# Probing the Nonlinear Chiroptical Activity of Multiturn Aromatic Helices Using Linearly Polarized Light

Rita Borges-Anastácio, Eric Merlet, Frédéric Adamietz, Brice Kauffmann, Yann Ferrand, Céline Olivier, Vincent Rodriguez

► To cite this version:

Rita Borges-Anastácio, Eric Merlet, Frédéric Adamietz, Brice Kauffmann, Yann Ferrand, et al. Prob-
ing the Nonlinear Chiroptical Activity of Multiturn Aromatic Helices Using Linearly Polarized Light.
Angewandte Chemie International Edition, 2025, 64 (29), pp.e202503025. 10.1002/anie.202503025.
hal-05344248

HAL Id: hal-05344248

https://hal.science/hal-05344248v1

Submitted on 3 Nov 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Probing the Nonlinear Chiroptical Activity of Multi-Turn Aromatic Helices Using Linearly Polarized Light

Rita Borges-Anastácio,[ab] Eric Merlet,[b] Frédéric Adamietz,[a] Brice Kauffmann,[c] Yann Ferrand,[b] Céline Olivier*[a] and Vincent Rodriguez*[a]

[a] R. Borges-Anastacio, F. Adamietz, Dr. C. Olivier, Prof. Dr. V. Rodriguez, Institut des Sciences Moléculaires Université de Bordeaux 351 cours de la Libération 33400 Talence E-mail: celine.olivier@u-bordeaux.fr, vincent.rodriguez@u-bordeaux.fr

[b] E. Merlet, Dr. Y. Ferrand CBMN, UMR Univ. Bordeaux, CNRS, Bordeaux INP F-33600 Pessac France

[c] Dr. B. Kauffmann UAR 3033, US1 Univ. Bordeaux, CNRS, Inserm F-33600 Pessac France

Supporting information for this article is given via a link at the end of the document.

**Abstract:** Four quinoline-based oligoamide foldamers of varying lengths, from 6 Å to 28 Å, were synthesized in both of their enantiomeric forms, exhibiting between 1.6 and 6 helical turns. The helically chiral structures were analyzed using hyper-Rayleigh scattering (HRS) in solution to evaluate their chiroptical nonlinear activity in second-harmonic generation, exclusively employing linear polarization of the incident light. To achieve this, we completely overhauled our homemade equipment setup. By applying a nonlinear chiroptical model developed by us, we were able to distinguish between the achiral and chiral contributions to the nonlinear response of the samples. Surprisingly, the effect of helix elongation on the chiral response, as monitored by HRS, exhibited a non-monotonic trend, which contrasts with the behavior observed with classical linear optical techniques. A detailed investigation revealed that the number of helical turns in the foldamers governs the magnitude of the nonlinear optical (NLO) response, exhibiting a periodic evolution rather than a linear increase with length.

## Introduction

Chirality is essential in numerous chemical and biological processes since most natural bioactive substances are chiral. At the molecular level, enantiomers—pairs of isomers that are non-superimposable mirror images of each other—demonstrate significant differences in their effects despite having similar physical and chemical properties. One enantiomer can be safe and effective as a medication, while the other can pose serious toxicity.¹ Therefore, it is imperative to master universal and highly sensitive sensing techniques for the detection and discrimination of chirality. The interactions between polarized light and chiral substances are foundational in achieving this objective, making chirality detection a critical area of focus.²

Electronic circular dichroism (ECD) and optical rotatory dispersion (ORD) are essential chiroptical effects that highlight the intriguing properties of light polarization. ECD refers to the unique differential absorption of left- and right-circularly polarized light by chiral systems. Meanwhile, ORD demonstrates how a chiral medium can rotate the plane of linearly polarized light, revealing the complex behavior of light in these substances.

