Catalytic isomerization of branched allylic alcohols by water-soluble [RuCp(OH₂)(PTA)₂](CF₃SO₃) and [RuCp(OH₂)(mPTA)₂](CF₃SO₃)₃

Abstract

The isomerization of substituted allylic alcohols, including α-vinyl benzyl alcohol, trans-1,3-diphenyl-2-propen-1-ol, cinnamyl alcohol, coniferyl alcohol, 4-nitrocinnamyl alcohol, farnesol, 1,5-hexadien-3,4-diol, (1R)-(−)-myrtenol and S,R-(−)-carveol, catalyzed by the [RuCp(OH₂)(PTA)₂](CF₃SO₃) (1) and [RuCp(OH₂)(mPTA)₂](CF₃SO₃)₃ (2) (PTA = 1,3,5-triaza-7-phosphaadamantane, mPTA = N-methyl-1,3,5-triaza-7-phosphaadamantane) complexes was examined in pure water and water-containing media. The isomerization of the chalcone trans-1,3-diphenyl-2-propen-1-ol catalyzed by 1 to produce the natural product propiophenone displays the highest known turnover number for this reaction to date (TON = 200 and TOF_5h = 40 h⁻¹). A study delving into the catalytic reaction mechanisms was carried out, aiming to understand the influence of different functional groups on the studied isomerization processes. The intermediates of the isomerization of α-vinylbenzyl alcohol and 1,5-hexadien-3,4-diol catalyzed by 1 and 2 were isolated and characterized by NMR spectroscopy.

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Introduction

In the last decades, it was proven that allylic alcohols can be conveniently converted into their respective carbonyl compounds via one-step isomerization reactions catalyzed by suitable metal complexes under mild conditions and in harmless solvents such as water.^1,2 This synthetic process is influenced by the size of the substrate and the substituents on the double bond.³ However, although numerous transition metal complexes^4–7 have been found to be useful in isomerizing linear allylic alcohols,^8–10 the number that can be employed for the isomerization of substituted allylic alcohols is considerably lower. Particularly, the list of catalysts for the isomerization of allylic alcohols bearing bulky groups is notably short, and in some instances, no example has been described. In this regard, the evaluation of water-soluble catalysts for the isomerization of branched allylic alcohols could be a sustainable and environmentally friendly approach, achieving significant products with potential applications in medicinal and fine chemistry, as well as in the field of natural products.¹¹

Ruthenium complexes featuring hydrophilic tertiary organophosphine ligands,¹² such as triphenylphosphines (Na-mTPPMS and Na₃-mTPPTS),¹³ and the adamantane-like ligand 1,3,5-triaza-7-phosphaadamantane (PTA) and derivatives^14–16 are among the wide variety of catalysts used. To date, the efficacy of various water-soluble ruthenium complexes containing PTA and its monomethylated derivative mPTA (N-methyl-1,3,5-triaza-7-phosphaadamantane) has been supported by several significant results.^17–21 In particular, the [RuCp(OH₂)(PTA)₂](CF₃SO₃) (1) and [RuCp(H₂O)(mPTA)₂](CF₃SO₃)₃ (2) complexes are active catalysts for isomerizing a wide variety of linear^20–24 and cyclic^25–27 allylic alcohols in aqueous environments (Scheme 1). Despite the similarities in the structure and composition of these complexes, they display significant catalytic differences such as conversion and a better reaction medium.^20,21,27

Scheme 1 Isomerization of allylic alcohols catalysed by ruthenium complexes bearing PTA (1) and mPTA (2).

It is important to note that complex 1 was found to be useful for the easy synthesis of some pheromones^28–38 involved in the natural aggregation/anti-aggregation system of the Douglas-fir beetle (Dendroctonus pseudotsugae), which is known to be the major killer of conifers.³⁹ Therefore, the study of the catalytic properties of these complexes not only provides a new insight about how the substituents of the allylic alcohols influence their catalytic activity in aqueous media, but also provides new useful synthetic procedures for obtaining valuable compounds.

Herein, the catalytic applications of 1 and 2 were studied in water and reaction media containing water (henceforth denoted as aqueous media) for the isomerization of allylic alcohols bearing unsubstituted and substituted aromatic rings and/or multiple double bonds, including α-vinylbenzyl alcohol, cinnamyl alcohol, trans-1,3-diphenyl-2-propen-1-ol, coniferyl alcohol, and 4-nitrocinnamyl alcohol, farnesol and 1,5-hexadien-3,4-diol. Finally, the cyclic allylic alcohols 3-methyl-2-cyclohexen-1-ol, (1R)-(−)-myrtenol and S,R-(−)-carveol were also tested (Fig. 1). Most of them and/or their isomerization products come from can be in found natural resources,^40–42 such as essential oils.^43–45 They play pivotal roles as starting materials or major components in food,^40,46 fragrances,^47,48 pharmaceuticals^49–51 or synthetic applications.^52,53 For instance, (1R)-(−)-myrtenol, found in certain aromatic plants, is used in the fragrance^54,55 and pharmaceutical industries due to its anti-inflammatory, antioxidant and antimicrobial properties.^56–58 Similarly, cinnamyl alcohol, found in plants such as cinnamon,^59,60 is widely used in the fragrance, cosmetics and deodorant industries,⁴⁸ as well as an intermediate compound in various manufacturing processes.⁶¹

Fig. 1 Substituted allylic alcohols evaluated for catalytic isomerization in aqueous media.

