# s-Block Metal-Mediated Hydroelementation

## Introduction

The addition of P(III) and P (V) compounds across alkynes or diynes is an example of formation of new P-C bonds in an atom-economic way [1-4]. However, this addition necessitates catalysts to overcome electrostatic and kinetic barriers [3,5-7]. As a method to this approach, we propose the use of alkali metal-based catalysts, which are ideal candidates for this task due to their non-toxicity, global abundance, and environmentally benign properties [8,9]. Nonetheless, the outcome of these reactions strongly depends on the nature of the alkali metal and the bulkiness of P-bound substituents [10,11]. It should be noted that there is no fundamental understanding of electronic and steric control for these reactions, particularly in terms of predictive experimental and theoretical capability, because these metals lack directing d-orbitals.

With the aim of forming stereo- and regioselectively P-C bonds via alkali-metal catalyzed reactions, this work focuses on a combined approach involving experimental and theoretical methods to determine the mechanistic steps by which these reactions ensue, to identify and underline the decisive factors which govern the stereo- and regio-selectivity and to ascertain which alkali metal is the most suited one. The combination of these two methods also enables us to understand why these reactions do not happen with several combinations of alkali cation and phosphine substituents. This project was initially divided into two parts: i) alkali metal mediated hydrophosphorylation (Pudovik reaction) of alkynes and diynes and ii) alkali metal catalyzed hydrophosphination of diynes. We set to achieve this goal by using M-HMDS (metal bis(trimethylsilyl)amides; M = Li, Na, and K) as precatalysts for the formation of new P-C bonds. For both projects we employed the same precatalyst and the same loading as to establish a homogenous protocol. We chose bis(trimethylsilyl)amide complexes as our precatalysts as they are commonly available, easy to synthesize from inexpensive starting materials, highly soluble in common organic solvents, and cheap. To elucidate the experimental outcome of the reactions, we have performed DFT calculations to achieve an understanding of the results from a theoretical standpoint.

Additionally, we also explored the oxidation of hetero cyclopentadienes with an incorporated phosphorus atom (product from the alkali metal-catalyzed hydrophosphination of diynes) and the subsequent dimerization of the oxidized product into a [2+2] adduct under visible light irradiation. In this part of the project, we aimed to evaluate the properties, which promoted the formation of oxide and the subsequent formation of the [2+2] adduct, in terms of HOMO-LUMO gap and the energy barriers facilitating the photoinduced cycloaddition. This additional project also combined DFT and experimental techniques.

## Alkali metal mediated Pudovik reaction

*Pudovik reaction Part I: alkali metal-mediated addition of di(organyl)phosphine oxides across phenylacetylene.*

In the initial stages of the project, we decided to elucidate the energy profile for the alkali metal mediated Pudovik reaction onto phenylacetylene (Scheme 1). For this section, we took the experimental data obtained by Westerhausen *et al.* [8].
<figure><img src="image_76.png" /><figcaption>**Scheme 1.** Alkali metal-mediated hydrophosphorylation of phenylacetylene with di(organyl)phosphine oxides via catalytic amounts of M-HMDS (M = Li, Na and K).</figcaption></figure>

Interestingly the experimental results for the Pudovik reaction revealed a significant dependency on both the P-bound substituent and the nature of the s-block metal leading to different reaction times and product ratios. The following reactions were conducted in THF as a solvent. The summary of the experimental results is depicted in Tables 1 and 2.

<table><caption>**Table 1.** Dependency of the Pudovik reaction (addition of dimesitylphosphine oxide across phenylacetylene) on the alkali metal of the utilized bis(trimethylsilyl)amide precatalyst.</caption><thead><tr><th rowspan="2">Entry</th><th rowspan="2">Metal</th><th colspan="2">After 1h</th><th colspan="2">After 27 h</th></tr><tr><th>Conv. [%]</th><th>E/Z</th><th>Conv. [%]</th><th>E/Z</th></tr></thead><tbody><tr><td>1</td><td>Li</td><td>0</td><td>-</td><td>&gt;8</td><td>5/1</td></tr><tr><td>2</td><td>Na</td><td>31</td><td>3/1</td><td>&gt;99</td><td>31/1*</td></tr><tr><td>3</td><td>K</td><td>93</td><td>3/1</td><td>&gt;99</td><td>5/1</td></tr></tbody></table>

<table><caption>**Table 2.** Dependency of the hydrophosphination across phenylacetylene on the P-bound group of the di(organyl)phosphine oxide, using K-HMDS as precatalyst.</caption><thead><tr><th rowspan="2">Entry</th><th rowspan="2">P-bound group</th><th colspan="3">After 1h</th></tr><tr><th>Conv. [%]</th><th>1-Ar (E/Z)</th><th>2-Ar</th></tr></thead><tbody><tr><td>1</td><td>Mes</td><td>93</td><td>3/1</td><td>/</td></tr><tr><td>2</td><td>Mes/Ph</td><td>76</td><td>36 (100/0)</td><td>64</td></tr><tr><td>3</td><td>Ph</td><td>14</td><td>&lt;1</td><td>&gt;99</td></tr><tr><td>4</td><td>Cy</td><td>0</td><td>/</td><td>/</td></tr><tr><td>5</td><td>OEt</td><td>0</td><td>/</td><td>/</td></tr></tbody></table>

To elucidate the experimental results, we considered the postulated mechanism presented in the original study as a basis for our present in silico study. The postulated reaction mechanism on which the computational study is based is depicted in Scheme 2. Before we started the exploration of the mechanism, we estimated the thermodynamic feasibility of the formation of the alkali metal phosphinites M-OPAr₂, which are the active catalytic species, starting from the corresponding M-HMDS precatalyst and using stoichiometric amounts of HP(O)Ar₂ (reaction 1). For these calculations, we additionally considered the aggregation degree of M-HMDS in THF, a dimer for M = K, Li and a trimer for M = Na (Scheme 3) [12,13]. Furthermore, in the instance of M = K, we also examined the impact of different P-bound groups on the formation of the active catalytic species. We determined that in all cases the formation is feasible, regardless of the alkali cation and the P-bound substituent, according to the computed Gibbs energies for the reactions.

<footnote>* The quantity of Z-1-Mes is reduced because of a preferred second Na-mediated hydrophosphorylation yielding 2-Mes.</footnote>
<figure><img src="image_85.png" /><figcaption>**Scheme 1.** Alkali metal-mediated hydrophosphorylation of phenylacetylene with di(organyl)phosphine oxides via catalytic amounts of M-HMDS (M = Li, Na and K).</figcaption></figure>

Interestingly the experimental results for the Pudovik reaction revealed a significant dependency on both the P-bound substituent and the nature of the s-block metal leading to different reaction times and product ratios. The following reactions were conducted in THF as a solvent. The summary of the experimental results is depicted in Tables 1 and 2.

<table><caption>**Table 1.** Dependency of the Pudovik reaction (addition of dimesitylphosphine oxide across phenylacetylene) on the alkali metal of the utilized bis(trimethylsilyl)amide precatalyst.</caption><thead><tr><th rowspan="2">Entry</th><th rowspan="2">Metal</th><th colspan="2">After 1h</th><th colspan="2">After 27 h</th></tr><tr><th>Conv. [%]</th><th>E/Z</th><th>Conv. [%]</th><th>E/Z</th></tr></thead><tbody><tr><td>1</td><td>Li</td><td>0</td><td>-</td><td>&gt;8</td><td>5/1</td></tr><tr><td>2</td><td>Na</td><td>31</td><td>3/1</td><td>&gt;99</td><td>31/1*</td></tr><tr><td>3</td><td>K</td><td>93</td><td>3/1</td><td>&gt;99</td><td>5/1</td></tr></tbody></table>

<table><caption>**Table 2.** Dependency of the hydrophosphination across phenylacetylene on the P-bound group of the di(organyl)phosphine oxide, using K-HMDS as precatalyst.</caption><thead><tr><th rowspan="2">Entry</th><th rowspan="2">P-bound group</th><th colspan="3">After 1h</th></tr><tr><th>Conv. [%]</th><th>1-Ar (E/Z)</th><th>2-Ar</th></tr></thead><tbody><tr><td>1</td><td>Mes</td><td>93</td><td>3/1</td><td>/</td></tr><tr><td>2</td><td>Mes/Ph</td><td>76</td><td>36 (100/0)</td><td>64</td></tr><tr><td>3</td><td>Ph</td><td>14</td><td>&lt;1</td><td>&gt;99</td></tr><tr><td>4</td><td>Cy</td><td>0</td><td>/</td><td>/</td></tr><tr><td>5</td><td>OEt</td><td>0</td><td>/</td><td>/</td></tr></tbody></table>

To elucidate the experimental results, we considered the postulated mechanism presented in the original study as a basis for our present in silico study. The postulated reaction mechanism on which the computational study is based is depicted in Scheme 2. Before we started the exploration of the mechanism, we estimated the thermodynamic feasibility of the formation of the alkali metal phosphinites M-OPAr₂, which are the active catalytic species, starting from the corresponding M-HMDS precatalyst and using stoichiometric amounts of HP(O)Ar₂ (reaction 1). For these calculations, we additionally considered the aggregation degree of M-HMDS in THF, a dimer for M = K, Li and a trimer for M = Na (Scheme 3) [12,13]. Furthermore, in the instance of M = K, we also examined the impact of different P-bound groups on the formation of the active catalytic species. We determined that in all cases the formation is feasible, regardless of the alkali cation and the P-bound substituent, according to the computed Gibbs energies for the reactions.

<footnote>* The quantity of Z-1-Mes is reduced because of a preferred second Na-mediated hydrophosphorylation yielding 2-Mes.</footnote>
<figure><img src="image_77.png" /><figcaption>**Scheme 2.** Postulated mechanism for the formation of the **1-Ar** and the bis-phosphorylated compound **2-Ar** adapted from ref. [1].</figcaption></figure>

$$ n \text{ "M"HMDS"} + n \text{H}P(O)R_2 \rightarrow n \text{H-HMDS} + n \text{ "M"OPR}_2 \quad (1) $$

<figure><img src="image_78.png" /><figcaption>**Scheme 3.** General scheme for generation of active catalyst species M-OPAr₂ (M = Li, Na and K*; R = Mes). *For M = K also Ar = Mes, Ph, OEt and Cy.</figcaption></figure>

However, it is known that the alkali metal phosphinites M-OPAr₂ can form aggregates in solvents such as THF where tetrameric, dimeric, and monomeric species can (co)exist [2,13]. However, the only
<figure><img src="image_86.png" /><figcaption>**Scheme 2.** Postulated mechanism for the formation of the **1-Ar** and the bis-phosphorylated compound **2-Ar** adapted from ref. [1].</figcaption></figure>

$$ n \text{ "M HMDS"} + n \text{H(P(O)R$_2$}} \rightarrow \text{n H-HMDS} + n \text{ "M-OPR$_2$"} \quad (1) $$

<figure><img src="image_87.png" /><figcaption>**Scheme 3.** General scheme for generation of active catalyst species M-OPAr₂ (M = Li, Na and K*; R = Mes). *For M = K also Ar = Mes, Ph, OEt and Cy.</figcaption></figure>

However, it is known that the alkali metal phosphinites M-OPAr₂ can form aggregates in solvents such as THF where tetrameric, dimeric, and monomeric species can (co)exist [2,13]. However, the only
active form is the monomeric complex. For this reason, we estimated the dissociation energies of the aggregates according to Scheme 4.

<figure><img src="image_79.png" /><figcaption>**Scheme 4.** General scheme of deaggregation for the clusters of active catalytic species (M = Li, Na, K); P-bound groups 2 Mes, Mes/Ph and 2 Ph).</figcaption></figure>

This part of the calculations provided some answers regarding the aspect why some of the reactions are hampered and do not ensue. The influence of the stepwise substitution of P-bound mesityl groups by phenyl groups on the dissociation/deaggregation energy is rather low with no significant trend. All the transformations are endergonic for the first transformation (tetramer into dimer), ranging from 27.9 to 29.4 kcal mol⁻¹, and for the second transformation (dimer into monomer) from 17.5 to 22.1 kcal mol⁻¹. Even though they are slightly elevated, all the conversions may be facilitated under the reaction conditions, which is in accordance with experimental data. However, we observed notable alkali metal-dependent variation for (Ar = Mes). The highest dissociation energy for the deaggregation for the tetrameric into the dimeric species for lithium metal mediated reaction is 42.3 kcal mol⁻¹. Such a high dissociation energy could be one of the reasons suppressing this reaction. The rest of the dissociation energies were estimated to be lower than 30.0 kcal mol⁻¹, and as such they could be surmounted under the reaction conditions. The estimated dissociation energies are in accordance with the analyzed experimental outcome.

Having estimated the Gibbs energy of the reaction of formation of the active catalytic species we then moved onto the calculation of energy profiles for the postulated mechanism (Figure 1). We were able to ascertain fully the reaction mechanisms for M = Li, Na and K with Ar = Mes and for M = K with Ar = Ph, Cy, OEt and a mixture of Ph and Mes as P-bound substituents. Addition of phosphorous nucleophile to the triple bond can give both *E*- and *Z*-isomers of the hydrophosphorylated products (Scheme 1). However, we were unable to locate a TS for the first nucleophilic attack that directly generates the intermediate which would be the precursor for the formation of the *E*-isomer. The calculated intermediate from the nucleophilic attack always formed as a precursor for the formation of the *Z*-isomer. The formation of the *E*-product takes place through an isomerization step of the initially formed pro-*Z*-intermediate (Figure 1B). All the computed barriers are lower than 30.0 kcal mol⁻¹. The computed energy profiles suggest that the origin of the non-reaction observed in several cases was not in the barrier for the reaction, but rather in the steps beforehand (formation of the catalytically active species). Barriers are influenced by the nature of the alkali cation. The energy barriers were the highest with lithium and lowest with potassium which is in accordance with the experimental results of the best catalyst being the potassium complex and the worst being the lithium congener. The energy profile for the sodium-mediated reaction has barriers between potassium- and lithium-mediated reactions. Hence, it may be deduced that the identity of the alkali cation does play a significant role in the reaction mechanism, and it is inaccurate to look at alkali cations as spectators and as freely interchangeable. On the contrary, the energy barriers did not show significant difference amongst the different P-bound substituents, hence it was concluded that for P-bound Cy and OEt the prevailing factor which hinders this reaction is the lack of formation of the active mononuclear catalytic species.
active form is the monomeric complex. For this reason, we estimated the dissociation energies of the aggregates according to Scheme 4.

<figure><img src="image_88.png" /><figcaption>**Scheme 4.** General scheme of deaggregation for the clusters of active catalytic species (M = Li, Na, K); P-bound groups 2 Mes, Mes/Ph and 2 Ph).</figcaption></figure>

This part of the calculations provided some answers regarding the aspect why some of the reactions are hampered and do not ensue. The influence of the stepwise substitution of P-bound mesityl groups by phenyl groups on the dissociation/deaggregation energy is rather low with no significant trend. All the transformations are endergonic for the first transformation (tetramer into dimer), ranging from 27.9 to 29.4 kcal mol⁻¹, and for the second transformation (dimer into monomer) from 17.5 to 22.1 kcal mol⁻¹. Even though they are slightly elevated, all the conversions may be facilitated under the reaction conditions, which is in accordance with experimental data. However, we observed notable alkali metal-dependent variation for (Ar = Mes). The highest dissociation energy for the deaggregation for the tetrameric into the dimeric species for lithium metal mediated reaction is 42.3 kcal mol⁻¹. Such a high dissociation energy could be one of the reasons suppressing this reaction. The rest of the dissociation energies were estimated to be lower than 30.0 kcal mol⁻¹, and as such they could be surmounted under the reaction conditions. The estimated dissociation energies are in accordance with the analyzed experimental outcome.

Having estimated the Gibbs energy of the reaction of formation of the active catalytic species we then moved onto the calculation of energy profiles for the postulated mechanism (Figure 1). We were able to ascertain fully the reaction mechanisms for M = Li, Na and K with Ar = Mes and for M = K with Ar = Ph, Cy, OEt and a mixture of Ph and Mes as P-bound substituents. Addition of phosphorous nucleophile to the triple bond can give both *E*- and *Z*-isomers of the hydrophosphorylated products (Scheme 1). However, we were unable to locate a TS for the first nucleophilic attack that directly generates the intermediate which would be the precursor for the formation of the *E*-isomer. The calculated intermediate from the nucleophilic attack always formed as a precursor for the formation of the *Z*-isomer. The formation of the *E*-product takes place through an isomerization step of the initially formed pro-*Z*-intermediate (Figure 1B). All the computed barriers are lower than 30.0 kcal mol⁻¹. The computed energy profiles suggest that the origin of the non-reaction observed in several cases was not in the barrier for the reaction, but rather in the steps beforehand (formation of the catalytically active species). Barriers are influenced by the nature of the alkali cation. The energy barriers were the highest with lithium and lowest with potassium which is in accordance with the experimental results of the best catalyst being the potassium complex and the worst being the lithium congener. The energy profile for the sodium-mediated reaction has barriers between potassium- and lithium-mediated reactions. Hence, it may be deduced that the identity of the alkali cation does play a significant role in the reaction mechanism, and it is inaccurate to look at alkali cations as spectators and as freely interchangeable. On the contrary, the energy barriers did not show significant difference amongst the different P-bound substituents, hence it was concluded that for P-bound Cy and OEt the prevailing factor which hinders this reaction is the lack of formation of the active mononuclear catalytic species.
Experimentally, the addition reaction is regioselective and yields the anti-Markovnikov product. The regioselectivity is decided at the nucleophilic addition stage. To figure out why there is no formation of the Markovnikov product, we computed the pathway leading to it for M = K and Ar = Mes. We were able to determine an energy barrier of 19.8 kcal mol⁻¹ for the formation of the Markovnikov intermediate, whilst on the other hand the energy barrier for the formation of anti-Markovnikov was only 7.3 kcal mol⁻¹. Another noteworthy difference between these two steps is the different stability of the intermediates. According to the estimated calculations the anti-Markovnikov intermediate has a relative energy of -6.2 kcal mol⁻¹ below separated reactants, whilst the Markovnikov intermediate lies 10.0 kcal mol⁻¹ above separated reactants. Hence, it may be concluded that the formation of the anti-Markovnikov intermediate is thermodynamically and kinetically preferred.

Calculations with a hydrogen atom (formally a proton) in the place of the metal ion were performed to assess the influence of the metal cation over the reaction barriers. This calculation was also conducted for P-bound mesityl substituents. Interestingly, the energy barrier almost doubles from 10.2 kcal mol⁻¹ for the potassium mediated reaction (Ar = Mes) to 20.1 kcal mol⁻¹ for the metal free reaction. We were able to provide additional proof that the metal cation cooperates and lowers the energy barrier significantly, thus verifying one more evidence that alkali cations are not only spectators but that they rather play a significant role in the mechanism. Our findings regarding the role of the alkali cations in reaction mechanisms match with previous findings.

Overall, for this section we were able to calculate the Gibbs energy of the reaction of formation of the active catalytic species, the modes of interaction and to fully determine the postulated mechanism for the reactions depicted in Table 1 and 2. This allowed us to gain some in-depth knowledge on the steps which govern the regio- and stereoselectivity and allowed us to determine the influence of the nature of the cation and of the P-bound groups in the catalytic cycle. As an example, the Gibbs energy profiles calculated for the formation of E- and Z-isomers for the potassium-mediated Pudovik reaction (Ar = Mes) are illustrated in Figure 1.

<figure><img src="image_80.png" /></figure>
Experimentally, the addition reaction is regioselective and yields the anti-Markovnikov product. The regioselectivity is decided at the nucleophilic addition stage. To figure out why there is no formation of the Markovnikov product, we computed the pathway leading to it for M = K and Ar = Mes. We were able to determine an energy barrier of 19.8 kcal mol⁻¹ for the formation of the Markovnikov intermediate, whilst on the other hand the energy barrier for the formation of anti-Markovnikov was only 7.3 kcal mol⁻¹. Another noteworthy difference between these two steps is the different stability of the intermediates. According to the estimated calculations the anti-Markovnikov intermediate has a relative energy of -6.2 kcal mol⁻¹ below separated reactants, whilst the Markovnikov intermediate lies 10.0 kcal mol⁻¹ above separated reactants. Hence, it may be concluded that the formation of the anti-Markovnikov intermediate is thermodynamically and kinetically preferred.

Calculations with a hydrogen atom (formally a proton) in the place of the metal ion were performed to assess the influence of the metal cation over the reaction barriers. This calculation was also conducted for P-bound mesityl substituents. Interestingly, the energy barrier almost doubles from 10.2 kcal mol⁻¹ for the potassium mediated reaction (Ar = Mes) to 20.1 kcal mol⁻¹ for the metal free reaction. We were able to provide additional proof that the metal cation cooperates and lowers the energy barrier significantly, thus verifying one more evidence that alkali cations are not only spectators but that they rather play a significant role in the mechanism. Our findings regarding the role of the alkali cations in reaction mechanisms match with previous findings.

Overall, for this section we were able to calculate the Gibbs energy of the reaction of formation of the active catalytic species, the modes of interaction and to fully determine the postulated mechanism for the reactions depicted in Table 1 and 2. This allowed us to gain some in-depth knowledge on the steps which govern the regio- and stereoselectivity and allowed us to determine the influence of the nature of the cation and of the P-bound groups in the catalytic cycle. As an example, the Gibbs energy profiles calculated for the formation of E- and Z-isomers for the potassium-mediated Pudovik reaction (Ar = Mes) are illustrated in Figure 1.

A)

<figure><img src="image_89.png" /></figure>
<figure><img src="image_81.png" /><figcaption>**Figure 1.** Computed Gibbs energy profiles in THF (ΔG<sub>THF</sub> in kcal mol<sup>-1</sup>) at 298 K for potassium-mediated hydrophosphorylation of phenylacetylene for the formation of Z-isomer (A) and E-isomer (B) with di(mesityl)phosphine oxide, using K-HMDS as precatalyst at a B3LYP-D3/Def2TZVP level of theory. (SM = starting materials, Int = initial intermediate. P-product, ACS = active catalytic species).</figcaption></figure>

## Pudovik reaction Part II: alkali metal-mediated addition of diphenylphosphine oxide across diphenylbutadiyne

The successful addition of di(aryl)phosphine oxides Ar<sub>2</sub>P(O)H across phenylacetylene using hexamethyldisilazanides (HMDS) of the alkali metals, we wanted to explore how the hydrophosphorylation of diphenylbutadiyne proceeds. Hence, we decided to test addition of diphenylphosphine oxide across 1,4-diphenylbutadiyne whilst using the same precatalysts (Scheme 5) as in the previous section. This part of the thesis was conducted at the industrial partner Italmatch.

<figure><img src="image_82.png" /><figcaption>**Scheme 5.** Alkali metal-mediated hydrophosphorylation of diphenylbutadiyne with diphenylphosphine oxide, using M-HMDS (M = Li, Na, K) at room temperature yielding 1,4-diphenyl-2,3-bis(diphenylphosphoryl)buta-1,3-diene.</figcaption></figure>

Experimentally, the same relationship than for phenylacetylene was found regarding the ability of the alkali metals (K > Na > Li) to catalyze the Pudovik reaction and their chemical hardness M<sup>+</sup> (M = Li, Na, K). The reactions yielded a single product, namely 1,4-diphenyl-2,3-bis(diphenylphosphoryl)buta-1,3-diene. The reaction proceeded regio- and stereoselectively. The generated alkenylphosphine oxide is an already known compound and a comparison of the NMR parameters confirmed its identity. This compound was also obtained in the reaction catalyzed by [(THF)<sub>4</sub>Ca(PPh<sub>2</sub>)<sub>2</sub>] [14]. The change from alkaline earth- to alkali metal-based catalysts did not change the regio and stereoselectivity of this addition reaction.
<figure><img src="image_90.png" /><figcaption>**Figure 1.** Computed Gibbs energy profiles in THF (ΔG<sub>THF</sub> in kcal mol<sup>-1</sup>) at 298 K for potassium-mediated hydrophosphorylation of phenylacetylene for the formation of Z-isomer (A) and E-isomer (B) with di(mesityl)phosphine oxide, using K-HMDS as precatalyst at a B3LYP-D3/Def2TZVP level of theory. (SM = starting materials, Int = initial intermediate. P-product, ACS = active catalytic species).</figcaption></figure>

Pudovik reaction Part II: alkali metal-mediated addition of diphenylphosphine oxide across diphenylbutadiyne

The successful addition of di(aryl)phosphine oxides Ar₂P(O)H across phenylacetylene using hexamethyldisilazanides (HMDS) of the alkali metals, we wanted to explore how the hydrophosphorylation of diphenylbutadiyne proceeds. Hence, we decided to test addition of diphenylphosphine oxide across 1,4-diphenylbutadiyne whilst using the same precatalysts (Scheme 5) as in the previous section. This part of the thesis was conducted at the industrial partner Italmatch.