Understanding these effects is crucial for advancing research in chiral molecules and their applications.³

In a previous study, we unveiled the excellent chiral sensitivity of hyper-Rayleigh scattering (HRS), a powerful second-order nonlinear optical (NLO) process, commonly referred to as second-harmonic light scattering. By concentrating on aromatic foldamers, we demonstrated the potential of HRS as a very efficient complementary chiroptical technique.⁴ This method is especially adept at unraveling the complexity of chiral molecular and supramolecular systems in solution, making it a vital tool for advancing our understanding in this field. By employing this nonlinear chiroptical technique, we successfully demonstrated a hyper-Rayleigh optical activity (HROA) with a remarkable 40% dissymmetry. Notably, this achievement was mainly made possible through the use of circularly polarized light and to a lesser extent linearly polarized light. However, following this pioneering work, very few studies have been reported about the nonlinear chiroptical activity of chiral molecular systems.⁵

Nonetheless, in a recent study, we thoroughly examined the nonlinear light scattering properties of two chiral liquid compounds: carvone and limonene. This investigation was conducted using hyper-Rayleigh scattering and third-harmonic scattering methods.⁶ The study confirmed that incident linear polarization can be used to detect optical activity in NLO processes. Moreover, it led to the development of an NLO chiroptical model capable of distinguishing between the enantiomeric forms of these compounds.

Herein, we present the fascinating photophysical properties of a series of helical quinoline oligoamide foldamers, investigated exclusively with linearly-polarized (LP) light (Figure 1a), a light source that is significantly more accessible for practical use and applications than circular-polarized (CP) light. We aim at broadening the applicability of our innovative model to higher-dimensional molecular systems. Additionally, we provide a compelling explanation for the observed nonlinear chiroptical activity, grounded in our newly developed framework.⁶

8-amino-2-quinoline-carboxylic-based oligoamides are known to fold as canonical helices due to intramolecular interactions (Figure 1b).⁷ A series of quinoline-based oligoamide foldamers have been synthesized to investigate the potential of
linearly polarized light in probing the optical activity of helically-
locked architectures in a nonlinear regime. For this study, four
oligomers with increasing helical turn numbers were prepared,
each containing four to sixteen quinoline monomers equipped
with isobutoxy side chains to provide high solubility in chlorinated
solvents, and designated as **Q4**, **Q8**, **Q12**, and **Q16** (Figure 1c).
These oligomers were synthesized in both enantiomeric forms (as
detailed in the Supporting Information). The eight sequences
were first prepared following a segment doubling strategy,⁸ then
a (1*R*)-(+)- or (1*S*)-(-)-camphanyl moiety was introduced as acyl
chloride on the N-terminus of the helices to fully bias the helicity
of quinoline oligoamides (d.e.>99%) towards either *M* (left) or *P*
(right) handedness, respectively.⁹ All the intermediates and final
compounds were fully characterized by ¹H and ¹³C NMR, and by
HR-MS.

**Results and Discussion**

Structural Studies

Initially, the foldamers were examined in the solid state
before investigating their properties in solutions. To achieve this,
several crystallization attempts were made, resulting in the
successful growth of single crystals suitable for X-ray diffraction
analysis from a racemic mixture of the dodecamer P-Q12 and M-
Q12.¹⁰ Single crystals were obtained by slowly diffusing hexane
into a dichloromethane solution of the dodecamers. The structure

of the oligoamide was solved in the triclinic and centrosymmetric
P-1 space group with left (M) and right (P) helices coexisting in a
1 : 1 ratio in the unit cell (see Supporting Information and Figure
1d).¹¹ The structure confirmed the canonical helical folding of the
oligomer, which spans 2.5 quinoline units per turn with a helical
pitch of 3.5 Å. The Q12 foldamer therefore shows 4.8 turns for a
total length of 17.2 Å.

**Chiroptical Properties**

We first characterized the oligomers using classical linear
optical and chiroptical methods, specifically UV-visible absorption
(Figure S1), optical rotatory dispersion (ORD) and electronic
circular dichroism (ECD). As anticipated, both chiroptical
techniques revealed mirror-image responses for the two
enantiomers of each foldamer (Figure 2). The maximum molar
circular dichroism (Δε) and optical rotation angle ([α]) increase
linearly with the length of the aromatic helices Qn, where n = 4, 8,
12, 16. The P-helices exhibited a characteristic positive Cotton
effect in the wavelength range of 360-420 nm,¹² which followed a
linear increase from 110 cm⁻¹.M⁻¹ for Q4 to 450 cm⁻¹.M⁻¹ for Q16
(Figure 2b). Similarly, the P-helices showed a comparable trend
in ORD, showing positive values with optical rotation angles at
725 nm ([α]~725~¹³ increasing from +1240 to +4800 deg.dm⁻¹.M⁻¹
over the series (Figure 2c, Table S1). Both linear chiroptical
techniques displayed mirror-image negative signals for the M-
helices.