This study represents the first example of the use of water-soluble cyclopentadienyl Ru(II) complexes bearing phosphine ligands for the isomerisation of these allylic alcohols. Related systems found in the literature include Ru(II)-arene complexes such as [RuCl₂(mTHPA)(η⁶-C₆H₆)] (mTHPA = N-methyl-trihydrazinophosphaadamantane),¹² as well as complexes featuring substituted hydroxyethoxy-arene and phosphine ligands, for example [RuCl₂(η⁶-C₆H₅OCH₂CH₂OH)P(OMe)₃] and [RuCl₂(η⁶-C₆H₅OCH₂CH₂OH)P(OⁱPr)₃].⁶² Additionally, a heterodimetallic Ru/Fe complex, [Ru(η⁶-p-cymene)Cl₂(1-(diphenylphosphanyl)-1’-[N-(2-hydroxyethyl)-carbamoyl]ferrocene-κP)], has been reported.⁶³ Several Ru(IV) complexes bearing the 2,7-dimethylocta-2,6-diene and dodeca-2,6,10-triene ligands have been studied, including [Ru(η³:η³-C₁₀H₁₆)Cl(κ²O,O–CH₃CO₂)],³ [Ru(η³:η³-C₁₀H₁₆)(Cl)₂(pyrazole)],⁶⁴ [Ru(η³:η³-C₁₀H₁₆)(Cl)₂(benzimidazole)],^65,66 and [Ru(η³:η²:η³-C₁₂H₁₈)Cl₂].⁶² In the case of Rh-complexes, catalytic systems formed by the combination of [Rh(COD)Cl]₂ with the phosphine PTA or aryl sulfonated phosphines have also been reported.⁷

Results and discussion

Catalytic reactions

Linear allylic alcohols containing aromatic rings: trans-1,3-diphenyl-2-propen-1-ol, α-vinylbenzyl alcohol, cinnamyl alcohol, 4-nitrocinnamyl alcohol, and coniferyl alcohol.

The isomerization of trans-1,3-diphenyl-2-propen-1-ol into dihydrochalcone was performed in CH₃OH/H₂O (1 : 1) at 70 °C and ⁱPrOH/H₂O (1 : 1) at 80 °C, with varying catalyst loadings (Table S1). Table 1 summarizes the results obtained, along with a comparison with published catalysts. It is significant to stress that complete substrate conversion was achieved within 4 h using 1 mol% of 1 in CH₃OH/H₂O (TOF_4h = 24.8 h⁻¹). Decreasing the catalyst to 0.2 mol% in ⁱPrOH/H₂O resulted in 40% conversion (TOF_5h = 40 h⁻¹) after 5 h. In contrast, 1 mol% of 2 in MeOH/H₂O failed to isomerize the substrate, as no more than 5% conversion (TOF_4h = 2.6 h⁻¹) was obtained in 4 h. Therefore, the catalyst loading was increased to 10 mol%, leading to a conversion of 53% in 24 h (TOF_24h = 0.22 h⁻¹). Dihydrochalcone was obtained with 99% conversion. The resulting pure product was characterized by ¹H NMR (Fig. S81). It was obtained by extracting the reaction mixture with CHCl₃, drying over CaCl₂, filtering the collected organic layers through a silica gel column, and drying under vacuum overnight.

Table 1 Catalytic isomerization of trans-1,3-diphenyl-2-propen-1-ol into dihydrochalcone by 1 and 2: comparison with bibliographic results

Catalyst	[Cat] mol%	T (h)	T (°C)	Solvent	Additive	TOF^a (h^−1)	Conversion (%)	Ref.
a TOF = turn over frequency, N2, ROH/H2O (1 : 1) = 1 mL, % measured by ^1H NMR.
1	1	2	70	MeOH/H2O	—	37.5	75	This work
1	1	4	70	MeOH/H2O	—	24.8	>99	This work
1	0.2	5	70	MeOH/H2O	—	12.4	12.4	This work
1	0.2	5	80	^iPrOH/H2O	—	40	40	This work
2	1	2	70	MeOH/H2O	—	2.6	5	This work
[Ru(η^6-p-cymene)Cl2(1-(diphenylphosphanyl)-1′-[N-(2-hydroxyethyl)-carbamoyl]ferrocene-κP)]	2	20	80	H2O	KOtBu	2.5	99	63

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Although the catalytic redox isomerization of trans-1,3-diphenyl-2-propen-1-ol has been extensively reviewed in organic media, fewer studies were reported in aqueous environments, where a heterodimetallic Ru/Fe complex is the most efficient catalyst in water reported so far, achieving TON = 49 and TOF = 2.5 h⁻¹ at 80 °C and in the presence of KO^tBu.⁶³ Thus, complex 1 showed the best catalytic profile for this reaction in terms of both TON and TOF.

The isomerization of α-vinylbenzyl alcohol into propiophenone was evaluated under the same conditions as the previous substrate in CH₃OH/H₂O (1 : 1) at 70 °C or ⁱPrOH/H₂O (1 : 1) at 80 °C (Table S2). Using 1 mol% of 1 or 2 in CH₃OH/H₂O (1 : 1), 40% conversion into propiophenone was achieved in both cases after 24 h (TOF_24h = 1.7 h⁻¹). Changing the solvent to ⁱPrOH/H₂O (1 : 1) resulted in higher and faster transformation into propiophenone, achieving a conversion of 44% with 1 at 8 h (TOF_8h = 5.5 h⁻¹) and of 71% with 2 (TOF_8h = 8.9 h⁻¹). Increasing the catalyst loading of both complexes to 2 mol% led to complete isomerization, in both CH₃OH/H₂O (1 : 1) and ⁱPrOH/H₂O (1 : 1), and evidenced that complex 2 is more active (CH₃OH/H₂O (1 : 1): TOF_4h = 3.1 h⁻¹; ⁱPrOH/H₂O (1 : 1): TOF_1h = 34.5 h⁻¹, TOF_4h = 12.4 h⁻¹) than 1 (CH₃OH/H₂O (1 : 1): TOF_4h = 3.3 h⁻¹; ⁱPrOH/H₂O (1 : 1): TOF_4h = 8.4 h⁻¹, TOF_8h = 6.2 h⁻¹). Complex 2 clearly showed higher activity in the ⁱPrOH/H₂O (1 : 1) mixture than in CH₃OH/H₂O (1 : 1). Propiophenone synthesis was achieved with 99% conversion. The process was the same as that used to obtain dihydrochalcone. Its characterization by ¹H NMR is shown in Fig. S82.

