pH Dependent Chiroptical Properties of (1R,2R)- and (1S,2S)-trans

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pH Dependent Chiroptical Properties of (1R,2R)- and (1S,2S)-transCyclohexane Diesters and Diamides from VCD, ECD, and CPL Spectroscopy Giuseppe Mazzeo, Sergio Abbate, Giovanna Longhi, Ettore Castiglioni, Stefan E Boiadjiev, and David A. Lightner J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.5b11223 • Publication Date (Web): 06 Feb 2016 Downloaded from http://pubs.acs.org on February 11, 2016

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The Journal of Physical Chemistry

pH Dependent Chiroptical Properties of (1R,2R)- and (1S,2S)trans-Cyclohexane Diesters and Diamides from VCD, ECD, and CPL Spectroscopy

Giuseppe Mazzeo1, Sergio Abbate1,2, Giovanna Longhi1,2, Ettore Castiglioni1,3, Stefan E. Boiadjiev4, David A. Lightner5 1

Dipartimento di Medicina Molecolare e Traslazionale, Università di Brescia, Viale Europa 11,

25123 Brescia, Italy 2

CNISM Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia,Via della

Vasca Navale, 84, 00146 Roma, Italy 3

4

JASCO Europe, via Cadorna 1, 23894 Cremella (LC), Italy

Department of Chemistry and Biochemistry, Medical University-Pleven, 1 St. Kl. Ohridski Str.,

5800 Pleven, Bulgaria 5

Department of Chemistry, University of Nevada, Reno, Nevada 89557-0020

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ABSTRACT Diesters of (1R,2R)- and (1S,2S)-cyclohexanediols and diamides of (1R,2R)- and (1S,2S)diaminocyclohexane with p-hydroxycinnamic acid have been known for some time to exhibit intense bisignate electronic circular dichroism (ECD) spectra in CH3OH. It was also known that added NaOH causes a bathochromic shift of ∼50 nm in CH3OH, and an even higher one in DMSO. We have measured vibrational circular dichroism (VCD) spectra both for neutral compounds and in the presence of NaOH and other bases. The VCD and IR spectra in the mid IR region for CD3OD and DMSO-d6 solution exhibit high sensitivity to the charged state for the diesters. They possess two strong bisignate features in the presence of bases in the mid IR, which are interpreted in terms of vibrational exciton couplets, while this phenomenon is less evident in diamides. VCD allied to Density Functional Theory (DFT) calculations allows one to shed some light on the spectral differences of diesters and diamides by studying their conformational properties. Optical rotatory dispersion (ORD) curves confirm the ECD data. Circularly polarized luminescence (CPL) data have been also acquired, which are rather intense in basified solution: the CPL spectra are monosignate and are as intense in the diester and in the diamide case.

KEYWORDS Vibrational Circular Dichroism (VCD); Electronic Circular Dichroism (ECD); Optical Rotatory Dispersion (ORD); Circularly Polarized Luminescence (CPL); Density Functional Theory (DFT) Calculations; pH; Vibrational Excitons


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INTRODUCTION The presence of exciton transitions in the electronic circular dichroism (ECD) spectra has been demonstrated to be quite useful for interpreting molecular stereochemistry with numerous chromophores, such as benzoate, naphtoate, anthroate, etc.1-4 Earlier ECD studies focused on pH dependent exciton Cotton effects associated with p-hydroxycinnamate5 and cyanine dye6 chromophores that were pH-sensitive in high pH and low pH range, respectively. Diesters of (1S,2S)- and

(1R,2R)-cyclohexanediols (1 and 3) and diamides of

(1S,2S)- and (1R,2R)-

diaminocyclohexane (2 and 4) with p-hydroxycinnamic acid were synthesized to the scope (Scheme 1), and it was found that in their ECD spectra addition of NaOH to methanol or DMSO solutions promoted bathochromic shifts up to 90 nm with 20-40% intensity (∆ε) enhancements.5 The exciton chirality method was introduced and discussed in the field of vibrational circular dichroism (VCD) spectroscopy7-9 in the eighties, see for example refs.10-12: at that time the vibrational exciton method had been called the coupled oscillator or coupled dipoles method. More recently, consideration of the C=O stretching vibration13-18 led to rationalization or reconsideration of VCD data from related examples19,20 and also to reconduct them to the corresponding handy rule given in ECD;1,2,13-14 however different coupled normal modes, for examples antisymmetric CH2stretchings12, 21-23, had also been called previously “vibrational excitons”. Stimulated by all this, we undertook a VCD study of molecules 1 and 2, and 3 and 4, to learn (i) whether and how pH dependence might be observable by VCD, and (ii) if exciton features are manifested in VCD spectra. Additional information coming from VCD can help distinguish the diamide from the diester case. In our studies, two major chiroptical properties of 1-4 were found to be pH dependent: optical rotatory dispersion (ORD) and circularly polarized luminescence (CPL). While the former exhibits information quite similar to ECD, the latter (made available in our lab and used on various systems24-26) exhibits peculiar differences from ECD, VCD and in diesters and diamides. SCHEME 1 about here 3 ACS Paragon Plus Environment