<figure><img src="image_2.png" /><figcaption>**Figure 1.** a) Schematic representation of the LP-HROA experimental setup used to reveal the nonlinear chiroptical properties of quinoline-oligoamide foldamers. b) Chemical structures of quinoline-based oligoamide foldamers with camphanyl chiral inducers at the N-terminus. The hydrogen bonds, electrostatic repulsions, and aromatic stacking that promote the helical folding are highlighted in gray. c) Side views of energy minimized structures (Maestro version 6.5 using MMFFs force field in CHCl₃) of the *P*-helices of *S-camph*-Q4, -Q8, -Q12, and -Q16. The helices are shown in stick representation and the non-polar hydrogens are omitted for clarity. d) X-ray crystal structure (side and top view) of **Q12** crystallized as a racemate in CHCl₃/hexane. The helices are shown in stick representation, the white spheres denote the isobutoxy side chain positions, and the non-polar hydrogens/solvent molecules are omitted for clarity. The blue color denotes the *P*-handedness, whereas the orange color denotes the *M*-handedness.</figcaption></figure>
<figure><img src="image_3.png" /><figcaption>**Figure 2.** a) ECD spectra of the *P-Qn* and *M-Qn* series in CHCl<sub>3</sub> (enantiomers *P* in blue; enantiomers *M* in red-orange-yellow). b) Evolution of the molar circular dichroism (Δε) at λ = 383-388 nm for the *Qn* series (enantiomers *P* in blue; enantiomers *M* in red). c) Evolution of the optical rotation angle [α]<sup>20</sup><sub>725</sub> measured at 725 nm as described in the Supporting Information (same color code).</figcaption></figure>

## NLO Properties

We then focused on the non-linear optical activity of the oligomers. The HRS measurements were conducted on solutions of foldamers in CD<sub>2</sub>Cl<sub>2</sub>, a non-absorbing solvent in the near-infrared (NIR) region of the incident light. To determine the HROA parameters, all nonlinear optical experiments were performed with the two enantiomers of each foldamer, as well as with the racemic mixture that consists of an equimolar blend of the enantiomers. The excitation wavelength was set to off-resonance at 1350 nm to minimize any undesired competing phenomena (i.e. interactions with the laser, self-excitation of the compounds by third-harmonic scattering). As a result, the second-harmonic signal was detected at 675 nm (Figure S2), while the third-harmonic appeared at 450 nm. These wavelengths are sufficiently distant from the range of foldamer absorption (Figure S1) and their fluorescence emission, allowing for accurate extraction of the HRS intensity. The detailed experimental setup and procedure are described in the Supporting Information (section S2.7).

HROA intensities (*I*) and effective hyperpolarizabilities (β<sub>vv</sub>) (defined in Supporting Information, Equations S2 and S5) were evaluated by varying the power of incident light and the concentration of the solutions from C<sub>0</sub> = 10 mM to C<sub>3</sub> = 2.5 mM. The resulting power scans are presented in Figures S3-S6 and the extracted values are reported in Tables 1 and S2. Overall, we observed an increase in the nonlinear response intensity across the series, with values ranging from 3.80 × 10<sup>5</sup> [a.u.]<sup>2</sup> (*M-Q4*) to 28.09 × 10<sup>5</sup> [a.u.]<sup>2</sup> (*P-Q16*). These values are in line with those previously obtained from short quinoline oligoamide foldamers, despite the dispersion (λ<sub>exc</sub>, from 1064 nm to 1350 nm).<sup>4</sup>