As shown in Table 2, previously published results showed that some Ru(II) and various Ru(IV) complexes and Rh complexes exhibit notable catalytic activity for the isomerization of α-vinylbenzyl alcohol in aqueous media.^{3,7,62,64–67} The most notable contribution was the Ru(IV) complex bearing η³:η³-C₁₀H₁₆ and a bidentate acetate ligand, [Ru(η³:η³-C₁₀H₁₆)Cl(κ²O,O–CH₃CO₂)], which was found to be a highly efficient catalyst for this reaction in water at 75 °C (TON = 99, TOF = 1200 h⁻¹).³ Other studies include the complex [Ru(η³:η³-C₁₀H₁₆)(Cl)₂(pyrazole)], which also achieved high TOF values (495 h⁻¹) in water at 75 °C (TON = 99);⁶⁴ and/or the [Ru(η³:η³-C₁₀H₁₆)(Cl)₂(benzimidazole)] complex⁶⁵ in KH₂PO₄ phosphate buffer containing MgSO₄ (39.6 h⁻¹, TON = 99) at 50 °C.⁶⁶ The Ru(IV)-complex [Ru(η³:η²:η³-C₁₂H₁₈)Cl₂] also exhibited high catalytic activity for the transformation of this allylic alcohol, with TOF values of 20 h⁻¹ (TON = 99) in water and 80 (TON = 99) in H₂O/CsCO₃ at 75 °C.⁶² Among the Ru(II) compounds, the Ru-arene complex bearing mTHPA, [RuCl₂(mTPHA)(η⁶-C₆H₆)], proved to be a suitable catalyst for this reaction in water with KO^tBu at 75 °C (TON = 97, TOF = 129 h⁻¹).¹² However, the highest catalytic activity for this reaction with Ru(II)-arene complexes was obtained with [RuCl₂(η⁶-C₆H₅OCH₂CH₂OH)P(OMe)₃] and [RuCl₂(η⁶-C₆H₅OCH₂CH₂OH)P(OⁱPr)₃], achieving both of them TOF values of 600 h⁻¹ (TON = 99) in water and KO^tBu at 75 °C.⁶² Regarding the Rh-complexes, active catalytic systems were generated in situ upon using [Rh(COD)Cl]₂ and PTA or aryl sulfonated phosphines as cocatalysts, affording the highest activity when PTA was used.⁷ It is important to stress that complexes 1 and 2 are also the first Ru(II)-cyclopentadienyl complexes evaluated for this reaction in water, and although the results show that they are efficient and useful for this reaction, they do not equal or surpass previously published catalysts.

Table 2 Catalytic isomerization of α-vinylbenzyl alcohol into propiophenone by 1 and 2, including significant bibliographic results

Catalyst	[Cat] mol%	t (h)	T (°C)	Solvent	Additive	TOF^a (h^−1)	Conversion (%)	Ref.
a TOF = turn over frequency, N2, ROH/H2O (1 : 1) = 1 mL, % measured by ^1H NMR.
1	1	8	70	MeOH/H2O	—	3.5	28	This work
1	1	8	80	^iPrOH/H2O	—	5.5	44	This work
1	2	4	70	MeOH/H2O	—	3.1	25	This work
1	2	8	70	MeOH/H2O	—	2.6	41	This work
1	2	4	80	^iPrOH/H2O	—	8.4	67	This work
1	2	8	80	^iPrOH/H2O	—	6.2	99	This work
2	1	24	70	MeOH/H2O	—	1.7	40	This work
2	1	24	80	^iPrOH/H2O	—	3.1	73	This work
2	2	4	80	MeOH/H2O	—	3.5	28	This work
2	2	8	80	MeOH/H2O	—	2.6	42	This work
2	2	1	80	^iPrOH/H2O	—	34.5	69	This work
2	2	4	80	^iPrOH/H2O	—	12.4	>99	This work
[Rh(COD)Cl]2	5	17	80	H2O	MeO-TPPMS	1.2	99	7
[Rh(COD)Cl]2	5	18	80	H2O	PTA NaOH	1.1	99	7
[Rh(COD)(CH3CN)2]BF4	2	0.08	23	H2O	PTA NaOH	594	99	7
[RuCl2(mTHPA)(η^6-C6H6)]	1	0.75	75	H2O	KO^tBu	129	97	12
[RuCl2(η^6-C6H5OCH2CH2OH)(P(O^iPr)3)]	1	10	75	H2O	KO^tBu	600	99	62
[{Ru(η^3:η^3-C10H16)(μ-Cl)Cl2}]	5	1	75	H2O	—	20	99	62
[{Ru(η^3:η^3-C10H16)(μ-Cl)Cl2}]	5	0.25	75	H2O/Cs2CO3	—	80	99	62
[Ru(η^3:η^3-C10H16)(Cl)2(benzimidazole)]	1	3 h	50	H2O	^iPrNH2 KH2PO4 buffer	33	99	67
[Ru(η^3:η^3-C10H16)(Cl)2(benzimidazole)]	1	0.25	75	H2O	—	396	99	65
[Ru(η^3:η^3-C10H16)(Cl)2(pyrazole)]	0.2	1	75	H2O	—	495	99	64
[Ru(η^3:η^3-C10H16)Cl(κ^2O,O–CH3CO2)]	1	2.5	50	H2O	MgSO4 KH2PO4 buffer	39.6	99	66
[Ru(η^3:η^3-C10H16)Cl(benzimidazole)]	1	2.5	50	H2O	MgSO4 KH2PO4 buffer	39.6	99	66
[Ru(η^3:η^3-C10H16)Cl(κ^2O,O–CH3CO2)]	1	0.08	75	H2O	—	1200	99	3