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EXPERIMENTAL The Synthesis and NMR Characterization of the four compounds was carried out in ref. 5 and ECD spectra were also measured. VCD and IR (Vibrational Absorption = VA) Spectra. All spectra were taken with a Jasco FVS6000 FTIR VCD spectrometer equipped with a wire-grid linear polarizer, a ZnSe Photo Elastic Modulator (PEM) to produce 50 kHz modulated circularly polarized radiation over a rather wide range (from 3000 to 800 cm-1) and a liquid N2-cooled MCT detector. The spectra were taken in the range 0.020-0.035 M CD3OD or DMSO-d6 solutions, in 200 µm BaF2 cells. 6000 scans were taken for each spectra and subtraction of VA and VCD spectra of the solvent were performed. For basified solutions of 1-4, following the procedure of ref. 5, the same stock solution in the range 0.020-0.035 M of NaOH in CD3OD was first prepared then used to dissolve the compounds under study. In order to compare the spectroscopic behavior of 1 and 3 in the (i) neutral vs. (ii) deprotonated states in DMSO-d6, we added a small volume of the stock CD3OD/NaOH solution to give a ratio 1:50 (vol./vol.) of base to DMSO for (ii). Similar studies with 2 and 4 could not be conducted due to their insolubility in DMSO. ECD and UV Spectra. The spectra were taken with a Jasco 815SE spectrometer and 2 mm quartz cells were employed; with ca. 2x10-4 M solutions in each undeuterated solvent of interest. The procedure for adding NaOH was the same as described above in the VCD experimental part. ORD Curves. OR measurements were carried out with Jasco P-2000 digital polarimeter at four different wavelengths (589, 546, 435, 405 nm), when possible. They were taken with solutions 0.5g per 100 ml; a 100 mm, 1 ml volume optical glass cell was employed at room temperature. Reduction to specific rotation and the three (or four) OR points were connected by straight lines in the graphs presented in SI.


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Fluorescence and CPL spectra. The CPL and Fluorescence spectra were taken on a home-built apparatus described in ref. 24, with excitation radiation brought to the sample through an optical fiber from a Jasco FP8200 fluorimeter; the latter served also to check fluorescence and excitation spectra. The same solution employed in ECD measurements were used here in 10 mm x 2 mm fluorescence quartz cells. 5 scans were accumulated for each spectrum, with the conditions: incident bandwidth 20 nm, emission bandpass approximately 10 nm, scan speed 2.5 nm/sec. The gain of the CPL instrument was adjusted to have similar fluorescence (I) scales in different cases; the relative scale between CPL (∆I) and fluorescence (I) is determined.24 Density Functional Theory (DFT) Calculations. Prior to DFT calculations, Molecular Mechanics (MM) evaluation of minimum energy conformers was performed. The few conformers thus found (within 5 Kcal/mol) were fed into the DFT module of Gaussian09;27 several functionals and basis sets were tested (vide infra), two choices being extensively used: first B3LYP/TZVP and finally PBE0/6-31+G*.28 In addition to providing better definition of the conformers found at the MM level, including reliable statistical weights, calculation of Dipole and Rotational Strengths through the field-response approach29 was possible. Computations were run for molecules either in vacuo or solvated, as treated by the IEFPCM approach resident in the Gaussian code.30 From the calculated frequencies, Dipole and Rotational Strengths, VA and VCD spectra were generated by assigning 10 cm-1 bandwidth Lorentzian bandshape to each vibrational transition using a program resident on the Jasco VCD Software package. A scaling factor of 0.965 for PBE0 functional was applied to all bands. Time Dependent DFT calculations were also performed to predict ECD spectra,31 the results of which are presented in the Supplementary Information part of this manuscript (the CAM-B3LYP functional was employed within the PCM approximation). 30 transitions were considered. To plot the resulting spectra we assumed a 0.2 eV bandwidth for Gaussian type bands32.

RESULTS AND DISCUSSION 5 ACS Paragon Plus Environment


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a) Analysis of VCD spectra In Figures 1 and 2 the superimposed experimental VCD spectra of the enantiomers (1S,2S)and

(1R,2R)-cyclohexane-diester derivatives (1 and 3) and of the enantiomers

(1S,2S)- and

(1R,2R)-cyclohexane-diamide derivatives (2 and 4) respectively are reported, both for the neutral (left) and charged state (right). In the figures we report also IR (VA) spectra in the same region. Figure 1 about here Figure 2 about here For purposes of comparison, the spectra are limited to the 1700-1250 cm-1 region, which is transparent to both two deuterated solvents employed, CD3OD and DMSO-d6, even though we have VCD data for 2 and 4 just in CD3OD solution, since insufficient solubility in DMSO was experienced for them; in CDCl3, good enantiomericity is also observed for the neutral diesters-data not reported herein. In the neutral state VCD signals are very weak with g factors of the order of 2-3 x 10-5; yet it was possible to have good results due to good purity of the samples and to the fact that the compounds possess C2-symmetry and consequently this favors the presence of A/B-species corresponding to (+,-) couplets. In the charged species case, the two IR bands, at ca. 1570 (1580 for CD3OD solution) cm-1 and 1504 cm-1 for compounds 1 and 3 and the band at 1500 cm-1 for 2 and 4 double their intensity (the rest of the spectrum being essentially unchanged) with respect to the corresponding bands in the neutral state at 1600 and 1512 cm-1 for 1 and 3 and at 1514 cm-1 for 2 and 4. In correspondence with the intensified IR bands, one notices in the case of 1 and 3 two VCD couplets with a g factor increasing by an order of magnitude to 2-3 x 10-4; the same happens, to a lesser extent, for the 1500 cm-1 band of 2 and 4. In all cases the couplets appear to exhibit positive exciton chirality for the (1S,2S)-case and negative chirality for the (1R,2R)-case: indeed for (1S,2S)molecules at lower frequencies one observes the positive component and at higher frequencies the negative component (vice versa for (1R,2R)-molecules). 6 ACS Paragon Plus Environment