<figure><img src="image_91.png" /><figcaption>**Scheme 5.** Alkali metal-mediated hydrophosphorylation of diphenylbutadiyne with diphenylphosphine oxide, using M-HMDS (M = Li, Na, K) at room temperature yielding 1,4-diphenyl-2,3-bis(diphenylphosphoryl)buta-1,3-diene.</figcaption></figure>

Experimentally, the same relationship than for phenylacetylene was found regarding the ability of the alkali metals (K > Na > Li) to catalyze the Pudovik reaction and their chemical hardness M⁺ (M = Li, Na, K). The reactions yielded a single product, namely 1,4-diphenyl-2,3-bis(diphenylphosphoryl)buta-1,3-diene. The reaction proceeded regio- and stereoselectively. The generated alkenylphosphine oxide is an already known compound and a comparison of the NMR parameters confirmed its identity. This compound was also obtained in the reaction catalyzed by [(THF)₄Ca(PPh₂)₂] [14]. The change from alkaline earth- to alkali metal-based catalysts did not change the regio and stereoselectivity of this addition reaction.
Intriguingly for this section, the metal cations change their preferred mode of interaction with the π-system when switching from acetylene to diyne derivatives. In the latter instance, the metal cations will preferably interact with the diyne system instead of the aryl ring (Figure 2).

<figure><img src="image_83.png" /><figcaption>**Figure 2.** Most stable conformations computed for interactions of 1,4-diphenylbutadiyne with M-OPPh₂ (M = Li (green), Na (purple), K(blue)). The binding energy ΔG was calculated in kcal mol⁻¹.</figcaption></figure>

As a basis of our hypothetical mechanism for this section, we took the mechanism already computed for phenylacetylene and described in the previous section (Figure 1). We are currently still in the process of ascertaining the regioselective TS for this Section. However, from the estimated energy barrier for the TSs for 1st nucleophilic attack, 1st protonation, 2nd nucleophilic attack and 2nd protonation we can say that they follow the same trend as the empirical findings when varying the alkali metal cation, i.e., the highest energy barriers for all the steps were estimated for lithium and lowest for potassium, whilst sodium displays energy barriers between these two.

## Alkali metal mediated hydrophosphination

In this part of the thesis, we focused on the formation of new C-P bonds via hydrophosphination of alkynes, i.e., alkali metal-mediated addition of mesitylphosphine across diphenylbutadiyne via hexamethyldisilazanides. More precisely, we focused on conducting a combined computational and experimental analysis with the aim to shed more light on the reaction mechanism involved in the intramolecular hydrophosphination of butadiynes (Scheme 6).

### Influence of the metal on hydrophosphination

To get accurate outcomes, we utilized freshly prepared alkali metal-mediated mesityl phosphinide and followed the methodology outlined below. The alkali metal phosphinide M-P(H)Mes was synthesized in situ by metalizing H₂PMes with 5 mol% of alkali metal hexamethyldisilazanides (M = Li, Na, and K), resulting in the corresponding metal phosphinide (Scheme 6). The ³¹P NMR spectroscopy was used to confirm quantitative conversion. Mesityl phosphine and 5 mol% M-HMDS were combined in 5 mL of THF in a Schlenk flask at room temperature, followed by an addition of a stoichiometric quantity of 1,4-diphenylbutadiene, upon which the aliquot was protolyzed with methanol and the resulting product was identified by ³¹P NMR spectroscopy.
Intriguingly for this section, the metal cations change their preferred mode of interaction with the π-system when switching from acetylene to diyne derivatives. In the latter instance, the metal cations will preferably interact with the diyne system instead of the aryl ring (Figure 2).

<figure><img src="image_92.png" /><figcaption>**Figure 2.** Most stable conformations computed for interactions of 1,4-diphenylbutadiyne with M-OPPh₂ (M = Li (green), Na (purple), K(blue)). The binding energy ΔG was calculated in kcal mol⁻¹.</figcaption></figure>

As a basis of our hypothetical mechanism for this section, we took the mechanism already computed for phenylacetylene and described in the previous section (Figure 1). We are currently still in the process of ascertaining the regioselective TS for this Section. However, from the estimated energy barrier for the TSs for 1st nucleophilic attack, 1st protonation, 2nd nucleophilic attack and 2nd protonation we can say that they follow the same trend as the empirical findings when varying the alkali metal cation, i.e., the highest energy barriers for all the steps were estimated for lithium and lowest for potassium, whilst sodium displays energy barriers between these two.

## Alkali metal mediated hydrophosphination

In this part of the thesis, we focused on the formation of new C-P bonds via hydrophosphination of alkynes, i.e., alkali metal-mediated addition of mesitylphosphine across diphenylbutadiyne via hexamethyldisilazanides. More precisely, we focused on conducting a combined computational and experimental analysis with the aim to shed more light on the reaction mechanism involved in the intramolecular hydrophosphination of butadiynes (Scheme 6).

### Influence of the metal on hydrophosphination

To get accurate outcomes, we utilized freshly prepared alkali metal-mediated mesityl phosphinide and followed the methodology outlined below. The alkali metal phosphinide M-P(H)Mes was synthesized in situ by metalizing H₂PMes with 5 mol% of alkali metal hexamethyldisilazanides (M = Li, Na, and K), resulting in the corresponding metal phosphinide (Scheme 6). The ³¹P NMR spectroscopy was used to confirm quantitative conversion. Mesityl phosphine and 5 mol% M-HMDS were combined in 5 mL of THF in a Schlenk flask at room temperature, followed by an addition of a stoichiometric quantity of 1,4-diphenylbutadiene, upon which the aliquot was protolyzed with methanol and the resulting product was identified by ³¹P NMR spectroscopy.
<figure><img src="image_84.png" /><figcaption>**Scheme 6.** Alkali metal-mediated hydrophosphination of diphenylbutadiyne with mesitylphosphine, using M-HMDS (M = Li, Na and K) at room temperature yielding 1-mesityl-2,5-diphenylphosphole.</figcaption></figure>

The outcome of the reactivity study is summarized in Table 3. In less than an hour 1-mesityl-2,5-diphenyl-1H-phosphole formed quantitatively at room temperature. Thus, it was deduced that the alkali metal-mediated hydrophosphination proceeded regio- and stereo-selectively to generate the 1H-phosphole. This process could not be mediated by the pre-catalysts based on harder alkali metals, such as Li-HMDS (entry 1). However, fast conversion was detected for the complexes of the heavier metals such as sodium and potassium (entries 2 and 3). Surprisingly, in the case of lithium-mediated hydrophosphination neither addition of 18-crown-6 nor increasing the reaction temperature increased the rate of conversion. The conversion rate was determined via ³¹P NMR spectroscopically after one hour and it remained unchanged after 24 hours. No other products were formed, thus indicating that the generated phosphole is the single product from the reaction under these reaction conditions.

<table><caption>**Table 3.** Dependency of the hydrophosphination (addition of mesitylphosphine across 1,4-diphenylbutadiyne) on the alkali metal of the tested bis(trimethylsilyl)amides as pre-catalysts.</caption><thead><tr><td>Entry</td><td>Metal</td><td>Conversion after 1h (%)</td></tr></thead><tbody><tr><td>1</td><td>Li</td><td>/</td></tr><tr><td>2</td><td>Na</td><td>63</td></tr><tr><td>3</td><td>K</td><td>&gt;99</td></tr></tbody></table>

Hence, the nature (hardness) of the alkali cation determines the conversion rate and, consequently, considering alkali cations as interchangeable and spectators in this hydrophosphination reaction is inherently wrong again.

### *Postulated reaction mechanism*

As we experimentally observed different conversion rates for the formation of the phosphole depending on the alkali metal atom, we investigated the mechanism of this reaction via theoretical methods to understand the influence and bonding pattern of the cation (cation hardness-reactivity relationship). Since the reaction strongly depends on the cation present in the system, the alkali cation cannot be neglected in our calculations. The postulated mechanism is depicted in Scheme 7. Before continuing onto discussing our postulated mechanism and the estimated energy barriers for those steps, it should be noted that Roesler *et al.* [15,16] have already proposed such a mechanism of formation of phosphole [17]. However, in their mechanism they suggested different reaction steps and the exclusion of the alkali cation i.e., they proposed a “naked” anionic mechanism. However, as experimentally verified in our case, we detected a dependence on the alkali cation and decided that incorporation of the cation in the postulated mechanism is imperative. Nonetheless, we also explored the reaction steps proposed by Roesler *et al.* in analogous manner for our model and we were able to exclude this proposal because it led to a higher energy barrier (above 25.0 kcal mol⁻¹).
<figure><img src="image_93.png" /><figcaption>**Scheme 6.** Alkali metal-mediated hydrophosphination of diphenylbutadiyne with mesitylphosphine, using M-HMDS (M = Li, Na and K) at room temperature yielding 1-mesityl-2,5-diphenylphosphole.</figcaption></figure>

The outcome of the reactivity study is summarized in Table 3. In less than an hour 1-mesityl-2,5-diphenyl-1H-phosphole formed quantitatively at room temperature. Thus, it was deduced that the alkali metal-mediated hydrophosphination proceeded regio- and stereo-selectively to generate the 1H-phosphole. This process could not be mediated by the pre-catalysts based on harder alkali metals, such as Li-HMDS (entry 1). However, fast conversion was detected for the complexes of the heavier metals such as sodium and potassium (entries 2 and 3). Surprisingly, in the case of lithium-mediated hydrophosphination neither addition of 18-crown-6 nor increasing the reaction temperature increased the rate of conversion. The conversion rate was determined via <sup>31</sup>P NMR spectroscopically after one hour and it remained unchanged after 24 hours. No other products were formed, thus indicating that the generated phosphole is the single product from the reaction under these reaction conditions.

<table><caption>**Table 3.** Dependency of the hydrophosphination (addition of mesitylphosphine across 1,4-diphenylbutadiyne) on the alkali metal of the tested bis(trimethylsilyl)amides as pre-catalysts.</caption><thead><tr><td>Entry</td><td>Metal</td><td>Conversion after 1h (%)</td></tr></thead><tbody><tr><td>1</td><td>Li</td><td>/</td></tr><tr><td>2</td><td>Na</td><td>63</td></tr><tr><td>3</td><td>K</td><td>&gt;99</td></tr></tbody></table>

Hence, the nature (hardness) of the alkali cation determines the conversion rate and, consequently, considering alkali cations as interchangeable and spectators in this hydrophosphination reaction is inherently wrong again.

### *Postulated reaction mechanism*

As we experimentally observed different conversion rates for the formation of the phosphole depending on the alkali metal atom, we investigated the mechanism of this reaction via theoretical methods to understand the influence and bonding pattern of the cation (cation hardness-reactivity relationship). Since the reaction strongly depends on the cation present in the system, the alkali cation cannot be neglected in our calculations. The postulated mechanism is depicted in Scheme 7. Before continuing onto discussing our postulated mechanism and the estimated energy barriers for those steps, it should be noted that Roesler *et al.* [15,16] have already proposed such a mechanism of formation of phosphole [17]. However, in their mechanism they suggested different reaction steps and the exclusion of the alkali cation i.e., they proposed a “naked” anionic mechanism. However, as experimentally verified in our case, we detected a dependence on the alkali cation and decided that incorporation of the cation in the postulated mechanism is imperative. Nonetheless, we also explored the reaction steps proposed by Roesler *et al.* in analogous manner for our model and we were able to exclude this proposal because it led to a higher energy barrier (above 25.0 kcal mol<sup>-1</sup>).
<figure><img src="image_85.png" /><figcaption>**Scheme 7.** Postulated mechanism for formation of the phosphole resulting from alkali metal-mediated hydrophosphination of diphenylbutadiyne (M = alkali metal).</figcaption></figure>

We propose that the initial step is the metalation of phosphine by M-HMDS (M = Li, Na, and K) in order to generate the active catalytic species (i.e. metal phosphinides). Before continuing with the discussion for the reaction mechanism we will discuss the thermodynamic feasibility of producing the alkali metal phosphinides that will act as the catalytic active species. The complexes M-P(H)Mes were synthesized *in situ* by metalating mesityl phosphines with alkali metal hexamethyldisilazanides according to reaction 2. The aggregation modes considered for M-HMDS (M = Li, Na, K) are identical to the ones used in the alkali metal-mediated Pudovik reaction.

$$ n \text{"MHMDS"} + n \text{MesPH}_2 \rightarrow n \text{H-HMDS} + n \text{"MP(H)Mes} \quad (2) $$

We estimated a dissociation energy of 34.6 kcal mol⁻¹ for Li-P(H)Mes formation, while the values for Na-P(H)Mes and K-P(H)Mes were 30.1 and 10.2 kcal mol⁻¹, respectively. This tendency of an increasing dissociation energy for the synthesis of active catalytic species in smaller congeners corresponded to the experimental trend of decreasing reactivity. As a result, this finding might be one of the factors prohibiting the lithium-mediated process giving rise to the active monometallic active species, compared to sodium- or potassium-mediated reactions. Having established the formation of the active catalytic species, we calculated the subsequent reaction steps. As an example, the Gibbs energy profile calculated for the most likely reaction pathway is illustrated in Figure 3 for potassium-mediated formation of phosphole, and the corresponding TS structures are depicted in Figure 4. The ensuing step was the addition of the metal-phosphorous bond onto the triple bond i.e., nucleophilic
<figure><img src="image_94.png" /><figcaption>**Scheme 7.** Postulated mechanism for formation of the phosphole resulting from alkali metal-mediated hydrophosphination of diphenylbutadiyne (M = alkali metal).</figcaption></figure>

We propose that the initial step is the metalation of phosphine by M-HMDS (M = Li, Na, and K) in order to generate the active catalytic species (i.e. metal phosphinides). Before continuing with the discussion for the reaction mechanism we will discuss the thermodynamic feasibility of producing the alkali metal phosphinides that will act as the catalytic active species. The complexes M-P(H)Mes were synthesized *in situ* by metalating mesityl phosphines with alkali metal hexamethyldisilazanides according to reaction 2. The aggregation modes considered for M-HMDS (M = Li, Na, K) are identical to the ones used in the alkali metal-mediated Pudovik reaction.

$$ n \text{"M HMDS"} + n \text{MesPH}_2 \rightarrow n \text{H-HMDS} + n \text{"M-P(H)Mes} \quad (2) $$

We estimated a dissociation energy of 34.6 kcal mol⁻¹ for Li-P(H)Mes formation, while the values for Na-P(H)Mes and K-P(H)Mes were 30.1 and 10.2 kcal mol⁻¹, respectively. This tendency of an increasing dissociation energy for the synthesis of active catalytic species in smaller congeners corresponded to the experimental trend of decreasing reactivity. As a result, this finding might be one of the factors prohibiting the lithium-mediated process giving rise to the active monometallic active species, compared to sodium- or potassium-mediated reactions. Having established the formation of the active catalytic species, we calculated the subsequent reaction steps. As an example, the Gibbs energy profile calculated for the most likely reaction pathway is illustrated in Figure 3 for potassium-mediated formation of phosphole, and the corresponding TS structures are depicted in Figure 4. The ensuing step was the addition of the metal-phosphorous bond onto the triple bond i.e., nucleophilic
attack from M-P(H)Ar onto the C<sub>internal</sub><sup>1</sup> from one of the C≡C triple bonds. This step showed a clear dependence on the metal cation. For this step we estimated energy barriers of 11.3 kcal mol<sup>-1</sup>, 11.9 kcal mol<sup>-1</sup>, and 16.9 kcal mol<sup>-1</sup> for potassium, sodium, and lithium, respectively. The intermediates for all three cations have Z configurations. This configuration is more suitable to proceed with ring closure through a nucleophilic attack onto the adjacent C<sub>internal</sub> triple bond unit yielding a 5-membered ring instead of E-intermediate. The latter intermediate would be more suitable to undergo double addition.

For the ensuing step to postulate a protonation step, instead of the isomerization as suggested by Roesler *et al.* [15], we were able to find two suitable routes: i) protonation by an additional molecule of mesitylphosphine or ii) protonation by an H-HMDS molecule. Regardless of the alkali cation present, the mesitylphosphine as a proton donor was favored with a slight preference of 2-3 kcal mol<sup>-1</sup> over H-HMDS. As the energy difference is so small it might be obvious that in the reaction mixture both molecules acted as proton donors. Regarding the cation, the energy barrier for the protonation varied from the lowest 4.9 kcal mol<sup>-1</sup> for potassium to the highest 16.8 kcal mol<sup>-1</sup> for the lithium case. It should be noted that during this step regeneration of M-P(H)Mes or M-HMDS ensued. We also checked the possibility of an intramolecular protonation via a phosphorous to carbon 1,4-proton migration. However, the lowest energy barrier we estimated for this process (24.1 kcal mol<sup>-1</sup>, potassium case) is much higher than that of the intermolecular mechanism commented above, and hence it was ruled out. Having fully formed Z-mono-phosphinated product, the ensuing step would be the deprotonation of the P-bound proton. We determined that the anions generated in the previous protonation step are able to do the deprotonation of the P-H proton. The estimated deprotonations were conducted with M-P(H)Mes and their barriers fell in the range between 7.6 (M = K) and 11.4 kcal mol<sup>-1</sup> (M = Li), whilst for M-Na we estimated a middle barrier of 9.2 kcal mol<sup>-1</sup>.

Having removed the proton, the ensuing step is the ring closure through a nucleophilic attack of phosphorous onto the adjacent C<sub>internal</sub> of the triple bond unit yielding a 5-membered ring (Figure 3). For this step we estimated energy barriers of 19.9 kcal mol<sup>-1</sup>, 22.0 kcal mol<sup>-1</sup>, and 16.5 kcal mol<sup>-1</sup> for potassium, sodium, and lithium, respectively. The final step yielding the phosphole was also estimated to proceed via the two routes as the previous protonation step. In this step, regeneration of M-P(H)Mes or M-HMDS, akin to the first protonation step, will proceed. The newly formed M-P(H)Mes or M-HMDS could be looped back into the catalytic cycle and as such they would be able to start the catalytic cycle again. It is noteworthy to mention that experimentally only formation of phosphole was observed.

<footnote n="1">¹ By C₁ or C<sub>internal</sub> we mean the C atom closest to the phenyl from the one of C≡C triple bonds present in the butadiyne.</footnote>
attack from M-P(H)Ar onto the C<sub>internal</sub><sup>1</sup> from one of the C≡C triple bonds. This step showed a clear dependence on the metal cation. For this step we estimated energy barriers of 11.3 kcal mol<sup>-1</sup>, 11.9 kcal mol<sup>-1</sup>, and 16.9 kcal mol<sup>-1</sup> for potassium, sodium, and lithium, respectively. The intermediates for all three cations have Z configurations. This configuration is more suitable to proceed with ring closure through a nucleophilic attack onto the adjacent C<sub>internal</sub> triple bond unit yielding a 5-membered ring instead of E-intermediate. The latter intermediate would be more suitable to undergo double addition.

For the ensuing step to postulate a protonation step, instead of the isomerization as suggested by Roesler *et al.* [15], we were able to find two suitable routes: i) protonation by an additional molecule of mesitylphosphine or ii) protonation by an H-HMDS molecule. Regardless of the alkali cation present, the mesitylphosphine as a proton donor was favored with a slight preference of 2-3 kcal mol<sup>-1</sup> over H-HMDS. As the energy difference is so small it might be obvious that in the reaction mixture both molecules acted as proton donors. Regarding the cation, the energy barrier for the protonation varied from the lowest 4.9 kcal mol<sup>-1</sup> for potassium to the highest 16.8 kcal mol<sup>-1</sup> for the lithium case. It should be noted that during this step regeneration of M-P(H)Mes or M-HMDS ensued. We also checked the possibility of an intramolecular protonation via a phosphorous to carbon 1,4-proton migration. However, the lowest energy barrier we estimated for this process (24.1 kcal mol<sup>-1</sup>, potassium case) is much higher than that of the intermolecular mechanism commented above, and hence it was ruled out. Having fully formed Z-mono-phosphinated product, the ensuing step would be the deprotonation of the P-bound proton. We determined that the anions generated in the previous protonation step are able to do the deprotonation of the P-H proton. The estimated deprotonations were conducted with M-P(H)Mes and their barriers fell in the range between 7.6 (M = K) and 11.4 kcal mol<sup>-1</sup> (M = Li), whilst for M-Na we estimated a middle barrier of 9.2 kcal mol<sup>-1</sup>.

Having removed the proton, the ensuing step is the ring closure through a nucleophilic attack of phosphorous onto the adjacent C<sub>Internal</sub> of the triple bond unit yielding a 5-membered ring (Figure 3). For this step we estimated energy barriers of 19.9 kcal mol<sup>-1</sup>, 22.0 kcal mol<sup>-1</sup>, and 16.5 kcal mol<sup>-1</sup> for potassium, sodium, and lithium, respectively. The final step yielding the phosphole was also estimated to proceed via the two routes as the previous protonation step. In this step, regeneration of M-P(H)Mes or M-HMDS, akin to the first protonation step, will proceed. The newly formed M-P(H)Mes or M-HMDS could be looped back into the catalytic cycle and as such they would be able to start the catalytic cycle again. It is noteworthy to mention that experimentally only formation of phosphole was observed.

<footnote n="1">¹ By C₁ or C<sub>Internal</sub> we mean the C atom closest to the phenyl from the one of C≡C triple bonds present in the butadiyne.</footnote>
<figure><img src="image_86.png" /><figcaption>**Figure 3.** Computed Gibbs energy profile in THF (ΔG<sub>THF</sub> kcal mol<sup>-1</sup>) at 298 K for potassium-mediated formation of phosphole at a B3LYP-D3/Def2TZVP level of theory.</figcaption></figure>
<figure><img src="image_95.png" /><figcaption>**Figure 3.** Computed Gibbs energy profile in THF (ΔG<sub>THF</sub> kcal mol<sup>-1</sup>) at 298 K for potassium-mediated formation of phosphole at a B3LYP-D3/Def2TZVP level of theory.</figcaption></figure>
<figure><img src="image_87.png" /><figcaption>**Figure 4.** Optimized structures for transition states of the potassium-mediated formation of phosphole. Certain H atoms are omitted for clarity reasons. Distances are shown in Å.</figcaption></figure>

## Oxidation of 2,5-disubstituted 1-*H*-phosphole and subsequent [2+2]-dimerization

Hitherto, chalcogen derivatives of phospholes are known adducts. The successful formation of the 1-mesityl-2,5-diphenyl-1*H*-phosphole convinced us to add an additional topic to this thesis: oxidation of 1-mesityl-2,5-diphenylphosphole [18-21]. We wanted to explore this topic to see how the addition of a chalcogen element would influence the properties of 2,5-disubstituted phospholes. Albeit we were trying to synthesize solely the phosphole oxide we serendipitously synthesized also the “head-to-tail” dimer of the phosphole oxide formed by a [2+2]-cycloaddition (Scheme 8). It should be noted that akin structures have been reported, more specifically, the [2+2]-cycloadduct of 1,2,5-triphenylphosphole has been obtained by irradiation [22]. Moreover, the [2+2]-cycloaddition product of the 1,2,5-triphenylphosphole oxide was obtained by oxidation of the parent phosphole by the water adduct of di(hydroperoxy)adamantane [23]. Looking through the literature and simultaneously conducting our own experiments we concluded that the newly formed dimer was generated by photo induction [24-26]. Hence, we decided to conduct combined experimental and theoretical studies on oxidation of 2,5-disubstituted 1*H*-phosphole and subsequent [2+2]-dimerization. To the best of our knowledge there is no such study conducted thus far.
<figure><img src="image_96.png" /><figcaption>**Figure 4.** Optimized structures for transition states of the potassium-mediated formation of phosphole. Certain H atoms are omitted for clarity reasons. Distances are shown in Å.</figcaption></figure>

## Oxidation of 2,5-disubstituted 1-*H*-phosphole and subsequent [2+2]-dimerization

Hitherto, chalcogen derivatives of phospholes are known adducts. The successful formation of the 1-mesityl-2,5-diphenyl-1*H*-phosphole convinced us to add an additional topic to this thesis: oxidation of 1-mesityl-2,5-diphenylphosphole [18-21]. We wanted to explore this topic to see how the addition of a chalcogen element would influence the properties of 2,5-disubstituted phospholes. Albeit we were trying to synthesize solely the phosphole oxide we serendipitously synthesized also the “head-to-tail” dimer of the phosphole oxide formed by a [2+2]-cycloaddition (Scheme 8). It should be noted that akin structures have been reported, more specifically, the [2+2]-cycloadduct of 1,2,5-triphenylphosphole has been obtained by irradiation [22]. Moreover, the [2+2]-cycloaddition product of the 1,2,5-triphenylphosphole oxide was obtained by oxidation of the parent phosphole by the water adduct of di(hydroperoxy)adamantane [23]. Looking through the literature and simultaneously conducting our own experiments we concluded that the newly formed dimer was generated by photo induction [24-26]. Hence, we decided to conduct combined experimental and theoretical studies on oxidation of 2,5-disubstituted 1*H*-phosphole and subsequent [2+2]-dimerization. To the best of our knowledge there is no such study conducted thus far.
<figure><img src="image_88.png" /><figcaption>**Scheme 8.** Experimental conditions of the [2+2] cycloaddition reaction examined in this study.</figcaption></figure>

### Computed reaction mechanism for oxidation and subsequent [2+2]-dimerization of 2,5-diphenylphosphole oxide

Before postulating and determining the energy barrier for the dimerization of 1-mesityl-2,5-diphenylphosphole oxide we attempted to determine the energy barrier for the oxidation step, using $H_2O_2$ as oxidant. We found that the oxidation proceeded by a single step, with an energy barrier of 20.6 kcal mol$^{-1}$. The obtained phosphole oxide may be found at -78.0 kcal mol$^{-1}$ below separated reactants, thus making this step very exergonic.

