# Rational Control of C-N Axial Chirality in Bis-Pentatomic N-Pyrazolyl Maleimides through an Experimental and Computational Approach

Adrián López-francés, Jessica Rodrigues, Stéphane Humbel, Jean Rodriguez, Muriel Amatore, Thierry Constantieux

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## ► To cite this version:

Adrián López-francés, Jessica Rodrigues, Stéphane Humbel, Jean Rodriguez, Muriel Amatore, et al.. Rational Control of C-N Axial Chirality in Bis-Pentatomic N-Pyrazolyl Maleimides through an Experimental and Computational Approach. European Journal of Organic Chemistry, 2025, 28 (31), pp.e202500485. 10.1002/ejoc.202500485. hal-05452352

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Submitted on 10 Jan 2026

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# Rational Control of C-N Axial Chirality in Bis-Pentatomic N-Pyrazolyl Maleimides through an Experimental and Computational Approach

Adrián López-Francés,* Jessica Rodrigues, Stéphane Humbel, Jean Rodriguez, Muriel Amatore,* and Thierry Constantieux

The control of axial chirality in atropisomeric compounds has gained significant importance in modern synthetic chemistry due to their relevance in the design of materials and biologically active molecules. The study investigates the configurational stability of a series of axially chiral *N*-pyrazolyl maleimides through a combined theoretical and experimental approach. Initially, density functional theory (DFT) computations are used to predict the corresponding barriers to enantiomerisation of multiple derivatives holding a large variety of substituents at different positions of both heterocyclic nuclei on either side of the C-N bond. Then, the predicted barriers are validated through dynamic chiral high performance liquid chromatography analysis, providing experimental evidence for the configurational stability of these challenging

*bis*-pentatomic C-N atropisomers. Compounds featuring a 1-*N*-t-butyl group as well as a C-4-substituent on the aminopyrazole ring exhibit high barriers to enantiomerisation, confirming their potential as a new family of atropisomerically stable heterocyclic compounds. Variation of the substitution on the maleimide nucleus has no significant influence on the overall configurational stability. The good correlation between theoretical predictions and experimental findings highlights the strength of the DFT computations in predicting configurational stability of chiral *N*-pyrazolyl maleimides, providing a predictive framework for designing new atropisomeric *N*-pyrazolyl maleimides with restricted rotation around the C-N bond.

## 1. Introduction

The control of axial chirality of atropisomers has become a main stage in modern synthetic chemistry, offering access to unique structural features that transcend traditional stereochemical concepts.[1–5] In contrast with classical central chirality, typically derived from a stereogenic tetravalent carbon center, the axial chirality of atropisomers originates from the restricted rotation around a sigma bond in biarylic and heterobiarylic systems.[6–8] These structures are highly valued not only for their prevalence in natural products[9–12] but also for their diverse applications as chiral materials,[13–15] in the synthesis of multiple ligands,[3,16–18] and organocatalysts,[19,20] and for their relevance in medicinal chemistry.[21–23] Across the broad field, *N*-pentatomic atropisomeric maleimides, such as *N*-arylmaleimides, represent interesting frameworks as model systems for the study of the atropisomerism

phenomenon (Figure 1A).[24] Extensive studies have shown their ability to form stable atropisomers with a well-defined stereogenic axis, making them ideal candidates for investigating the stereochemical properties of these axially chiral systems. For instance, multiple studies on the enantioselective functionalization of *N*-arylmaleimides have been done using organo-[25–27] and metal-[28–30] catalysis, giving access to the synthesis of enantioenriched C-N axially chiral scaffolds.[3,7,31–34] Furthermore, this type of structure has shown promising results in medicinal chemistry, as their atropisomeric forms are usually associated with enhanced biological activity and selectivity,[11,22,35] making them valuable structures for drug discovery and development.