Polarization scans were conducted at an initial concentration of 10 mM and constant incident power. The angle of the incident linearly polarized (LP) light was varied stepwise from vertical (V) to horizontal (H), while

detection was maintained at a vertical angle. The results of these polarization scans (see Figures S3-S6) allowed for the determination of the Depolarization Ratio (DR) for each oligomer, as outlined in Equations S4-S5. The calculated values are presented in Table 1. The DR parameter provides insight into the dipolar and octupolar characteristics of the systems, considering only the electric dipole interaction.<sup>14,15</sup> The DR obtained for the foldamer series, ranging from 1.48 (*P-Q12*) to 3.36 (*M-Q16*), showed a consistent and pronounced octupolar behavior<sup>16</sup> that aligns well with the canonical folding of the oligomer chain. It is important to note that this octupolar behavior was observed in the absence of electronically active substituents on the foldamer backbone, as demonstrated in our previous study.<sup>4</sup> Additionally, it is noteworthy that, regardless of the length of the foldamer, the average enantiomeric DR value (i.e., the average <DR> of the *P* and *M* enantiomers, as shown in Table 1) differs from the DR measured for the corresponding racemate. This difference arises from the mixed electric and magnetic dipole interactions that contribute to the chiroptical nonlinear optical (NLO) signatures.

<table><caption>**Table 1.** NLO parameters of the quinoline foldamers obtained from HRS experiments. [a]</caption><thead><tr><th></th><th>I [b]</th><th>&lt;I&gt; [c]</th><th>β<sub>vv</sub> [d]</th><th>&lt;β<sub>vv</sub>&gt; [e]</th><th>DR [f]</th><th>&lt;DR&gt; [g]</th></tr></thead><tbody><tr><td><b>P-Q4</b></td><td>5.03</td><td>4.42</td><td>709</td><td>662</td><td>2.43</td><td>2.06</td></tr><tr><td><b>M-Q4</b></td><td>3.80</td><td></td><td>616</td><td></td><td>1.69</td><td></td></tr><tr><td><b>rac-Q4</b></td><td><b>4.20</b></td><td></td><td><b>648</b></td><td></td><td><b>2.87</b></td><td></td></tr><tr><td><b>P-Q8</b></td><td>7.50</td><td>8.52</td><td>866</td><td>921</td><td>2.07</td><td>2.22</td></tr><tr><td><b>M-Q8</b></td><td>9.53</td><td></td><td>976</td><td></td><td>2.37</td><td></td></tr><tr><td><b>rac-Q8</b></td><td><b>10.30</b></td><td></td><td><b>1015</b></td><td></td><td><b>2.29</b></td><td></td></tr><tr><td><b>P-Q12</b></td><td>12.67</td><td>12.57</td><td>1126</td><td>1121</td><td>1.48</td><td>2.04</td></tr><tr><td><b>M-Q12</b></td><td>12.47</td><td></td><td>1117</td><td></td><td>2.61</td><td></td></tr><tr><td><b>rac-Q12</b></td><td><b>12.74</b></td><td></td><td><b>1129</b></td><td></td><td><b>2.81</b></td><td></td></tr><tr><td><b>P-Q16</b></td><td>28.09</td><td>21.16</td><td>1676</td><td>1434</td><td>2.73</td><td>3.04</td></tr><tr><td><b>M-Q16</b></td><td>14.23</td><td></td><td>1193</td><td></td><td>3.36</td><td></td></tr><tr><td><b>rac-Q16</b></td><td><b>17.26</b></td><td></td><td><b>1314</b></td><td></td><td><b>3.08</b></td><td></td></tr></tbody></table>

[a] Measurements in CD<sub>2</sub>Cl<sub>2</sub> (298 K, C= 20 mM – 2.5 mM); λ<sub>excitation</sub> = 1350 nm; λ<sub>detection</sub> = 675 nm. [b] LP-HROA intensity (× 10<sup>5</sup> [a.u.]<sup>2</sup>) (relative error 6%) with T-convention: 1 atomic unit (a.u.) = 3.621 × 10<sup>-42</sup> m<sup>4</sup> V<sup>-1</sup> = 8.639 × 10<sup>-33</sup> esu. [c] Average enantiomeric intensity (× 10<sup>5</sup> [a.u.]<sup>2</sup>). [d] Effective hyperpolarizability (relative error 6%). [e] Average enantiomeric hyperpolarizability. [f] Depolarization ratio (relative error 5-15%). [g] Average enantiomeric depolarization ratio.