Having estimated the energy barrier with which the oxidation will proceed, we analyzed the mechanism by which the [2+2]-cycloaddition product formed. We first studied the photochemically induced excitation of the phosphole oxide, which happens upon absorption of light, by means of Time-Dependent DFT calculations (TD-DFT) (Scheme 9).

<figure><img src="image_89.png" /><figcaption>**Scheme 9.** Optimized structures for $S_0$, $T_1$ and $S_1$ (from left to right) involved in the [2+2]-cycloaddition via light excitation leading to the [2+2]-cycloaddition product. The unpaired electrons are expressed with red arrows. Distances are shown in Å.</figcaption></figure>

Phosphole oxide is excited from the ground singlet electronic state ($S_0$) to the first singlet excited state ($S_1$), that evolves to the more stable triplet species ($T_1$). $S_1$ can be reached with an excitation of 2.82 eV, feasible under visible light irradiation. The triplet state $T_1$ lies below $S_1$, at 1.52 eV. The structures for the excited states which participate in the mechanism are depicted in Scheme 9. In this scheme we can see that the $S_1$ species presents noticeable structural differences with respect to the ground state geometry: it has one double bond in the phosphole ring instead of two i.e., the distances $C_1-C_2$ and $C_3-C_4$ are elongated by 0.07 Å, whilst the $C_2-C_3$ distance is shortened by 0.08 Å in comparison to the $S_0$ state. Conversion from singlet excited species to triplet excited species will proceed via an intersystem crossing process (ISC).

The configuration of the $T_1$ state is similar to the configuration of the $S_1$ state, with elongation and shortening of 0.02 Å for $C_1-C_2$ and $C_3-C_4$ and $C_2-C_3$ distance respectively. This change in bond lengths is induced by a change in the electron delocalization upon excitation. This species is a biradical, with two unpaired electrons at $C_1$ and $C_4$ carbon atoms of the ring. This phosphole oxide biradical
<figure><img src="image_97.png" /><figcaption>**Scheme 8.** Experimental conditions of the [2+2] cycloaddition reaction examined in this study.</figcaption></figure>

### Computed reaction mechanism for oxidation and subsequent [2+2]-dimerization of 2,5-diphenylphosphole oxide

Before postulating and determining the energy barrier for the dimerization of 1-mesityl-2,5-diphenylphosphole oxide we attempted to determine the energy barrier for the oxidation step, using $H_2O_2$ as oxidant. We found that the oxidation proceeded by a single step, with an energy barrier of 20.6 kcal mol$^{-1}$. The obtained phosphole oxide may be found at -78.0 kcal mol$^{-1}$ below separated reactants, thus making this step very exergonic.

Having estimated the energy barrier with which the oxidation will proceed, we analyzed the mechanism by which the [2+2]-cycloaddition product formed. We first studied the photochemically induced excitation of the phosphole oxide, which happens upon absorption of light, by means of Time-Dependent DFT calculations (TD-DFT) (Scheme 9).

<figure><img src="image_98.png" /><figcaption>**Scheme 9.** Optimized structures for $S_0$, $T_1$ and $S_1$ (from left to right) involved in the [2+2]-cycloaddition via light excitation leading to the [2+2]-cycloaddition product. The unpaired electrons are expressed with red arrows. Distances are shown in Å.</figcaption></figure>

Phosphole oxide is excited from the ground singlet electronic state ($S_0$) to the first singlet excited state ($S_1$), that evolves to the more stable triplet species ($T_1$). $S_1$ can be reached with an excitation of 2.82 eV, feasible under visible light irradiation. The triplet state $T_1$ lies below $S_1$, at 1.52 eV. The structures for the excited states which participate in the mechanism are depicted in Scheme 9. In this scheme we can see that the $S_1$ species presents noticeable structural differences with respect to the ground state geometry: it has one double bond in the phosphole ring instead of two i.e., the distances $C_1-C_2$ and $C_3-C_4$ are elongated by 0.07 Å, whilst the $C_2-C_3$ distance is shortened by 0.08 Å in comparison to the $S_0$ state. Conversion from singlet excited species to triplet excited species will proceed via an intersystem crossing process (ISC).

The configuration of the $T_1$ state is similar to the configuration of the $S_1$ state, with elongation and shortening of 0.02 Å for $C_1-C_2$ and $C_3-C_4$ and $C_2-C_3$ distance respectively. This change in bond lengths is induced by a change in the electron delocalization upon excitation. This species is a biradical, with two unpaired electrons at $C_1$ and $C_4$ carbon atoms of the ring. This phosphole oxide biradical
participates in the dimerization process, following the steps depicted in the Gibbs energy profile of the dimerization reaction (Figure 5). The optimized transition state structures associated with this reaction mechanism are depicted in Figure 6.

<figure><img src="image_90.png" /><figcaption>**Figure 5.** Computed Gibbs energy diagram in THF (ΔG<sub>THF</sub> kcal mol<sup>-1</sup>) at 298 K for formation of the [2+2] cycloaddition product at a B3LYP-D3/Def2TZVP level of theory.</figcaption></figure>

<figure><img src="image_91.png" /><figcaption>**Figure 6.** Selected optimized structures for the transition state and the MECP involved in the mechanism for formation of the [2+2]-cycloaddition product. Certain H atoms are omitted for clarity reasons. The distances presented are given in Å.</figcaption></figure>

The excited triplet phosphole molecule will then react with an additional phosphole, leading to formation of a C-C bond. This reaction takes place in the triplet electronic state. Right after this step, the system reaches the intersystem crossing point (minimum energy crossing point, MECP), relaxes to the singlet state and forms the second C-C bond which closes the four-membered ring. The Gibbs energy diagram shows that the light-induced [2+2]-dimerization in the P(V) derivative is an exergonic process by 20.8 kcal mol<sup>-1</sup>. Hence, it may be deduced that the formation of the first C-C bond is the most energy-intensive step and involves an energy barrier of 16.2 kcal mol<sup>-1</sup>. We have also performed computational studies on the formation of the Diels-Alder [4+2]-cycloadducts from 1-mesityl-2,5-
participates in the dimerization process, following the steps depicted in the Gibbs energy profile of the dimerization reaction (Figure 5). The optimized transition state structures associated with this reaction mechanism are depicted in Figure 6.

<figure><img src="image_99.png" /><figcaption>**Figure 5.** Computed Gibbs energy diagram in THF (ΔG<sub>THF</sub> kcal mol<sup>-1</sup>) at 298 K for formation of the [2+2] cycloaddition product at a B3LYP-D3/Def2TZVP level of theory.</figcaption></figure>

<figure><img src="image_100.png" /><figcaption>**Figure 6.** Selected optimized structures for the transition state and the MECP involved in the mechanism for formation of the [2+2]-cycloaddition product. Certain H atoms are omitted for clarity reasons. The distances presented are given in Å.</figcaption></figure>

The excited triplet phosphole molecule will then react with an additional phosphole, leading to formation of a C-C bond. This reaction takes place in the triplet electronic state. Right after this step, the system reaches the intersystem crossing point (minimum energy crossing point, MECP), relaxes to the singlet state and forms the second C-C bond which closes the four-membered ring. The Gibbs energy diagram shows that the light-induced [2+2]-dimerization in the P(V) derivative is an exergonic process by 20.8 kcal mol<sup>-1</sup>. Hence, it may be deduced that the formation of the first C-C bond is the most energy-intensive step and involves an energy barrier of 16.2 kcal mol<sup>-1</sup>. We have also performed computational studies on the formation of the Diels-Alder [4+2]-cycloadducts from 1-mesityl-2,5-
diphenylphosphole oxide by thermal activation. The computed barrier is much higher than that for the formation of the [2+2] adduct.

However, the preference for the formation of a syn-anti and simultaneously a "head-to-tail" arrangement in the adduct over the anti-anti, syn-syn and "head-to-head" would need to be explored in more depth in the future. Nonetheless, this ordination does allow for the best interactions from steric point of view.

## Conclusions

The objectives of this project included the elucidation of the key points for influencing the stereo- and regio-selective outcome during catalytic P-C bond formation across unsaturated substrates and to clarify the mode of action for the alkali metal ions during the reaction by means of experimental and mechanistic studies. More concretely, in this work we focused on clarifying the reaction mechanism for the alkali metal-mediated Pudovik reaction, the addition of secondary phosphine oxides across phenylacetylene and 1,4-diphenylbutadiyne via alkali metal hexamethyldidilazides (M-HMDS; M = Li, Na and K). Additionally, we investigated the addition of mesityl phosphine across 1,4-diphenylbutadiyne, promoted by the same pre-catalyst (M-HMDS; M = Li, Na, and K). This addition reaction yielded 1-mesityl-2,5-diphenylphosphole as the single product. Hence, we subsequently investigated the oxidation of the newly formed phosphole and its subsequent [2+2]-photo cycloaddition as additional objective both experimentally and theoretically.

In summary, we were able to achieve most of our objectives, however, we are still in the process of completion of the reaction mechanism for the addition of the alkali metal-mediated Pudovik reaction promoted by M-HMDS. Theoretical investigations on already published reactions and newly obtained experimental results for the alkali metal-catalyzed Pudovik reaction revealed the intricacy of these processes and offered a detailed description of the reaction mechanisms. To the best of our knowledge, these are the first reported mechanistic investigations on alkali metal-mediated Pudovik reactions. These calculations detailed the bonding mode of the alkali cations with the alkyne groups and the aryl substituents and how these modes influence the outcome of the reaction (i.e., the stereoselectivity, the conversion rate, etc.).

From the experimental results it can be deduced that the metal cations play a crucial role as the conversion showed dependence on the softness and the radius of the metal ions, regardless if we used P(III) or P(V) compounds for the addition. Overall, the lighter s-block metal congener Li-HMDS was not able to mediate any of the reactions, whilst the congeners of the heavier alkali metal bis(trimethylsilyl)amides M-HMDS (M = K and Na) effectively promoted both the hydrophosphination and the hydrophosphorylation. Therefore, we confirmed theoretically and experimentally that these cations are not only "spectator" species, but they rather play a significant role in the outcome of these conversions in each step of the reaction. Theoretical results also indicate that generation of the active monometallic species from the more stable aggregates is crucial for the activity shown by the metal. The new proposed method of phosphole synthesis in a single pot and at room temperature offers an alternative approach which may be implemented later for the synthesis of polyphospholes, which are highly promising material for use as organic light-emitting diodes (OLED) [18,20]. The serendipitous formation of the [2+2]-photo-cycloaddition product disclosed another property of phosphole oxides, which would need to be explored in the future.

These discoveries emphasize the potential that alkali metal-based catalysts hold for future catalytic applications, especially for formation of stereo- and regio-selective P-C bonds. Thus, it can be
diphenylphosphole oxide by thermal activation. The computed barrier is much higher than that for the formation of the [2+2] adduct.

However, the preference for the formation of a syn-anti and simultaneously a "head-to-tail" arrangement in the adduct over the anti-anti, syn-syn and "head-to-head" would need to be explored in more depth in the future. Nonetheless, this ordination does allow for the best interactions from steric point of view.

## Conclusions

The objectives of this project included the elucidation of the key points for influencing the stereo- and regio-selective outcome during catalytic P-C bond formation across unsaturated substrates and to clarify the mode of action for the alkali metal ions during the reaction by means of experimental and mechanistic studies. More concretely, in this work we focused on clarifying the reaction mechanism for the alkali metal-mediated Pudovik reaction, the addition of secondary phosphine oxides across phenylacetylene and 1,4-diphenylbutadiyne via alkali metal hexamethyldidilazides (M-HMDS; M = Li, Na and K). Additionally, we investigated the addition of mesityl phosphine across 1,4-diphenylbutadiyne, promoted by the same pre-catalyst (M-HMDS; M = Li, Na, and K). This addition reaction yielded 1-mesityl-2,5-diphenylphosphole as the single product. Hence, we subsequently investigated the oxidation of the newly formed phosphole and its subsequent [2+2]-photo cycloaddition as additional objective both experimentally and theoretically.

In summary, we were able to achieve most of our objectives, however, we are still in the process of completion of the reaction mechanism for the addition of the alkali metal-mediated Pudovik reaction promoted by M-HMDS. Theoretical investigations on already published reactions and newly obtained experimental results for the alkali metal-catalyzed Pudovik reaction revealed the intricacy of these processes and offered a detailed description of the reaction mechanisms. To the best of our knowledge, these are the first reported mechanistic investigations on alkali metal-mediated Pudovik reactions. These calculations detailed the bonding mode of the alkali cations with the alkyne groups and the aryl substituents and how these modes influence the outcome of the reaction (i.e., the stereoselectivity, the conversion rate, etc.).

From the experimental results it can be deduced that the metal cations play a crucial role as the conversion showed dependence on the softness and the radius of the metal ions, regardless if we used P(III) or P(V) compounds for the addition. Overall, the lighter s-block metal congener Li-HMDS was not able to mediate any of the reactions, whilst the congeners of the heavier alkali metal bis(trimethylsilyl)amides M-HMDS (M = K and Na) effectively promoted both the hydrophosphination and the hydrophosphorylation. Therefore, we confirmed theoretically and experimentally that these cations are not only "spectator" species, but they rather play a significant role in the outcome of these conversions in each step of the reaction. Theoretical results also indicate that generation of the active monometallic species from the more stable aggregates is crucial for the activity shown by the metal. The new proposed method of phosphole synthesis in a single pot and at room temperature offers an alternative approach which may be implemented later for the synthesis of polyphospholes, which are highly promising material for use as organic light-emitting diodes (OLED) [18,20]. The serendipitous formation of the [2+2]-photo-cycloaddition product disclosed another property of phosphole oxides, which would need to be explored in the future.

These discoveries emphasize the potential that alkali metal-based catalysts hold for future catalytic applications, especially for formation of stereo- and regio-selective P-C bonds. Thus, it can be
deduced that the understanding of reaction mechanisms is highly advantageous for the development of non-toxic and easily available catalysts for future applications in homogeneous catalytic reactions. Expansion of this concept might lead to interesting applications also in hydrogenation, hydrosilylation, and hydroamination processes and beyond.

## References

[1] T. M. A. Al-Shboul, V. K. Pálfi, L. A. Yu, R. Kretschmer, K. Wimmer, R. Fischer, H. Görls, M. Reiher, M. Westerhausen, *J. Organomet. Chem.* **2011**, *696*, 216–227. DOI: **10.1016/j.jorganchem.2010.08.058**.

[2] S. Krieck, M. Westerhausen, *Inorganics* **2017**, *5*, 17. DOI: **10.3390/inorganics5010017**.

[3] C. A. Bange, R. Waterman, *Chem. Eur. J.* **2016**, *22*, 12598–12605. DOI: **10.1002/chem.201602749**.

[4] S. Lau, T. M. Hood, R. L. Webster, *ACS Catal.* **2022**, *12*, 10939–10949. DOI: **10.1021/acscatal.2c03144**.

[5] B. T. Novas, R. Waterman, *ChemCatChem* **2022**, *14*, e202200988. DOI: **10.1002/cctc.202200988**.

[6] M. T. Whitelaw, S. Banerjee, A. R. Kennedy, A. Van Teijlingen, T. Tuttle, R. E. Mulvey, *Cell Rep.* **2022**, *3*, 100942. DOI: **10.1016/j.xcrp.2022.100942**.

[7] A. W. J. Platten, A. M. Borys, E. Hevia, *ChemCatChem* **2022**, *14*, e202101853. DOI: **10.1002/cctc.202101853**.

[8] B. E. Fener, P. Schüler, N. Ueberschaar, P. Bellstedt, H. Görls, S. Krieck, M. Westerhausen, *Chem. Eur. J.* **2020**, *26*, 7235–7243. DOI: **10.1002/chem.201905565**.

[9] S. M. Härling, B. E. Fener, S. Krieck, H. Görls, M. Westerhausen, *Organometallics* **2018**, *37*, 4380–4386. DOI: **10.1021/acs.organomet.8b00368**.

[10] V. Koshti, S. Gaikwad, S. H. Chikkali, *Coord. Chem. Rev.* **2014**, *265*, 52–73. DOI: **10.1016/j.ccr.2014.01.006**.

[11] K. Hirano, M. Miura, *Tetrahedron Lett.* **2017**, *58*, 4317–4322. DOI: **10.1016/j.tetlet.2017.10.018**.

[12] R. A. Bartlett, M. M. Olmstead, P. P. Power, G. A. Sigel, *Inorg. Chem.* **1987**, *26*, 1941–1946. DOI: **10.1021/ic00259a026**.

[13] S. M. Härling, B. E. Fener, S. Krieck, H. Görls, M. Westerhausen, *Organometallics* **2018**, *37*, 4380–4386. DOI: **10.1021/acs.organomet.8b00368**.

[14] T. M. A. Al-Shboul, H. Görls, S. Krieck, M. Westerhausen, *Eur. J. Inorg. Chem.* **2012**, 5451–5455. DOI: **10.1002/ejic.201201138**.

[15] F. Roesler, M. Kovács, C. Bruhn, Z. Kelemen, R. Pietschnig, *Organometallics* **2023**, *42*, 793–802. DOI: **10.1021/acs.organomet.3c00019**.

[16] F. Roesler, M. Kovács, C. Bruhn, Z. Kelemen, R. Pietschnig, *Chem. Eur. J.* **2021**, *27*, 9782–9790. DOI: **10.1002/chem.202101298**.

[17] Y. Matano, M. Nakashima, H. Imahori, *Angew. Chem., Int. Ed.* **2009**, *121*, 4062–4065. DOI: **10.1002/ange.200900542**.

[18] M. Hissler, C. Lescop, R. Réau, *Compt. Rend. Chim.* **2008**, *11*, 628–640. DOI: **10.1016/j.crci.2008.01.010**.

[19] L. D. Quin, X. P. Wu, *Heteroat. Chem.* **1991**, *2*, 359–367. DOI: **10.1002/hc.520020303**.

[20] D. Joly, D. Tondelier, V. Deborde, B. Geffroy, M. Hissler, R. Réau, *New J. Chem.* **2010**, *34*, 1603. DOI: **10.1039/c0nj00122h**.

[21] E. Deschamps, L. Ricard, F. Mathey, *ChemInform* **1994**, *25*(44). DOI: **10.1002/chin.199444188**.

[22] T. J. Barton, A. Nelson, *Tetrahedron Lett.* **1969**, *10*, 5037–5040. DOI: **10.1016/S0040-4039(01)88878-X**.

[23] F. F. Arp, R. Ashirov, N. Bhuvanesh, J. Blümel, *Dalton Trans.* **2021**, *50*, 15296–15309. DOI: **10.1039/d1dt03243g**.

[24] M. P. Duffy, Y. Lin, L. Y. Ting, F. Mathey, *New J. Chem.* **2011**, *35*, 2001–2003. DOI: **10.1039/c1nj20087a**.

[25] G. Bousrez, E. Nicolas, A. Martinez, S. Chevreux, F. Jaroschik, *Heteroatom Chem.* **2019**, *1–10*. DOI: **10.1155/2019/2596405**.

[26] Y. Matano, *Phospholes and Related Compounds: Syntheses, Redox Properties, and Applications to Organic Electronic Devices*, in *Organic Redox Systems* (T. Nishinaga, Editor), Wiley: **2016**, pp 477–501 (Wiley, 2016). DOI: **10.1002/9781118858981.ch16**.
deduced that the understanding of reaction mechanisms is highly advantageous for the development of non-toxic and easily available catalysts for future applications in homogeneous catalytic reactions. Expansion of this concept might lead to interesting applications also in hydrogenation, hydrosilylation, and hydroamination processes and beyond.

## References

[1] T. M. A. Al-Shboul, V. K. Pálfi, L. A. Yu, R. Kretschmer, K. Wimmer, R. Fischer, H. Görls, M. Reiher, M. Westerhausen, *J. Organomet. Chem.* **2011**, *696*, 216–227. DOI: **10.1016/j.jorganchem.2010.08.058**.

[2] S. Krieck, M. Westerhausen, *Inorganics* **2017**, *5*, 17. DOI: **10.3390/inorganics5010017**.

[3] C. A. Bange, R. Waterman, *Chem. Eur. J.* **2016**, *22*, 12598–12605. DOI: **10.1002/chem.201602749**.

[4] S. Lau, T. M. Hood, R. L. Webster, *ACS Catal.* **2022**, *12*, 10939–10949. DOI: **10.1021/acscatal.2c03144**.

[5] B. T. Novas, R. Waterman, *ChemCatChem* **2022**, *14*, e202200988. DOI: **10.1002/cctc.202200988**.

[6] M. T. Whitelaw, S. Banerjee, A. R. Kennedy, A. Van Teijlingen, T. Tuttle, R. E. Mulvey, *Cell Rep.* **2022**, *3*, 100942. DOI: **10.1016/j.xcrp.2022.100942**.

[7] A. W. J. Platten, A. M. Borys, E. Hevia, *ChemCatChem* **2022**, *14*, e202101853. DOI: **10.1002/cctc.202101853**.

[8] B. E. Fener, P. Schüler, N. Ueberschaar, P. Bellstedt, H. Görls, S. Krieck, M. Westerhausen, *Chem. Eur. J.* **2020**, *26*, 7235–7243. DOI: **10.1002/chem.201905565**.

[9] S. M. Härling, B. E. Fener, S. Krieck, H. Görls, M. Westerhausen, *Organometallics* **2018**, *37*, 4380–4386. DOI: **10.1021/acs.organomet.8b00368**.

[10] V. Koshti, S. Gaikwad, S. H. Chikkali, *Coord. Chem. Rev.* **2014**, *265*, 52–73. DOI: **10.1016/j.ccr.2014.01.006**.

[11] K. Hirano, M. Miura, *Tetrahedron Lett.* **2017**, *58*, 4317–4322. DOI: **10.1016/j.tetlet.2017.10.018**.

[12] R. A. Bartlett, M. M. Olmstead, P. P. Power, G. A. Sigel, *Inorg. Chem.* **1987**, *26*, 1941–1946. DOI: **10.1021/ic00259a026**.

[13] S. M. Härling, B. E. Fener, S. Krieck, H. Görls, M. Westerhausen, *Organometallics* **2018**, *37*, 4380–4386. DOI: **10.1021/acs.organomet.8b00368**.

[14] T. M. A. Al-Shboul, H. Görls, S. Krieck, M. Westerhausen, *Eur. J. Inorg. Chem.* **2012**, 5451–5455. DOI: **10.1002/ejic.201201138**.

[15] F. Roesler, M. Kovács, C. Bruhn, Z. Kelemen, R. Pietschnig, *Organometallics* **2023**, *42*, 793–802. DOI: **10.1021/acs.organomet.3c00019**.

[16] F. Roesler, M. Kovács, C. Bruhn, Z. Kelemen, R. Pietschnig, *Chem. Eur. J.* **2021**, *27*, 9782–9790. DOI: **10.1002/chem.202101298**.

[17] Y. Matano, M. Nakashima, H. Imahori, *Angew. Chem., Int. Ed.* **2009**, *121*, 4062–4065. DOI: **10.1002/ange.200900542**.

[18] M. Hissler, C. Lescop, R. Réau, *Compt. Rend. Chim.* **2008**, *11*, 628–640. DOI: **10.1016/j.crci.2008.01.010**.

[19] L. D. Quin, X. P. Wu, *Heteroat. Chem.* **1991**, *2*, 359–367. DOI: **10.1002/hc.520020303**.

[20] D. Joly, D. Tondelier, V. Deborde, B. Geffroy, M. Hissler, R. Réau, *New J. Chem.* **2010**, *34*, 1603. DOI: **10.1039/c0nj00122h**.