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The DFT calculations (carried out for the (1R,2R)-case, molecules 3 and 4) allow to gain some understanding of what is happening both in the neutral and in the charged species. There are three most stable almost equi-populated conformers for the diesters (top structures of Figure 3, (1R,2R)enantiomer) and four equi-populated conformers for the diamides (top structures of Figure 4, (1R,2R)-enantiomer). The conformers correspond to the possible positions of the phenolic OH bond. In the diester case the two arms lie in parallel planes so they are symmetric, while in the diamide case the two planes are not parallel. The two moieties on the cyclohexane (1R,2R) are in equatorial positions and are like two arms in a relative staggered conformation, forming a dihedral angle close to 50°. When the OH is deprotonated, evidently only one conformer remains. Subsequent calculations of spectra was carried for this conformer. Figure 3 about here Figure 4 about here However, to be precise, these are not the only conformers which are predicted by DFT. For 3 indeed we find that some conformers may be present with =CH bonds syn to the adjacent C=O bonds. The latter conformers account for about 20%-30% of the full population, if evaluated in terms of either ∆G or ∆E respectively; we excluded them from ensuing computations, while admitting only the conformers with =CH bonds anti to the nearby C=O bonds (evidenced in the shaded area of Table SI-1 of the Supplementary Material). (Last but not least, we noticed that populations based over ∆E values rather than ∆G are quite similar for all functionals/basis sets.16,33,34) On the contrary, only the anti/anti conformations of 4 have non-negligible population. Here an intramolecular NH...O=C hydrogen bond predicted between the two molecular arms (chromophore units) considerably stabilizes this conformation, making the syn/syn or syn/anti quite unlikely. In the left part of Figure 5 (top) we compare the experimental and the IEF-PCM calculated IR and VCD spectra of neutral (1R,2R)-diester 3 in CD3OD (lower two curves) and in 7 ACS Paragon Plus Environment


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DMSO-d6 (top two curves). Note that in the simulated (R,R)-3 molecule for the CD3OD solution the OH groups become OD, but not in DMSO-d6). We see that every observed individual feature is matched by the calculated one averaged over the ∆E values, with correct intensity and frequency. One exception is constituted by the weak doublet observed in DMSO-d6 at ca. 1700 cm-1, which is predicted to be oppositely signed. Figure 5 about here

The calculated VCD spectra of the single conformers are compared with the calculated population average and with the experimental spectra in Figure SI-2 of the Supplementary Material. The same comparison is provided there also for the IR spectra. The latter are calculated to possess somewhat higher intensity than observed; in particular this happens for the feature at ca. 1600 cm-1 in CD3OD. In the right part of Figure 5 we compare the experimental and calculated IR and VCD spectra of charged (1R,2R)-diester 3 in CD3OD (lower two curves) and in DMSO-d6 (top two curves). The calculations were conducted in presence of solvent (in implicit form as in the PCM model) and in presence of two explicit Na+ ions, so as to neutralize the simulated system. The prediction from the calculations is pretty good except for the calculated strong, narrow features with alternating signs at ca. 1350 cm-1: they are indeed observed, but with much lower intensity. However the other bands in that part of the VCD spectrum and the two intense couplets at 1600 and 1510 cm-1, which are the most interesting characteristic spectroscopic features for pH sensing, are indeed reproduced with the correct intensity and sign order. Running the calculations without the Na+ counterions (Figure SI-3) does not provide optimal results for the latter features, while not producing the anomalously intense VCD features at 1350 cm-1. We observe that the neutral species simulation provides better calculated IR spectra than in the charged case (Figure SI-3). In the latter case all IR bands are predicted to be twice as intense as observed, with the relative values being acceptable: for this reason in the lower part of Figure 5 we divide the calculated spectra by 3, to 8 ACS Paragon Plus Environment

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allow better comparison between experiment end calculations. In Figure SI-4 we report the calculated IR and VCD spectra of 3 for a set of seven choices for functionals/basis sets. This test indicated that the PBE0/TZVP and PBE0/6-31+G* choices are optimal for predicting VCD data and for this reason we sticked to PBE0/6-31+G*; however none of the employed choices gave lower calculated IR intensities for the charged case. Figure 6 about here

Similar phenomena are noticed in neutral diamides, but for the charged case predictions for IR bands still exceed those from experiment, and for VCD fewer additional problems are met. In Figure 6 we compare the experimental to the IEF-PCM calculated VCD spectra of neutral (left) and charged (right) of (1R,2R)-diamide 4 in CD3OD (the only solvent where we succeeded getting VCD data). We notice that the simulated (R,R)-4 molecule in the neutral case contains four deuterium atoms, one for each OH and one for each NH, while in the charged case simulations we have (R,R)4-d2 molecules. In Figure SI-5, we report the comparison of calculated VCD and IR spectra for the neutral case of all four major equi-populated conformers, in addition to the Boltzmann average one. In the neutral case the comparison is pretty good for VCD and good for the IR in terms of intensities, frequencies and signs. For the charged case (Figure 6, bottom), for which only one conformer is present, we ran two types of simulations in presence of two Na+ counterions with NH or ND in order to simulate possible H/D exchange with the CD3OD solvent. In Figure 6 we report just the deuterated case. In both simulations, the calculated IR and VCD spectra are predicted too intense compared to experiments. (Please also compare in Figure SI-6 the test of all the same functionals on diamides, as we had tried for diesters in Figure SI-4) The negative chirality couplet at ca. 1500 cm-1 corresponding to the most intense IR band is the most relevant feature of the VCD spectrum, and is matched by the 1500 cm-1 feature predicted by calculations.