Most studies on axial chirality of *N*-arylmaleimides have focused on the well-defined C-N stereogenic axis, where the restricted rotation between the five- and six-membered rings offers stable 5,6-atropisomers (Figure 1A)[36,37] However, the exploration of related *N*-bis-pentatomic atropisomeric maleimides (Figure 1B), bonding two different five-membered rings to form more challenging atropisomers, remains underdeveloped.[27] The difficulty encountered in controlling the configurational stability of these scaffolds compared with 6,6- or 5,6-atopisomers is essentially due to the larger distance between the *ortho*-groups around the stereogenic axis, which reduces the barriers to enantiomerisation. In this field, aminopyrazoles have recently been described as promising platforms as the substitution of the pyrazole ring provides sufficient steric hindrance to prevent free rotation around the C-N bond in succinimide derivatives (Figure 1C),[38] revealing an axial chirality of particular interest to us. Indeed, inspired by this result, we decided to explore the possibility of accessing

A. López-Francés, J. Rodrigues, S. Humbel, J. Rodriguez, M. Amatore, T. Constantieux

Centrale Méditerranée, CNRS

Aix-Marseille Université

iSm2 UMR 7313, 13397 Marseille, France

E-mail: adrian.lopez-frances@univ-amu.fr

muriel.amatore@univ-amu.fr

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Supporting information for this article is available on the WWW under https://doi.org/10.1002/ejoc.202500485

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© 2025 The Author(s). European Journal of Organic Chemistry published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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<figure><img src="image_7.png" /><figcaption>**Figure 1.** Comparison on the development of atropisomeric *N*-substituted-maleimides.</figcaption></figure>

*N*-pyrazolyl substituted maleimide atropisomers (Figure 1D), not described to date in the literature, and to evaluate their configurational stability as a function of the nature of the substituents on both pentatomic heterocycles[39] at either side of the C—N bond. With this purpose, a combined experimental and theoretical approach was carried out. First, DFT computations were used to predict the barriers to enantiomerisation $\Delta G^{\ddagger}_{\text{theo}}$ of compounds bearing various substituents at the different positions of the aminopyrazole moiety. Subsequently, a selection of the corresponding racemic compounds was synthesized to experimentally determine their enantiomerisation Gibbs free energy ($\Delta G^{\ddagger}_{\text{exp}}$) through chiral high performance liquid chromatography (HPLC) analyses. The aim is to demonstrate the robustness and reliability of the computational method, to ultimately turn it into a predictive tool for evaluating barriers to enantiomerisation of these challenging *bis*-pentatomic atropisomers.

## 2. Results and Discussion

To test our hypothesis on the suitability of aminopyrazoles to prevent free rotation around the C—N bond in *N*-pyrazolyl substituted maleimides, we began our investigation with the synthesis of bromomaleimide **3a**, obtained through the reaction between diphenyl aminopyrazole **1a** and 3-bromofuran-2,5-dione **2** in chloroform at room temperature (**Scheme 1**). With this product in hand, we proceeded with the experimental evaluation of its configurational stability by the determination of its barrier to enantiomerisation using dynamic chiral HPLC.

Surprisingly, the analysis revealed that compound **3a** has an experimental enantiomerisation Gibbs free energy ($\Delta G^{\ddagger}_{\text{exp}}$) below 85.0 kJ mol$^{-1}$, indicating a free rotation of the C—N bond

at room temperature with a half lifetime ($t^{1/2}$) of seconds. We then decided to increase the steric hindrance generated by the pyrazole substituent by introducing a bromine atom at position C-4. Di-bromo-maleimide **4a** was thus easily obtained by the bromination of the free position of **3a** using an excess of *N*-bromosuccinimide (Scheme 1). Disappointingly, experimental determination of the barrier to enantiomerisation of **4a**, measured at 95.3 kJ mol$^{-1}$, which corresponds to a slightly higher half lifetime ($t^{1/2}$) of around 1.5 h at 25 °C compared to **3a**, indicates that maleimide **4a** cannot be considered as a stable atropisomer.

With these results in hand, we decided to get key insights into the configurational stability by computing the theoretical Gibbs free energy $\Delta G^{\ddagger}_{\text{theo}}$ using DFT for a series of *N*-pyrazolyl maleimides **3–4** holding various substituents at both the aminopyrazole and maleimide nuclei. All values were computed at the PBE0/def2-SVP level—with D3 dispersion terms (noted PBE0-D3/def2-SVP, see computational details below).