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The catalytic isomerization of cinnamyl alcohol to obtain hydrocinnamaldehyde showed that both catalysts display a performance significantly lower than that previously published in the literature in aqueous media (Table 3).^{3,7,62,64,65,67} No conversion was observed in CH₃OH/H₂O (1 : 1) at 70 °C, with 1 mol% of both complexes, and also in ⁱPrOH/H₂O (1 : 1) at 80 °C with 10% of catalyst, the conversion remained very low after 24 h (1 : 5% and 2 : 11%) (Table S3). However, some of the Ru(IV) and Rh complexes reported in the literature are more efficient for the isomerization of cinnamyl alcohol in aqueous media, where the most active Ru(IV)-complex is [Ru(η³:η³-C₁₀H₁₆)(Cl)₂(benzimidazole)] in phosphate buffer containing ⁱPrNH₂ at 50 °C (TON = 99, TOF = 33 h⁻¹)⁶⁷ and the most active reported Rh-complex is [Rh(COD)(CH₃CN)₂]BF₄ in the presence of PTA in H₂O at 45 °C (TON = 29.5, TOF = 39.3 h⁻¹).⁷

Table 3 Catalytic isomerization of cinnamyl alcohol into hydrocinnamaldehyde alcohols by 1 and 2: comparison with bibliographic results

Catalyst	[Cat] mol%	t (h)	T (°C)	Solvent	Additive	TOF^a (h^−1)	Conversion (%)	Ref.
a TOF = turn over frequency, N2, ROH/H2O (1 : 1) = 1 mL, % measured by ^1H NMR.
1	10	24	80	^iPrOH/H2O	—	0.02	5	This work
2	10	24	80	^iPrOH/H2O	—	0.05	11	This work
[Rh(COD)(CH3CN)2]BF4	2	0.75	45	H2O	PTA	39.3	59	7
[{Ru(η^3:η^3-C10H16)(μ-Cl)Cl2}]	10	3	75	H2O	—	3	99	68
[{Ru(η^3:η^3-C10H16)(μ-Cl)Cl2}]	10	2.5	75	H2O/Cs2CO3	—	4	99	68
[Ru(η^3:η^3-C10H16)Cl(κ^2O,O–CH3CO2)]	5	2	75	H2O	—	7	74	3
[Ru(η^3:η^3-C10H16)(Cl)2(benzimidazole)]	5	2.5	75	H2O	—	4	50	65
[Ru(η^3:η^3-C10H16)(Cl)2(benzimidazole)]	1	4	50	H2O	^iPrNH2 KH2PO4 buffer	33	99	67
[Ru(η^3:η^3-C10H16)(Cl)2(pyrazole)]	5	1	75	H2O	—	9.4	47	64

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In view of the obtained results for the catalytic isomerization of allylic alcohols containing unsubstituted aromatic compounds, the catalytic isomerization of some examples of para-phenyl-substituted allylic alcohols was assessed. Thus, catalytic isomerization of 4-nitrocinnamyl alcohol and coniferyl alcohol into 3,4-nitrobenzenepropanal and dihydroconiferyl aldehyde, respectively, was evaluated with complexes 1 and 2. No conversion of the substrates into dihydroconiferyl aldehyde was observed under the tested conditions in CH₃OH/H₂O (1 : 1) at 70 °C and ⁱPrOH/H₂O (1 : 1) at 80 °C. Nevertheless, minor conversion (<5%) for the isomerization of 4-nitrocinnamyl alcohol was achieved with 10 mol% of both catalysts after 48 h (Table S4), which is a very low conversion, but it is the first reported for this substrate to the best of our knowledge.

Linear allylic alcohols containing multiple double bonds: farnesol and 1,5-hexadiene-3,4-diol. The catalytic efficiency of both complexes was evaluated against farnesol and 1,5-hexadiene-3,4-diol. Despite employing a high catalyst loading of 10 mol%, the isomerization of farnesol in CH₃OH/water (1 : 1) at 75 °C did not occur, and in ⁱPrOH/H₂O (1 : 1) at 80 °C, only a low conversion to dihydrofarnesal was obtained after 48 h (1 : 3%; 2 : 1%). Likewise, the isomerization of 1,5-hexadiene-3,4-diol in methanol at 70 °C and in water up to 100 °C did not occur (Table S5).