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We focus now on the most interesting features, namely the two VCD couplets from the ionized diesters at ca. 1510 and 1600 cm-1 and the VCD couplet at ca. 1510 cm-1 from the charged diamides. In the case of the ionized diesters, wherein intensification of the corresponding IR bands is observed, we indeed find three calculated couplets, two almost degenerate at 1510 cm-1 and one at 1600 cm-1. The normal modes associated with the bands are combinations of CH bendings of the phenyl rings and of side chains’ C=C-H bendings. There is also contribution from the terminal CPhO stretching, which, in the ionized state, acquires an increased double bond character, according to the bond length analysis of Table SI-7 (the latter data were derived by DFT calculations). The latter fact provides a partial explanation of the IR and VCD intensification of the 1510 and 1600 cm-1 features. The DFT calculations of bond lengths reported in Table SI-7 further show that conjugation over a longer moiety takes place, involving the terminal CPhO, the phenyl CC bonds, till the side chain C=C bond: the vibrational normal modes of the three relevant couplets are delocalized over this long fragment. (Similar modes are found for the neutral case in correspondence of the 1514 and 1602 cm-1 features, but are not as intense, due to lower delocalization). For this reason we considered in Figure SI-8 a cyclohexanol monoester ionized molecule and found that three vibrational transitions are quite similar to the calculated three ones in correspondence to the two experimental couplets at 1600 and 1510 cm-1 in the diesters. Using the values for dipole strengths D1, D2 and D3 and frequencies ν1, ν2 and ν3 evaluated in the model molecule, and the geometrical parameters calculated by DFT in equations 1-3 of ref. 17, we were able to obtain the values of Table 1 for the diester case, where they compare quite well with the values obtained by full DFT. The equations of ref. 17 are based on electrostatic interaction between the two units carrying large electric dipole transition moments. A more general approach is presented in ref. 18, but we limit ourselves to the simplified model of ref. 17 and we conclude that the vibrational exciton model applies not only to C=O stretchings,13,17,18 but also for other normal modes carrying high electric dipole transition moments. The excellent agreement between model and full DFT calculations is also due to the fact that the symmetric combination of the vibrational modes has higher frequency 10 ACS Paragon Plus Environment

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than the antisymmetric one, as required by the negative chirality.13,17,18 We think that these kinds of vibrational excitons can be useful in monitoring the charge state. Table 1 about here b) Analysis of ECD and ORD spectra Figure 7 about here The usefulness of ECD spectra to monitor the charge state had been pointed out previously by two of us.5 We report again the ECD spectra in Figure 7 for completeness of current presentation. Note that the bathochromic and hyperchromic effects are most important in the diester case in DMSO solution. With such effect on ECD being so large, it may be expected that ORD would also be sensitive to the charged state (and potentially to pH). We had noticed that the reported values of specific rotation at the Sodium D-line were quite large,5 as is typical for exciton-coupled electronic transitions. In Figure SI-9 we report the measured ORD values for neutral and charged diester molecules 1 and 3 and diamide molecules 2 and 4 in methanol and dimethyl sulfoxide. While in the neutral case the ORD behavior of the two molecules is similar in both solvents, in the charged state they differ considerably. The charge effect in DMSO is so big that we were able to measure optical rotations only at the two longest wavelengths, sufficiently removed from where the first Cotton Effect (CE) takes place. Indeed, from the ORD and CD phenomena being related by the KronigKramers (KK) relation,35-37 one expects that the CE associated to the longest wavelength electronic transition determines to a large extent, in sign and magnitude, the behavior of ORD. In fact, since for (S,S) molecules we observe a positive CE at 380 nm for the neutral case and at 500 nm for the ionized (charged) case, we observe positive OR in the neutral and charged cases (the opposite for (R,R) molecules). Even if in the present case the sign and magnitude of OR relate to the longest wavelength CE, in general OR does not carry only information about the longest wavelength CE: 11 ACS Paragon Plus Environment


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from the KK relation, which “incorporates” the Rosenfeld formula,38 measuring ORD brings in more info than just measuring CD. Anyhow, we observe that ORD allows one to monitor the pH dependence of these chiral molecules in addition to ECD and VCD, and may be a more economical alternative thereof. Returning to ECD, we have performed TDDFT calculations of ECD spectra for both (1R,2R)diester 3 and (1R,2R)-diamide 4. The results are given in Figure SI-10 and we may appreciate that the method allows one to correctly predict the bathochromic shift in an almost quantitative way. The hyperchromic effect for 3 is also accounted for, even though not to the extent which is observed. Further understanding of the observed phenomena may come from looking at the major contributions to the electronic transitions from the localized Molecular Orbital (MOs), as described by the Gaussian routine (The MO analysis was carried out for charged molecules: Figure SI-11 for (1R,2R)-diester 3 and Figure SI-12 for (1R,2R)-diamide 4). For 3 the MO description indicates that the two components of the bisignate feature are associated to HOMO → LUMO transition and (HOMO-1) → LUMO transition, from longest to shortest wavelength respectively. Even from the MO perspective, the two electronic transitions can be defined as the two components of an exciton couple. In contrast, for 4 the two transitions associated with the couplet are determined by major contributions from (HOMO-1) → LUMO and HOMO → (LUMO+1), and the final state does not appear to be equally distributed on the two arms of the molecule. Consequently, it does not strictly look like an exciton in molecule 4. We surmise that this is characteristically related to the somewhat different conformation of diamides with respect to diesters, as a consequence of the internal hydrogen bond between the NH in one arm of the molecule and the C=O of the other arm. Finally we checked if similar effects on ECD spectra are present when the same base (NaOH) is added to different solvents like ethylene glycol, or when weaker bases, like Cs2CO3, are appropriately chosen (Figure SI-13). A systematic study of the dependence of chiroptical phenomena (ECD, VCD, ORD) on the kind of solvent and base used is beyond the scopes of this 12 ACS Paragon Plus Environment