[21] E. Deschamps, L. Ricard, F. Mathey, *ChemInform* **1994**, *25*(44). DOI: **10.1002/chin.199444188**.

[22] T. J. Barton, A. Nelson, *Tetrahedron Lett.* **1969**, *10*, 5037–5040. DOI: **10.1016/S0040-4039(01)88878-X**.

[23] F. F. Arp, R. Ashirov, N. Bhuvanesh, J. Blümel, *Dalton Trans.* **2021**, *50*, 15296–15309. DOI: **10.1039/d1dt03243g**.

[24] M. P. Duffy, Y. Lin, L. Y. Ting, F. Mathey, *New J. Chem.* **2011**, *35*, 2001–2003. DOI: **10.1039/c1nj20087a**.

[25] G. Bousrez, E. Nicolas, A. Martinez, S. Chevreux, F. Jaroschik, *Heteroatom Chem.* **2019**, *1–10*. DOI: **10.1155/2019/2596405**.

[26] Y. Matano, *Phospholes and Related Compounds: Syntheses, Redox Properties, and Applications to Organic Electronic Devices*, in *Organic Redox Systems* (T. Nishinaga, Editor), Wiley: **2016**, pp 477–501 (Wiley, 2016). DOI: **10.1002/9781118858981.ch16**.
Zinnia ARORA

ESR4

**Thesis co-directors**

Prof. Vasile Pârvulescu Universitatea din Bucuresti, Bucharest, Romania

Dr. Jérôme Durand,

Dr. Maryse Gouygou Laboratoire de Chimie de Coordination, Toulouse, France

Dr. Karine Philippot

**Thesis defense**

Laboratoire de Chimie de Coordination, Toulouse, France, 15 March 2024
Zinnia ARORA

ESR4

**Thesis co-directors**

Prof. Vasile Pârvulescu Universitatea din Bucuresti, Bucharest, Romania

Dr. Jérôme Durand,

Dr. Maryse Gouygou Laboratoire de Chimie de Coordination, Toulouse, France

Dr. Karine Philippot

**Thesis defense**

Laboratoire de Chimie de Coordination, Toulouse, France, 15 March 2024
<figure><img src="image_92.png" /></figure>
<figure><img src="image_101.png" /></figure>
# Carbon Nanomaterial Supported Metal Complexes and Nanoparticles for Asymmetric Catalysis

## Introduction

Catalytic asymmetric synthesis is the "art" of providing exclusively one of the enantiomers of a target product in the presence of sub-stoichiometric amount of the suitable chiral catalyst. The synthesis of enantiomerically pure compounds requires to understand and follow the rules developed by nature in order to generate assimilable molecules by the living world [1]. Without the development of asymmetric catalysts, it would not have been possible to reach the actual level of advancement in pharmacy, or medicine domains [2–5].

The creativity developed in asymmetric catalysis offers not only the possibility to synthesize nature-like molecules but also to open new fields in chemistry. A perspective looks over organic synthesis would reveal that the need for enantiomerically enriched compounds is an ultimate challenge and that the search for efficient catalytic processes has pioneered this area of research. Despite the advantages of homogeneous catalytic systems, such as high enantioselectivities and activities for a wide range of chemical transformations, drawbacks like limited recovery and reuse of the expensive chiral catalysts and/or metal contamination of the products, particularly unacceptable for pharmaceutical production, significantly obstructed their practical applications [6,7]. The immobilization of the chiral catalytic phase has recently attracted a great deal of attention and appears as a promising solution to the above-mentioned problem. In addition, the demand for environmentally acceptable processes determined the minimization of waste whether from reagents or solvents and so the use of performant and recyclable catalysts. Immobilization of molecular catalysts is thus an attractive approach to combine the advantages of both homogeneous and heterogeneous catalysis [8].

Most reports describe the use of organic polymers and porous inorganic materials, such as zeolites, mesoporous silicas, and alumina as metal complex supports [9–12]. Carbon materials, especially nanostructured ones like carbon nanotubes (CNTs) or few-layer graphene, represent an interesting alternative to these conventional supports. However, despite the significant progress on nanocarbon-based catalysts, only a few applications in catalytic asymmetric transformations have been reported mainly for enantioselective hydrogenation reactions [13,14]. Not only metal complexes, metal nanoparticles (MNPs) are also currently largely studied for catalysis as they bring a bridge between the domains of homogeneous and heterogeneous catalysis [15].

Given these considerations, the main goal of this PhD project was to design new catalytic tools by immobilization of chiral species (complexes or nanoparticles) on the surface of nanostructured carbons (nanotubes or graphene) for enantioselective hydrogenations.

To achieve this, the primary goal was subdivided into sub-objectives. **a)** The synthesis of non-structured carbon materials CNTs, and their functionalization. **b)** The synthesis of phosphine-type chiral ligands to prepare metal complexes, immobilization of the obtained complexes on different functionalized CNTs, and catalytic application in asymmetric hydrogenation of C=C substrate. **c)** The development of synthesis tools to achieve small and well-defined chiral rhodium nanoparticles in the presence of phosphine-type chiral ligands as stabilizers, immobilization of the NPs on different functionalized CNTs, and catalytic application in asymmetric hydrogenation of C=C substrate.
# Carbon Nanomaterial Supported Metal Complexes and Nanoparticles for Asymmetric Catalysis

## Introduction

Catalytic asymmetric synthesis is the "art" of providing exclusively one of the enantiomers of a target product in the presence of sub-stoichiometric amount of the suitable chiral catalyst. The synthesis of enantiomerically pure compounds requires to understand and follow the rules developed by nature in order to generate assimilable molecules by the living world [1]. Without the development of asymmetric catalysts, it would not have been possible to reach the actual level of advancement in pharmacy, or medicine domains [2–5].

The creativity developed in asymmetric catalysis offers not only the possibility to synthesize nature-like molecules but also to open new fields in chemistry. A perspective looks over organic synthesis would reveal that the need for enantiomerically enriched compounds is an ultimate challenge and that the search for efficient catalytic processes has pioneered this area of research. Despite the advantages of homogeneous catalytic systems, such as high enantioselectivities and activities for a wide range of chemical transformations, drawbacks like limited recovery and reuse of the expensive chiral catalysts and/or metal contamination of the products, particularly unacceptable for pharmaceutical production, significantly obstructed their practical applications [6,7]. The immobilization of the chiral catalytic phase has recently attracted a great deal of attention and appears as a promising solution to the above-mentioned problem. In addition, the demand for environmentally acceptable processes determined the minimization of waste whether from reagents or solvents and so the use of performant and recyclable catalysts. Immobilization of molecular catalysts is thus an attractive approach to combine the advantages of both homogeneous and heterogeneous catalysis [8].

Most reports describe the use of organic polymers and porous inorganic materials, such as zeolites, mesoporous silicas, and alumina as metal complex supports [9–12]. Carbon materials, especially nanostructured ones like carbon nanotubes (CNTs) or few-layer graphene, represent an interesting alternative to these conventional supports. However, despite the significant progress on nanocarbon-based catalysts, only a few applications in catalytic asymmetric transformations have been reported mainly for enantioselective hydrogenation reactions [13,14]. Not only metal complexes, metal nanoparticles (MNPs) are also currently largely studied for catalysis as they bring a bridge between the domains of homogeneous and heterogeneous catalysis [15].

Given these considerations, the main goal of this PhD project was to design new catalytic tools by immobilization of chiral species (complexes or nanoparticles) on the surface of nanostructured carbons (nanotubes or graphene) for enantioselective hydrogenations.

To achieve this, the primary goal was subdivided into sub-objectives. **a)** The synthesis of non-structured carbon materials CNTs, and their functionalization. **b)** The synthesis of phosphine-type chiral ligands to prepare metal complexes, immobilization of the obtained complexes on different functionalized CNTs, and catalytic application in asymmetric hydrogenation of C=C substrate. **c)** The development of synthesis tools to achieve small and well-defined chiral rhodium nanoparticles in the presence of phosphine-type chiral ligands as stabilizers, immobilization of the NPs on different functionalized CNTs, and catalytic application in asymmetric hydrogenation of C=C substrate.
# Synthesis of non-structured carbon materials CNTs, and their functionalization

CNTs were prepared by the catalytic-CVD method according to a procedure developed in LCC using AlFeCoO₄ as a catalyst at a temperature of 650 °C. To introduce functionalities on the surface of CNTs, it is necessary to activate their surface. The prevalent method to introduce surface hydroxyl, carbonyl, and carboxylic acid groups is the oxidation of CNTs using nitric acid (HNO₃) as an oxidative reagent.

To improve the affinity between the CNTs and chiral cationic rhodium complexes, the CNT surface was negatively charged. The CNT-O obtained through the oxidative treatment with HNO₃ was further modified by two different routes to afford the functionalized supports i.e., CNT-COO⁻Na⁺, and CNT-HPA.

## Synthesis of CNT-COO⁻Na⁺

Purified CNT-O were neutralized with sodium hydroxide (NaOH) under stirring for 24 h at room temperature (RT). The resulted sodium salt of CNT-O was then separated from the solution *via* filtration, washed with distilled water until reaching a neutral pH, and dried at 120 °C for 2 days (Scheme 1).

<figure><img src="image_93.png" /><figcaption>**Scheme 27.** Deprotonation of the oxidized carbon nanotubes (CNT-O) by NaOH.</figcaption></figure>

## Synthesis of CNT-HPA

The synthesis of CNT-HPA (HPA= silicotungstic acid; H₄[SiW₁₂O₄₀]) has been carried out in two steps. In the first step, the dried CNT-O was reacted with 3-aminopropyl triethoxysilane (3-APTES) in ethanol at 70 °C for 4 h resulting in silanized CNTs referred to as CNT-Si. The CNT-Si were then dried under a high vacuum at 80 °C for 24 h. In the second step, a 2-propanol solution of silicotungstic acid (HPA) was slowly added to the CNT-Si previously dispersed in 2-propanol (Scheme 2).

<figure><img src="image_94.png" /><figcaption>**Scheme 28.** Synthesis of CNT-HPA support using the silicotungstic acid.</figcaption></figure>
# Synthesis of non-structured carbon materials CNTs, and their functionalization

CNTs were prepared by the catalytic-CVD method according to a procedure developed in LCC using AlFeCoO₄ as a catalyst at a temperature of 650 °C. To introduce functionalities on the surface of CNTs, it is necessary to activate their surface. The prevalent method to introduce surface hydroxyl, carbonyl, and carboxylic acid groups is the oxidation of CNTs using nitric acid (HNO₃) as an oxidative reagent.

To improve the affinity between the CNTs and chiral cationic rhodium complexes, the CNT surface was negatively charged. The CNT-O obtained through the oxidative treatment with HNO₃ was further modified by two different routes to afford the functionalized supports i.e., CNT-COO⁻Na⁺, and CNT-HPA.

## Synthesis of CNT-COO⁻Na⁺

Purified CNT-O were neutralized with sodium hydroxide (NaOH) under stirring for 24 h at room temperature (RT). The resulted sodium salt of CNT-O was then separated from the solution *via* filtration, washed with distilled water until reaching a neutral pH, and dried at 120 °C for 2 days (Scheme 1).

<figure><img src="image_102.png" /><figcaption>**Scheme 27.** Deprotonation of the oxidized carbon nanotubes (CNT-O) by NaOH.</figcaption></figure>

## Synthesis of CNT-HPA

The synthesis of CNT-HPA (HPA= silicotungstic acid; H₄[SiW₁₂O₄₀]) has been carried out in two steps. In the first step, the dried CNT-O was reacted with 3-aminopropyl triethoxysilane (3-APTES) in ethanol at 70 °C for 4 h resulting in silanized CNTs referred to as CNT-Si. The CNT-Si were then dried under a high vacuum at 80 °C for 24 h. In the second step, a 2-propanol solution of silicotungstic acid (HPA) was slowly added to the CNT-Si previously dispersed in 2-propanol (Scheme 2).

<figure><img src="image_103.png" /><figcaption>**Scheme 28.** Synthesis of CNT-HPA support using the silicotungstic acid.</figcaption></figure>
## Synthesis of CNT-CO-HAD

In order to confine rhodium nanoparticles into the CNTs, long alkyl chains were introduced at the surface. The CNT-O was modified by acylation reactions to afford the CNT-CO-HDA support. The CNT-O was firstly treated with a solution of thionyl chloride ($SOCl_2$) for 24 h at 80 °C. This treatment aimed to produce CNT-COCl as an intermediate for a subsequent amidation reaction. With this aim CNT-COCl was further reacted with hexadecyl amine (HDA; $CH_3-(CH_2)_{15}-NH_2$) for 24 h at 65 °C, in order to attach long alkyl chains-bearing amido groups on the CNTs surface (Scheme 3).

<figure><img src="image_95.png" /><figcaption>**Scheme 29.** The formation of long alkyl chain-bearing amido groups on the surface of CNT.</figcaption></figure>

All the functionalized CNTs were fully characterized by FT-IR, TGA, RAMAN, BET, TEM, and HR-TEM techniques. The different supports prepared were further used for the immobilization of Rh catalysts. CNT, CNT-COO⁻Na⁺, and CNT-HPA samples were used as support for the immobilization of rhodium complexes. CNT-O and CNT-CO-HDA were selected for the immobilization of the rhodium nanoparticles.

## Preparation of chiral rhodium complexes

Asymmetric ligands from the group of C1-diphosphines with a chiral pyrrolidine backbone have been selected because the phosphinopyrrolidine-rhodium catalysts have been shown to be performant for the hydrogenation of many unsaturated substrates.

We chose the commercially available ligand $(2S,4S)$-BPPM to synthesize the cationic rhodium complex $[Rh(COD)(2S,4S)-BPPM]BF_4$. Additionally, the $(2S,4S)$-PPM ligand was modified by pyrene group to produce the PPM-pyrene group to synthesize the $[Rh(COD)((2S,4S)-PPM-pyrene)]BF_4$ complex. Both complexes were selected strategically to capitalize on electrostatic interaction or π-π stacking, respectively, aiming to facilitate their immobilization on carbon nanotubes.

### Synthesis of $[Rh(COD)((2S,4S)-BPPM)]BF_4$

The chiral $[Rh(COD)(2S,4S)-BPPM]BF_4$ complex was prepared by mixing $(2S,4S)$-(-)-2-(diphenylphosphinomethyl)-4-(diphenylphosphino)-N-(*t*-butoxycarbonyl)pyrrolidine $( (2S,4S)-BPPM )$ ligand with bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (1:1 ratio) in dry dichloromethane (DCM) for 2 h at room temperature (Scheme 4). The complex was isolated as a yellow solid and characterized by $^{31}$P NMR and mass spectrometry.
## Synthesis of CNT-CO-HAD

In order to confine rhodium nanoparticles into the CNTs, long alkyl chains were introduced at the surface. The CNT-O was modified by acylation reactions to afford the CNT-CO-HDA support. The CNT-O was firstly treated with a solution of thionyl chloride ($SOCl_2$) for 24 h at 80 °C. This treatment aimed to produce CNT-COCl as an intermediate for a subsequent amidation reaction. With this aim CNT-COCl was further reacted with hexadecyl amine (HDA; $CH_3-(CH_2)_{15}-NH_2$) for 24 h at 65 °C, in order to attach long alkyl chains-bearing amido groups on the CNTs surface (Scheme 3).

<figure><img src="image_104.png" /><figcaption>**Scheme 29.** The formation of long alkyl chain-bearing amido groups on the surface of CNT.</figcaption></figure>

All the functionalized CNTs were fully characterized by FT-IR, TGA, RAMAN, BET, TEM, and HR-TEM techniques. The different supports prepared were further used for the immobilization of Rh catalysts. CNT, CNT-COO⁻·Na⁺, and CNT-HPA samples were used as support for the immobilization of rhodium complexes. CNT-O and CNT-CO-HDA were selected for the immobilization of the rhodium nanoparticles.

## Preparation of chiral rhodium complexes

Asymmetric ligands from the group of C1-diphosphines with a chiral pyrrolidine backbone have been selected because the phosphinopyrrolidine-rhodium catalysts have been shown to be performant for the hydrogenation of many unsaturated substrates.

We chose the commercially available ligand $(2S,4S)$-BPPM to synthesize the cationic rhodium complex $[Rh(COD)(2S,4S)-BPPM]BF_4$. Additionally, the $(2S,4S)$-PPM ligand was modified by pyrene group to produce the PPM-pyrene group to synthesize the $[Rh(COD)((2S,4S)-PPM-pyrene)]BF_4$ complex. Both complexes were selected strategically to capitalize on electrostatic interaction or π-π stacking, respectively, aiming to facilitate their immobilization on carbon nanotubes.

### Synthesis of $[Rh(COD)((2S,4S)-BPPM)]BF_4$

The chiral $[Rh(COD)(2S,4S)-BPPM]BF_4$ complex was prepared by mixing $(2S,4S)$-(-)-2-(diphenylphosphinomethyl)-4-(diphenylphosphino)-N-(*t*-butoxycarbonyl)pyrrolidine $([2S,4S]-BPPM)$ ligand with bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (1:1 ratio) in dry dichloromethane (DCM) for 2 h at room temperature (Scheme 4). The complex was isolated as a yellow solid and characterized by $^{31}$P NMR and mass spectrometry.
<figure><img src="image_96.png" /><figcaption>**Scheme 30.** Synthesis of [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄</figcaption></figure>

The chiral pyrene ligand was prepared by condensation of (2S,4S)-4-(diphenylphosphino)-2-[(diphenyl-phosphino)methyl]pyrrolidine (2S,4S)-PPM with 1-pyrenebutyric acid in the presence of 4-dimethylaminopyridine (DMAP) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in dry DCM as a solvent for 24 h under an argon inert atmosphere. Reaction of bis(1,5-cyclooctadiene) rhodium (I) tetrafluoroborate in dichloromethane with one equivalent of (2S,4S)-PPM-pyrene ligand quantitatively led to the cationic complex [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ (Scheme 5).

<figure><img src="image_97.png" /><figcaption>**Scheme 31:** Synthesis of (2S,4S)-PPM-pyrene ligand and [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ complex.</figcaption></figure>

These complexes were immobilized using non-covalent interactions on three distinct carbon nanotube (CNT) supports, namely, CNT, CNT-COO⁻Na⁺, and CNT-HPA. Different systems of supported chiral rhodium complexes each distinguished by the different nature of chiral ligands, and different functionalized carbon supports were synthesized. A comprehensive overview of all the synthesized complexes and carbon supports that are used is given in Figure 1.
<figure><img src="image_105.png" /><figcaption>**Scheme 30.** Synthesis of [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄</figcaption></figure>

The chiral pyrene ligand was prepared by condensation of (2S,4S)-4-(diphenylphosphino)-2-[(diphenyl-phosphino)methyl]pyrrolidine (2S,4S)-PPM with 1-pyrenebutyric acid in the presence of 4-dimethylaminopyridine (DMAP) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in dry DCM as a solvent for 24 h under an argon inert atmosphere. Reaction of bis(1,5-cyclooctadiene) rhodium (I) tetrafluoroborate in dichloromethane with one equivalent of (2S,4S)-PPM-pyrene ligand quantitatively led to the cationic complex [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ (Scheme 5).

<figure><img src="image_106.png" /><figcaption>**Scheme 31:** Synthesis of (2S,4S)-PPM-pyrene ligand and [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ complex.</figcaption></figure>

These complexes were immobilized using non-covalent interactions on three distinct carbon nanotube (CNT) supports, namely, CNT, CNT-COO⁻Na⁺, and CNT-HPA. Different systems of supported chiral rhodium complexes each distinguished by the different nature of chiral ligands, and different functionalized carbon supports were synthesized. A comprehensive overview of all the synthesized complexes and carbon supports that are used is given in Figure 1.
<figure><img src="image_98.png" /><figcaption>**Figure 6.** Rhodium complexes and functionalized carbon supports.</figcaption></figure>

We have studied the non-covalent immobilization of all rhodium complexes, [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ (**Complex A**) and [Rh(COD)((2S,4S)-BPPM)]BF₄ (**Complex B**), and [Rh(COD)((2S,5S)-Et-Ferrocelane)]BF₄ (**Complex C**) onto carbon nanotubes as a support and their application in the enantioselective hydrogenation of dimethyl itaconate as a model substrate. The immobilization of the rhodium complexes on the CNT supports was first done by applying a π-π interaction that relies on aromatic rings between the pristine CNT and all three complexes. The second strategy for immobilization of the rhodium complexes on the CNT supports was done by applying an ionic anchoring strategy that relies on the electrostatic interaction between the cationic Rh complex and the surface negatively charged of carboxylate-functionalized CNTs (CNT-COO⁻). The third strategy also implied an ionic anchoring but through a spacer-type anchoring agent, heteropoly acid HPA, that was previously grafted at the CNT surface thanks to an acid-base interaction. This approach induced an electrostatic interaction between the Rh complexes and the HPA-functionalized CNT far away from the CNT surface. The motivation of this HPA approach was to study the effect of distance from the CNT surface on the Rh complex performance. All three strategies are shown on the next page.

The obtained **CNT@Complex A**, **CNT@Complex B**, **CNT@Complex C**, **CNT-COO⁻@Complex A**, **CNT-COO⁻@Complex B**, **CNT-COO⁻@Complex C**, **CNT-HPA@Complex A**, **CNT-HPA@complex B**, and **CNT-HPA@Complex C** materials were characterized by complementary techniques. The characterization results confirmed the anchoring of the Rh complexes in 7 cases out of 9 thus highlighting the all strategies were quite successful. Interestingly, XPS data evidenced that the Rh complexes interacted with both the ligand phosphorus atoms and CNT support with no electronic differences between the three complexes whatever the nature of the CNTs. This thus allowed to compare the effect of the support on the catalysis performance depending on the nature of CNTs.
<figure><img src="image_107.png" /><figcaption>**Figure 6.** Rhodium complexes and functionalized carbon supports.</figcaption></figure>

We have studied the non-covalent immobilization of all rhodium complexes, [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ (**Complex A**) and [Rh(COD)((2S,4S)-BPPM)]BF₄ (**Complex B**), and [Rh(COD)((2S,5S)-Et-Ferrocelane)]BF₄ (**Complex C**) onto carbon nanotubes as a support and their application in the enantioselective hydrogenation of dimethyl itaconate as a model substrate. The immobilization of the rhodium complexes on the CNT supports was first done by applying a π-π interaction that relies on aromatic rings between the pristine CNT and all three complexes. The second strategy for immobilization of the rhodium complexes on the CNT supports was done by applying an ionic anchoring strategy that relies on the electrostatic interaction between the cationic Rh complex and the surface negatively charged of carboxylate-functionalized CNTs (CNT-COO⁻). The third strategy also implied an ionic anchoring but through a spacer-type anchoring agent, heteropoly acid HPA, that was previously grafted at the CNT surface thanks to an acid-base interaction. This approach induced an electrostatic interaction between the Rh complexes and the HPA-functionalized CNT far away from the CNT surface. The motivation of this HPA approach was to study the effect of distance from the CNT surface on the Rh complex performance. All three strategies are shown on the next page.