As shown in **Figure 2**, the theoretical $\Delta G^{\ddagger}_{\text{theo}}$ values for compounds **3a** and **4a**, align reasonably well with the experimental findings. Specifically, compound **3a** showed an estimated barrier to enantiomerisation of 48.2 kJ mol$^{-1}$, which is consistent with the experimental result ($<85$ kJ mol$^{-1}$) where enantiomeric separation was not feasible. In the case of brominated compound **4a**, the obtained computational value was 105.0 kJ mol$^{-1}$, showing a slight overestimation of less than 10.0 kJ mol$^{-1}$. Nevertheless, this result was close enough to the experimental value, supporting the reliability of the computational model. Based on this theoretical approach, the replacement of bromine with a larger iodine atom in **4b** did not result in a significant increase of the barrier ($\Delta\Delta G^{\ddagger}_{\text{the}} = 2.6$ kJ mol$^{-1}$), suggesting that the introduction of a bulkier halogen atom at this position of the aminopyrazole has a minimal impact on the configurational stability of the

<figure><img src="image_8.png" /><figcaption>**Scheme 1.** Synthesis of *N*-pyrazolyl bromomaleimides **3a** and **4a**.</figcaption></figure>
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<figure><img src="image_10.png" /><figcaption>**Figure 2.** DFT calculated $\Delta G^{\ddagger}_{\text{theo}}$ values for *N*-pyrazolyl maleimides **3** and **4**. Values (kJ mol⁻¹) computed at PBE0-D3/def2-SVP level.</figcaption></figure>

molecule. More generally, these results suggest that the presence of 1-*N*-phenyl group on the aminopyrazole in compounds **3a**, **4a**, and **4b** is not sufficient to achieve configurational stability. Thus, we decided to incorporate bulkier 1-*N*-t-Bu group to increase the barrier to enantiomerisation of the corresponding derivatives **3b** and **4c**. In complement, the calculated values for the corresponding 3-t-Bu derivatives **3c** ($\Delta G^{\ddagger}_{\text{theo}} = 81.7$ kJ mol⁻¹) and **4d** ($\Delta G^{\ddagger}_{\text{theo}} = 156.9$ kJ mol⁻¹), clearly show a very small contribution of the nature of the substitution at position 3 of the pyrazole nucleus and highlights the importance of holding both 1-N and 4-C substituents bulky enough to ensure atropisomeric stability. To support this argument, by comparison with **4d**, the estimated barriers to enantiomerisation of compounds **4e–g**, respectively bearing methyl, ethyl and isopropyl substituents in position 1-N of the pyrazole, ranging from 104.9 to 120.7 kJ mol⁻¹, confirm the need for the presence of a substituent on 1-N position as bulky as t-butyl to obtain configurationally stable atropisomers.

Then, we studied the influence of the substituent on the maleimide moiety through the analysis of compounds **5a** and **6a** bearing a methyl group instead of a bromine (**Figure 3**). Minimal changes in the barrier to enantiomerisation were observed in both cases ($\Delta G^{\ddagger}_{\text{theo}} = 78.2$ kJ mol⁻¹ for compound **5a**, and $\Delta G^{\ddagger}_{\text{theo}} = 155.3$ kJ mol⁻¹ for compound **6a**), suggesting that the substitution pattern of the maleimide nucleus does not have a significant influence on the overall configurational stability.

Considering the excellent value obtained for 4-brominated compound **6b**, the impact of a smaller chlorine atom in **6c** was studied, observing a slight decrease of only 6.0 kJ mol⁻¹

(Figure 3, $\Delta G^{\ddagger}_{\text{theo}} = 149.3$ kJ mol⁻¹), but the barrier remained sufficiently high to retain configurational stability. This difference between halogens was comparable to that observed between bromine and iodine (see above), pointing out the minimal effect on the barrier of the halogen atom size at position 4-C of the aminopyrazole. Furthermore, the introduction of a phenyl selection moiety or a thiophenyl substituent at the same position in compound **6d** and **6e**, respectively, was carried out, yielding results in line with a high atropisomeric stability (Figure 3, $\Delta G^{\ddagger}_{\text{theo}}$ of 164.8 and 165.3 kJ mol⁻¹ for **6d** and **6e**, respectively). Several other substituents were examined, including aryl groups such as phenyl (**6f**) and $\alpha$-naphthyl (**6g**), alkyl groups such as isopropyl (**6h**) and t-butyl (**6i**), and nitro group (**6j**), all of them resulting in high barriers to enantiomerisation, ranging from 138.3 kJ mol⁻¹ for the $NO_2$ derivative **6j** to 171.1 kJ mol⁻¹ for the derivative bearing three t-Bu groups **6i**. This suggests that regardless of its nature, the presence of a substituent at this position plays a decisive role in stabilizing the atropisomeric configuration. The decisive substitution at position 4 of the pyrazole is highlighted with compound **6k** (Figure 3) bearing only a methyl group resulting in a high barrier to enantiomerisation of 134.0 kJ mol⁻¹, which is only 5 kJ mol⁻¹ lower compared to the 3,4-disubstituted analog **6l**. Additionally, and as expected, the introduction of a bulkier iodine substituent in **6m** and **6n**, results in a significant increase of the corresponding barriers to enantiomerisation of 150.0 and 160.5 kJ mol⁻¹, respectively.