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work. We find the preliminary results from studying these variables quite encouraging for further exploration.

c) Analysis of CPL spectra Figure 8 about here

In Figure 8 we report the CPL and fluorescence spectra of ionized (charged) (1S,2S)- and (1R,2R)diesters, molecules 1 and 3 (top two rows), and of ionized (charged) (1S,2S)- and (1R,2R)-diamides, compounds 2 and 4 (lower two rows). (The solution containing the corresponding neutral compounds exhibited so little fluorescence, that CPL could not be observed within the limits of our instrumentation.) CPL spectra show good enantiomeric behavior, even for 1 and 3 in methanol solution where signals are quite weak. The dissymmetry glum = (∆I/I) factors for 1, 3 in DMSO and for 2, 4 in CH3OH and DMSO is ∼10-3. The sign of the single observed CPL band, corresponding to the transition to the ground state from the lowest energy excited state is the same as the longest wavelength CE observed in ECD, and this appears to be a general rule25,26 (even for 1 and 3 in CH3OH this sign rule holds). The most intriguing fact is that CPL for ionized (1S,2S)- and (1R,2R)diamides (2 and 4) in methanol has moderate to strong intensity, whereas CPL for (1S,2S)- and (1R,2R)-diesters (1 and 3) is quite weak. We do not have an explanation for this phenomenon, since the calculated CPL spectra, which were run according to refs. 25 and 26 in the PCM approximation for the methanol solvent, are not so different in intensity for the diester and diamide. However, it is nice to notice that calculations predict the observed right sign (see Figure SI-14 and SI-15 respectively). At this point we think it is worthwhile to list three possibly relevant facts from experiments and DFT calculations: 1) the CPL spectra of ionized 1 or 3 are considerably different in methanol and in DMSO, while the CPL spectra of ionized 2 or 4 are quite similar in the two 13 ACS Paragon Plus Environment


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solvents; 2) the geometries of the excited and ground state for the diamides are not symmetrical, due to internal hydrogen bond and the arms of the molecule not being parallel; symmetry is observed instead for diesters; 3) finally the MOs of the first excited state for the diamides are also characteristically asymmetric, MOs being localized on one arm only. A potentially useful conclusion for this is that only from the charged state does one observe the fluorescence and CPL phenomena, which may become a yes-or-no probe of the charged state. CONCLUSIONS In this work we have studied several chiroptical phenomena associated with the transition from neutral to ionized state. Each phenomenon brings in a characteristic piece of information, which may help us to complete a general picture. ECD was first used5 to monitor the charged state and showed an enhancement of the exciton interaction of two aromatic dissymetrically disposed arms upon ionization of the phenol moieties. DFT calculations nicely account for the effect and show that application of the exciton model first predicated on a correlative basis is theoretically justified in the diester case (1 and 3), whereas in the diamide case (2 and 4) the excitons are perturbed by the relative conformation of the amide-arms. The latter arms in 2 and 4 that are indeed involved in intramolecular hydrogen bonding, whereas in diesters 1 and 3 they are not correlated by this interaction: this has an effect on the MO appearance of 3 vs. 4. VCD in the diester case provides two strong vibrational excitons which are particularly sensitive to the charged state. They are due to normal modes formed by aromatic and side chains HC=C bendings and CPhO stretchings, leading to strongly delocalized motions and producing strong dipole moments over the two arms of the diester (a similar observation has been recently reported in the literature39). In the diamide case a similar but less intense phenomenon is observed.


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CPL is also found to be sensitive to the charged state of these molecules. Indeed for the neutral molecule fluorescence is so weak that CPL could not be observed at present; yet the two phenomena emerge at high pH. The differences found between diamides and diesters in different solvents are not fully interpretable, but different conformational properties and MO structures of the molecular systems between diesters and diamides have been found and documented in the present work. Table 1. (1R,2R)-diester (3): Comparison of frequencies, dipole strengths and rotational strengths calculated by the exciton model of ref. 17 and by full DFT calculations for the three normal modes couples with frequencies between 1500 and 1600 cm-1 (geometrical values from DFT: ϕ=-53°, d=7.4 Å, α1= α2=116°)* (Angles ϕ and α and distance d defined with the four-atom fragment O-C-CO; O are the terminal oxygen atoms and C are the carbon atom in para positions with respect to the Os). For each N.M. first column exciton coupling model, second column complete normal mode analysis as from Gaussian09. ν (cm ) D (10-40 esu2cm2)

N.M. 1 1583.29 4851.4

N.M. 2 1535.68 2475.1

ν+ (cm-1) ν- (cm-1) D+ (10-40 esu2cm2) D- (10-40 esu2cm2) R+ (10-44 esu2cm2) R- (10-44 esu2cm2)

1588.5 1582.7 1578.1 1582.3 6274.1 6332.6 3428.7 3384.5 5824.5 4079.6 -5786.4 -4047.0

1538.3 1533.0 3200.9 1749.3 2877.7 -2867.8

-1

N.M. 3 1525.98 3705.43 1535.4 1535.3 3478.8 1946.6 1104.7 -1030.2

1529.9 1522.0 4792.1 2618.8 4284.7 -4262.5

1525.7 1525.2 4071.4 3302.3 2494.8 -2605.0

*Values for ν and D derived from DFT calculations on monoester of cyclohexanol. The monester

model and the representation of the three relevant normal modes are presented in Figure SI-8.