The HRS intensity of the oligomer racemic mixtures (I<sup>rac</sup>) showed a quasi-linear increase with
oligomer length (Table 1), ranging from 4.20 x 10⁵ [a.u.]² for rac-Q4 to 17.3 x 10⁵ [a.u.]² for rac-Q16. To illustrate the relationship between the oligomer structure and their NLO properties, Figure 3 depicts the evolution of *I*^rac^ as a function of turns per helices. As described above, the helical pitch is 3.5 Å, which corresponds to the height of a full turn and requires 2.5 quinoline-based monomers. Thus, Q4 corresponds to 1.6 helical turns, Q8 to 3.2 turns, Q12 to 4.8 turns and Q16 to 6.4 turns. This plot demonstrates a deviation in intensities from a linear increase with length, influenced by the fraction of helical turns.

<figure><img src="image_4.png" /><figcaption>**Figure 3.** Evolution of the effective LP-HRS intensity (square) and DR (circle) of the racemic mixtures with the number of helical turns of the foldamers.</figcaption></figure>

This oscillating behavior is also reflected in the depolarization ratio of the racemate (DR^rac^) (Figure 3), whose values oscillate around the mean value of 2.7. This low value indicates a predominant octupolar contribution over a dipolar one, which is expected for helical structures where the β<sub>xyz</sub> component is significant.[17] However, the observed oscillations suggest that the octupolar contributions from purely electric dipole interactions are sensitive to the fraction of helical turns. To the best of our knowledge, this is the first example where NLO contributions demonstrate such sensitivity to axial symmetry. It is important to note that the two parameters represented in Figure 3 were determined using independent methods, so the oscillating behavior as a function of the number of helical turns cannot be dismissed as an artifact. While Botek et al. predicted the periodicity of the first hyperpolarizability β of helical oligomers at a computational level,¹⁸ this study aims to experimentally confirm these theoretical calculations.

Furthermore, if we closely examine the pure electric dipole interactions (*I*^rac^/DR^rac^), Figure S7 enlightens the detail of dipolar versus octupolar contributions to the intensity of the racemic mixture. It appears that the (minor) dipolar contribution shows a linear increase across the series, similar to the observables determined by linear chiroptical techniques. In contrast the (dominant) octupolar contribution shows

a periodicity with regard to the number of helical turns, which thus seems to be a specificity related to the quadratic NLO parameters.

In line with previous observations,⁴ significant differences were noted in NLO responses for the left and right enantiomers of the foldamers (Table 1). In the following, we further explore the loss of symmetry in the responses between the enantiomers and in comparison, to the racemic mixture. As illustrated in Figure 4, for the Q4 and Q16 compounds, the *P* enantiomer exhibited a higher LP-HROA intensity than the racemic mixture, while the *M* enantiomer displayed a lower intensity. Conversely, in the cases of Q8 and Q12, the intensity of the racemic mixture was found to be slightly higher than that of the individual enantiomers.

To rationalize these observations, we applied the theoretical model we recently developed (section S2.7).⁶ This model enables us to combine the effective experimental LP-HROA intensities, namely, *I*^P^, *I*^M^, and *I*^rac^, to derive the contributions of the achiral (Δ*I*^ach^) and chiral (Δ*I*^ch^) components of the NLO response, such as:

$$ \Delta I^{ach} = (I^{P} - I^{M})/2 $$

$$ \Delta I^{ch} = (I^{P} + I^{M})/2 - I^{rac} $$

Eq. 1

Thereby, the Δ*I*^ach^ terms quantify the variations observed in the intensities of the enantiomeric responses. The LP-HROA parameters for each series of oligomers, based on their size and calculated according to this model, are presented in Table 2. The LP-HROA intensities *I*^ach+ch^ for the two enantiomers of each foldamer can be calculated using Equation 2:

$$ I^{ach+ch} = I^{rac} \pm \Delta I^{ach} + \Delta I^{ch} $$

Eq. 2

The sign of Δ*I*^ach^ and Δ*I*^ch^ for each enantiomer is defined in the Supporting Information (Equation S6). The LP-HROA intensities calculated according to Equation 2 (Table S3) consistently correspond to those extracted from the HRS experiments (Table 1).