To validate the predictive character of this theoretical model, which has already shown good consistency with the experimental values of the barriers to enantiomerisation for compounds **3a** and **4a**, we then undertook the synthesis of a series of
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<figure><img src="image_12.png" /><figcaption>Figure 3. DFT calculated ΔG\*<sub>theo</sub> values for *N*-pyrazolyl maleimides 5 and 6. Values (kJ mol\*-1) computed at PBE0-D3/def2-SVP level.</figcaption></figure>

<figure><img src="image_13.png" /><figcaption>Scheme 2. Synthesis of 5-aminopyrazole derivatives 1a-e.</figcaption></figure>

*bis*-pentatomic axially chiral maleimides to experimentally determine their Gibbs free energy ΔG\*<sub>exp</sub> and to compare them with the computed values. To begin with, we first carried out the

synthesis of several 5-aminopyrazole derivatives 1 through the reaction of the corresponding β-ketonitriles 7 and hydrazine hydrochlorides 8 under acidic conditions (Scheme 2).[40] The
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reaction worked well for the synthesis of disubstituted aminopyrazoles **1** holding substituent at positions 1-N and 3-C of the ring (Scheme 2, 1a-1c), giving moderate to excellent yields. On the other hand, two trisubstituted aminopyrazoles were synthesized, compound **1d** which contains an aromatic ring at positions 1-N and 4-C, and compound **1e** holding three different alkyl moieties.

After that, we proceeded with the synthesis of the proposed di-substituted bromomaleimides **3** and C-4 halogenated bromomaleimides **4** (Scheme 3). Following the procedure described above for the obtention of compound **3a** (Scheme 1), we successfully obtained the corresponding di-t-butyl analog **3c** from aminopyrazole **1b** and 3-bromofuran-2,5-dione (2) in chloroform at room temperature. Subsequently, iodinated compound **4b** was synthesized in good yield (77%) by treatment of **3a** with N-iodosuccinimide in chloroform under reflux. Additionally, di-t-butyl dibromomaleimide **4d** was afforded under the same conditions as compound **4a**.

For the synthesis of methyl-substituted maleimides **5** ($R^3 = H$) and **6** ($R^3 \neq H$), a two-step procedure was developed, with prior formation of a maleimide derivative **10** by reaction between maleic anhydride (9) and an aminopyrazole **1**, followed by desymmetrisation of the maleimide unit by a domino nitromethane addition/elimination/isomerization sequence (Scheme 4).

Maleimides **10**, precursors of compounds **5** and **6**, were first obtained in a two-step process (Scheme 5).[38] Initially, the corresponding aminopyrazoles **1** were stirred in chloroform in the presence of maleic anhydride (9) at room temperature for 4 h, affording the intermediate maleic acid derivative **11**, followed by reaction with sodium acetate at 85 °C for another 4 h to

complete the formation of the desired maleimides **10**. Following this procedure, four different maleimides were obtained in low to moderate yields, featuring various substituents at positions 1-N, 3-C, and 4-C of the aminopyrazole ring. In this context, disubstituted derivatives **10a**, bearing two t-butyl groups at positions one and three of the pyrazole ring, and **10b** with a meta-chloro phenyl group in the 3-C position were available, together with trisubstituted N-pyrazolyl maleimides **10c** and **10d**.