The obtained **CNT@Complex A**, **CNT@Complex B**, **CNT@Complex C**, **CNT-COO⁻@Complex A**, **CNT-COO⁻@Complex B**, **CNT-COO⁻@Complex C**, **CNT-HPA@Complex A**, **CNT-HPA@complex B**, and **CNT-HPA@Complex C** materials were characterized by complementary techniques. The characterization results confirmed the anchoring of the Rh complexes in 7 cases out of 9 thus highlighting the all strategies were quite successful. Interestingly, XPS data evidenced that the Rh complexes interacted with both the ligand phosphorus atoms and CNT support with no electronic differences between the three complexes whatever the nature of the CNTs. This thus allowed to compare the effect of the support on the catalysis performance depending on the nature of CNTs.
<figure><img src="image_99.png" /></figure>

[Rh]

CNT@Complex A

CNT@Complex B

CNT@Complex C

CNT

<figure><img src="image_100.png" /></figure>

<figure><img src="image_101.png" /></figure>

[Rh]

CNT-COONa⁺

<figure><img src="image_102.png" /></figure>

[Rh]

electrostatic
interaction

CNT-COO@Complex A

CNT-COO@Complex B

CNT-COO@Complex C

<figure><img src="image_103.png" /></figure>

[Rh]

Complex A

[Rh(COD)(25,55)PPM(pTrene)]BF₄

<figure><img src="image_104.png" /></figure>

<figure><img src="image_105.png" /></figure>

Complex B

[Rh(COD)(25,55)BPPM)]BF₄

Complex C

[Rh(COD)(25,55)Et-Ferrochane)]BF₄

<figure><img src="image_106.png" /></figure>

[Rh]

electrostatic
interaction

<figure><img src="image_107.png" /></figure>

<figure><img src="image_108.png" /></figure>

HPA

acid-base
interaction

[Rh]

CNT+HPA

HPA = Silicotungsticacid

CNT-HPA@Complex A

CNT-HPA@Complex B

CNT-HPA@Complex C

<figure><img src="image_109.png" /></figure>

3-APTES

CNT-O

4h, 70°C
<figure><img src="image_108.png" /></figure>
The catalytic hydrogenation of dimethyl itaconate was studied with all the CNT-immobilized Rh-complexes in mild reaction conditions (RT, 5.5 bar H₂) and the results were compared to those obtained with the non-immobilized complexes in the same reaction conditions (Table 1). Firstly, the three A, B, and C complexes in homogeneous conditions proved good activity and selectivity for the hydrogenation of DMI with 100% conversion in 0.5 h with 57%, 72%, and 71% of enantioselectivities respectively (Table 1, entries 1-3). The immobilized Rh complexes showed to be less rapid in hydrogenating DMI than their free counterparts, as usually observed in catalysis, but increasing the reaction time allowed to get full conversions. CNT@Complex A showed good activity with 34% of ee towards (S) methyl succinate (Table 1, entry 4) whereas CNT@Complex B produced low activity and enantioselectivity (10% towards (S) methyl succinate) (Table 1, entry 6). The recycling of the CNT@Complex A indicated good stability, namely, with a small change in the catalytic performances (Table 1, entry 4 vs 5). Such difference in enantioselectivity compared to the values collected with the free Rh complexes (ca. 56%) indicated that the support affected the hydrogenation reaction probably due to a modification of the ligand geometry that reduced the enantioselective hydrogenation of DMI. The immobilization of complexes on the CNT-COO⁻·Na⁺ support by electrostatic interactions occurs with partial (complex B and C) or total decoordination (complex A) of the chiral diphosphine ligand and probably partial or total direct coordination of Rh (I) to the carboxylate group on the surface. CNT-COO⁻@Complex B afforded a rather moderate activity compared to CNT-COO⁻@Complex C. Also, low enantioselectivity was observed with CNT-COO⁻@Complex B (8% ee towards (S) methyl succinate) while CNT-COO⁻@Complex C provided good ee to (R) methyl succinate (64-65%) (Table 1, entries 7-8). A recyclability study performed with recovered CNT-COO⁻@Complex C catalyst indicated the conversion remained total but with no ee was detected (Table 1, entry 9). Moreover, TEM analysis revealed the presence of Rh nanoparticles, thus indicating the decomposition of the catalyst in the recovering conditions applied. The presence of these Rh nanoparticles may explain the absence of enantioselectivity as the ligand may be not strongly attached to their surface. The catalytic tests with the CNT-HPA@Complex A, CNT-HPA@Complex B, and CNT-HPA@Complex C also showed high conversions in the hydrogenation of DMI into methyl succinate (83-100%) (Table 1, entries 10-16). In terms of enantioselectivity, CNT-HPA@Complex A showed moderate enantioselectivity (20% to (S) methyl succinate) (Table 1, entry 10). The CNT-HPA@Complex B generated a high ee of 57% to the (S) methyl succinate which was much higher than that generated by the CNT-COO⁻@Complex B (8%) (Table 1, entry 11 vs 7). The recyclability tests with the CNT-HPA@Complex B showed the catalysts remain active till 4 catalytic runs and showed a small decrease in the enantioselectivity after 3rd run (Table 1, entries 11-14). CNT-HPA@Complex C achieved a 58% ee to (R) methyl succinate (Table 1, entry 15). CNT-HPA@Complex C were less active but still enantioselective in the hydrogenation of DMI after recycling, showing a different behavior than their CNT-COO⁻ counterparts. This emphasizes that in the presence of CNT-HPA support the chiral ligand of Rh complexes is less affected by the proximity of the support contrarily to catalysts based on CNT-COO⁻. It corroborates the interest in adding a spacer such as HPA between the Rh complex and the CNT support to limit the effect of the CNT surface environment on the catalytic behavior of the Rh immobilized complexes. Both catalysts CNT-HPA@Complex B and CNT-HPA@Complex C were tested in continuous flow conditions after showing good results in batch conditions. These both catalysts were active and selective in flow conditions. CNT-HPA@Complex B showed 47% of conversion with 43% of ee towards (S) methyl succinate in the first 20 minutes whereas CNT-HPA@Complex C showed 29% of conversion with 30% of ee towards (R) methyl succinate under the same conditions. This flow study was done only in the primary stage. More optimizations are required to obtain better results and understanding.
The catalytic hydrogenation of dimethyl itaconate was studied with all the CNT-immobilized Rh-complexes in mild reaction conditions (RT, 5.5 bar H₂) and the results were compared to those obtained with the non-immobilized complexes in the same reaction conditions (Table 1). Firstly, the three A, B, and C complexes in homogeneous conditions proved good activity and selectivity for the hydrogenation of DMI with 100% conversion in 0.5 h with 57%, 72%, and 71% of enantioselectivities respectively (Table 1, entries 1-3). The immobilized Rh complexes showed to be less rapid in hydrogenating DMI than their free counterparts, as usually observed in catalysis, but increasing the reaction time allowed to get full conversions. CNT@Complex A showed good activity with 34% of ee towards (S) methyl succinate (Table 1, entry 4) whereas CNT@Complex B produced low activity and enantioselectivity (10% towards (S) methyl succinate) (Table 1, entry 6). The recycling of the CNT@Complex A indicated good stability, namely, with a small change in the catalytic performances (Table 1, entry 4 vs 5). Such difference in enantioselectivity compared to the values collected with the free Rh complexes (ca. 56%) indicated that the support affected the hydrogenation reaction probably due to a modification of the ligand geometry that reduced the enantioselective hydrogenation of DMI. The immobilization of complexes on the CNT-COO⁻·Na⁺ support by electrostatic interactions occurs with partial (complex B and C) or total decoordination (complex A) of the chiral diphosphine ligand and probably partial or total direct coordination of Rh (I) to the carboxylate group on the surface. CNT-COO⁻·@Complex B afforded a rather moderate activity compared to CNT-COO⁻·@Complex C. Also, low enantioselectivity was observed with CNT-COO⁻·@Complex B (8% ee towards (S) methyl succinate) while CNT-COO⁻·@Complex C provided good ee to (R) methyl succinate (64-65%) (Table 1, entries 7-8). A recyclability study performed with recovered CNT-COO⁻·@Complex C catalyst indicated the conversion remained total but with no ee was detected (Table 1, entry 9). Moreover, TEM analysis revealed the presence of Rh nanoparticles, thus indicating the decomposition of the catalyst in the recovering conditions applied. The presence of these Rh nanoparticles may explain the absence of enantioselectivity as the ligand may be not strongly attached to their surface. The catalytic tests with the CNT-HPA@Complex A, CNT-HPA@Complex B, and CNT-HPA@Complex C also showed high conversions in the hydrogenation of DMI into methyl succinate (83-100%) (Table 1, entries 10-16). In terms of enantioselectivity, CNT-HPA@Complex A showed moderate enantioselectivity (20% to (S) methyl succinate) (Table 1, entry 10). The CNT-HPA@Complex B generated a high ee of 57% to the (S) methyl succinate which was much higher than that generated by the CNT-COO⁻·@Complex B (8%) (Table 1, entry 11 vs 7). The recyclability tests with the CNT-HPA@Complex B showed the catalysts remain active till 4 catalytic runs and showed a small decrease in the enantioselectivity after 3rd run (Table 1, entries 11-14). CNT-HPA@Complex C achieved a 58% ee to (R) methyl succinate (Table 1, entry 15). CNT-HPA@Complex C were less active but still enantioselective in the hydrogenation of DMI after recycling, showing a different behavior than their CNT-COO⁻· counterparts. This emphasizes that in the presence of CNT-HPA support the chiral ligand of Rh complexes is less affected by the proximity of the support contrarily to catalysts based on CNT-COO⁻·. It corroborates the interest in adding a spacer such as HPA between the Rh complex and the CNT support to limit the effect of the CNT surface environment on the catalytic behavior of the Rh immobilized complexes. Both catalysts CNT-HPA@Complex B and CNT-HPA@Complex C were tested in continuous flow conditions after showing good results in batch conditions. These both catalysts were active and selective in flow conditions. CNT-HPA@Complex B showed 47% of conversion with 43% of ee towards (S) methyl succinate in the first 20 minutes whereas CNT-HPA@Complex C showed 29% of conversion with 30% of ee towards (R) methyl succinate under the same conditions. This flow study was done only in the primary stage. More optimizations are required to obtain better results and understanding.
<figure><img src="image_110.png" /><figcaption>**Table 4.** Catalytic results for the hydrogenation of dimethyl itaconate onto the functionalized CNT immobilized Rh-complexes. <sup>a</sup></figcaption></figure>

<table><thead><tr><th>Entry</th><th>Catalyst</th><th>S/C</th><th>Run</th><th>Time (h)</th><th>Conv.<sup>b</sup> (%)</th><th>Selectivity (%)</th><th>ee<sup>b</sup> (%)</th></tr></thead><tbody><tr><td>1</td><td>Complex A</td><td>80</td><td></td><td>0.5</td><td>100</td><td>100</td><td>57 (S)</td></tr><tr><td>2</td><td>Complex B</td><td>80</td><td></td><td>0.5</td><td>100</td><td>100</td><td>72 (S)</td></tr><tr><td>3</td><td>Complex C</td><td>100</td><td></td><td>0.5</td><td>100</td><td>100</td><td>71 (R)</td></tr><tr><td>4</td><td>CNT@Complex A</td><td>95</td><td>1</td><td>4</td><td>29</td><td>100</td><td>34 (S)</td></tr><tr><td>5</td><td>CNT@Complex A</td><td>95</td><td>2</td><td>4</td><td>26</td><td>100</td><td>28 (S)</td></tr><tr><td>6</td><td>CNT@Complex B</td><td>128</td><td>1</td><td>24</td><td>40</td><td>100</td><td>10 (S)</td></tr><tr><td>7</td><td>CNT-COO<sup>-</sup>@Complex B</td><td>124</td><td>1</td><td>24</td><td>60</td><td>100</td><td>8 (S)</td></tr><tr><td>8</td><td>CNT-COO<sup>-</sup>@Complex C</td><td>303</td><td>1</td><td>24</td><td>100</td><td>100</td><td>64 (R)</td></tr><tr><td>9</td><td>CNT-COO<sup>-</sup>@Complex C</td><td>303</td><td>2</td><td>24</td><td>100</td><td>100</td><td>-</td></tr><tr><td>10</td><td>CNT-HPA@Complex A</td><td>217</td><td>1</td><td>24</td><td>100</td><td>100</td><td>20 (S)</td></tr><tr><td>11</td><td>CNT-HPA@Complex B</td><td>192</td><td>1</td><td>7</td><td>100</td><td>100</td><td>57 (S)</td></tr><tr><td>12</td><td>CNT-HPA@Complex B</td><td>192</td><td>2</td><td>7</td><td>100</td><td>100</td><td>54 (S)</td></tr><tr><td>13</td><td>CNT-HPA@Complex B</td><td>192</td><td>3</td><td>7</td><td>95</td><td>100</td><td>47 (S)</td></tr><tr><td>14</td><td>CNT-HPA@Complex B</td><td>192</td><td>4</td><td>7</td><td>88</td><td>100</td><td>43 (S)</td></tr><tr><td>15</td><td>CNT-HPA@Complex C</td><td>277</td><td>1</td><td>15</td><td>100</td><td>100</td><td>58 (R)</td></tr><tr><td>16</td><td>CNT-HPA@Complex C</td><td>277</td><td>2</td><td>15</td><td>25</td><td>100</td><td>27 (R)</td></tr></tbody></table>

<footnote><sup>a</sup> Reaction conditions for CNT@Complex A: 0.060 g of immobilized Rh-complex; for CNT@Complex B: 0.090 g of immobilized Rh-complex; CNT-COO<sup>-</sup>@Complex B: 0.09 g of immobilized Rh-complex; for CNT-COO<sup>-</sup>@Complex C: 0.050 g of immobilized Rh-complex; CNT-HPA@Complex A: 0.08 g of immobilized Rh-complex; for CNT-HPA@Complex B: 0.06 g of immobilized Rh-complex; and CNT-HPA@Complex C: 0.06 g of immobilized Rh-complex, 0.16 g of substrate, 5.5 bars of H<sub>2</sub>, 4 ml of MeOH. <sup>b</sup>Determined by chiral GC using a Beta DEX™ 225 column.</footnote>
<figure><img src="image_109.png" /><figcaption>**Table 4.** Catalytic results for the hydrogenation of dimethyl itaconate onto the functionalized CNT immobilized Rh-complexes. <sup>a</sup></figcaption></figure>

<table><thead><tr><th>Entry</th><th>Catalyst</th><th>S/C</th><th>Run</th><th>Time (h)</th><th>Conv.<sup>b</sup> (%)</th><th>Selectivity (%)</th><th>ee<sup>b</sup> (%)</th></tr></thead><tbody><tr><td>1</td><td>Complex A</td><td>80</td><td></td><td>0.5</td><td>100</td><td>100</td><td>57 (S)</td></tr><tr><td>2</td><td>Complex B</td><td>80</td><td></td><td>0.5</td><td>100</td><td>100</td><td>72 (S)</td></tr><tr><td>3</td><td>Complex C</td><td>100</td><td></td><td>0.5</td><td>100</td><td>100</td><td>71 (R)</td></tr><tr><td>4</td><td>CNT@Complex A</td><td>95</td><td>1</td><td>4</td><td>29</td><td>100</td><td>34 (S)</td></tr><tr><td>5</td><td>CNT@Complex A</td><td>95</td><td>2</td><td>4</td><td>26</td><td>100</td><td>28 (S)</td></tr><tr><td>6</td><td>CNT@Complex B</td><td>128</td><td>1</td><td>24</td><td>40</td><td>100</td><td>10 (S)</td></tr><tr><td>7</td><td>CNT-COO<sup>-</sup>@Complex B</td><td>124</td><td>1</td><td>24</td><td>60</td><td>100</td><td>8 (S)</td></tr><tr><td>8</td><td>CNT-COO<sup>-</sup>@Complex C</td><td>303</td><td>1</td><td>24</td><td>100</td><td>100</td><td>64 (R)</td></tr><tr><td>9</td><td>CNT-COO<sup>-</sup>@Complex C</td><td>303</td><td>2</td><td>24</td><td>100</td><td>100</td><td>-</td></tr><tr><td>10</td><td>CNT-HPA@Complex A</td><td>217</td><td>1</td><td>24</td><td>100</td><td>100</td><td>20 (S)</td></tr><tr><td>11</td><td>CNT-HPA@Complex B</td><td>192</td><td>1</td><td>7</td><td>100</td><td>100</td><td>57 (S)</td></tr><tr><td>12</td><td>CNT-HPA@Complex B</td><td>192</td><td>2</td><td>7</td><td>100</td><td>100</td><td>54 (S)</td></tr><tr><td>13</td><td>CNT-HPA@Complex B</td><td>192</td><td>3</td><td>7</td><td>95</td><td>100</td><td>47 (S)</td></tr><tr><td>14</td><td>CNT-HPA@Complex B</td><td>192</td><td>4</td><td>7</td><td>88</td><td>100</td><td>43 (S)</td></tr><tr><td>15</td><td>CNT-HPA@Complex C</td><td>277</td><td>1</td><td>15</td><td>100</td><td>100</td><td>58 (R)</td></tr><tr><td>16</td><td>CNT-HPA@Complex C</td><td>277</td><td>2</td><td>15</td><td>25</td><td>100</td><td>27 (R)</td></tr></tbody></table>

<footnote><sup>a</sup> Reaction conditions for CNT@Complex A: 0.060 g of immobilized Rh-complex; for CNT@Complex B: 0.090 g of immobilized Rh-complex; CNT-COO<sup>-</sup>@Complex B: 0.09 g of immobilized Rh-complex; for CNT-COO<sup>-</sup>@Complex C: 0.050 g of immobilized Rh-complex; CNT-HPA@Complex A: 0.08 g of immobilized Rh-complex; for CNT-HPA@Complex B: 0.06 g of immobilized Rh-complex; and CNT-HPA@Complex C: 0.06 g of immobilized Rh-complex, 0.16 g of substrate, 5.5 bars of H<sub>2</sub>, 4 ml of MeOH. <sup>b</sup>Determined by chiral GC using a Beta DEX™ 225 column.</footnote>
## Synthesis of chiral rhodium nanoparticles

Different systems of chiral rhodium nanoparticles were synthesized, each distinguished by the nature of the precursor or stabilizer, the carbon support, or also by the reaction conditions used for their synthesis. The organometallic approach for synthesizing metallic nanostructures capitalizes on the principles of organometallic and coordination chemistry. Based on previous results in the synthesis of small Rh NPs, the [Rh(η³-C₃H₅)₃][16–18], and [Rh(µ-Cl)(C₈H₁₂)]₂ [19] were chosen as Rh precursors. Two chiral ligands (2S,4S)-BPPM and (2S,4S)-PPM-pyrene, were selected as stabilizing ligands to synthesize chiral Rh NPs.

### Synthesis of chiral Rh nanoparticles from [Rh(η³-C₃H₅)₃] and the (2S,4S)-BPPM ligand

The synthesis of chiral Rh NPs using the [Rh(η³-C₃H₅)₃] precursor and the (2S,4S)-BPPM ligand revealed that heating was required to decompose the Rh(III) precursor in the presence of the diphosphine ligand. Also, a molar ratio of [P]/[Rh] = 0.6 was found necessary to produce small-sized and well-controlled chiral NPs. This combination of Rh precursor and ligand allowed forming **Rh-(2S,4S)-BPPM-NPs-1** constituted of ca. 1.7 ± 0.3 nm size well-dispersed RhNPs. EDX analysis coupled to HR-TEM performed on different areas of the grid showed the presence of both Rh and P elements, thus indicating the presence of the (2S,4S)-BPPM ligand close to the Rh NPs (Figure 2).

<figure><img src="image_111.png" /><figcaption>**Figure 7.** a) HR-TEM image of Rh-(2S,4S)-BPPM-NPs-1 (0.3 eq) (scale bar = 50 nm) and b) the corresponding EDX spectrum.</figcaption></figure>

Oxidized CNTs (CNT-O) were used as support to immobilize Rh NPs prepared from [Rh(η³-C₃H₅)₃] precursor and (2S,4S)-BPPM ligand. The synthesis was done in one-pot conditions by adding the CNT-O to the reaction mixture composed of precursor and ligand in THF. The obtained **Rh-(2S,4S)-BPPM@CNT-O** NPs did not undergo agglomeration, yet they did not exhibit optimal dispersion in the CNT-O. Indeed, the confinement of NPs within the oxidized CNTs exhibited an alignment of close RhNPs, akin to a necklace formation (Figure 3).

<figure><img src="image_112.png" /><figcaption>**Figure 8.** TEM images of Rh-(2S,4S)-BPPM@CNT-O at two different magnifications.</figcaption></figure>
## Synthesis of chiral rhodium nanoparticles

Different systems of chiral rhodium nanoparticles were synthesized, each distinguished by the nature of the precursor or stabilizer, the carbon support, or also by the reaction conditions used for their synthesis. The organometallic approach for synthesizing metallic nanostructures capitalizes on the principles of organometallic and coordination chemistry. Based on previous results in the synthesis of small Rh NPs, the [Rh(η³-C₃H₅)₃][16–18], and [Rh(µ-Cl)(C₈H₁₂)]₂ [19] were chosen as Rh precursors. Two chiral ligands (2S,4S)-BPPM and (2S,4S)-PPM-pyrene, were selected as stabilizing ligands to synthesize chiral Rh NPs.

### Synthesis of chiral Rh nanoparticles from [Rh(η³-C₃H₅)₃] and the (2S,4S)-BPPM ligand

The synthesis of chiral Rh NPs using the [Rh(η³-C₃H₅)₃] precursor and the (2S,4S)-BPPM ligand revealed that heating was required to decompose the Rh(III) precursor in the presence of the diphosphine ligand. Also, a molar ratio of [P]/[Rh] = 0.6 was found necessary to produce small-sized and well-controlled chiral NPs. This combination of Rh precursor and ligand allowed forming **Rh-(2S,4S)-BPPM-NPs-1** constituted of ca. 1.7 ± 0.3 nm size well-dispersed RhNPs. EDX analysis coupled to HR-TEM performed on different areas of the grid showed the presence of both Rh and P elements, thus indicating the presence of the (2S,4S)-BPPM ligand close to the Rh NPs (Figure 2).

<figure><img src="image_110.png" /><figcaption>**Figure 7.** a) HR-TEM image of Rh-(2S,4S)-BPPM-NPs-1 (0.3 eq) (scale bar = 50 nm) and b) the corresponding EDX spectrum.</figcaption></figure>

Oxidized CNTs (CNT-O) were used as support to immobilize Rh NPs prepared from [Rh(η³-C₃H₅)₃] precursor and (2S,4S)-BPPM ligand. The synthesis was done in one-pot conditions by adding the CNT-O to the reaction mixture composed of precursor and ligand in THF. The obtained **Rh-(2S,4S)-BPPM@CNT-O** NPs did not undergo agglomeration, yet they did not exhibit optimal dispersion in the CNT-O. Indeed, the confinement of NPs within the oxidized CNTs exhibited an alignment of close RhNPs, akin to a necklace formation (Figure 3).

<figure><img src="image_111.png" /><figcaption>**Figure 8.** TEM images of Rh-(2S,4S)-BPPM@CNT-O at two different magnifications.</figcaption></figure>
Synthesis of chiral Rh nanoparticles from [Rh($\eta^3$-C$_3$H$_5$)$_3$] and the (2S,4S)-PPM-pyrene ligand

The (2S,4S)-PPM-pyrene ligand was also used as a stabilizer for the synthesis of chiral Rh NPs from [Rh($\eta^3$-C$_3$H$_5$)$_3$] precursor, leading to **Rh-(2S,4S)-PPM-pyrene-NPs-2**. TEM analysis showed that the obtained Rh NPs were very close to each other and embedded within an organic matrix, probably due to the ligand, making a precise determination of their size was not possible. Compared to the first (2S,4S)-BPPM ligand, (2S,4S)-PPM-pyrene was found less effective for the formation of well-dispersed Rh NPs. This may be the effect of the presence of the pyrene groups that can interact each other by $\pi$-stacking and lead to the agglomeration of the NPs while remaining individual. To gain deeper insights into the embedding nature of the NPs, EDX-coupled HR-TEM results evidenced that the NPs were not well crystallized and that they all are in close proximity to the (2S,4S)-PPM-pyrene ligand, as phosphorous was clearly detected as surrounding the Rh metal. Inspired by previous results in the confinement of PtRu NPs, CNTs were modified by the grafting of amide groups with long alkyl chains at their surface (CNT-CO-HDA) in order to improve the confinement of Rh NPs synthesized from [Rh($\eta^3$-C$_3$H$_5$)$_3$] precursor and (2S,4S)-PPM-pyrene ligand (eq 1).

<figure><img src="image_113.png" /></figure>

These synthesis conditions led to a very efficient confinement of the chiral Rh NPs within the channels of CNT-CO-HDA, the surface amide groups repelling the deposition of Rh NPs at the external surface of the support (Figure 4).

<figure><img src="image_114.png" /><figcaption>**Figure 9.** Bright field HR-TEM images of Rh-(2S,4S)-PPM-pyrene@CNT-CO-HDA at three different magnifications.</figcaption></figure>
Synthesis of chiral Rh nanoparticles from [Rh($\eta^3$-C$_3$H$_5$)$_3$] and the (2S,4S)-PPM-pyrene ligand

The (2S,4S)-PPM-pyrene ligand was also used as a stabilizer for the synthesis of chiral Rh NPs from [Rh($\eta^3$-C$_3$H$_5$)$_3$] precursor, leading to **Rh-(2S,4S)-PPM-pyrene-NPs-2**. TEM analysis showed that the obtained Rh NPs were very close to each other and embedded within an organic matrix, probably due to the ligand, making a precise determination of their size was not possible. Compared to the first (2S,4S)-BPPM ligand, (2S,4S)-PPM-pyrene was found less effective for the formation of well-dispersed Rh NPs. This may be the effect of the presence of the pyrene groups that can interact each other by $\pi$-stacking and lead to the agglomeration of the NPs while remaining individual. To gain deeper insights into the embedding nature of the NPs, EDX-coupled HR-TEM results evidenced that the NPs were not well crystallized and that they all are in close proximity to the (2S,4S)-PPM-pyrene ligand, as phosphorous was clearly detected as surrounding the Rh metal. Inspired by previous results in the confinement of PtRu NPs, CNTs were modified by the grafting of amide groups with long alkyl chains at their surface (CNT-CO-HDA) in order to improve the confinement of Rh NPs synthesized from [Rh($\eta^3$-C$_3$H$_5$)$_3$] precursor and (2S,4S)-PPM-pyrene ligand (eq 1).