ACKNOWLEDGEMENTS We thank Prof. K. Kostova and Prof. V. Kurteva, Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, for providing lab space for synthesis of 1 and 3 quantities.



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We thank Jasco Europe for allowing us to take ORD measurements in their facility in Northern Italy. We thank also CINECA-Bologna, Italy for computational facilities and Regione Lombardia for LISA grant “ChirConj: Chirooptical properties of conjugated systems”.

SUPPORTING INFORMATION AVAILABLE: Supporting Information may be found in the online version of this article, it contains several computational tests of performance of functionals and basis sets in predicting IR and VCD spectra; ECD experimental spectra of neutral and charged diesters in a few solvents, ORD experimental curves of neutral and charged diesters and diamides, and finally localized MO analysis of electronic transitions in ECD spectra of charged diesters. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHORS INFORMATION Corresponding Author: [email protected] NOTES: The Authors declare no conflict of interests.


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CAPTION TO SCHEME AND FIGURES Scheme 1 Diesters of (1S,2S)- and (1R,2R)-cyclohexanediols (1 and 3) and diamides of (1R,2R) and (1S,2S)diaminocyclohexane (2 and 4) with p-hydroxycinnamic acid and schematics of charge state change under increase of pH. Figure 1 Vibrational Circular Dichroism (VCD) and IR spectra in the mid-IR region of the diesters of (1S,2S)- and (1R,2R)-cyclohexanediols (1 and 3) in CD3OD and DMSO-d6 in the neutral state (left side) and in CD3OD and DMSO-d6 in the charged state, obtained as indicated in the text (right side). In all panels the two top traces are for CD3OD solutions and the two lower traces for DMSOd6 solutions. Figure 2 Vibrational Circular Dichroism (VCD) and IR spectra in the mid-IR region of the diamides of (1S,2S)- and (1R,2R)- diaminocyclohexanes (2 and 4) in CD3OD in the neutral state (left side) and in the charged state, obtained as indicated in the text (right side). Figure 3 Most populated conformers of the diester of (1R,2R)-cyclohexanediol in the neutral case (top row) and in the charged case (lower row), as predicted by DFT calculations (PBE0/IEFPCM(MeOH)/631+G*). Population factors for the conformers of the neutral molecule in the order left-to-right: 29.8% and 36.7%, 33.5%. (See Table SI-1) For definition of ϕ see text. Figure 4



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Most populated conformers of the diamide of (1R,2R)-diaminocyclohexane in the neutral case (top and middle row) and in the charged case (lower row), as predicted by DFT calculations (PBE0/IEFPCM(MeOH)6-31+G*). Population factors for the conformers of the neutral molecule: 24.5%, 22.0%, 28.3%, and 25.2%. (See Table SI-1) For definition of ϕ see text. Figure 5 Comparison of experimental and calculated average VCD and IR spectra in the mid-IR region of the diester of (1R,2R)-cyclohexanediol (3) in CD3OD and DMSO-d6 in the neutral state (left panels) and in the charged state (right panels). In each panel the top curves refer to data in DMSO and the lower ones to data in methanol. The experimental VCD spectra are obtained as semi-differences of the VCD spectra of Figure 1 for the (1R,2R) and (1S,2S) enantiomer. Computations for the CD3OD solution are in PCM approximation with substitution of the OH group with OD, while simulations for solutions in DMSO-d6 are in PCM approximation in presence of OH. The population factors for the conformers in the neutral case are 29.8%, 36.7%, and 33.5% for the methanol case and 30.0%, 37.1%, and 32.9% for the DMSO case. (PBE0/6-31+G*). IR calculated spectra have been divided by 3 (see text). For all bands assumed FWHM is 10 cm-1. Figure 6 Comparison of experimental and calculated average and single conformer VCD and IR spectra in the mid-IR region of the diamide of (1R,2R)-diaminocyclohexane (4) in CD3OD in the neutral state (left panels) and in the ionized (charged) state (right panels). The experimental VCD spectra are obtained as semi-differences of the VCD spectra of Figure 2 for the (1R,2R) and (1S,2S) enantiomer. The population factors for the four conformers in the neutral case are 24.5%, 22.0%, 28.3% and 25.2%. (PBE0/6-31+G*) Please notice that the computed IR and VCD spectra were divided by 3, to allow comparison with experimental data (see text). For all bands assumed FWHM is 10 cm-1. 18 ACS Paragon Plus Environment