Subsequently, desymmetrisation of N-pyrazolyl maleimides **10a-d** was achieved through the domino sequence involving conjugate addition of nitromethane, followed by Et<sub>3</sub>N-promoted

<figure><img src="image_15.png" /><figcaption>Scheme 5. Synthesis of N-pyrazolyl maleimides **10a-d**.</figcaption></figure>

<figure><img src="image_16.png" /><figcaption>Scheme 3. Synthesis of N-pyrazolyl bromomaleimides **3a** and **3c**, and trisubstituted N-pyrazolyl bromomaleimides **4b** and **4d**.</figcaption></figure>

<figure><img src="image_17.png" /><figcaption>Scheme 4. Two-step procedure for methyl-substituted maleimides **5** and **6** synthesis.</figcaption></figure>
<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /><figcaption>**Scheme 6.** Desymmetrisation of N-pyrazolyl maleimides 10a–d via domino sequence.</figcaption></figure>

elimination of HNO₂ and subsequent isomerization, affording the corresponding N-pyrazolyl methylmaleimides **5a**, **5b**, **6a**, and **6l** in moderate to good overall yields (**Scheme 6**).[41]

The synthesis of the C-4 halogenated maleimides **6b-d** was carried out by treating the substrates **5a** or **5b** with the corresponding N-halosuccinimide in chloroform (**Scheme 7**). Thus, the brominated compound **6b** was obtained in 39% yield by the reaction of **5a** with N-bromosuccinimide at room temperature. However, similar chlorination and iodination reactions had to be carried out in refluxing chloroform. In this way, chlorinated maleimide **6c** and iodinated maleimide **6n** were obtained from **5a** with N-chlorosuccinimide and from **5b** with N-iodosuccinimide, respectively, with good to excellent yields.

Finally, we completed the synthesis with selenated derivative **6d** through the electrophilic selenation of maleimide **5a** (**Scheme 8**). Initial attempts using diphenyl diselenide (PhSeSePh) as the selenium source did not provide the target molecule. However, in situ generated phenylselenyl chloride (PhSeCl), formed from the reaction between NCS and PhSeSePh, proved to be a more electrophilic selenium source, successfully affording compound **6d** in very good yield (89%) after stirring the reaction overnight in refluxing chloroform.

Furthermore, we performed the large-scale synthesis of trisubstituted N-pyrazolyl bromomaleimide **12** as a key

representative example (**Scheme 9**). Aminopyrazole **1b** was first synthesized on an 80 mmol scale, affording 11.7 g of product in 75% yield. Subsequently, maleimide **10a** was obtained through the reaction of **1b** with maleic anhydride **9**, giving the desired compound 34% yield (5.6 g). Finally, the bromination reaction of **10a** using NBS provided compound **12** in an excellent yield (84%, 6.1 g). Overall, compound **12** was obtained in 21% yield over three steps, highlighting the robustness and scalability of the whole process.

With these compounds in hands, for which their theoretical Gibbs free energy ΔG‡theo were predicted in Figure 2 and 3, we proceeded with the experimental determination of their barriers to enantiomerisation using dynamic HPLC on a chiral stationary phase.[42] In general, this comparison revealed a systematic overestimation of the barriers to enantiomerisation by a mean signed error of (MSE) = +10 kJ mol⁻¹. To determine if this deviation could be reduced, we further tested higher levels of theory and basis sets (**Figure 4**). Neither reoptimization nor single-point calculations at the PBE0-D3/def2-TZVP level significantly improved the agreement (MSE = +11.0 and +11.1 kJ mol⁻¹, respectively) (see Supporting Information). The use of a more advanced double-hybrid functional (B2P-LYP)[43] also yielded similar results (MSE = +10.0 kJ mol⁻¹), and MP2[44] gives an ever-larger overestimation (MSE = +13 kJ mol⁻¹). Notably, M06-2X/def2-TZVP

<figure><img src="image_20.png" /><figcaption>**Scheme 7.** Halogenation on C-4 position of the pyrazole ring.</figcaption></figure>

<figure><img src="image_21.png" /><figcaption>**Scheme 8.** Selenation of 5a via in situ generation of PhSeCl, affording selenated derivative 6d.</figcaption></figure>
<figure><img src="image_22.png" /></figure>

<figure><img src="image_23.png" /><figcaption>Scheme 9. Scale-up synthesis of trisubstituted N-pyrazolyl bromomaleimide 12.</figcaption></figure>