<figure><img src="image_112.png" /></figure>

These synthesis conditions led to a very efficient confinement of the chiral Rh NPs within the channels of CNT-CO-HDA, the surface amide groups repelling the deposition of Rh NPs at the external surface of the support (Figure 4).

<figure><img src="image_113.png" /><figcaption>**Figure 9.** Bright field HR-TEM images of Rh-(2S,4S)-PPM-pyrene@CNT-CO-HDA at three different magnifications.</figcaption></figure>
The asymmetric hydrogenation of dimethyl itaconate (DMI) was studied using these four systems of chiral NPs as catalysts: a) **Rh-(2S,4S)-BPPM-NPs-1**, b) **Rh-(2S,4S)-BPPM@CNT-O**, c) **Rh-(2S,4S)-PPM-pyrene-NPs-2**, and d) **Rh-(2S,4S)-PPM-pyrene-NPs-2@CNT-CO-HDA**. In all cases an excellent activity was obtained but with no enantioselectivity. The lack of enantioselectivity indicates that even in the case of the well-confined Rh NPs (**Rh-(2S,4S)-PPM-pyrene-NPs-2@CNT-CO-HDA**) the ligand is not blocked enough at the NP surface to allow the selective hydrogenation of the DMI in one preferential side.

### Synthesis of chiral Rh nanoparticles from [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> using the (2S,4S)-BPPM and (2S,4S)-PPM-pyrene ligands

Following the protocol with the [Rh(η<sup>3</sup>-C<sub>3</sub>H<sub>5</sub>)<sub>3</sub>] precursor, Rh NPs, Rh-(2S,4S)-BPPM-NPs-3a stabilized by (2S,4S)-BPPM were synthesized from the [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> in THF solution under 3 bar of H<sub>2</sub>, using a [P]/[Rh] ratio of 0.6 and 1eq. TEM images from the crude colloidal suspension at higher magnification allowed a better identification of the individual NPs indicating that they result from the agglomeration of NPs with the absence of coalescence. Similarly, Rh NPs, Rh-(2S,4S)-PPM-pyrene-NPs-4a stabilized by (2S,4S)-PPM-pyrene were synthesized from the [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> in THF solution resulting in the agglomerations of NPs (Figure 5). While the [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> complex decomposed easily at room temperature, that was different to the previous [Rh(η<sup>3</sup>-C<sub>3</sub>H<sub>5</sub>)<sub>3</sub>], a less efficient Rh NP stabilization was observed in the presence of both ligand, even at a high [P]/[Rh] ratio as agglomerates were formed. This result prompted us to evaluate the synthesis of Rh NPs taking (2S,4S)-BPPM and (2S,4S)-PPM-pyrene as a stabilizer and [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> as a metal precursor in catalysis conditions, namely in the presence of DMI.

<figure><img src="image_115.png" /><figcaption>**Figure 10.** TEM images of Rh-(2S,4S)-BPPM-NPs-3a (left) and Rh-(2S,4S)-PPM-pyrene-NPs-4a (right) obtained with ([P]/[Rh] = 1).</figcaption></figure>

### Synthesis of chiral Rh nanoparticles from [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> using the (2S,4S)-BPPM and (2S,4S)-PPM-pyrene ligands under in-situ conditions

Enantioselective hydrogenation of DMI could be achieved by forming the Rh NPs *in-situ* in catalysis conditions, namely in the presence of DMI. A series of experiments were done by modifying different parameters, such as the nature of Rh precursor ([Rh(η<sup>3</sup>-C<sub>3</sub>H<sub>5</sub>)<sub>3</sub>] or [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub>) or ligand ((2S,4S)-BPPM or (2S,4S)-PPM-pyrene), or changing the solvent (THF, toluene, isopropanol) or the temperature (RT, 40 °C, 60 °C). Different results in terms of Rh NP synthesis and catalytic performance were obtained, offering plenty of room to optimize the systems. Two systems that provided the best enantioselectivity results are highlighted. Using [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> precursor with (2S,4S)-BPPM with a ratio of [P]/[Rh] = 1 led to *ca.* 2.5 nm size of sponge-like large Rh NPs (**Rh-(2S,4S)-BPPM-NPs-3b* sample)
The asymmetric hydrogenation of dimethyl itaconate (DMI) was studied using these four systems of chiral NPs as catalysts: a) **Rh-(2S,4S)-BPPM-NPs-1**, b) **Rh-(2S,4S)-BPPM@CNT-O**, c) **Rh-(2S,4S)-PPM-pyrene-NPs-2**, and d) **Rh-(2S,4S)-PPM-pyrene-NPs-2@CNT-CO-HDA**. In all cases an excellent activity was obtained but with no enantioselectivity. The lack of enantioselectivity indicates that even in the case of the well-confined Rh NPs (**Rh-(2S,4S)-PPM-pyrene-NPs-2@CNT-CO-HDA**) the ligand is not blocked enough at the NP surface to allow the selective hydrogenation of the DMI in one preferential side.

### Synthesis of chiral Rh nanoparticles from [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> using the (2S,4S)-BPPM and (2S,4S)-PPM-pyrene ligands

Following the protocol with the [Rh(η<sup>3</sup>-C<sub>3</sub>H<sub>5</sub>)<sub>3</sub>] precursor, Rh NPs, Rh-(2S,4S)-BPPM-NPs-3a stabilized by (2S,4S)-BPPM were synthesized from the [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> in THF solution under 3 bar of H<sub>2</sub>, using a [P]/[Rh] ratio of 0.6 and 1eq. TEM images from the crude colloidal suspension at higher magnification allowed a better identification of the individual NPs indicating that they result from the agglomeration of NPs with the absence of coalescence. Similarly, Rh NPs, Rh-(2S,4S)-PPM-pyrene-NPs-4a stabilized by (2S,4S)-PPM-pyrene were synthesized from the [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> in THF solution resulting in the agglomerations of NPs (Figure 5). While the [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> complex decomposed easily at room temperature, that was different to the previous [Rh(η<sup>3</sup>-C<sub>3</sub>H<sub>5</sub>)<sub>3</sub>], a less efficient Rh NP stabilization was observed in the presence of both ligand, even at a high [P]/[Rh] ratio as agglomerates were formed. This result prompted us to evaluate the synthesis of Rh NPs taking (2S,4S)-BPPM and (2S,4S)-PPM-pyrene as a stabilizer and [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> as a metal precursor in catalysis conditions, namely in the presence of DMI.

<figure><img src="image_114.png" /><figcaption>**Figure 10.** TEM images of Rh-(2S,4S)-BPPM-NPs-3a (left) and Rh-(2S,4S)-PPM-pyrene-NPs-4a (right) obtained with ([P]/[Rh] = 1).</figcaption></figure>

### Synthesis of chiral Rh nanoparticles from [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> using the (2S,4S)-BPPM and (2S,4S)-PPM-pyrene ligands under in-situ conditions

Enantioselective hydrogenation of DMI could be achieved by forming the Rh NPs *in-situ* in catalysis conditions, namely in the presence of DMI. A series of experiments were done by modifying different parameters, such as the nature of Rh precursor ([Rh(η<sup>3</sup>-C<sub>3</sub>H<sub>5</sub>)<sub>3</sub>] or [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub>) or ligand ((2S,4S)-BPPM or (2S,4S)-PPM-pyrene), or changing the solvent (THF, toluene, isopropanol) or the temperature (RT, 40 °C, 60 °C). Different results in terms of Rh NP synthesis and catalytic performance were obtained, offering plenty of room to optimize the systems. Two systems that provided the best enantioselectivity results are highlighted. Using [Rh(μ-Cl)(C<sub>8</sub>H<sub>12</sub>)]<sub>2</sub> precursor with (2S,4S)-BPPM with a ratio of [P]/[Rh] = 1 led to *ca.* 2.5 nm size of sponge-like large Rh NPs (**Rh-(2S,4S)-BPPM-NPs-3b* sample)
(Figure 6). This sample led to an activity of 96 %, and more interestingly to a 16% of ee in asymmetric hydrogenation of DMI at 40 °C.

<figure><img src="image_116.png" /><figcaption>**Figure 11.** TEM images of Rh-(2S,4S)-BPPM-NPs-3b at two different magnifications.</figcaption></figure>

Also, the synthesis of **Rh-(2S,4S)-PPM-pyrene-NPs-4b** performed with [Rh(µ-Cl)(C₈H₁₂)]₂ precursor and (2S,4S)-PPM-pyrene ligand showed well-controlled and well dispersed Rh NPs of ca. 2.6 nm (Figure 7). These NPs exhibited moderate catalytic activity (69%) and enantioselectivity (32%) for the DMI substrate at 40 °C. Effects of hydrogen pressure, temperature, and solvent were observed but complementary experiments are needed to enable a rationalization of their influence. Also, mercury tests have been done with **Rh-(2S,4S)-PPM-pyrene-NPs-4b**, which confirmed the role of the Rh NPs as catalytic species in the hydrogenation of DMI.

<figure><img src="image_117.png" /><figcaption>**Figure 12.** a) and b) TEM images of Rh-(2S,4S)-PPM-pyrene-NPs-4b at two different magnifications, and c) corresponding size distribution.</figcaption></figure>

This work shows that the synthesis of chiral Rh NPs was possible starting from organometallic complexes and diphosphine-type ligands in mild conditions (low H₂ pressure and temperature). The study performed in the hydrogenation of dimethyl itaconate with the different systems of Rh NPs prepared revealed either an excellent activity (100% conversion in 4 h at RT and 40 °C) but either no enantioselectivity or a moderate activity but with positive enantioselectivity (up to 36% ee). This work thus opened a new avenue for the preparation of chiral rhodium nanocatalysts but an optimization is required to develop more efficient nanocatalysts.

Given the observation of achieving ee when using Rh NPs of ca. 2.5 and 2.6 nm in size but not with smaller NPs, a perspective could be to develop the synthesis of larger Rh NPs. This could allow a more efficient anchoring of the chiral ligand at the Rh surface and favor a higher enantioselectivity.
(Figure 6). This sample led to an activity of 96 %, and more interestingly to a 16% of ee in asymmetric hydrogenation of DMI at 40 °C.

<figure><img src="image_115.png" /><figcaption>**Figure 11.** TEM images of Rh-(2S,4S)-BPPM-NPs-3b at two different magnifications.</figcaption></figure>

Also, the synthesis of **Rh-(2S,4S)-PPM-pyrene-NPs-4b** performed with [Rh(µ-Cl)(C₈H₁₂)]₂ precursor and (2S,4S)-PPM-pyrene ligand showed well-controlled and well dispersed Rh NPs of ca. 2.6 nm (Figure 7). These NPs exhibited moderate catalytic activity (69%) and enantioselectivity (32%) for the DMI substrate at 40 °C. Effects of hydrogen pressure, temperature, and solvent were observed but complementary experiments are needed to enable a rationalization of their influence. Also, mercury tests have been done with **Rh-(2S,4S)-PPM-pyrene-NPs-4b**, which confirmed the role of the Rh NPs as catalytic species in the hydrogenation of DMI.

<figure><img src="image_116.png" /><figcaption>**Figure 12.** a) and b) TEM images of Rh-(2S,4S)-PPM-pyrene-NPs-4b at two different magnifications, and c) corresponding size distribution.</figcaption></figure>

This work shows that the synthesis of chiral Rh NPs was possible starting from organometallic complexes and diphosphine-type ligands in mild conditions (low H₂ pressure and temperature). The study performed in the hydrogenation of dimethyl itaconate with the different systems of Rh NPs prepared revealed either an excellent activity (100% conversion in 4 h at RT and 40 °C) but either no enantioselectivity or a moderate activity but with positive enantioselectivity (up to 36% ee). This work thus opened a new avenue for the preparation of chiral rhodium nanocatalysts but an optimization is required to develop more efficient nanocatalysts.

Given the observation of achieving ee when using Rh NPs of ca. 2.5 and 2.6 nm in size but not with smaller NPs, a perspective could be to develop the synthesis of larger Rh NPs. This could allow a more efficient anchoring of the chiral ligand at the Rh surface and favor a higher enantioselectivity.
Chemistry of copper metal

The chemistry of the copper metal was also studied. The focus was on the synthesis of copper complexes employing chiral Schiff-base ligands. The subsequent step involves the immobilization of these complexes onto graphene oxide, and their effectiveness in catalyzing diverse reactions, namely the Henry reaction, cyanoisilylation reaction, and aldol reaction, is thoroughly investigated and examined. The study aims to contribute to the understanding of the catalytic performance of these immobilized copper complexes and their significance in the context of asymmetric synthesis.

Synthesis of [Cu(D-valmet)(H₂O)]·H₂O or Cu-D-valmet complex

In the synthesis of the [Cu(D-valmet)(H₂O)]·H₂O or Cu-D-valmet complex, the initial step involved the preparation of the Na-D-valmet precursor. This precursor was synthesized through a condensation reaction between D-methionine and o-vanillin in the presence of NaOH, using MeOH as the solvent. Subsequently, a solution containing Na-D-valmet in a methanol-water mixture (5:1, v/v) was mixed with a solution of Cu(CH₃COO)₂·H₂O in MeOH (Scheme 6). After approximately one week, blue-greenish single crystals formed which were isolated via filtration and dried under ambient air. Likewise the synthesis of [Cu(L-valmet)(H₂O)]·H₂O or Cu-L-valmet complex was done.

<figure><img src="image_118.png" /><figcaption>**Scheme 32.** Synthesis of [Cu(D-valmet)(H₂O)]·H₂O or Cu-D-valmet complex.</figcaption></figure>

Considering the favorable attributes associated with the metal-to-oxygen bond, the immobilization of copper complexes onto the GO-COOH support was accomplished. The methanolic solution containing copper complexes was added with the methanolic solution of the GO-COOH support. The resulting mixture was agitated for 24 h, allowing for sufficient interaction between the components. Subsequently, the desired product was obtained by subjecting the mixture to centrifugation and filtration, a process that was repeated 4-5 times to ensure proper purification. Finally, the obtained product was dried in an oven for 24 h to remove any residual solvent and moisture content. The carboxyl groups of the modified GO served as linkers for the immobilization of the chiral complexes (Scheme 7).

The catalytic potential of the synthesized complexes was examined through three constructed systems
Chemistry of copper metal

The chemistry of the copper metal was also studied. The focus was on the synthesis of copper complexes employing chiral Schiff-base ligands. The subsequent step involves the immobilization of these complexes onto graphene oxide, and their effectiveness in catalyzing diverse reactions, namely the Henry reaction, cyanoisilylation reaction, and aldol reaction, is thoroughly investigated and examined. The study aims to contribute to the understanding of the catalytic performance of these immobilized copper complexes and their significance in the context of asymmetric synthesis.

Synthesis of [Cu(D-valmet)(H₂O)]·H₂O or Cu-D-valmet complex

In the synthesis of the [Cu(D-valmet)(H₂O)]·H₂O or Cu-D-valmet complex, the initial step involved the preparation of the Na-D-valmet precursor. This precursor was synthesized through a condensation reaction between D-methionine and o-vanillin in the presence of NaOH, using MeOH as the solvent. Subsequently, a solution containing Na-D-valmet in a methanol-water mixture (5:1, v/v) was mixed with a solution of Cu(CH₃COO)₂·H₂O in MeOH (Scheme 6). After approximately one week, blue-greenish single crystals formed which were isolated via filtration and dried under ambient air. Likewise the synthesis of [Cu(L-valmet)(H₂O)]·H₂O or Cu-L-valmet complex was done.

<figure><img src="image_117.png" /><figcaption>**Scheme 32.** Synthesis of [Cu(D-valmet)(H₂O)]·H₂O or Cu-D-valmet complex.</figcaption></figure>

Considering the favorable attributes associated with the metal-to-oxygen bond, the immobilization of copper complexes onto the GO-COOH support was accomplished. The methanolic solution containing copper complexes was added with the methanolic solution of the GO-COOH support. The resulting mixture was agitated for 24 h, allowing for sufficient interaction between the components. Subsequently, the desired product was obtained by subjecting the mixture to centrifugation and filtration, a process that was repeated 4-5 times to ensure proper purification. Finally, the obtained product was dried in an oven for 24 h to remove any residual solvent and moisture content. The carboxyl groups of the modified GO served as linkers for the immobilization of the chiral complexes (Scheme 7).

The catalytic potential of the synthesized complexes was examined through three constructed systems
i) A chiral ligand obtained *via* the condensation reaction of o- vanillin and D-, or L-methionine respectively, (i.e., **L-valmet**, **D-valmet**) in the enantiomeric sodium complexes, Na-D-valmet and Na-L-valmet.

ii) In the form of copper (II) complexes (i.e., **Cu-D-valmet** and **Cu-L-valmet**).

iii) Immobilized complexes (i.e., **GO-COOH/Cu(D-valmet)** and **GO-COOH/Cu(L-valmet)**).

Ligands **L-** and **D-valmet** in the Na form demonstrate base properties, making them potential homogeneous organocatalysts. When complexed with copper, these ligands act as homogeneous catalysts in all the three reactions, with the active species associated with basic nitrogen or free nitrogen complexated copper.

<figure><img src="image_119.png" /><figcaption>**Scheme 33:** Immobilization of Cu-D-valmet complex on GO-COOH support via coordinate covalent bond.</figcaption></figure>

In the case of the Henry reaction, dominant role is played by the ligand's, resulting in an asymmetric Henry reaction in water. Supported copper complexes of L-valmet chiral Schiff-base ligand proved to be particularly active in asymmetric Henry reaction. It performed the coupling reaction of benzaldehyde and nitromethane in water with a spectacular increase of the conversion (92% vs 39%) and ee (96 vs 62%) compared to the free complex.

For the cyanosilylation reaction, the free nitrogen of copper complexes acts as the active species. The racemic formation in this case can be attributed to the involvement of an unsaturated Cu center (Lewis active sites), enabling the reaction but lacking stereoselectivity. The copper complexes exhibit high conversions even at RT. However, some of the coupling product undergoes hydrolysis to cyanohydrins due to the presence of coordinated water molecules after drying. The involvement of water in the hydrolysis of α-(trimethylsilyl)-phenylacetonitrile becomes evident with increasing temperature, leading to an increased ratio between the two products as conversion increases. Immobilizing these complexes on GO-COOH results in either inhibited activity or minimal conversion, with complete hydrolysis of α-(trimethylsilyl)-phenylacetonitrile to cyanohydrin.

Furthermore, the base properties of both ligands were also demonstrated in the aldol condensation reaction. Complexation of copper by these ligands decreases conversion but increases
i) A chiral ligand obtained *via* the condensation reaction of o- vanillin and D-, or L-methionine respectively, (i.e., **L-valmet**, **D-valmet**) in the enantiomeric sodium complexes, Na-D-valmet and Na-L-valmet.

ii) In the form of copper (II) complexes (i.e., **Cu-D-valmet** and **Cu-L-valmet**).

iii) Immobilized complexes (i.e., **GO-COOH/Cu(D-valmet)** and **GO-COOH/Cu(L-valmet)**).

Ligands **L-** and **D-valmet** in the Na form demonstrate base properties, making them potential homogeneous organocatalysts. When complexed with copper, these ligands act as homogeneous catalysts in all the three reactions, with the active species associated with basic nitrogen or free nitrogen complexated copper.

<figure><img src="image_118.png" /><figcaption>**Scheme 33:** Immobilization of Cu-D-valmet complex on GO-COOH support via coordinate covalent bond.</figcaption></figure>

In the case of the Henry reaction, dominant role is played by the ligand's, resulting in an asymmetric Henry reaction in water. Supported copper complexes of L-valmet chiral Schiff-base ligand proved to be particularly active in asymmetric Henry reaction. It performed the coupling reaction of benzaldehyde and nitromethane in water with a spectacular increase of the conversion (92% vs 39%) and ee (96 vs 62%) compared to the free complex.

For the cyanosilylation reaction, the free nitrogen of copper complexes acts as the active species. The racemic formation in this case can be attributed to the involvement of an unsaturated Cu center (Lewis active sites), enabling the reaction but lacking stereoselectivity. The copper complexes exhibit high conversions even at RT. However, some of the coupling product undergoes hydrolysis to cyanohydrins due to the presence of coordinated water molecules after drying. The involvement of water in the hydrolysis of α-(trimethylsilyl)-phenylacetonitrile becomes evident with increasing temperature, leading to an increased ratio between the two products as conversion increases. Immobilizing these complexes on GO-COOH results in either inhibited activity or minimal conversion, with complete hydrolysis of α-(trimethylsilyl)-phenylacetonitrile to cyanohydrin.

Furthermore, the base properties of both ligands were also demonstrated in the aldol condensation reaction. Complexation of copper by these ligands decreases conversion but increases
selectivity towards the mono-condensated product. Immobilizing these complexes on GO-COOH slightly reduces conversion without significantly impacting selectivity. The GO-COOH support, with its mixed acid and base properties due to oxygenated functionalities, facilitates a catalytic aldol reaction with a balanced ratio between the two products. The results are shown in Figure 8.

<figure><img src="image_120.png" /><figcaption>**Figure 13:** Catalytic potential of the synthesized complexes in Henry, cyanosilylation and aldol reaction.</figcaption></figure>

In conclusion, valmet ligands serve as reliable catalysts for stereoselective reactions and, when complexed with copper, demonstrate effectiveness in cyanosilylation reaction. The immobilization of these complexes generates efficient heterogeneous catalysts for aldol condensation.

## Conclusions

This work first focused on the non-covalent immobilization of three chiral cationic rhodium complexes [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ (complex A), [Rh(COD)((2S,4S)-BPPM)]BF₄ (complex B) and [Rh(COD)((2S,5S)-Et-Ferrocelane)]BF₄ (complex C), onto functionalized or non-functionalized carbon nanotubes as a support and their application in the enantioselective hydrogenation of dimethyl itaconate as a model substrate. This involved the preparation and characterization of a series of carbon nanotubes, the initial CNTs, the oxidized carbon nanotubes CNT-O, and the functionalized carbon nanotubes CNT-COO⁻·Na⁺, CNT-HPA, CNT-CO-HDA from CNT-O. On the other hand, suitable chiral cationic rhodium complexes for immobilization, [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ (complex A) and [Rh(COD)((2S,4S)-BPPM)]BF₄ (complex B) were successfully prepared starting from (2S,4S)-BPPM and synthesized (2S,4S)-PPM-pyrene ligands.

Immobilization of the rhodium complexes A, B, C on CNT, CNT-COO⁻·Na⁺, and CNT-HPA carbon nanotube supports was studied according to three different strategies.

The first approach was based on π-π interaction between the sp² graphitic structure of CNTs and aromatic moieties present in the ligands of the Rh-complexes. Among these three complexes, complex A allowed efficient immobilization on CNTs through π-π interaction. The immobilized complex demonstrated good stability during the recycling study which took place without any change in catalytic performances.
selectivity towards the mono-condensated product. Immobilizing these complexes on GO-COOH slightly reduces conversion without significantly impacting selectivity. The GO-COOH support, with its mixed acid and base properties due to oxygenated functionalities, facilitates a catalytic aldol reaction with a balanced ratio between the two products. The results are shown in Figure 8.

<figure><img src="image_119.png" /><figcaption>**Figure 13:** Catalytic potential of the synthesized complexes in Henry, cyanosilylation and aldol reaction.</figcaption></figure>

In conclusion, valmet ligands serve as reliable catalysts for stereoselective reactions and, when complexed with copper, demonstrate effectiveness in cyanosilylation reaction. The immobilization of these complexes generates efficient heterogeneous catalysts for aldol condensation.

## Conclusions

This work first focused on the non-covalent immobilization of three chiral cationic rhodium complexes [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ (complex A), [Rh(COD)((2S,4S)-BPPM)]BF₄ (complex B) and [Rh(COD)((2S,5S)-Et-Ferrocelane)]BF₄ (complex C), onto functionalized or non-functionalized carbon nanotubes as a support and their application in the enantioselective hydrogenation of dimethyl itaconate as a model substrate. This involved the preparation and characterization of a series of carbon nanotubes, the initial CNTs, the oxidized carbon nanotubes CNT-O, and the functionalized carbon nanotubes CNT-COO⁻·Na⁺, CNT-HPA, CNT-CO-HDA from CNT-O. On the other hand, suitable chiral cationic rhodium complexes for immobilization, [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ (complex A) and [Rh(COD)((2S,4S)-BPPM)]BF₄ (complex B) were successfully prepared starting from (2S,4S)-BPPM and synthesized (2S,4S)-PPM-pyrene ligands.