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Figure 7 Experimental ECD spectra of the diesters of (1S,2S)- and (1R,2R)-cyclohexanediols (1 and 3) (top panels) and of the diamides of (1R,2R) and (1S,2S)-diaminocyclohexane (2 and 4) (lower panels) in the neutral case (left panels) and in the charged case (right panels). Figure 8 Experimental CPL and Fluorescence spectra of charged diesters of (1S,2S)- and (1R,2R)cyclohexanediols (1 and 3) (panels in first two top lines) and of charged diamides of (1R,2R) and (1S,2S)-diaminocyclohexane (2 and 4) (panels in the lower two lines) in methanol and DMSO solution. REFERENCES 1) Harada, N.; Nakanishi, K. Circular Dichroism Spectroscopy: Exciton Coupling in Organic Stereochemistry. University Science Books, Mill Valley, CA (USA), 1983 2) Berova, N.; Nakanishi, K. Exciton Chirality Method: Principles and Applications. In: Circular Dichroism: Principles and Applications. Nakanishi K, Berova N, Woody RW, Eds.; Wiley-VCH Publishers: New York; 2000, Chapter 12, p 337-382 3) Kasha, M; Rawls, H.F.; El-Bayoumi, S.A. The Exciton Model in Molecular Spectroscopy, Pure Appl. Chem., 1965, 11, 371-392 4) Harada, N.; Nakanishi, K.; Berova, N. Electronic CD Exciton Chirality Method: Principles and Applications. In “Comprehensive Chiroptical Spectroscopy”, Volume Two, Edited by Berova, N.; Polavarapu, P.L.; Nakanishi, K.; Woody, R.W. 2012, Wiley, Hoboken, NJ, Chapter 4, 115-166 5) Boiadjiev, S.E.; Lightner, D.A. pH-Sensitive Exciton Chirality Chromophore: Solvatochromic Effects on Circular Dichroism Spectra. Tetrahedron Asymmetry, 1996, 7, 2825-2832 19 ACS Paragon Plus Environment


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22) Abbate, S.; Burgi, L.F.; Gangemi, F.; Gangemi. R.; Lebon, F.; Longhi, G.; Pultz, V.M.; Lightner, D.A. Comparative Analysis of IR and Vibrational Circular Dichroism Spectra for a Series of Camphor-Related Molecules. J. Phys. Chem. A 2009, 113, 11390-11405 23) Gangemi, R.; Longhi, G.; Abbate, S.; Giorgio, E.; Rosini, C. Fenchone, Camphor, 2Methylenefenchone and 2-Methylenecamphor: A Vibrational Circular Dichroism Study. J. Phys. Chem. A, 2006, 110, 4958-4968 24) Castiglioni, E.; Abbate, S.; Longhi, G. Revisiting with Updated Hardware an Old Spectroscopic Technique: Circularly Polarized Luminescence. Appl. Spectrosc. 2010, 64, 1416-1419 25) Longhi, G.; Castiglioni, E.; Abbate, S.; Lebon, F.; Lightner, D.A. Experimental and Calculated CPL Spectra and Related Spectroscopic Data of Camphor and Other Simple Chiral Bicyclic Ketones. Chirality 2013, 25, 589-599 26) Abbate, S.; Longhi, G.; Lebon, F.; Castiglioni, E.; Superchi, S.; Pisani, L.; Fontana, F.; Torricelli, F.; Caronna, T.; Villani, et al. Helical Sense-Responsive and Substituent-Sensitive Features in Vibrational and Electronic Circular Dichroism, in Circularly Polarized Luminescence and in Raman Spectra of Some Simple Optically Active Hexahelicenes, J. Phys. Chem. C 2014, 118, 1682-1695 27) Gaussian 09, Revision A.02, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A. et al. Gaussian, Inc., Wallingford CT, 2009 28) Stephens, P.J.; Devlin, F.J.; Cheeseman, J.R. VCD Spectroscopy for Organic Chemists, 2013, CRC Press, Boca Raton, FL, U.S.A. 29) Stephens, P.J. The Theory of Vibrational Circular Dichroism, J. Phys. Chem. 1985, 89, 748-750


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30) Tomasi, J.; Mennucci, B.; Cammi, R. Quantum Mechanical Continuum Solvation Models, Chem. Rev., 2006, 105, 2999-3093 31) Furche, F.; Ahlrichs, R.; Wachsmann, C.; Weber, E.; Sobanski, A.; Vogtle,F.; Grimme, S. Circular Dichroism of Helicenes Investigated by Time-Dependent Density Functional Theory J. Am. Chem. Soc. 2000, 122, 1717-1724 32) Bruhn, A.; Schaumlöffel, T.; Hemberger, Y.; Bringmann, G. SpecDis version 1.62, University of Würzburg, Germany, 2014 33) Scafato, P.; Caprioli, F.; Pisani, L.; Padula, D.; Santoro, F.; Mazzeo, G.; Abbate, S.; Lebon, F.; Longhi, G. Combined Use of Three Forms of Chiroptical Spectroscopies in the Study of the Absolute Configuration and Conformational Properties of 3-Phenylcyclopentanone, 3Phenylcyclohexanone, and 3-Phenylcycloheptanone. Tetrahedron, 2013, 69, 10752-10762 34) Longhi, G.; Abbate, S.; Scafato, P.; Rosini, C. A Vibrational Circular Dichroism Approach to the Determination of the Absolute Configuration of Flexible and Transparent Molecules: Fluorenone Ketals of 1,N-Diols. Phys. Chem. Chem. Phys. 2010, 12, 4703-4712 35) Moscowitz, A. Theoretical Aspects of Optical Activity. Part One: Small Molecules. Adv. Chem. Phys. 1962, Vol. IV, 67-112, Ed. Prigogine, I. Interscience, NY 36) Polavarapu, P.L.; Petrovic, A.G.; Zhang, P.; Kramers-Kronig Transformation of Experimental Electronic Circular Dichroism: Application to the Analysis of Optical Rotatory Dispersion in Dimethyl-L-tartrate. Chirality, 2006, 18, 723-732 37) Giorgio, E.; Viglione, R.G.; Zanasi, R.; Rosini, C. Ab Initio of Optical Rotatory Dispersion (ORD) Curves: A Simple an Reliable Approach to the Assignment of the Molecular Absolute Configuration, J. Am. Chem. Soc., 2004, 126, 12968-12976 38) Rosenfeld, L. Quantenmechanische Theorie der natürlichen optischen Aktivität von Flüssigkeiten und Gasen. Z. Physik 1928, 52, 161-174 23 ACS Paragon Plus Environment