<figure><img src="image_24.png" /><figcaption>**Figure 4.** Comparison between experimental and theoretical enantiomerisation Gibbs free energies (ΔG‡ in kJ mol⁻¹) of synthesized N-pyrazolyl maleimides 4, and 6. Positive values means that the computation overestimates the experimental value ΔGexp. Legend (TZ) indicate a def2-TZVP basis set single point performed on the PBE0/def2-SVP geometries, (TZ opt) indicates that the basis set def2-TZVP was used for both the geometry optimization and energy.</figcaption></figure>

provided a slightly improved performance across all eight cases, with a reduced and systematic overestimation (MSE = +7.7 kJ mol⁻¹).[45] Given this balance between accuracy and computational cost, we retained PBE0-D3/def2-SVP as our reference level for the full dataset, while also reporting M06-2X values for comparative purposes.

Compounds featuring C-4 unsubstituted aminopyzarole moieties (Table 1, compounds entries 1, 2,6, and 7) exhibited very low barriers to enantiomerisation, with experimental values below the HPLC detection limit (ΔG‡exp = <85.0 kJ mol⁻¹) in all cases, in excellent agreement with the theoretical predictions. In contrast, compounds 4, bearing a halogen atom at position 4 of
<figure><img src="image_25.png" /></figure>

<figure><img src="image_26.png" /><figcaption>**Table 1.** Comparison between experimental and theoretical enantiomerisation Gibbs free energies (ΔG‡ in kJ mol⁻¹) of synthesized N-pyrazolyl maleimides 3, 4, 5, and 6.</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Compound</th><th>R<sup>1</sup></th><th>R<sup>2</sup></th><th>R<sup>3</sup></th><th>R<sup>4</sup></th><th>Theoretical ΔG<sup>‡</sup></th><th>Experimental ΔG<sup>‡</sup></th></tr></thead><tbody><tr><td>1</td><td><b>3a</b></td><td>Ph</td><td>Ph</td><td>H</td><td>Br</td><td>48.2</td><td>&lt;85</td></tr><tr><td>2</td><td><b>3c</b></td><td>t-Bu</td><td>t-Bu</td><td>H</td><td>Br</td><td>81.7</td><td>&lt;85</td></tr><tr><td>3</td><td><b>4a</b></td><td>Ph</td><td>Ph</td><td>Br</td><td>Br</td><td>105.0</td><td>95.3</td></tr><tr><td>4</td><td><b>4b</b></td><td>Ph</td><td>Ph</td><td>I</td><td>Br</td><td>107.6</td><td>97.5</td></tr><tr><td>5</td><td><b>4d</b></td><td>t-Bu</td><td>t-Bu</td><td>Br</td><td>Br</td><td>156.9</td><td>147.5</td></tr><tr><td>6</td><td><b>5a</b></td><td>t-Bu</td><td>t-Bu</td><td>H</td><td>CH<sub>3</sub></td><td>78.2</td><td>&lt;85</td></tr><tr><td>7</td><td><b>5b</b></td><td>t-Bu</td><td>m-ClPh</td><td>H</td><td>CH<sub>3</sub></td><td>77.2</td><td>&lt;85</td></tr><tr><td>8</td><td><b>6a</b></td><td>Ph</td><td>i-Pr</td><td>Ph</td><td>CH<sub>3</sub></td><td>92.3</td><td>&lt;85</td></tr><tr><td>9</td><td><b>6b</b></td><td>t-Bu</td><td>t-Bu</td><td>Br</td><td>CH<sub>3</sub></td><td>155.3</td><td>146.6</td></tr><tr><td>10</td><td><b>6c</b></td><td>t-Bu</td><td>t-Bu</td><td>Cl</td><td>CH<sub>3</sub></td><td>149.3</td><td>141.5</td></tr><tr><td>11</td><td><b>6d</b></td><td>t-Bu</td><td>t-Bu</td><td>SePh</td><td>CH<sub>3</sub></td><td>164.8</td><td>145.9</td></tr><tr><td>12</td><td><b>6l</b></td><td>t-Bu</td><td>i-Pr</td><td>CH<sub>3</sub></td><td>CH<sub>3</sub></td><td>141.2</td><td>134.7</td></tr><tr><td>13</td><td><b>6n</b></td><td>t-Bu</td><td>m-ClPh</td><td>I</td><td>CH<sub>3</sub></td><td>160.5</td><td>145.7</td></tr></tbody></table>