Cyclic allylic alcohols: 3-methyl-2-cyclohexen-1-ol, S,R-(−)carveol and (1R)-(−)-myrtenol. The last group of substrates tested included the cyclic allylic alcohols 3-methyl-2-cyclohexen-1-ol, S,R-(−)-carveol, and (1R)-(−)-myrtenol. We showed that complex 1 exhibited very high activity for the catalytic isomerization of 2-cyclohexen-1-ol into cyclohexenone (H₂O: TOF = 324 h⁻¹; CH₃OH: TOF = 49 h⁻¹; H₂O/cyclohexane: TOF = 163 h⁻¹)²⁵ and 3-methyl-2-cyclohexen-1-ol into 3-methylcyclohexenone (H₂O: TOF_5h = 17 h⁻¹; CH₃OH: TOF_2h = 17 h⁻¹).²⁶ The activity of 2 in the isomerization of 2-cyclohexen-1-ol was also evaluated, obtaining good results,²⁷ although inferior to that obtained with complex 1.²⁵ Table S6 summarizes the reaction conditions for the isomerization of 3-methyl-2-cyclohexen-1-ol in the presence of 1 and 2, where it is also observed that for this reaction, complex 2 is less active than 1. With 1 mol% of 2 in methanol no isomerization was observed, and in water only 18% conversion was achieved after 5 h (TOF_5h = 3.6 h⁻¹). Similarly, the isomerization of S,R-(−)-carveol did not proceed employing 10 mol% of both complexes (Table S7). Notably, the catalytic isomerization of (1R)-(−)-myrtenol with 10 mol% of 1 in ⁱPrOH/H₂O (1 : 1) at 80 °C achieved a conversion of 70% after 48 h (TOF_48h = 0.15 h⁻¹), while with 2 the conversion was 43% (TOF_48h = 0.1 h⁻¹) (Table 4). Myrtanal was obtained from (1R)-(−)-myrtenol with a conversion of 70%. The process was the same as that followed to obtain dihydrochalcone and propiophenone. The resulting mixture was characterized by ¹H NMR, as shown in Fig. S84. It is important to stress that to the best of our knowledge, this is the first example of the isomerization of this alcohol in aqueous media at 80 °C.⁶⁹

Table 4 Catalytic isomerization of (1R)-(−)-myrtenol into myrtanal catalyzed by 1 and 2

Catalyst	[Ru] mol%	T (°C)	Time (h)	Solvent	TON	TOF^a (h^−1)	Conversion (%)
a TON = turn over number, TOF = turn over frequency, N2, ROH/H2O 1 : 1 = 1 mL, % measured by ^1H NMR.
1	10	70	8	MeOH/H2O	3	0.4	30
1	10	80	8	^iPrOH/H2O	3.5	0.4	35
1	10	80	48	^iPrOH/H2O	7.0	0.2	70
2	10	80	24	^iPrOH/H2O	2.5	0.1	25
2	10	80	48	^iPrOH/H2O	4.3	0.1	43

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Catalytic isomerization mechanism

Study of the reactivity of branched allylic alcohols against 1 and 2. To gain a better understanding of the isomerization of the studied allylic alcohols, representative catalytic reactions were studied by ³¹P{¹H} NMR and ¹H NMR in D₂O and CD₃OD/D₂O (2 : 1) in a 5 mm NMR tube. In the latter solvent mixture, complexes 1 and 2 are in substitutional equilibrium with methanol, forming a certain amount of the respective [RuCpL₂(CD₃OD)]ⁿ⁺ (L: PTA, n = 2, δ³¹P = −25.8 ppm; mPTA, n = 2, δ³¹P = −10.3 ppm). Additionally, complex 2 partially deprotonates into [RuCp(OD)(mPTA)₂]²⁺, which is characterized by a singlet at −8.6 ppm.^20,27

Regarding the study of the reactions with the substrates (1R)-(−)-myrtenol, S,R-(−)-carveol, farnesol, 4-nitrocinnamyl alcohol, farnesol, and coniferyl alcohol, in which a range of modest to no conversion was observed, no additional signals were detected in the ³¹P{¹H} and ¹H NMR spectra even after 72 h at 80 °C, apart from the abovementioned signals, which is a consequence of the reaction with the solvent media. The lack of isomerization of (1R)-(−)-myrtenol and S,R-(−)-carveol, but also of observable intermediates, is likely due to steric hindrance. These substrates are constituted by bulky substituents, such as a bicyclic group in the case of (1R)-(−)-myrtenol and a methyl group at the vinyl position in S,R-(−)-carveol, which is also a cyclic substrate. These bulky substituents make difficult the coordination of the allylic alcohols to the metal centre by the double bond and OH. The substrates 4-nitrocinnamyl alcohol and coniferyl alcohol also have bulky groups in their structure. Alternatively, farnesol has a long chain containing methyl groups and multiple double bonds, which compete with the allylic C=C group for coordination with the metal. Finally, it seems that when the phenyl groups are in the vinyl position and para-substituted with electron-withdrawing groups, the isomerization process is hindered. Nevertheless, despite being substituted alkenes, 3-methyl-2-cylohexen-1-ol, trans-1,3-diphenyl-2-propen-1-ol, cinnamyl alcohol, α-vinyl benzyl alcohol and 1,5-hexadien-3,4-diol underwent transformations. The follow-up reactions of 3-methyl-2-cylohexen-1-ol with 2 both in CD₃OD and in D₂O are illustrated in Fig. S1–S4. Notably, the ³¹P{¹H} NMR spectra over time suggested the decomposition of 2 as the signal at −10.3 ppm decreased, but no additional peak appeared. In contrast, the catalyst gave rise to new species different from that expected by reaction with the solvent when the catalytic isomerization of trans-1,3-diphenyl-2-propen-1-ol with 1 (Fig. S5–S8) was studied by ³¹P{¹H} NMR (Fig. S6), which are assigned to O=PTA (−7.2 ppm) and [RuCpH(PTA)₂] (−10.73 ppm).^70,71 Nevertheless, no signals ascribed to reaction intermediates were observed. Considering that this catalyst facilitates the isomerization more effectively and faster than 2, the obtained results suggest that once the respective intermediates are formed, they evolve faster than possible to be determined by NMR. Although this is also a bulky substrate, its electron-withdrawing group in the allylic position appears to aid the isomerisation process. Besides the abovementioned substrates, the study of the catalytic isomerization with 1 of cinnamyl alcohol (Fig. S9 and S10) showed that two doublets arise in the ³¹P{¹H} NMR spectra. Their weak abundance prevented the complete characterization of these species, but their chemical shifts at −26.9 ppm and −36.6 ppm, together with the magnitude of their coupling constant of ²J_PP = 46.0 Hz, suggested that the CH=CH group of cinnamyl alcohol is coordinated to the metal, similar to that found with 1,5-hexenadien-3,4-diol and α-vinyl benzyl alcohol.