<table><caption>**Table 2.** LP-HROA parameters of the Qn foldamers, calculated according to the model in ref 6, using vertical/vertical excitation/detection polarizations (VV).[a]</caption><thead><tr><th></th><th><i>I</i><sup>rac</sup>[a]</th><th>Δ<i>I</i><sup>ach</sup> [a]</th><th>Δ<i>I</i><sup>ch</sup> [a]</th><th>Δ<i>I</i><sup>ch</sup>/Δ<i>I</i><sup>ach</sup></th></tr></thead><tbody><tr><td>Q4<sup>[b]</sup></td><td>4.20 x 10<sup>5</sup></td><td>6.13 x 10<sup>4</sup></td><td>2.07 x 10<sup>4</sup></td><td>0.34</td></tr><tr><td>Q8<sup>[b]</sup></td><td>1.03 x 10<sup>6</sup></td><td>-1.01 x 10<sup>5</sup></td><td>-1.78 x 10<sup>5</sup></td><td>1.76</td></tr><tr><td>Q12<sup>[b]</sup></td><td>1.27 x 10<sup>6</sup></td><td>9.94 x 10<sup>3</sup></td><td>-1.65 x 10<sup>4</sup></td><td>-1.66</td></tr><tr><td>Q16<sup>[b]</sup></td><td>1.73 x 10<sup>6</sup></td><td>6.93 x 10<sup>5</sup></td><td>3.88 x 10<sup>5</sup></td><td>0.56</td></tr></tbody></table>

[a] Intensity in [a.u.]². [b] Generic designation corresponding to Qn foldamers regardless of the helicity.
<figure><img src="image_5.png" /><figcaption>**Figure 4.** a) Effective LP-HROA intensities of the foldamers in vertical/vertical excitation/detection polarizations (VV). b) LP-HROA plot for P-, M- and rac-Q16 according to Eq. 2 and Eq. S6.</figcaption></figure>

The LP-HROA parameters (Table 2) enabled us to distinguish the responses between a specific racemic mixture and its two parent enantiomers, which are summarized in the plots presented in Figures 4b and S8. These diagrams illustrate, for each oligomer, how the responses of the two enantiomers compare to that of the racemic mixture. The achiral HRS activities of the *P* and *M* enantiomers (represented as grey circles) are mirror images relative to the racemate expressed as *I*<sup>ach</sup> = *I*<sup>rac</sup> ± *ΔI*<sup>ach</sup>. Here, the chiral contribution *ΔI*<sup>ch</sup> accounts for the discrepancies observed between the enantiomers and the apparent loss of symmetry in the overall LP-HROA responses (as detailed in Eq. 2). This behavior significantly differs from that of classical linear chiroptical techniques.

Furthermore, we observed that the extent of both the achiral and chiral contributions (Δ*I*<sup>ach</sup> and Δ*I*<sup>ch</sup>) is not proportional to the length of the helix across the oligomer series. Other factors appear to influence the magnitude of the response. Specifically, for oligomers **Q8** and **Q12**, the chiral contribution Δ*I*<sup>ch</sup> was found to be greater than the achiral contribution Δ*I*<sup>ach</sup>, while for **Q4** and **Q16**, the chiral contribution was lower (Table 2). Additionally, the values in Table 2 show that **Q12** is the only oligomer for which the extracted achiral and chiral contributions (Δ*I*<sup>ach</sup> and Δ*I*<sup>ch</sup>) are relatively weak compared to *I*<sup>rac</sup>, and exhibit opposite signs. As a result, these two contributions somehow cancel each other out, leading to a weaker NLO chiral discrimination for **Q12** compared to the other foldamers.

To further clarify the structure-property relationships, we calculated the ratio of the chiral to achiral contributions, Δ*I*<sup>ch</sup> / Δ*I*<sup>ach</sup> (Table 2). This ratio includes only the NLO terms since the linear chiroptical factor *G*<sup>ch</sup> (gyrotropic term) is excluded (see section S2.7.3). The evolution of this ratio as a function of the number of helical turns is depicted in Figure 5. Interestingly, the Δ*I*<sup>ch</sup> / Δ*I*<sup>ach</sup> ratio displayed a periodic evolution, albeit with out-of-phase oscillations (within experimental error), which can be compared to those

observed for the depolarization ratio DR<sup>rac</sup> (Figure 3). Interestingly, the oligomers that are closer to an integer number of helical turns, specifically **Q8** and **Q12**, exhibited a dominant chiral contribution over the achiral contribution (|Δ*I*<sup>ch</sup>/Δ*I*<sup>ach</sup>| = 1.76 and 1.66, respectively). In contrast, the oligomers that are further away from a complete helical turn, namely **Q4** and **Q16**, displayed a dominant achiral contribution (|Δ*I*<sup>ch</sup>/Δ*I*<sup>ach</sup>| = 0.34 and 0.56, respectively). This suggests that fragments with incomplete helical turns significantly impact the LP-HROA response. We hypothesize that, at certain locations along the helix, a planar (achiral) gyrotropic charge flow might exist, similar to that in a quinoline monomer or any aromatic ring. However, when fragments (i.e., monomers) are added to the helix backbone, resulting in a new helical pitch, the (chiral) charge flow deviates from planarity. This modulation affects the extent of chiral contribution in the NLO response of the molecule.

