method, B3LYP/def2TZVP/PCM level, Fig. S14). Such a barrier is high enough to conserve the identity of the two types of conformers because the Ninversion mode is equal to ca. 450 cm-1. In contrast to the medium height barrier for the (S,RN) conformers conversion into the (S,SN) ones (2134 cm-1), all barriers connected with the thiophene ring rotation, are lower than 210 cm-1 i.e. lower than the energy of thermal motions at 300 K (Fig. 5). Thus, all the (S,RN) and (S,SN) conformers but 4 and 7 are likely to be metastable states (Fig. 5). Notice, that presence of two slightly different conformers in crystal is probably a result of only one barrier that in room temperature of crystallization efficiently separates the conformers.

(a)

(b)

Figure 5. The B3LYP/def2TZVP/PCM energy profiles and barriers for the thiophene ring rotation (χ1) in the (S,RN) (a) and (S,SN) (b) types of TSA conformers. 3.2.1.2 VCD spectra The calculated IR (Fig. 6a) and VCD spectra of the conformers depend not only on configuration of the stereogenic N-atom but also on rotation of the thiophene ring (Fig. 6b and 6c, respectively). The VCD bands above 1400 cm-1 and the band at ca. 1130 cm-1 of positive intensity are common for all (S,RN) conformers. On the other hand, the band at ca. 1130 cm-1 is also common for the (S,SN) conformers, yet, it has a negative intensity (Fig. 6b). Thus, the band at ca. 1130 cm-1, associated with the νs(SO2) symmetric stretching, distinguishes conformers with different configuration at the N-atom (Fig. 6b).


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(a)

(b)

(c)

Figure 6. The calculated IR (a) and VCD (b) spectra of the (S,RN)- and (S,SN)-TSA conformers. (c) Comparison of the IR and VCD spectra of conformers with similar thiophene rotation but different configurations at the N atom. The B3LYP/def2TZVP/PCM level is applied. As the barriers between the conformers are small and they can be easily overcome due to thermal collisions, simulation of the VCD spectra in solution can be performed in several ways (Fig. 7): i. the All-M (All Minima) approach: all conformers from 1 to 7 are used to simulate the spectra based on their ΔE or ΔG derived population factors (Table 1). The All-M approach is commonly used in simulations of vibrational spectra assuming that the barriers between conformers are high enough to separate individual forms in a given temperature. ii. the TOTAL approach: all structures which exhibit positive frequencies on PESs scan (Fig. 5) probed by 10° step are taken (without population factors) for (S,RN) and (S,SN) spectra simulations. The physical sense of such an approach is based on the remark that in temperature in which large amplitude motions occur all possible conformers (with all real frequencies) can absorb or scatter the light.88 We found 22 and 15 out of 36 such structures for (S,RN) and (S,SN) types, respectively. Then, the spectra of the (S,RN) and (S,SN) types are weighted with the ΔE and ΔG factors equal to 60/40 and 90/10, respectively. iii. the EQUAL approach: all conformers from 1 to 7 factors are used to simulate the spectra without any population factors. This approach is a compromise between the approach considering all possible forms which are populated in a large amplitude motion and possibility for an effective performing the calculations at desired level of theory. In the same time it follows the remark that use of population factors in the all minima approach is not rational because in a very shallow well all forms are equipopulated. Evaluation of similarity between the experimental and computational spectra was performed using CompareVOA program.89,90 The spectra were divided into two ranges, 16001350 and 1350-1000 cm-1, because different band anharmonicities occur in these two regions (Fig. 7 and Table S6). The first range is well or fair reproduced in all three approximations. For the PCM model of solvent, the 1350-1000 cm-1 range is similarly reproduced by most of the approaches based on ΔE populations (Table S6, Fig. 7a). However, it seems that ΔG populations overestimate the role of the (S,RN) conformers which is probably connected, inter alia, to 11 ACS Paragon Plus Environment


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inaccuracies of the thermal contributions to population factors produced by the harmonic approximation (Fig. 7b). Notice that such very population factors are commonly used for simulations of spectra of flexible molecules. So, our calculations suggest that maybe it would be worth to check if the weights based on ΔEs could provide a better agreement between experimental and theoretical spectra. Finally remark that none of the approaches correctly predicts the doublet of positive bands at ca. 1130 cm-1.

(a)

(b)

Figure 7. Comparison of VCD spectra of (S)-TSA measured in CDCl3 with simulated using three different approaches: All-M, TOTAL and EQUAL (see text). The spectra were calculated at the B3LYP/def2TZVP/PCM level and weighted according to ΔE (a) and ΔG (b) population factors, except for EQUAL approach for which no factors were applied. 3.2.1.3 ROA spectra As before, the calculated Raman (Fig. 8a) and ROA spectra depend on both the configuration at the stereogenic N-atom and rotation of the thiophene ring (Fig. 8b and 8c,respectively). In contrast to VCD, there is neither a characteristic ROA band specific to (S,RN) nor to (S,SN) conformers.