the pyrazole ring, resulted in a substantial increase in the barrier to enantiomerisation (Table 1, entries 3, 4, and 5). Notably, a consistent overestimation of ≈9 to 10 kJ mol⁻¹ was observed between the theoretical and experimental values. Compound 6a, bearing a phenyl substituent at C-4, showed a predicted barrier of 92.3 kJ mol⁻¹ (Table 1, entry 8), whereas the experimental value remained below the detection limit (ΔG‡exp = <85.0 kJ mol⁻¹), suggesting a slight overestimation of the calculated barrier (Table 1). Similarly, for compound 6, this overestimation of around 10 kJ mol⁻¹ in the calculated barriers was also observed. Interestingly, selenated compound 6d displayed a larger deviation, with a theoretical value exceeding the experimental one by about 20 kJ mol⁻¹ (Table 1, entry 11). In general, this comparison revealed a systematic overestimation of the barriers to enantiomerisation by around 10 kJ mol⁻¹, although the deviation varies depending on the substituents. Nevertheless, the computed values ΔG‡theo are in good agreement with the experimental results. Overall, these results underscore the robustness of the computational approach in predicting the barriers to enantiomerisation of N-pyrazolyl maleimides, showing a strong correlation between theoretical and experimental values across the studied derivatives.

### 3. Conclusion

In conclusion, we have successfully demonstrated the efficiency of these computations in predicting the barriers to enantiomerisation of a series of new bis-pentatomic N-pyrazolyl maleimides, showing a good correlation between theoretical and experimental values. This comparison revealed a consistent overestimation of the computed barriers of ≈10 kJ mol⁻¹, while maintaining the

predictive power of the method across the studied derivatives. Through a systematic evaluation of various substituents at key positions of the aminopyrazole ring, we identified that if the substitution of the maleimide ring has practically no effect, the presence of both a 1-N-t-butyl group and a C-4-substituent at the pyrazole nucleus is essential to achieve configurational stability around the C-N axis. Notably, substituents at position 3-C, hold a minor influence on the barrier value, as demonstrated by the small differences observed between some di- and trisubstituted derivatives. Moreover, the synthesis of these C-N atropisomeric compounds was successfully carried out, including desymmetrisation, halogenation or selenation reactions. Some reactions were also carried out on a multigram scale, enabling further applications of these scaffolds. The experimental barrier values were determined through dynamic HPLC, validating the theoretical predictions, and the applicability of the computational approach. Overall, these findings further confirm that DFT computations are a valuable tool to provide a reliable approximation of the barriers to enantiomerisation of bis-pentatomic N-pyrazolyl maleimide atropisomers, facilitating the rational design of this type of challenging C-N atropisomers. Moreover, these computational approaches can also be applied to other families of plausible atropisomers, saving valuable time and resources while delivering realistic predictions.

### 4. Computational Details

The optimization and frequency calculations were done with gaussian 16[46] Unless stated, the optimizations used PBE0[47] and the def2-SVP basis set[48] with the D3 correction for the
<figure><img src="image_27.png" /></figure>

dispersion effects.[49] Additional calculations were done with the
def2-TZVP basis set.[48] PBE0 geometry optimizations and M06-2X,
MP2 en B2P-LYP single points. The second derivative analysis
showed the appropriate number of negative eigenvalues (1 for a
transition state and 0 for a minimum).

Acknowledgements

A.L.-F. acknowledge ANR for the financial support for DINATROP project (no. ANR-23-CE07-0044), which funded his postdoctoral stage. J.R.S. acknowledge French research ministry, Aix-Marseille Université, and CNRS for her financial Ph.D. support. The authors warmly thank Dr. N. Vanthuyne, M. Jean, and Dr. M. Albalat for HPLC analyses on the determination of experimental barriers to enantiomerisation, and the whole team of the Spectropole for NMR and mass spectrometry analyses. The Centre de Calcul Intensif d'Aix-Marseille (mesocentre) is acknowledged for granting access to its high-performance computing resources (project b289).

Conflict of Interest

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available in
the Supporting Information of this article.

Keywords: atropisomeric stability · axial chirality · bis-pentatomic C-N atropisomers · DFT computations · N-pyrazolyl maleimides

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Manuscript received: May 7, 2025

Revised manuscript received: June 17, 2025

Version of record online: July 14, 2025