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39) Bruhn, T.; Pescitelli, G.; Jurinovich, S.; Schaumloeffel, A.; Witterau, F.; Ahrens, J.; Broering, M.; Bringmann, G. Axially Chiral BODIPY DYEmers: An Apparent Exception to the Exciton Chirality Rule. Angew. Chemie Intnl. Ed. 2014, 53, 14592-14595


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Scheme1: Diesters of (1S,2S)- and (1R,2R)-cyclohexanediols (1 and 3) and diamides of (1R,2R) and (1S,2S)-diaminocyclohexane (2 and 4) with p-hydroxycinnamic acid and schematics of charge state change under increase of pH. 84x41mm (300 x 300 DPI)

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Vibrational Circular Dichroism (VCD) and IR spectra in the mid-IR region of the diesters of (1S,2S)- and (1R,2R)-cyclohexanediols (1 and 3) in CD3OD and DMSO-d6 in the neutral state (left side) and in CD3OD and DMSO-d6 in the charged state, obtained as indicated in the text (right side). In all panels the two top traces are for CD3OD solutions and the two lower traces for DMSO-d6 solutions. 84x65mm (300 x 300 DPI)


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Figure 2: Vibrational Circular Dichroism (VCD) and IR spectra in the mid-IR region of the diamides of (1S,2S)- and (1R,2R)- diaminocyclohexanes (2 and 4) in CD3OD in the neutral state (left side) and in the charged state, obtained as indicated in the text (right side). 84x63mm (300 x 300 DPI)



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Most populated conformers of the diester of (1R,2R)-cyclohexanediol in the neutral case (top row) and in the charged case (lower row), as predicted by DFT calculations (PBE0/IEFPCM(MeOH)/6-31+G*). Population factors for the conformers of the neutral molecule in the order left-to-right: 29.8% and 36.7%, 33.5%. (See Table SI-1) For definition of ϕ see text. 78x45mm (300 x 300 DPI)


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Most populated conformers of the diamide of (1R,2R)-diaminocyclohexane in the neutral case (top and middle row) and in the charged case (lower row), as predicted by DFT calculations (PBE0/IEFPCM(MeOH)631+G*). Population factors for the conformers of the neutral molecule: 24.5%, 22.0%, 28.3%, and 25.2%. (See Table SI-1) For definition of φ see text. 56x57mm (300 x 300 DPI)



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Comparison of experimental and calculated average VCD and IR spectra in the mid-IR region of the diester of (1R,2R)-cyclohexanediol (3) in CD3OD and DMSO-d6 in the neutral state (left panels) and in the charged state (right panels). In each panel the top curves refer to data in DMSO and the lower ones to data in methanol. The experimental VCD spectra are obtained as semi-differences of the VCD spectra of Figure 1 for the (1R,2R) and (1S,2S) enantiomer. Computations for the CD3OD solution are in PCM approximation with substitution of the OH group with OD, while simulations for solutions in DMSO-d6 are in PCM approximation in presence of OH. The population factors for the conformers in the neutral case are 29.8%, 36.7%, and 33.5% for the methanol case and 30.0%, 37.1%, and 32.9% for the DMSO case. (PBE0/6-31+G*). IR calculated spectra have been divided by 3 (see text). For all bands assumed FWHM is 10 cm-1. 84x64mm (300 x 300 DPI)


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Comparison of experimental and calculated average and single conformer VCD and IR spectra in the mid-IR region of the diamide of (1R,2R)-diaminocyclohexane (4) in CD3OD in the neutral state (left panels) and in the ionized (charged) state (right panels). The experimental VCD spectra are obtained as semi-differences of the VCD spectra of Figure 2 for the (1R,2R) and (1S,2S) enantiomer. The population factors for the four conformers in the neutral case are 24.5%, 22.0%, 28.3% and 25.2%. (PBE0/6-31+G*) Please notice that the computed IR and VCD spectra were divided by 3, to allow comparison with experimental data (see text). For all bands assumed FWHM is 10 cm-1. 84x64mm (300 x 300 DPI)



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Figure 7: Experimental ECD spectra of the diesters of (1S,2S)- and (1R,2R)-cyclohexanediols (1 and 3) (top panels) and of the diamides of (1R,2R) and (1S,2S)-diaminocyclohexane (2 and 4) (lower panels) in the neutral case (left panels) and in the charged case (right panels). 84x96mm (300 x 300 DPI)


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Figure 8: Experimental CPL and Fluorescence spectra of charged diesters of (1S,2S)- and (1R,2R)cyclohexanediols (1 and 3) (panels in first two top lines) and of charged diamides of (1R,2R) and (1S,2S)diaminocyclohexane (2 and 4) (panels in the lower two lines) in methanol and DMSO solution. 84x145mm (300 x 300 DPI)



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TOC or Graphical Abstract 84x73mm (300 x 300 DPI)


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pH Dependent Chiroptical Properties of (1R,2R)- and (1S,2S)-trans

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