Immobilization of the rhodium complexes A, B, C on CNT, CNT-COO⁻·Na⁺, and CNT-HPA carbon nanotube supports was studied according to three different strategies.

The first approach was based on π-π interaction between the sp² graphitic structure of CNTs and aromatic moieties present in the ligands of the Rh-complexes. Among these three complexes, complex A allowed efficient immobilization on CNTs through π-π interaction. The immobilized complex demonstrated good stability during the recycling study which took place without any change in catalytic performances.
The second strategy implied electrostatic interaction between the cationic Rh complexes and the surface negatively charged of carboxylate-functionalized CNTs (CNT-COO⁻). The immobilization of the complexes occurs with partial **(complex B and C)** or total decoordination **(complex A)** of the chiral diphosphine ligand and probably partial or total direct coordination of Rh (I) to the carboxylate group on the surface. However, the immobilized [Rh(COD)((2S,5S)-Et-Ferrocelane)]BF₄ **Complex C** displayed good enantioselectivity, reaching an enantiomeric excess of 65% toward (R)-methyl succinate almost comparable to that of the free complex. However it was found unstable under the catalytic conditions since the formation Rh(0) nanoparticles (NPs) were observed, which were found to be very active but not enantioselective in the hydrogenation of DMI.

The third approach implied an ionic anchoring based on the use of a spacer-type anchoring agent, heteropoly acid HPA, that was previously grafted at the CNTs surface thanks to an acid-base interaction. **Complexes A, B, and C** were successfully immobilized on CNT-HPA. They were found active in asymmetric hydrogenation providing different enantioselectivities, 20%, 63%, and 58% for **complexes A, B, and C**, respectively. In addition, the immobilized **complex B** was found stable and recyclable up to 4 times with a moderate loss of enantioselectivity. This result corroborates the interest in adding a spacer such as HPA between the Rh complex and the CNT support to limit the effect of the CNT surface environment on the catalytic behavior of the Rh immobilized complexes.

Immobilization of chiral rhodium complexes showed the best results with [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ **complex A** immobilized via π-π stacking on CNTs and [Rh(COD)((2S,4S)-BPPM)]BF₄ **complex B** immobilized on CNT-HPA via an ionic anchoring through a spacer. Perspectives would be to improve the activity and enantioselectivity in asymmetric catalytic hydrogenation, which requires: i) optimization of the catalytic conditions, ii) variation of the chiral rhodium complexes immobilized on the support, iii) extension to other asymmetric hydrogenation and other asymmetric reactions. iv) transfer of batch-catalyzed hydrogenation into flow processes should also be considered in the future.

The synthesis of chiral rhodium nanoparticles (RhNPs) and their immobilization on functionalized carbon nanotubes were also studied. Well-dispersed chiral RhNPs could be prepared by decomposition of [Rh(η³-C₃H₅)₃] precursor in the presence of (2S,4S)-BPPM ligand. A good confinement of these RhNPs was observed when using the CNT-O support. In addition, chiral RhNPs obtained from [Rh(η³-C₃H₅)₃] and (2S,4S)-PPM-pyrene ligand were immobilized on CNT-CO-HDA with efficient confinement within the channels of these functionalized CNTs. In asymmetric hydrogenation of DMI, these immobilized RhNPs provided excellent activity but without enantioselectivity. The lack of enantioselectivity indicates that even in the case of the well-confined RhNPs the ligand is not blocked enough at the NP surface to allow the enantioselective hydrogenation of the DMI in one preferential side. However, we were able to demonstrate that it was possible to carry out the asymmetric hydrogenation with chiral Rh NPs formed *in-situ* in catalysis conditions that implied in the presence of DMI. Using [Rh(μ-Cl)(C₈H₁₂)]₂ precursors with (2S,4S)-BPPM ligand, the sponge-like large RhNPs led to an activity of 96 %, and more interestingly to an enantioselectivity of 16%. With [Rh(μ-Cl)(C₈H₁₂)]₂ precursor and (2S,4S)-PPM-pyrene ligand, the well-controlled and well-dispersed RhNPs exhibited moderate catalytic activity (69%) but with higher enantioselectivity (32%).

These results show the successful synthesis of chiral RhNPs and their use in asymmetric hydrogenation. This work has thus opened a new avenue for the preparation of chiral rhodium nanocatalysts but optimization is necessary to develop more efficient chiral nanocatalysts for asymmetric catalysis.

Finally, coordination immobilization of copper(II) complexes onto graphene oxide (GO) was performed by direct coordination of the metal center on –COOH surface group. Supported copper
The second strategy implied electrostatic interaction between the cationic Rh complexes and the surface negatively charged of carboxylate-functionalized CNTs (CNT-COO⁻). The immobilization of the complexes occurs with partial **(complex B and C)** or total decoordination (**complex A**) of the chiral diphosphine ligand and probably partial or total direct coordination of Rh (I) to the carboxylate group on the surface. However, the immobilized [Rh(COD)((2S,5S)-Et-Ferrocelane)]BF₄ **Complex C** displayed good enantioselectivity, reaching an enantiomeric excess of 65% toward (R)-methyl succinate almost comparable to that of the free complex. However it was found unstable under the catalytic conditions since the formation Rh(0) nanoparticles (NPs) were observed, which were found to be very active but not enantioselective in the hydrogenation of DMI.

The third approach implied an ionic anchoring based on the use of a spacer-type anchoring agent, heteropoly acid HPA, that was previously grafted at the CNTs surface thanks to an acid-base interaction. **Complexes A, B, and C** were successfully immobilized on CNT-HPA. They were found active in asymmetric hydrogenation providing different enantioselectivities, 20%, 63%, and 58% for **complexes A, B, and C**, respectively. In addition, the immobilized **complex B** was found stable and recyclable up to 4 times with a moderate loss of enantioselectivity. This result corroborates the interest in adding a spacer such as HPA between the Rh complex and the CNT support to limit the effect of the CNT surface environment on the catalytic behavior of the Rh immobilized complexes.

Immobilization of chiral rhodium complexes showed the best results with [Rh(COD)((2S,4S)-PPM-pyrene)]BF₄ **complex A** immobilized via π-π stacking on CNTs and [Rh(COD)((2S,4S)-BPPM)]BF₄ **complex B** immobilized on CNT-HPA via an ionic anchoring through a spacer. Perspectives would be to improve the activity and enantioselectivity in asymmetric catalytic hydrogenation, which requires: i) optimization of the catalytic conditions, ii) variation of the chiral rhodium complexes immobilized on the support, iii) extension to other asymmetric hydrogenation and other asymmetric reactions. iv) transfer of batch-catalyzed hydrogenation into flow processes should also be considered in the future.

The synthesis of chiral rhodium nanoparticles (RhNPs) and their immobilization on functionalized carbon nanotubes were also studied. Well-dispersed chiral RhNPs could be prepared by decomposition of [Rh(η³-C₃H₅)₃] precursor in the presence of (2S,4S)-BPPM ligand. A good confinement of these RhNPs was observed when using the CNT-O support. In addition, chiral RhNPs obtained from [Rh(η³-C₃H₅)₃] and (2S,4S)-PPM-pyrene ligand were immobilized on CNT-CO-HDA with efficient confinement within the channels of these functionalized CNTs. In asymmetric hydrogenation of DMI, these immobilized RhNPs provided excellent activity but without enantioselectivity. The lack of enantioselectivity indicates that even in the case of the well-confined RhNPs the ligand is not blocked enough at the NP surface to allow the enantioselective hydrogenation of the DMI in one preferential side. However, we were able to demonstrate that it was possible to carry out the asymmetric hydrogenation with chiral Rh NPs formed *in-situ* in catalysis conditions that implied in the presence of DMI. Using [Rh(µ-Cl)(C₈H₁₂)]₂ precursors with (2S,4S)-BPPM ligand, the sponge-like large RhNPs led to an activity of 96 %, and more interestingly to an enantioselectivity of 16%. With [Rh(µ-Cl)(C₈H₁₂)]₂ precursor and (2S,4S)-PPM-pyrene ligand, the well-controlled and well-dispersed RhNPs exhibited moderate catalytic activity (69%) but with higher enantioselectivity (32%).

These results show the successful synthesis of chiral RhNPs and their use in asymmetric hydrogenation. This work has thus opened a new avenue for the preparation of chiral rhodium nanocatalysts but optimization is necessary to develop more efficient chiral nanocatalysts for asymmetric catalysis.

Finally, coordination immobilization of copper(II) complexes onto graphene oxide (GO) was performed by direct coordination of the metal center on –COOH surface group. Supported copper
complexes of L-valmet chiral Schiff-base ligand proved to be particularly active in asymmetric Henry reaction. It performed the coupling reaction of benzaldehyde and nitromethane in water with a spectacular increase of the conversion (92% vs 39%) and ee (95 vs 62%) compared to the free complex.

References

[1] R. E. Gawley, J. Aube, *Principal of Asymmetric Synthesis*, Elsevier, 2012. DOI: [10.1016/C2009-0-06104-2](https://doi.org/10.1016/C2009-0-06104-2).

[2] J. Gal, *Chirality*, **2012**, *24*, 959–976. DOI: [10.1002/chir.22071](https://doi.org/10.1002/chir.22071).

[3] T. J. Leitereg, D. G. Guadagni, J. Harris, T. R. Mon, R. Teranishi, *J. Agric. Food Chem.*, **1971**, *19*, 785–787. DOI: [10.1038/230455a0](https://doi.org/10.1038/230455a0).

[4] U. Lepola, A. Wade, H. F. Andersen, *Int. Clin. Psychopharmacol.*, **2006**, *19*, 149. DOI: [10.1097/00004850-200405000-00005](https://doi.org/10.1097/00004850-200405000-00005).

[5] J. Hyttel, K. P. Bøgesø, J. Perregaard, C. Sánchez, *J. Neural. Transm.*, **1992**, *88*, 157–160. DOI: [10.1007/BF01244820](https://doi.org/10.1007/BF01244820).

[6] K. Motokura, S. Ding, K. Usui, Y. Kong, *ACS Catal.*, **2021**, *11*, 11985–12018. DOI: [10.1021/acscatal.1c03426](https://doi.org/10.1021/acscatal.1c03426).

[7] T. Cheng, Q. Zhao, D. Zhang, G. Liu, *Green Chemistry*, **2015**, *17*, 2100–2122. DOI: [10.1039/C4GC02204A](https://doi.org/10.1039/C4GC02204A).

[8] M. R. Axet, O. Dechy-Cabaret, J. Durand, M. Gouygou, P. Serp, *Coord. Chem. Rev.*, **2016**, *308*, 236–345. DOI: [10.1016/j.ccr.2015.06.005](https://doi.org/10.1016/j.ccr.2015.06.005).

[9] B. Pugin, H. U. Blaser, *Top Catal.*, **2010**, *53*, 953–962. DOI: [10.1007/s11244-010-9514-8](https://doi.org/10.1007/s11244-010-9514-8).

[10] R. Selke, M. Čapka, *J. Mol. Catal.*, **1990**, *63*, 319–334. DOI: [10.1016/0304-5102(90)85124-7](https://doi.org/10.1016/0304-5102(90)85124-7).

[11] M. Mazzel, W. Marconi, M. Riocci, *J. Mol. Catal.*, **1980**, *9*, 381–387. DOI: [10.1016/0304-5102%2880%2980030-7](https://doi.org/10.1016/0304-5102%2880%2980030-7).

[12] R. Augustine, S. Tanielyan, S. Anderson, H. Yang, *Chem. Commun.*, **1999**, 1257–1258. DOI: [10.1039/A903205C](https://doi.org/10.1039/A903205C).

[13] L. J. Lemus-Yegres, M. C. Román-Martínez, C. S.-M. de Lecea, *J. Nanosci. Nanotechnol.*, **2009**, *9*, 6034–6041. DOI: [10.1016/j.micromeso.2007.05.005](https://doi.org/10.1016/j.micromeso.2007.05.005).

[14] C. C. Gheorghiu, B. F. Machado, C. Salinas-Martínez de Lecea, M. Gouygou, M. C. Román-Martínez, P. Serp, *Dalton Trans.*, **2014**, *43*, 7455. DOI: [10.1039/C3DT53301H](https://doi.org/10.1039/C3DT53301H).

[15] P. Serp, K. Philippot (Editors), *Nanomaterials in Catalysis*, Wiley-VCH: Weinheim, Germany, **2012**. ISBN: 9783527656875. DOI: [10.1002/9783527656875](https://doi.org/10.1002/9783527656875).

[16] M. Ibrahim, M. A. S. Garcia, L. L. R. Vono, M. Guerrero, P. Lecante, L. M. Rossi, K. Philippot, *Dalton Trans.*, **2016**, *45*, 17782–17791. DOI: [10.1039/C6DT03104H](https://doi.org/10.1039/C6DT03104H).

[17] M. Ibrahim, M. M. Wei, E. Deydier, E. Manoury, R. Poli, P. Lecante, K. Philippot, *Dalton Trans.*, **2019**, *48*, 6777–6786. DOI: [10.1039/c9dt01006h](https://doi.org/10.1039/c9dt01006h).

[18] M. Ibrahim, R. Poreddy, K. Philippot, A. Riisager, E. J. Garcia-Suarez, *Dalton Trans.*, **2016**, *45*, 19368–19373. DOI: [10.1039/C6DT03668F](https://doi.org/10.1039/C6DT03668F).

[19] C. J. Abou-Fayssal, C. Fliedel, R. Poli, A. Riisager, K. Philippot, E. Manoury, *Mater. Today Chem.*, **2023**, *34*, 101752. DOI: [10.1016/j.mtchem.2023.101752](https://doi.org/10.1016/j.mtchem.2023.101752).
complexes of L-valmet chiral Schiff-base ligand proved to be particularly active in asymmetric Henry reaction. It performed the coupling reaction of benzaldehyde and nitromethane in water with a spectacular increase of the conversion (92% vs 39%) and ee (95 vs 62%) compared to the free complex.

References

[1] R. E. Gawley, J. Aube, *Principal of Asymmetric Synthesis*, Elsevier, 2012. DOI: [10.1016/C2009-0-06104-2](https://doi.org/10.1016/C2009-0-06104-2).

[2] J. Gal, *Chirality*, **2012**, *24*, 959–976. DOI: [10.1002/chir.22071](https://doi.org/10.1002/chir.22071).

[3] T. J. Leitereg, D. G. Guadagni, J. Harris, T. R. Mon, R. Teranishi, *J. Agric. Food Chem.*, **1971**, *19*, 785–787. DOI: [10.1038/230455a0](https://doi.org/10.1038/230455a0).

[4] U. Lepola, A. Wade, H. F. Andersen, *Int. Clin. Psychopharmacol.*, **2006**, *19*, 149. DOI: [10.1097/00004850-200405000-00005](https://doi.org/10.1097/00004850-200405000-00005).

[5] J. Hyttel, K. P. Bøgesø, J. Perregaard, C. Sánchez, *J. Neural. Transm.*, **1992**, *88*, 157–160. DOI: [10.1007/BF01244820](https://doi.org/10.1007/BF01244820).

[6] K. Motokura, S. Ding, K. Usui, Y. Kong, *ACS Catal.*, **2021**, *11*, 11985–12018. DOI: [10.1021/acscatal.1c03426](https://doi.org/10.1021/acscatal.1c03426).

[7] T. Cheng, Q. Zhao, D. Zhang, G. Liu, *Green Chemistry*, **2015**, *17*, 2100–2122. DOI: [10.1039/C4GC02204A](https://doi.org/10.1039/C4GC02204A).

[8] M. R. Axet, O. Dechy-Cabaret, J. Durand, M. Gouygou, P. Serp, *Coord. Chem. Rev.*, **2016**, *308*, 236–345. DOI: [10.1016/j.ccr.2015.06.005](https://doi.org/10.1016/j.ccr.2015.06.005).

[9] B. Pugin, H. U. Blaser, *Top Catal.*, **2010**, *53*, 953–962. DOI: [10.1007/s11244-010-9514-8](https://doi.org/10.1007/s11244-010-9514-8).

[10] R. Selke, M. Čapka, *J. Mol. Catal.*, **1990**, *63*, 319–334. DOI: [10.1016/0304-5102(90)85124-7](https://doi.org/10.1016/0304-5102(90)85124-7).

[11] M. Mazzel, W. Marconi, M. Riocci, *J. Mol. Catal.*, **1980**, *9*, 381–387. DOI: [10.1016/0304-5102%2880%2980030-7](https://doi.org/10.1016/0304-5102%2880%2980030-7).

[12] R. Augustine, S. Tanielyan, S. Anderson, H. Yang, *Chem. Commun.*, **1999**, 1257–1258. DOI: [10.1039/A903205C](https://doi.org/10.1039/A903205C).

[13] L. J. Lemus-Yegres, M. C. Román-Martínez, C. S.-M. de Lecea, *J. Nanosci. Nanotechnol.*, **2009**, *9*, 6034–6041. DOI: [10.1016/j.micromeso.2007.05.005](https://doi.org/10.1016/j.micromeso.2007.05.005).

[14] C. C. Gheorghiu, B. F. Machado, C. Salinas-Martínez de Lecea, M. Gouygou, M. C. Román-Martínez, P. Serp, *Dalton Trans.*, **2014**, *43*, 7455. DOI: [10.1039/C3DT53301H](https://doi.org/10.1039/C3DT53301H).

[15] P. Serp, K. Philippot (Editors), *Nanomaterials in Catalysis*, Wiley-VCH: Weinheim, Germany, **2012**. ISBN: 9783527656875. DOI: [10.1002/9783527656875](https://doi.org/10.1002/9783527656875).

[16] M. Ibrahim, M. A. S. Garcia, L. L. R. Vono, M. Guerrero, P. Lecante, L. M. Rossi, K. Philippot, *Dalton Trans.*, **2016**, *45*, 17782–17791. DOI: [10.1039/C6DT03104H](https://doi.org/10.1039/C6DT03104H).

[17] M. Ibrahim, M. M. Wei, E. Deydier, E. Manoury, R. Poli, P. Lecante, K. Philippot, *Dalton Trans.*, **2019**, *48*, 6777–6786. DOI: [10.1039/c9dt01006h](https://doi.org/10.1039/c9dt01006h).

[18] M. Ibrahim, R. Poreddy, K. Philippot, A. Riisager, E. J. Garcia-Suarez, *Dalton Trans.*, **2016**, *45*, 19368–19373. DOI: [10.1039/C6DT03668F](https://doi.org/10.1039/C6DT03668F).

[19] C. J. Abou-Fayssal, C. Fliedel, R. Poli, A. Riisager, K. Philippot, E. Manoury, *Mater. Today Chem.*, **2023**, *34*, 101752. DOI: [10.1016/j.mtchem.2023.101752](https://doi.org/10.1016/j.mtchem.2023.101752).
Sara BONFANTE

ESR5

**Thesis co-directors**

Dr. Antoine Simonneau Laboratoire de Chimie de Coordination, Toulouse, France

Prof. Jason Lynam,
Dr. John Slattery
University of York, York, United Kingdom

**Thesis defense**

Laboratoire de Chimie de Coordination, Toulouse, France, 5 April 2024
Sara BONFANTE

ESR5

**Thesis co-directors**

Dr. Antoine Simonneau Laboratoire de Chimie de Coordination, Toulouse, France

Prof. Jason Lynam, University of York, York, United Kingdom
Dr. John Slattery

**Thesis defense**

Laboratoire de Chimie de Coordination, Toulouse, France, 5 April 2024
<figure><img src="image_121.png" /></figure>
<figure><img src="image_120.png" /></figure>
# Zirconium- and Phosphine-assisted C–F Bond Activation and Functionalisation

## Introduction

Fluorine is the 9th element of the periodic table and it is the most electronegative, with a Pauling scale value ($\chi$) of 4.0 [1]. It also exhibits a high first ionisation energy ($IE_1$ = 1679 kJ/mol), making it challenging to abstract an electron from its 2p shell. Furthermore, fluorine exhibits a high electron affinity (EA = -328 kJ/mol), meaning that the addition of an electron to atomic fluorine releases energy [2]. Many of these effects are a consequence of fluorine having the smallest van der Waals atomic radius ($r_{vdW}$ = 1.47 Å) among the period 2 elements. The C–F bond is the strongest C–X bond (bond dissociation energy = 513 kJ/mol;

Table 5, bottom) [2], deriving its strength mainly from the high ionic character (approximately 43%) resulting from the electronegativity difference between C and F ($\Delta\chi$ = 1.5) [3]. Due to the high strength of this bond, the cleavage of C–F bonds is generally challenging.

<table><caption>**Table 5.** Bond dissociation energy (BDE) of relevant C–X bonds (bottom).</caption><thead><tr><td>Bond</td><td>BDE (kJ/mol)</td></tr></thead><tbody><tr><td>C–F</td><td>513</td></tr><tr><td>C–H</td><td>413</td></tr><tr><td>C–O</td><td>351</td></tr><tr><td>C–C</td><td>348</td></tr><tr><td>C–Cl</td><td>328</td></tr><tr><td>C–N</td><td>292</td></tr></tbody></table>

The high biological activity of fluorinated organic compounds stems from the fact that fluorine can be used as isostere for hydrogen in organic molecules, causing dramatic changes in the properties of the molecule comparing to the corresponding hydrocarbon but usually preserving its geometry and shape due to the small radius [4]. The incorporation of fluorine often results in an increase in the acidity of adjacent functional groups and organic acids, along with an enhancement in the lipophilicity of the molecule [5]. Furthermore, the presence of fluorine in an organic molecule facilitates the formation of hydrogen bonding interactions. These phenomena strongly influence the biological activity of fluorinated organic compounds [4].

Fluorine is the 13th most abundant element in the Earth's crust, mainly occurring in the form of fluoride minerals such as fluorite ($CaF_2$) [6]. However, naturally occurring fluorinated organic compounds are limited and their biosynthesis remains unclear [7]. The industrial synthesis of fluorine-containing organic molecules typically derives from the use of elemental $F_2$ or HF, both obtained from the upgrading of $CaF_2$ [8].

Fluorinated organic molecules can be found in a wide range of applications, including pharmaceuticals (where approximately 20% of commercial drugs contain at least one fluorine atom or a fluorinated functional group [9]), agrochemicals, medical imaging (such as Positron Emission Tomography [10]), materials (including fluoropolymers and liquid crystals), and more (Figure 14). Hence, there is a significant interest in developing efficient strategies for the synthesis of valuable fine chemicals that incorporate fluorine.
# Zirconium- and Phosphine-assisted C–F Bond Activation and Functionalisation

## Introduction

Fluorine is the 9th element of the periodic table and it is the most electronegative, with a Pauling scale value ($\chi$) of 4.0 [1]. It also exhibits a high first ionisation energy ($IE_1$ = 1679 kJ/mol), making it challenging to abstract an electron from its 2p shell. Furthermore, fluorine exhibits a high electron affinity (EA = -328 kJ/mol), meaning that the addition of an electron to atomic fluorine releases energy [2]. Many of these effects are a consequence of fluorine having the smallest van der Waals atomic radius ($r_{vdW}$ = 1.47 Å) among the period 2 elements. The C–F bond is the strongest C–X bond (bond dissociation energy = 513 kJ/mol;

Table 5, bottom) [2], deriving its strength mainly from the high ionic character (approximately 43%) resulting from the electronegativity difference between C and F ($\Delta\chi$ = 1.5) [3]. Due to the high strength of this bond, the cleavage of C–F bonds is generally challenging.

<table><caption>**Table 5.** Bond dissociation energy (BDE) of relevant C–X bonds (bottom).</caption><thead><tr><td>Bond</td><td>BDE (kJ/mol)</td></tr></thead><tbody><tr><td>C–F</td><td>513</td></tr><tr><td>C–H</td><td>413</td></tr><tr><td>C–O</td><td>351</td></tr><tr><td>C–C</td><td>348</td></tr><tr><td>C–Cl</td><td>328</td></tr><tr><td>C–N</td><td>292</td></tr></tbody></table>

The high biological activity of fluorinated organic compounds stems from the fact that fluorine can be used as isostere for hydrogen in organic molecules, causing dramatic changes in the properties of the molecule comparing to the corresponding hydrocarbon but usually preserving its geometry and shape due to the small radius [4]. The incorporation of fluorine often results in an increase in the acidity of adjacent functional groups and organic acids, along with an enhancement in the lipophilicity of the molecule [5]. Furthermore, the presence of fluorine in an organic molecule facilitates the formation of hydrogen bonding interactions. These phenomena strongly influence the biological activity of fluorinated organic compounds [4].

Fluorine is the 13th most abundant element in the Earth's crust, mainly occurring in the form of fluoride minerals such as fluorite ($CaF_2$) [6]. However, naturally occurring fluorinated organic compounds are limited and their biosynthesis remains unclear [7]. The industrial synthesis of fluorine-containing organic molecules typically derives from the use of elemental $F_2$ or HF, both obtained from the upgrading of $CaF_2$ [8].