<figure><img src="image_6.png" /><figcaption>**Figure 5.** Evolution of the ratio of chiral to achiral contributions (Δ*I*<sup>ch</sup> and Δ*I*<sup>ach</sup>) of LP-HROA with the number of turns of the foldamer helices.</figcaption></figure>

Finally, in line with the above observations, the evolution of the difference in depolarization ratio of the two enantiomers (DR<sup>P</sup>-DR<sup>M</sup>) also exhibits a periodic dependence on the fraction of turns of the foldamer
helices (Figure S9). However, the periodicity is roughly
half of that in Figure 5. This difference in periodicity can
be attributed to the fact that such quantity (DR²-DR⁴) involves multiple interactions, *i.e.* the purely electric
dipole interactions (like DRrac, Figure 3) and mixed
magnetic-electric dipole interactions (like ΔI ch / ΔI ach, Figure 5).

**Conclusion**

A series of quinoline-based oligoamide foldamers of
various lengths have been synthesized in both
enantiomeric forms to investigate the nonlinear
chiroptical activity of helically chiral architectures. The
oligomers were thoroughly characterized and initially
examined by linear chiroptical techniques, i.e. ECD and
ORD, predictably yielding mirror-image responses for
the two enantiomers of each foldamer. The non-linear
optical activity of the aromatic oligoamides was then
scrutinized using hyper-Rayleigh scattering, a second-
order NLO technique that allows second-harmonic
generation to be assessed. By employing only linearly-
polarized incident light and using a recently developed
NLO chiroptical model, we were able to quantify the
achiral and chiral contributions in the intensity of the
enantiomers NLO responses. The study revealed that
not only does the length of the oligomeric backbone
influence the magnitude of NLO response, but the latter
also shows a periodic evolution with respect to the
number of helical turns of the foldamers. The LP light
indeed reveals the extent of helical chirality within the
foldamers as well as the positive/negative effect of
incomplete helical turns on their chiroptical activity in a
nonlinear regime. Overall, this work significantly
enhances our understanding of HRS measurements on
chiral molecules, paving the way for future insightful
studies on complex chiral assemblies which will be
reported in due course.

**Supporting Information**

The authors have cited additional references within the
Supporting Information.[19-24]

**Acknowledgments**

V.R. thanks the Région Nouvelle Aquitaine for financial
support (CRA: 2015-1R10205-00004858). This work
has been carried out in the framework of the ANR
NLOChiraMat (ANR-21-CE06-0018). RBA thanks the
GPR Light of Université de Bordeaux for PhD grant. This
work benefited from the facilities of the Biophysical and
Structural Chemistry platform at IECB. CNRS UAR3033,
and Bordeaux University, France and from the CESAMO
(Univ. Bordeaux, France) for HR-MS analyses.

The authors declare no competing financial interests.

**Keywords:** Foldamers; Chirality; Optical activity; Nonlinear optics; Hyper-Rayleigh scattering.

ORCID

Vincent Rodriguez: 0000-0001-6804-9757

Céline Olivier: 0000-0002-3164-8403

Yann Ferrand: 0000-0002-6552-6914

Rita Borges Anastácio: 0000-0002-2628-7359

**References**

[1] M.E. Franks, G.R. Macpherson, W.D. Figg, *Lancet* **2004**, *363*, 1802.

[2] a) B. Kahr, *Chirality* **2018**, *30*, 351; b) C. Genet, *ACS Photonics* **2022**, *9*, 319; c) C. Zhang, H. Hu, C. Ma, Y. Li, X. Wang, D. Li, A. Movsesyan, Z. Wang, A. Govorov, Q. Gan, T. Ding, *Nature Commun.* **2024**, *15*, 2.