α-Vinylbenzyl alcohol was tested in CD₃OD/D₂O (2 : 1) at 70 °C and at room temperature with both complexes 1 and 2 (Fig. S11–S18). After 24 h, the ¹H NMR spectra evidence the formation of propiophenone (Fig. S11 and S13), while in the ³¹P{¹H} NMR spectra, two sets of doublets appeared, corresponding to two AB systems located in the range of −21.6 ppm to −26.6 ppm in the reaction with 1, and −6.0 ppm to 9.3 ppm with 2 (Fig. S12 and S14), respectively. Additionally, the ³¹P{¹H} NMR spectra display two less intense singlets at −10.23 ppm and −12.39 ppm (<4%), which were not possible to characterize (Fig. S14). The proportion of the two sets of doublets was 8.3 : 1.7 in the reaction with 1, and 7.5 : 2.5 in the reaction with 2. At room temperature, no conversion of the substrate was observed (Fig. S15 and S17), but ³¹P{¹H} NMR displayed the same peaks as that at 80 °C (Fig. S16 and S18). The reaction between α-vinylbenzyl alcohol and 2 in ⁱPrOH/H₂O was monitored at 25 °C and 60 °C by ³¹P{¹H} NMR experiments using a D₂O capillary (Fig. S19). At 25 °C, the ³¹P{¹H} NMR spectrum exhibited four doublets (54%), in a 7.7 : 2.3 proportion, along with a singlet corresponding to complex 2 (46%), where the exo/endo ratio remained constant after heating to 60 °C.

The observed intermediates were synthesized and characterized as complexes [RuCp(η²-CH₂=CH–CHOH–C₆H₅)(PTA)₂](CF₃SO₃) (3) and [RuCp(η²-CH₂=CH–CHOH–C₆H₅)(mPTA)₂](CF₃SO₃)₃ (4), which were obtained by reacting 1 and 2 with 50 eq. excess of α-vinylbenzyl alcohol in CH₃OH at room temperature and under N₂, followed by precipitation with diethyl ether (see SI, Section 9), respectively. Both complexes are stable in solution at room temperature up to 48 h under N₂ and were fully characterized by multinuclear NMR in CD₃OD (3: Fig. S32–S39 and 4: Fig. S40–S46). The ³¹P{¹H} NMR spectrum of 3 (Fig. S33) displays a set of four doublets between −23.00 ppm and −28.1 ppm, in an 8.7 : 1.3 ratio. In contrast, the ³¹P{¹H} NMR spectrum of 4 (Fig. S41) only shows two doublets in the range of −6.0 to ppm −10.0 ppm, along with four other singlets (<25%), which were assigned to 2, O = mPTA, [RuCp(OH)(mPTA)₂]²⁺ and [RuCp(OCD₃)(mPTA)₂]⁺. An additional singlet at −12.1 ppm was also observed, which could not be characterized.

The study of both complexes by ¹H–¹H ROESY experiments suggests that 3 in solution is mainly the isomer exo-[RuCp(η²-CH₂=CH–CHOH–C₆H₅)(PTA)₂](CF₃SO₃) (exo-3), as indicated by the correlation between the H^1a and H³ protons to the Cp protons, while the minor species is endo-[RuCp(η²-CH₂=CH–CHOH–C₆H₅)(PTA)₂](CF₃SO₃) (endo-3), where H^1b and H² are related to the Cp protons (Fig. S39). In contrast, only the exo-[RuCp(η²-CH₂=CH–CHOH–C₆H₅)(mPTA)₂](CF₃SO₃)₃ (exo-4) was observed in CD₃OD, which was supported by the cross peaks related to H^1a and H³ with Cp-H (Fig. S46 and 2). The endo-isomer was not detected, even at 60 °C, where only the transformation of complex 4 into 2, [RuCp(OCD₃)(mPTA)₂]⁺, O = mPTA, [RuCp(OH)(mPTA)₂]⁺ and an unidentified species (−12.5 ppm) was observed (Fig. S47). Notably, the addition of D₂O to a methanolic solution of exo-4 gave rise to the formation to two doublets corresponding to the endo-isomer (−7.19 ppm, d, mPTA, endo-4, ²J_PP = 41.52 Hz) and −8.85 ppm; d, mPTA, endo-4, ²J_PP = 41.52 Hz)), together with 2 and propiophenone (Fig. S48 and S49), respectively. The endo-isomer was characterized by multinuclear NMR in CD₃OD/D₂O 2 : 1 (Fig. S50–S58). The special disposition of this isomer was supported by the correlation between Cp-H and H^1b H⁻³ in the ¹H–¹H ROESY experiment (Fig. S58). The exo-4/endo-4 proportion in 2 : 1 CD₃OD/D₂O was 8.7 : 1.3, evidencing the strong importance of water in triggering the exo/endo isomerization of 4. In the temperature range of 25–60 °C the exo-4/endo-4 ratio decreased to 8.6 : 1.4, releasing 2 and propiophenone (Scheme 2 and Fig. S59).