(a)

(b)

(c)

Figure 8. The calculated Raman (a) and ROA (b) spectra of the (S,RN)- and (S,SN)-TSA conformers. (c) Comparison of the Raman and ROA spectra of conformers with similar thiophene rotation but different configurations at the N atom. The B3LYP/def2TZVP/PCM level is applied. 12 ACS Paragon Plus Environment

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Comparison of the three approximations of the experimental ROA spectrum shows that all approaches satisfactorily fit the measured spectra by using the ΔE (Fig. 9a) or ΔG (Fig. 9b) population factors. The only exception maybe worth noticing seems to be the small band at 1250 cm-1 in the TOTAL approach.

(a)

(b)

Figure 9. Comparison of ROA spectra of (S)-TSA measured in CHCl3 with simulated using three different approaches: All-M, TOTAL and EQUAL (see text). The spectra were calculated at the B3LYP/def2TZVP/PCM level and weighted according to ΔE (a) or ΔG (b) population factors except for EQUAL approach for which no factors were applied. 3.2.2 Hybrid model of solvation Interpretation of the chiroptical measurements requires influence of solvent on spectra to be taken into account. For hydrogen bonded systems, the implicit PCM method is usually insufficient. On the other hand, use of the hybrid model, in which few solvent molecules are placed around the solute is often a good solution to this problem. Moreover, often it is enough to saturate the most obvious centers of intermolecular interactions with a few solvent molecules.20 To improve simulation of the VCD and ROA spectra obtained with the sole PCM model we applied the hybrid model with different numbers of the solvent molecules interacting with TSA. The CHCl3 solvent forms rather weak hydrogen bonds. Indeed, after dissolving (R)-TSA, the ν(CD) stretching vibrations band of deuterated chloroform remains almost unshifted (2255 cm-1), yet, its intensity slightly increases (Fig. S15). However, an explicit presence of the chloroform molecules around TSA changes the conformer populations and affects the simulated chiroptical spectra. In this study, the TSA complexes with CHCl3, from (1:1) to (1:5), were considered for all seven TSA conformers. Because the interactions of chloroform with SO2 group are the most important, here, we show the spectra simulated only for such systems while the other ones can be find in the SI materials (Figs. S16-S20, Table S7). The energy profiles analogous to those presented in Fig. 5 were also calculated for the TSA solvated by two CHCl3 molecules (Fig. 10). The energy profile for the (S,RN) conformers was obtained with the def2TZVP basis set (Fig. 10a). However, because of unexpected convergence problems for the (S,SN) profile with the def2TZVP basis set, the curve was obtained with the TZVP basis (Fig. 10b). The energy profiles for the (S,RN) conformers 13 ACS Paragon Plus Environment


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obtained with the def2TZVP and TZVP basis sets are concordant except of some secondary details (Fig. S21). Observe that changing the model from PCM to hybrid does not qualitatively change the character of the total energy (ΔE) profiles (Fig. 5 vs Fig. 10). However, for hybrid models, the conformer populations calculated based on ΔG lead to the conclusion that the (S,SN) conformers are more stable (Table 1).

(a)

(b)

Figure 10. The energy profiles and barriers for the thiophene ring rotation (χ1) in the (S,RN) (a) and (S,SN) (b) types of TSA conformers. The B3LYP/def2TZVP/hybrid level was applied for the (S,RN) conformers while B3LYP/TZVP/hybrid for the (S,SN) ones. Comparison of the VCD and ROA spectra based on the three approaches are gathered in Figs. 11a and 11b, respectively. As for PCM, for the hybrid model of solvent, evaluation of similarity between the experimental and computational VCD spectra89,90 shows that the spectra in the 1600-1350 cm-1 range are well or fair reproduced in all three approximations (Fig. 11a and Table S6). The range below 1350 cm-1 is best reproduced in the EQUAL and All-M approach based on ΔE populations. This time it seems that the ΔG populations overestimate the (S,SN) conformers role. Summing up, we think that the EQUAL approach is successful irrespectively the solvent model applied because it is not biased by population factors. In consequence, this suggests that in dissolved state in 300 K TSA is present in a very shallow potential well and all its conformers can be present.

(a)

(b)

Figure 11. Comparison of VCD (a) ROA (b) spectra of (S)-TSA measured in chloroform with simulated ones calculated at the B3LYP/def2TZVP/hybrid level and using All-M and EQUAL approaches (see text). 14 ACS Paragon Plus Environment

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3.2.3 VCD spectra of TSA in solid and solution states The experimental IR and VCD spectra of (R)- and (S)-TSA enantiomers in solid state and in chloroform solution are juxtaposed in Fig. 12a and 12b, respectively. The IR spectra of TSA registered in the two states display differences that can be expected. In a doublet of bands at ca. 1300 cm-1, the IR intensity of the more red-shifted band is higher in pellet while the more blue-shifted is higher in solution. Because the band originate from asymmetric stretching vibrations of the SO2 group engaged in H-bonds in solid states while in weak H-bonds with the solvent molecules in chloroform, the differences in intensities just illustrate different hydrogen bonding pattern in the two media. Similar holds true for relatively weak IR bands at 1250 and 1200 cm-1. The bands can be assigned to C-C* stretching modes, in which the C*H…O=S angle is significantly different in the two media. Thus again, the IR pattern reveals differences in H-bonding of weak interactions of the C*-H moiety. The other differences in position and intensities of IR bands are quite common for a compound present in two phases.