[3] *Comprehensive Chiroptical Spectroscopy: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules*, Vol. 2 (Eds. N. Berova, P. L. Polavarapu, K. Nakanishi, R. W. Woody), John Wiley & Sons, **2012**.

[4] D. Verreault, K. Moreno, E. Merlet, F. Adamietz, B. Kauffmann, Y. Ferrand, C. Olivier, V. Rodriguez, *J. Am. Chem. Soc.* **2020**, *142*, 257.

[5] a) S. Roy, S. Kumar Nandi, D. Haldar, B. Pal, *J. Mater. Chem. C*, **2022**, *10*, 8767; b) A. Bonvicini, K. A. Forbes, D. L. Andrews, B. Champagne, *J. Chem. Phys.* **2023**, *158*, 204103; c) A. Bonvicini, B. Champagne, *Phys. Chem. Chem. Phys.* **2024**, *26*, 26377.

[6] V. Rodriguez, D. Verreault, *J. Phys. Chem. Lett.* **2024**, *15*, 6334.

[7] H. Jiang, J.-M. Léger, I. Huc, *J. Am. Chem. Soc.* **2003**, *125*, 3448.

[8] T. Qi, T. Deschrijver, I. Huc, *Nat. Protoc.* **2013**, *8*, 693.

[9] A. M. Kendhale, L. Poniman, Z. Dong, K. Laxmi-Reddy, B. Kauffmann, Y. Ferrand, I. Huc, *J. Org. Chem.* **2011**, *76*, 195.

[10] Note: P-Q12 and M-Q12 were prepared separately and then mixed in a 50/50 ratio since racemates are known to crystallize more readily than enantiomerically pure compounds.

[11] CCDC deposition number: 2421461 (for Q12).

[12] E. Merlet, K. Moreno, A. Tron, N. McClenaghan, B. Kauffmann, Y. Ferrand, C. Olivier, *Chem. Commun.* **2019**, *55*, 9825.

[13] V. Rodriguez, D. Verreault, F. Adamietz, A. Kalafatis, *ACS Photonics* **2022**, *9*, 2510.

[14] T. Verbiest, K. Clays, V. Rodriguez, *Second-Order Nonlinear Optical Characterization Techniques: An Introduction*, CRC Press, **2009**.

[15] Note: This only applies to the racemic mixtures where the magnetic dipole interaction is null. Thus, in the following, the magnetic dipole interaction is neglected in the expression of DR for the enantiomers.

[16] Note: For purely octupolar NLO chromophores such as crystal violet DR = 1.5, whereas for dipolar π-conjugated 1D push-pull systems DR = 5.
[17] a) B. J. Coe, D. Rusanova, V.D. Joshi, S. Sanchez, Jan Vavra, D. Khobragade, L. Severa, I. Císarová, D. Saman, R. Pohl, K. Clays, G.Depotter, B. S. Brunschwig, F. Teply, *J. Org. Chem.* **2016**, *81*, 1912; b) K. Clays, K. Wostyn, A. Persoons, S. Maiorana, a. Papagni, C. A. Daul, V. Weber, *Chem. Phys. Lett.* **2003**, *372*, 438.

[18] a) E.Botek, B. Champagne, M. Turki, J.-M. André, J. Chem. Phys. 120, 2042–2048 (2004); b) E. Botek, F. Castet, B. Champagne, *Chem. Eur. J.* **2006**, *12*, 8687.

[19] H. Reis, *J. Chem. Phys.*, **2006**, *125*, 014506.

[20] V. Rodriguez, *J. Raman Spectrosc.* **2012**, *43*, 627.

[21] V. Rodriguez, J. Grondin, F. Adamietz, Y. Danten, *J. Phys. Chem. B* **2010**, *114*, 15057.

[22] C. Bouquiaux, P. Beaujean, T. N. Ramos, F. Castet, V. Rodriguez, B. Champagne, *J. Chem. Phys.* **2023**, *159*, 174307.

[23] X. Li, T. Qi, K. Srinivas, S. Massip, V. Maurizot, I. Huc, *Org. Lett.* **2016**, *18*, 1044.

[24] H. E. Gottlieb, V. Kotlyar, A. Nudelman, *J. Org. Chem.* **1997**, *62*, 7512.