Scheme 2 Reactivity of intermediate 4 in CD₃OD, CD₃OD/D₂O, and ⁱPrOH/H₂O (D₂O capillary) at 25 °C and 60 °C. (a) In CD₃OD, other products correspond to 2, [RuCp(OCD₃)(mPTA)₂]⁺, O = mPTA, [RuCp(OD)(mPTA)₂]⁺ and another unidentified species; in CD₃OD/D₂O or ⁱPrOH/H₂O, other products correspond to 2, [RuCp(OCD₃)(mPTA)₂]⁺ or [RuCp(ⁱPrOH)(mPTA)₂]⁺. (b) Values in parentheses represent the exo/endo isomers ratio.

Furthermore, to understand why the substrate transformation catalyzed by 2 is more efficient in the mixture ⁱPrOH/H₂O than in CH₃OH/H₂O, the same experiment was conducted by replacing CD₃OD with ⁱPrOH (Fig. S60). In this solvent mixture, the exo/endo interconversion at room temperature shifted to the formation of endo-4 (exo/endo ratio = 8.5 : 1.5). After heating for 15 min at 60 °C, only the transformation of endo-4 into 2 and propiophenone was observed in the ³¹P{¹H} NMR spectrum (Fig. S60). Although all tests conducted in the presence of water show the presence of the exo and endo isomers, in ⁱPrOH/H₂O, the amount of endo isomer was the highest found. This may be the factor explaining the highest conversion obtained in ⁱPrOH/H₂O (Scheme 2).

The NMR spectra for the isomerization of 1,5-hexadien-3,4-diol are shown in Fig. S20–S31. Both catalysts tested were found to be inactive for its isomerization. In both solvents, D₂O and CD₃OD, the ³¹P{¹H} NMR spectra of the reactions between 1,5-hexadien-3,4-diol and 10 mol% of 1 and 2 displayed the formation of eight doublets for 1 between −20.0 ppm and −25.0 ppm, and for 2 in the range of −6.0 to −9.0 ppm. The powder obtained by precipitation with Et₂O from these solutions displayed identical patterns in the ³¹P{¹H} NMR spectra to that obtained during the reactions, independently of the solvent D₂O and CD₃OD. Due to the strong signal overlap, it was only possible to characterize two of the major species given by each starting complex. The analysis of the ¹H–¹H COSY, ¹H–¹³C HSQC, ¹H–¹³C HMBC and finally ¹H–¹H ROESY spectra (5: Fig. S61–S70 and 6: Fig. S71–S80) revealed that these species correspond to the complexes exo-[RuCp(η²-(+/−)-CH₂=CH–CHOH–CHOH–CH=CH₂)(PTA)₂](CF₃SO₃) (5a), exo-[RuCp(η²-meso-CH₂=CH–CHOH–CHOH–CH=CH₂)(PTA)₂](CF₃SO₃) (5b), exo-[RuCp(η²-(+/−)-CH₂=CH–CHOH–CHOH–CH=CH₂)(mPTA)₂](CF₃SO₃)₃ (6a) and exo-[RuCp(η²-meso-CH₂=CH–CHOH–CHOH–CH=CH₂)(mPTA)₂](CF₃SO₃)₃ (6b). The 1,5-hexadiane-3,4-diol disposition in all these species is an exo-η²-C=C–Ru configuration, as confirmed by the ROESY ¹H–¹H NMR experiment (Fig. S70 and S80), given that the Cp-H protons belonging to complexes 5 and 6 are coupled to H^1a/H³ (Fig. 2). The analysis of the ³J_H-H coupling constants between the vicinal hydrogens H³ and H⁴ (5a: ³J_H-H = 9.58 Hz; 5b: ³J_H-H = 12.20 Hz) suggests that the 1,5-hexadiane-3,4-diol ligand is syn in 5a and anti in 5b. Unfortunately, the signal overlapping prevented the measurement of the corresponding values for 6a and 6b. The overall results obtained for the reactions of 1 or 2 with 1,5-hexenadien-3,4-diol suggest that upon coordination to the catalyst, an exo-η²-allylic complex is formed, which is stable enough to stop the isomerization reaction.

Fig. 2 Proposed structure for the isomers in solution 5a, 5b, 6a and 6b. (a) ROE cross peaks between Cp-H (5a/5b: 5.25 ppm) and H^1a (5a: 3.03 ppm; 5b: 3.08 ppm) and H³ (5a: 2.94 ppm; 5b: 2.88 ppm); and ROE cross peaks between H⁵ (5a: 5.89 ppm) and H³ (5a: 2.94 ppm) and H² (5a: 2.68 ppm), and between H⁵ (5b: 5.88 ppm) and H^1a (5b: 3.08 ppm) and H³ (5b: 2.88 ppm). (b) ROE cross peaks between Cp-H (6a/6b: 5.56/5.57 ppm, respectively) and H^1a (6a: 3.29 ppm; 6b: 3.22 ppm) and H³ (6a: 2.99 ppm; 6b: 2.96 ppm).