(a)

(b)

Figure 12. Comparison of the IR and VCD spectra of (R)-TSA (a) and (S)-TSA (b) in CDCl3 and in KBr pellet. Astonishingly, the VCD spectra of TSA look like they would be registered for two enantiomers rather than for two physical states of the same enantiomer (Fig. 12). The first thought is that this is a common mistake and that the (S)- and (R)-TSA samples were simply interchanged. However, the VCD spectra measured for (S)-TSA solid and solvated states are fairly well reproduced by calculations presented in Figs. 3 and 7. Notice also that the (+,-,+,-) pattern of bands in the 1600-1350 cm-1 region of the two VCD spectra is concordant. One could suppose that, as for the IR spectra, the differences in the VCD spectra originate predominantly from differences in the H-bond interactions in the solid and solution states. However, the calculated spectrum of the sole conformer 4 located in solution, which structure is the most similar to the A crystal and the simulated solid state VCD spectrum based on the A structure tetramers, agree well (Fig. S22). In contrast, consideration of all TSA conformers present in chloroform 15 ACS Paragon Plus Environment


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solution, with both configurations on the trigonal N-atom and all thiophene ring rotations, yields a global VCD contour which looks almost like spectrum of the opposite enantiomer. 4.

Conclusions

Two enantiomers of 2-methyl-N-(1-thien-2-ylethyl)propane-2-sulfonamide (TSA), a new thiophene derivative, were synthesized and their VCD, ROA, IR, and Raman spectra were measured. To interpret the experimental data, different computational methods were tested. The B3LYP functional combined with the def2TZVP basis set and both PCM and hybrid models of solvation were found to satisfactorily reproduce the all studied experimental spectra. In the X-ray structure of (S)-TSA, a disorder connected to presence of two TSA conformers is observed. They are present in the 3:2 ratio and differ by a slight rotation of the thiophene ring. (S)-TSA crystallizes in the monoclinic P21 space group, with two molecules in the unit cell forming nets of NH∙∙∙OS and C*H∙∙∙OS hydrogen bonded. The IR and VCD spectra of the two TSA enantiomers were measured in KBr pellets. They were well reproduced by calculations performed at the B3LYP/def2TZVP/PCM level using H-bonded TSA dimers and tetramers, with two different positions of the thiophene ring taken into account. The VCD spectra measured in CDCl3 are completely different from those registered in KBr. This is connected with quite a conformational freedom of TSA in chloroform. Seven TSA conformers were predicted to be stable at the B3LYP/def2TZVP/PCM level. They fall into two groups of different configuration at the pyramidal N-atom which generates the additional stereogenic center. It is important that transition from one group of conformers to the other can be realized not by a simple inversion at the N atom but by rotation of the SO2(tBu) group. In each group of conformers, the structures differ by the rotation of the thiophene ring (χ1 angle). However, the set of the χ1 angles are quite similar in both groups. Moreover, the barriers between conformers in each group are lower than the energy of thermal motions at 300 K equal to ca. 210 cm-1. Thus, all conformers, but the most stable in each group, are likely to be metastable states. The calculated IR, VCD, Raman, and ROA spectra of the conformers depend not only on the stereogenic N-atom but also on thiophene ring rotation. Moreover, because of low barriers between the conformers a correct establishing the conformer equilibria is not obvious. This, makes challenging the simulation of the VCD and ROA spectra of the studied chiral thiophene sulfonamide in solution. Four approaches were tested to reproduce the chiroptical spectra in solution using PCM and hybrid solvation models. In consequence, we found that the model in which all conformers contribute to the spectra with equal populations seems to best reproduce the experimental data. Such a result suggests that in the dissolved state in 300 K, TSA occurs in a very shallow potential well and all its conformers can be present. Acknowledgements Critical and very constructive comments of anonymous referees to this paper, which allowed us to much better present the problem and to improve clarity of the text, are very gratefully acknowledged. This work was supported by the National Science Centre in Poland Grant No. 2013/09/B/ST5/03664. Świerk Computing Centre (CIS) is acknowledged for generous allotment of the computing time. Supplementary Information section The detailed energetics, structures, the IR/VCD and Raman/ROA spectra calculated at different theory levels, and Cartesian coordinates of the studied structures are available free of charge via the Internet at http://pubs.acs.org.


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Chiral Thiophene SulfonamideâA Challenge for VOA Calculations

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