Fluorinated organic molecules can be found in a wide range of applications, including pharmaceuticals (where approximately 20% of commercial drugs contain at least one fluorine atom or a fluorinated functional group [9]), agrochemicals, medical imaging (such as Positron Emission Tomography [10]), materials (including fluoropolymers and liquid crystals), and more (Figure 14). Hence, there is a significant interest in developing efficient strategies for the synthesis of valuable fine chemicals that incorporate fluorine.
<figure><img src="image_122.png" /><figcaption>**Figure 14.** Selected examples of fluorine-containing organic molecules employed in pharmaceutical and agrochemical industries.</figcaption></figure>

Moreover, due to their inert nature upon decomposition, fluorocarbons can be persistent in the environment. Hydrofluorocarbons (HFCs) and hydrofluoroolefins (HFOs) find applications in refrigeration, air-conditioning, foam-blowing, electronics and fire protection. Their high volatility leads to their release into the atmosphere as fluorinated gases, contributing to environmental pollution [11],[12]. Therefore, there is a need to explore alternative methods for the defluorination of fluorinated organic molecules. Two main pathways for the synthesis of partially fluorinated molecules have been developed:

I. selective fluorination of non-fluorinated substrates;

II. selective defluorination of perfluorinated and polyfluorinated molecules.

The first approach involves the use of fluorinating reagents, including nucleophilic, electrophilic and trifluoromethylating agents. The main challenge in this method arises from controlling the reactivity of fluorine sources. With strong nucleophilic fluoride sources (e.g. HF, KF or $Me_4NF$), the fluoride anion exhibits weak nucleophilicity in the presence of hydrogen bond donors, leading to the formation of the stable anion $HF_2^-$ [5]. When hydrogen bond donors are rigorously excluded, fluoride's strong basicity and nucleophilicity often result in undesired side reactions. Among the electrophilic fluorinating reagents, the simplest is fluorine gas, which is highly reactive, very difficult and hazardous to handle. It is often unselective and can react with many common functional groups. Consequently, due to the harsh conditions usually required in these systems, the substrate scope and selectivity of these reactions are restricted to simple substrates, which can be employed as building blocks for subsequent functionalisations [5].

Researchers are overcoming this limitation by developing mild electrophilic fluorination reagents that enable the late-stage fluorination of complex organic molecules. These reagents allow milder reaction conditions to be used, they are easy to handle, less toxic and hazardous than traditional fluorinating reagents and exhibit enhanced selectivity. For instance, among the electrophilic fluorination reagents, the so-called “NF-reagents” stand out. These compounds feature a fluorine atom directly bonded to the electronegative nitrogen, which can be further activated by electron-withdrawing groups (e.g. carbonyl, sulfonyl) or a positive charge in the molecule. The advantage of all these reagents is that most are solid, non-volatile and non-explosive compounds, which may be handled with standard synthetic chemistry techniques [4]. For example, Selectfluor, an NF-reagent
<figure><img src="image_121.png" /><figcaption>**Figure 14.** Selected examples of fluorine-containing organic molecules employed in pharmaceutical and agrochemical industries.</figcaption></figure>

Moreover, due to their inert nature upon decomposition, fluorocarbons can be persistent in the environment. Hydrofluorocarbons (HFCs) and hydrofluoroolefins (HFOs) find applications in refrigeration, air-conditioning, foam-blowing, electronics and fire protection. Their high volatility leads to their release into the atmosphere as fluorinated gases, contributing to environmental pollution [11],[12]. Therefore, there is a need to explore alternative methods for the defluorination of fluorinated organic molecules. Two main pathways for the synthesis of partially fluorinated molecules have been developed:

I. selective fluorination of non-fluorinated substrates;

II. selective defluorination of perfluorinated and polyfluorinated molecules.

The first approach involves the use of fluorinating reagents, including nucleophilic, electrophilic and trifluoromethylating agents. The main challenge in this method arises from controlling the reactivity of fluorine sources. With strong nucleophilic fluoride sources (e.g. HF, KF or $Me_4NF$), the fluoride anion exhibits weak nucleophilicity in the presence of hydrogen bond donors, leading to the formation of the stable anion $HF_2^-$ [5]. When hydrogen bond donors are rigorously excluded, fluoride's strong basicity and nucleophilicity often result in undesired side reactions. Among the electrophilic fluorinating reagents, the simplest is fluorine gas, which is highly reactive, very difficult and hazardous to handle. It is often unselective and can react with many common functional groups. Consequently, due to the harsh conditions usually required in these systems, the substrate scope and selectivity of these reactions are restricted to simple substrates, which can be employed as building blocks for subsequent functionalisations [5].

Researchers are overcoming this limitation by developing mild electrophilic fluorination reagents that enable the late-stage fluorination of complex organic molecules. These reagents allow milder reaction conditions to be used, they are easy to handle, less toxic and hazardous than traditional fluorinating reagents and exhibit enhanced selectivity. For instance, among the electrophilic fluorination reagents, the so-called “NF-reagents” stand out. These compounds feature a fluorine atom directly bonded to the electronegative nitrogen, which can be further activated by electron-withdrawing groups (e.g. carbonyl, sulfonyl) or a positive charge in the molecule. The advantage of all these reagents is that most are solid, non-volatile and non-explosive compounds, which may be handled with standard synthetic chemistry techniques [4]. For example, Selectfluor, an NF-reagent
developed thirty years ago, is industrially employed in the synthesis of fluticasone propionate, an active ingredient in Seretide, a drug used for asthma treatment [13]. Nevertheless, often directing groups (such as pyridyl, amino, N-perfluorotolylamide groups) are necessary to ensure regioselectivity in these reactions [14]. Alternatively, pre-activation of the substrate (β-ketocarbonyl compounds) can be necessary to promote the reaction [5].

The second strategy for the synthesis of complex fluorinated organic compounds is the selective activation of C–F bonds in polyfluorinated and perfluorinated organic molecules. This approach is interesting as it allows the transformation of highly fluorinated molecules, readily available through bulk industrial fluorination processes (e.g. employing HF, KF, F₂), into more valuable fluorinated compounds. This is achieved through the selective activation of C–F bonds, converting them into C–H, C–C, C–O, C–S, C–N, C–P bonds. Transition metals (TMs) mainly promote these processes, either catalytically or stoichiometrically, although examples involving main-group elements are also present in the literature [15]. Considering the high strength of the C–F bond, the thermodynamic requirement to make this process feasible is the formation of other strong E–F bonds form, where E typically is H, Si, B, Al and TMs [16]. This method is a viable alternative to the C–F formation strategy, as it can lead to the synthesis of new compounds, new selectivity and synthetic routes that might not be accessible with the first approach [17]. The challenges associated with this method involve achieving precise control over the regio- and stereoselectivity and improving the functional group tolerance of the transformation [15].

## Aims and objectives

The aim of this Ph.D. project was to explore novel strategies for the regioselective activation and functionalisation of C–F bonds in readily available polyfluoroaromatic compounds promoted by early-transition metals and by *p*-block elements.

This project is structured into three sections. The aim of the first section was to establish a novel synthetic protocol for the controlled and regioselective functionalisation of fluorinated pyridines using a strained zirconocene-cycloalkyne complex. The objective was to obtain a fluorinated pyridine alkenylated in *ortho*-position, which could subsequently be further functionalised to yield a more complex, stereo-defined fluorinated organic compound. This investigation demonstrated that the zirconocene-cycloalkyne complex followed three different reactivity pathways, depending on the fluorination pattern of the polyfluoropyridine.

In the second section, the investigation of a side reaction observed in the first section is described. This reaction involved the C–F bond activation in *para*-position of pentafluoropyridine (*Py-F₅*) promoted by simple trialkylphosphines. The outcome of this activation reaction depends on the reaction conditions, leading to either the hydrodefluorinated product or the reductive C–C homocoupling product. Additionally, the generation of differently substituted difluorophosphoranes was observed. This research highlighted the potential of metal-free systems, employing only simple phosphines to selectively and efficiently functionalise electron-poor perfluoroheteroaromatics.

The final objective was to demonstrate that simple trialkylphosphines are able to catalyse hydrodefluorination (HDF) and aminodefluorination reactions in the presence of silanes and silyl amides, without the need for complex constrained structures or the use of metals, as reported in the existing literature. The research showed that PⁿBu₃ could exhibit reactivity akin to TMs during the catalytic cycle, characterised by reversible two-electron redox processes like oxidative addition and reductive elimination.
developed thirty years ago, is industrially employed in the synthesis of fluticasone propionate, an active ingredient in Seretide, a drug used for asthma treatment [13]. Nevertheless, often directing groups (such as pyridyl, amino, N-perfluorotolylamide groups) are necessary to ensure regioselectivity in these reactions [14]. Alternatively, pre-activation of the substrate (β-ketocarbonyl compounds) can be necessary to promote the reaction [5].

The second strategy for the synthesis of complex fluorinated organic compounds is the selective activation of C–F bonds in polyfluorinated and perfluorinated organic molecules. This approach is interesting as it allows the transformation of highly fluorinated molecules, readily available through bulk industrial fluorination processes (e.g. employing HF, KF, F₂), into more valuable fluorinated compounds. This is achieved through the selective activation of C–F bonds, converting them into C–H, C–C, C–O, C–S, C–N, C–P bonds. Transition metals (TMs) mainly promote these processes, either catalytically or stoichiometrically, although examples involving main-group elements are also present in the literature [15]. Considering the high strength of the C–F bond, the thermodynamic requirement to make this process feasible is the formation of other strong E–F bonds form, where E typically is H, Si, B, Al and TMs [16]. This method is a viable alternative to the C–F formation strategy, as it can lead to the synthesis of new compounds, new selectivity and synthetic routes that might not be accessible with the first approach [17]. The challenges associated with this method involve achieving precise control over the regio- and stereoselectivity and improving the functional group tolerance of the transformation [15].

## Aims and objectives

The aim of this Ph.D. project was to explore novel strategies for the regioselective activation and functionalisation of C–F bonds in readily available polyfluoroaromatic compounds promoted by early-transition metals and by *p*-block elements.

This project is structured into three sections. The aim of the first section was to establish a novel synthetic protocol for the controlled and regioselective functionalisation of fluorinated pyridines using a strained zirconocene-cycloalkyne complex. The objective was to obtain a fluorinated pyridine alkenylated in *ortho*-position, which could subsequently be further functionalised to yield a more complex, stereo-defined fluorinated organic compound. This investigation demonstrated that the zirconocene-cycloalkyne complex followed three different reactivity pathways, depending on the fluorination pattern of the polyfluoropyridine.

In the second section, the investigation of a side reaction observed in the first section is described. This reaction involved the C–F bond activation in *para*-position of pentafluoropyridine (*Py-F₅*) promoted by simple trialkylphosphines. The outcome of this activation reaction depends on the reaction conditions, leading to either the hydrodefluorinated product or the reductive C–C homocoupling product. Additionally, the generation of differently substituted difluorophosphoranes was observed. This research highlighted the potential of metal-free systems, employing only simple phosphines to selectively and efficiently functionalise electron-poor perfluoroheteroaromatics.

The final objective was to demonstrate that simple trialkylphosphines are able to catalyse hydrodefluorination (HDF) and aminodefluorination reactions in the presence of silanes and silyl amides, without the need for complex constrained structures or the use of metals, as reported in the existing literature. The research showed that PⁿBu₃ could exhibit reactivity akin to TMs during the catalytic cycle, characterised by reversible two-electron redox processes like oxidative addition and reductive elimination.
### C–F bond functionalisation promoted by a zirconium-cyclohexyne complex

<figure><img src="image_123.png" /><figcaption>**Scheme 34.** Synthetic protocol for the synthesis of the zirconocene-η²-cyclohexyne (5) and its corresponding PMe₃ adduct (6).</figcaption></figure>

The investigation started with the study of the synthesis of the zirconocene-η²-cyclohexyne complex (5) reported by Buchwald and co-workers (Scheme 34) [18]. The targeted Zr complex was prepared by degradation of an *in situ* generated 1-cyclohexenyl-methyl-zirconocene complex (4) *via* β-H abstraction, leading to methane evolution and the zirconocene-cyclohexyne complex 5. To facilitate its isolation, Buchwald *et al*. stabilised 5 with PMe₃, resulting in the phosphine adduct 6. Complex 6, or *in situ* prepared 5, were shown to react with various unsaturated organic molecules by insertion in the Zr–C bond[19].

To begin, 1-bromocyclohexene (1) was synthesised by reacting cyclohexanone with a slight excess of bromine, triphenylphosphite and NEt₃ (Scheme 34) [20]. Subsequently, the formation of 2 *via* [(Cp₂ZrCl)₂(μ-O)] was carried out (ca. 50%) (Scheme 35) [21].

<figure><img src="image_124.png" /><figcaption>**Scheme 35.** Synthesis of the methylzirconocene chloride 2.</figcaption></figure>

The formation of the desired oxo-bridged complex [(Cp₂ZrCl)₂(μ-O)] was achieved in high isolated yields (78%) by reacting equimolar amounts of zirconocene dichloride, aniline and a slight excess of water (Scheme 35). The subsequent methylation with two equivalents of trimethylaluminum allowed the formation of 2 in moderate yields of 62% (relative to the oxo-bridged complex) and the reaction could be conducted on a relatively large scale (8 g).

The zirconocene-PMe₃ adduct 6 was successfully synthesised according to reaction Scheme 34 in 52% isolated yield. The formation of this complex was evidenced by the appearance of a singlet at δ = −2.3 ppm in the ³¹P{¹H} NMR spectrum, corresponding to the phosphorus nucleus of the coordinated phosphine, and the disappearance of the signal for free PMe₃ (δ(³¹P) = −62.0 ppm). The ¹H and 2D-NMR analyses further confirmed the formation of the phosphine adduct 6.
### C–F bond functionalisation promoted by a zirconium-cyclohexyne complex

<figure><img src="image_122.png" /><figcaption>**Scheme 34.** Synthetic protocol for the synthesis of the zirconocene-η²-cyclohexyne (5) and its corresponding PMe₃ adduct (6).</figcaption></figure>

The investigation started with the study of the synthesis of the zirconocene-η²-cyclohexyne complex (5) reported by Buchwald and co-workers (Scheme 34) [18]. The targeted Zr complex was prepared by degradation of an *in situ* generated 1-cyclohexenyl-methyl-zirconocene complex (4) *via* β-H abstraction, leading to methane evolution and the zirconocene-cyclohexyne complex 5. To facilitate its isolation, Buchwald *et al.* stabilised 5 with PMe₃, resulting in the phosphine adduct 6. Complex 6, or *in situ* prepared 5, were shown to react with various unsaturated organic molecules by insertion in the Zr–C bond[19].

To begin, 1-bromocyclohexene (1) was synthesised by reacting cyclohexanone with a slight excess of bromine, triphenylphosphite and NEt₃ (Scheme 34) [20]. Subsequently, the formation of 2 *via* [(Cp₂ZrCl)₂(μ-O)] was carried out (ca. 50%) (Scheme 35) [21].

<figure><img src="image_123.png" /><figcaption>**Scheme 35.** Synthesis of the methylzirconocene chloride 2.</figcaption></figure>

The formation of the desired oxo-bridged complex [(Cp₂ZrCl)₂(μ-O)] was achieved in high isolated yields (78%) by reacting equimolar amounts of zirconocene dichloride, aniline and a slight excess of water (Scheme 35). The subsequent methylation with two equivalents of trimethylaluminum allowed the formation of 2 in moderate yields of 62% (relative to the oxo-bridged complex) and the reaction could be conducted on a relatively large scale (8 g).

The zirconocene-PMe₃ adduct 6 was successfully synthesised according to reaction Scheme 34 in 52% isolated yield. The formation of this complex was evidenced by the appearance of a singlet at δ = −2.3 ppm in the ³¹P{¹H} NMR spectrum, corresponding to the phosphorus nucleus of the coordinated phosphine, and the disappearance of the signal for free PMe₃ (δ(³¹P) = −62.0 ppm). The ¹H and 2D-NMR analyses further confirmed the formation of the phosphine adduct 6.
The reactivity of complex **6** and the *in situ* generated **5** with differently fluorinated pyridines was investigated. **Py-F₅** was chosen as the initial polyfluorinated pyridine for this study due to its reported high reactivity in the C–F bond addition reaction, as indicated in the study conducted by Etienne and coworkers [22]. As the 16-electron complex **5** is expected to be the active species for the C–F activation process, a solution of the *in situ* generated complex was treated with an excess of **Py-F₅** but no reaction was observed according to ¹H and ¹⁹F NMR spectroscopy, even upon heating up to 60 °C for several hours (Scheme 36, top reaction). Surprisingly, when PMe₃ was added to the reaction mixture, the complete consumption of the heteroaromatic compound occurred after 16 hours at 20 °C (Scheme 36, bottom reaction). Analysis of the mixture by ¹⁹F NMR revealed a singlet at δ = 51.0 ppm in the spectrum, matching well with a Zr-bound fluoride, along with numerous signals in the region of the aromatic *ortho*, *meta* and *para* fluorine. From this observation, it was assumed that the presence of PMe₃ was crucial for the C–F bond activation and may act as an assisting ligand. As reported in the literature, phosphine assistance in metal-mediated C–F bond activation is a known phenomenon [23-26]. Typically, these examples involve the formation of a metallofluorophosphorane intermediate, which then undergoes either an alkyl or a fluoride transfer from the P<sup>V</sup> centre to the metal, leading to an alkylated or fluorinated metal complex, respectively [27].

<figure><img src="image_125.png" /><figcaption>**Scheme 36.** Attempts of C–F functionalisation of pentafluoropyridine with zirconocene-cyclohexyne complexes **5** and **6**.</figcaption></figure>

The reactivity of the isolated PMe₃ adduct **6** with an equimolar amount of **Py-F₅** (Scheme 36, bottom reaction) was therefore investigated. After four hours at 20 °C in C₆D₆, the starting complex, **6**, was fully converted into 1-cyclohexenylzirconocene fluoride (**7**), accompanied by the formation of an unidentified dark red solid (17 mg out of 43 mg of starting complex **6** used) and unreacted **Py-F₅**. Two more equivalents of **6** were needed to consume all the **Py-F₅**. Complex **7** was characterised by a singlet resonance in the ¹⁹F NMR spectrum at δ = 51.0 ppm corresponding to the Zr–F bond (the same chemical shift observed in the previous experiment). Traces of the hydrodefluorination product 2,3,5,6-tetrafluoropyridine (**Py-F₄**), F₂PMe₃ (**8**) and a fluorinated unidentified product were observed in the ¹⁹F NMR spectrum. These species were analysed by multinuclear (¹H, ³¹P, ¹⁹F, ¹³C) and 2D-NMR spectroscopy. The formation of **7** was further confirmed by protonation or iodinolisys of the organic ligand. Different conditions for the C–F bond activation reaction of **6** with **Py-F₅** were investigated
The reactivity of complex **6** and the *in situ* generated **5** with differently fluorinated pyridines was investigated. **Py-F₅** was chosen as the initial polyfluorinated pyridine for this study due to its reported high reactivity in the C–F bond addition reaction, as indicated in the study conducted by Etienne and coworkers [22]. As the 16-electron complex **5** is expected to be the active species for the C–F activation process, a solution of the *in situ* generated complex was treated with an excess of **Py-F₅** but no reaction was observed according to ¹H and ¹⁹F NMR spectroscopy, even upon heating up to 60 °C for several hours (Scheme 36, top reaction). Surprisingly, when PMe₃ was added to the reaction mixture, the complete consumption of the heteroaromatic compound occurred after 16 hours at 20 °C (Scheme 36, bottom reaction). Analysis of the mixture by ¹⁹F NMR revealed a singlet at δ = 51.0 ppm in the spectrum, matching well with a Zr-bound fluoride, along with numerous signals in the region of the aromatic *ortho*, *meta* and *para* fluorine. From this observation, it was assumed that the presence of PMe₃ was crucial for the C–F bond activation and may act as an assisting ligand. As reported in the literature, phosphine assistance in metal-mediated C–F bond activation is a known phenomenon [23-26]. Typically, these examples involve the formation of a metallofluorophosphorane intermediate, which then undergoes either an alkyl or a fluoride transfer from the P<sup>V</sup> centre to the metal, leading to an alkylated or fluorinated metal complex, respectively [27].

<figure><img src="image_124.png" /><figcaption>**Scheme 36.** Attempts of C–F functionalisation of pentafluoropyridine with zirconocene-cyclohexyne complexes **5** and **6**.</figcaption></figure>

The reactivity of the isolated PMe₃ adduct **6** with an equimolar amount of **Py-F₅** (Scheme 36, bottom reaction) was therefore investigated. After four hours at 20 °C in C₆D₆, the starting complex, **6**, was fully converted into 1-cyclohexenylzirconocene fluoride (**7**), accompanied by the formation of an unidentified dark red solid (17 mg out of 43 mg of starting complex **6** used) and unreacted **Py-F₅**. Two more equivalents of **6** were needed to consume all the **Py-F₅**. Complex **7** was characterised by a singlet resonance in the ¹⁹F NMR spectrum at δ = 51.0 ppm corresponding to the Zr–F bond (the same chemical shift observed in the previous experiment). Traces of the hydrodefluorination product 2,3,5,6-tetrafluoropyridine (**Py-F₄**), F₂PMe₃ (**8**) and a fluorinated unidentified product were observed in the ¹⁹F NMR spectrum. These species were analysed by multinuclear (¹H, ³¹P, ¹⁹F, ¹³C) and 2D-NMR spectroscopy. The formation of **7** was further confirmed by protonation or iodinolisys of the organic ligand. Different conditions for the C–F bond activation reaction of **6** with **Py-F₅** were investigated
(Scheme 36, bottom reaction), but changing the solvent (benzene, toluene and cyclohexane), concentration of the zirconocene-PMe₃ adduct (0.1 M, 0.3 M), reagent ratio (complex 6 : Py-F₅ = 1:1, 3:1, 5:1), lowering the temperature to 0 °C, and using pre-cooled solvent and reagents (–40 °C) had only little influence on the reaction outcome. At –40 °C the system was unreactive.

To shed more light on the mechanism of this reaction, a control experiment on the reactivity of trimethylphosphine towards pentafluoropyridine was carried out. Addition of an equimolar amount of PMe₃ to a solution of Py-F₅ in C₆D₆ or THF-d₈ at 20 °C triggered the formation of Py-F₄, F₂PMe₃, the 4-methylenetetrafluoropyridine-substituted difluorophosphorane 9 and a phosphonium salt 13, along with unreacted PMe₃ (Scheme 37). The red solid was not observed.

<figure><img src="image_126.png" /><figcaption>**Scheme 37.** Reactivity test of Py-F₅ (1 equiv.) with PMe₃ (1–3 equiv.) in C₆D₆ or THF-d₈ at 20 °C.</figcaption></figure>

The spontaneous reaction of PMe₃ with Py-F₅ casts doubt on a Zr-mediated C–F bond activation for this substrate. The treatment of the mixture produced by the 1:1 PMe₃/Py-F₅ reaction in C₆D₆ with the cyclohexyne complex 6, according to Scheme 38, resulted in the consumption of 8 and 9 and the appearance of the zirconocene-fluoride 7 after 3 hours at 20 °C, as evidenced by the ¹⁹F NMR spectrum. Three equivalents of 6 (vs. Py-F₅) were needed to consume all 8 and 9 to afford 7 rather selectively.

<figure><img src="image_127.png" /><figcaption>**Scheme 38.** Reaction of 6 (3 equiv.) with the compounds issued by the reaction of PMe₃ (1 equiv.) and Py-F₅ (1 equiv.) in C₆D₆ at 20 °C.</figcaption></figure>

This outcome strongly suggests that the C–F bond activation event observed in the reaction of 6 with Py-F₅ was initiated by dissociated PMe₃ reacting with the heteroaromatic to give 8 and 9, which subsequently reacted with 6 to provide 7. This is consistent with the dissociation energy values of the bonds involved: the Zr–F bond (BDE = 623 ± 63 kJ/mol) is indeed stronger than the P–F (BDE ≤ 405 kJ/mol) and C–F bonds (BDE = 513 kJ/mol [28]). Considering the nucleophilic attack of the phosphine on the fluoroheteroaromatic as a crucial mechanistic step in the reaction outlined in Scheme 37, it was expected that the use of a less electron-poor pyridine (e.g. with a reduced degree of fluorination) could circumvent the undesired reactivity of PMe₃ with the fluoroheteroarene. Therefore, Py-F₄, 2,4,6-trifluoropyridine (Py-F₃) and 2,6-difluoropyridine (Py-F₂) were identified as suitable candidates for this investigation.