Fig. 3 illustrates the proposed mechanism for the studied catalytic isomerization reactions. In addition, the highest turnover numbers for each aqueous isomerization reaction catalysed by both complexes are depicted, highlighting substrate-dependent differences. Overall, the lower catalytic activity of 2 compared to 1 is consistent with previous published results.^20,22,23,72 All the pieces of information collected across this study suggest some important facts, as follows: (a) the composition of the solvent mixture plays a crucial role in the process and (b) an electron-withdrawing group in the allylic position appears to aid the isomerisation process. Particularly, the presence of water facilitates the conversion of the active exo-isomer in the isomerization process into the inactive endo-isomer, which was also found for the catalytic activity of 1 and 2 with linear and cyclic allylic alcohols.²⁴ Conversely, the stabilization of the substrate in an inactive conformation (5a, 5b, 6a and 6b) could be also the reason for the null conversion of 1,5-hexadiane-3,4-diol. Also, the results showed that bulky-substituted substrates with an electron-withdrawing group in the vinylic position and with a terminal CH₂–OH group are poorly isomerised.⁷²

Fig. 3 Proposed mechanism for the aqueous isomerization of the studied allylic alcohols catalyzed by the water-soluble complexes 1 and 2.

Conclusions

The catalytic activity of the [RuCp(OH₂)(PTA)₂](CF₃SO₃) (1) and [RuCp(OH₂)(mPTA)₂](CF₃SO₃)₃ (2) complexes was assessed for the isomerization of the substituted allylic alcohols trans-1,3-diphenyl-2-propen-1-ol, vinylbenzyl alcohol, 3-methyl-2-cyclohexen-1-ol, (1R)-(−)-myrtenol, cinnamyl alcohol, 4-nitrocinnamyl alcohol, farnesol, coniferyl alcohol, S,R-(−)-carveol and 1,5-hexadien-3,4-diol in water and aqueous media. The catalytic activity of 1 was notable for the isomerization of trans-1,3-diphenyl-2-propen-1-ol into dihydrochalcone (TON = 200, TOF_5h = 40 h⁻¹), α-vinylbenzyl alcohol into propiophenone (TON = 34, TOF_4h = 8.4 h⁻¹), and 3-methyl-2-cyclohexen-1-ol into 3-methylcyclohexanone (TON = 285, TOF_15h = 19), while only modest activity was observed for the isomerization of (1R)-(−)-myrtenol into myrtanal (TON = 7, TOF_48h = 0.2 h⁻¹). In contrast, complex 2 exhibited good efficiency for the synthesis of propiophenone (TON = 35, TOF_1h = 35 h⁻¹) and moderate activity for the synthesis of 3-methylcyclohexanone (TON = 18, TOF_5h = 3.6). The remaining substrates were not isomerized.

Notably, the products obtained are key natural products, which have distinct roles across the pharmaceutical, synthetic, cosmetic, and food industries and pest management. Dihydrochalcone offers antimicrobial and anti-inflammatory properties and is also used in the food industry as a sweetener.^46,51,73,74 To the best of our knowledge, the obtained isomerization conversion of trans-1,3-diphenyl-2-propen-1-ol catalyzed by 1 (TON = 200 and TOF_5h = 40 h⁻¹) into dihydrochalcone is the highest known in aqueous medium to date. Propiophenone is a key intermediate for synthesizing drugs such as antidepressants and stimulants.^{44,45,75–78} Furthermore, it is an essential intermediate in complex drug synthesis and valued in cosmetics for its fragrances. Myrtanal possesses antioxidant and antiseptic properties,^79,80 and 3-methylcyclohexanone has a potential role as an anti-aggregation agent, which along with 1-methyl-2-cyclohexen-1-ol and 3-methyl-2-cyclohexenone, the 1,3-transposition and oxidation products of 3-methyl-2-cyclohexen-1-ol, respectively, are pheromones used in the natural aggregation/anti-aggregation system of the Douglas-fir beetle.³⁹

The obtained results support the hypothesis that the size and substitution of allylic alcohols influence the isomerization conversion, revealing that these complexes are more effective for isomerising branched substrates with electron-withdrawing groups in the allylic position, such as in trans-1,3-diphenyl-2-propen-1-ol and α-vinylbenzyl alcohol. Additionally, substrates with a CH₂OH terminal group such as cinnamyl alcohol, coniferyl alcohol and 4-nitrocinnamyl alcohol, were poorly converted. Steric hindrance, particularly from bulky groups and the methyl group in the vinyl position, may hinder the coordination to ruthenium. The combination of both steric hindrance and the presence of a CH₂OH terminal group seemed to impede the isomerization of (1R)-(−)-myrtenol. Additionally, mechanistic studies confirmed the formation of the [RuCp(η²-CH₂=CH–CHOH–C₆H₅)(PTA)₂](CF₃SO₃) (3) and [RuCp(η²-CH₂=CH–CHOH–C₆H₅)(mPTA)₂](CF₃SO₃)₃ (4) intermediates during the isomerization of α-vinylbenzyl alcohol. These findings support the proposed thermodynamic equilibrium of the η²-allylic-alcohol-intermediates (exo → endo) preceding the isomerization. Additionally, the low reactivity of 1,5-hexadien-3,4-diol was attributed to the formation of inactive intermediates, which probably block the reaction.

Conflicts of interest

The authors declare no conflict of interest.

Data availability

Supporting data have been included in the article's SI. See DOI: https://doi.org/10.1039/d5ra03564c.

Acknowledgements

The authors thank Junta de Andalucía for funding the group PAI FQM-317 and the University of Almería for the project P_LANZ_2023/006 and P_FORT_GRUPOS_2023/94 (both projects co-funded by the European Commission FEDER program).

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