Stereoisomeric Tris-BINOL-Menthol Bulky Monophosphites: Synthesis, Characterisation and Application in Rhodium-Catalysed Hydroformylation

Four stereoisomeric monoether derivatives, based on axially chiral (R)- or (S)-BINOL bearing a chiral (+)- or (−)-neomenthyloxy group were synthesised and fully characterised by NMR spectroscopy and X-ray crystallography. The respective tris-monophosphites were thereof prepared and fully characterised. The coordination ability of the new bulky phosphites with Rh(CO)2(acac), was attested by 31P NMR, which presented a doublet in the range of δ = 120 ppm, with a 1J(103Rh-31P) coupling constant of 290 Hz. The new tris-binaphthyl phosphite ligands were further characterised by DFT computational methods, which allowed us to calculate an electronic (CEP) parameter of 2083.2 cm−1 and an extremely large cone angle of 345°, decreasing to 265° upon coordination with a metal atom. Furthermore, the monophosphites were applied as ligands in rhodium-catalysed hydroformylation of styrene, leading to complete conversions in 4 h, 100% chemoselectivity for aldehydes and up to 98% iso-regioselectivity. The Rh(I)/phosphite catalytic system was also highly active and selective in the hydroformylation of disubstituted olefins, including (E)-prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene.


Introduction
Phosphite compounds play important roles in synthetic chemistry. For instance, they can be used as antioxidants or as complex formation agents for polymers stabilisation (e.g., polyolefins, polycarbonates, acrylonitrile-butadiene-styrene polymers, polyesters, etc) [1,2]. Furthermore, phosphites have a rich coordination chemistry, being able to form complexes with most transition metals, particularly with low-valent metal complexes, due to a predominant π-back bonding [3]. Therefore, they are widely used as outstanding ligands in catalysis [3,4], namely in olefin hydroformylation reactions [5][6][7][8][9][10][11][12][13]. In particular, rhodium(I) complexes modified with bulky aryl monophosphite ligands were found to lead to highly active, chemo-and regioselective catalysts in the hydroformylation of disubstituted and internal double bounds, under relatively mild conditions [14][15][16]. This exceptional activity results from both electronic and stereo effects: on one hand, the π-acidic character of the phosphite weakens the metal-CO bond, thereby allowing a faster CO dissociation; on the other hand, the ligand's large cone angle allows the coordination of only one phosphite to the metal centre, even when used in large excess, which results in a low global steric hindrance around the metal centre [17,18]. Moreover, the design and synthesis of chiral phosphite ligands also play a key role in the development of asymmetric catalysis [19][20][21][22]. Among them, monophosphite ligands based on the binaphthyl backbone [23] have earned a prominent status due to their synthetic availability and efficient applications in a large number of enantioselective catalytic reactions, namely in hydrogenation [24][25][26][27][28], hydrovinylation [29,30] and allylic substitutions [28,[31][32][33][34].
In our previous studies, we have developed a family of C 3 -symmetry binaphthyl-based monophosphites [35], whose rhodium complexes provided highly active and regioselective catalysts for the hydroformylation of aryl and alkyl olefins [36,37], including substituted and internal C=C double bonds of long-chain methyl esters, terpene and steroid derivatives. As a part of our continuous research in this field, in this paper we report the synthesis and characterisation of four stereoisomeric BINOL-menthol bulky monophosphite ligands, which have axial chirality provided by the binaphthyl backbone and central chirality provided by the menthol moiety. The Tolman's steric (cone angles) and electronic parameters were calculated using the B97D3 density functional method. In addition, 31 P NMR spectroscopy studies in solution were performed for Rh/phosphite complexes to assess their coordination ability. Finally, their evaluation in Rh-catalysed hydroformylation of styrene and two disubstituted aryl olefins is described.

Synthesis and Characterisation of Monophosphites
The synthesis of tris-BINOL-menthol-based phosphites consisted of a two-step procedure that involved the monoprotection of enantiomerically pure (S)-or (R)-BINOL with (+)or (−)-menthol, followed by PCl 3 phosphorylation, in the presence of a base (Scheme 1). The introduction of menthyloxy substituents at the 2-position of the 1,1'-binaphthyl backbone was intended to incorporate steric bulkiness, expecting that the three modified binaphthyloxy units at phosphorus would be "fixed" into a screw-like alignment and that this would subsequently induce helicity in order to obtain a single diastereomeric conformer for each monophosphite [27]. In addition, besides the axial chirality of (R)-or (S)-BINOL, both (+)-and (−)-menthol chiral enantiomers were used in order to obtain four different stereoisomers.
Molecules 2022, 27, x FOR PEER REVIEW 2 of 17 acidic character of the phosphite weakens the metal-CO bond, thereby allowing a faster CO dissociation; on the other hand, the ligand's large cone angle allows the coordination of only one phosphite to the metal centre, even when used in large excess, which results in a low global steric hindrance around the metal centre [17,18]. Moreover, the design and synthesis of chiral phosphite ligands also play a key role in the development of asymmetric catalysis [19][20][21][22]. Among them, monophosphite ligands based on the binaphthyl backbone [23] have earned a prominent status due to their synthetic availability and efficient applications in a large number of enantioselective catalytic reactions, namely in hydrogenation [24][25][26][27][28], hydrovinylation [29,30] and allylic substitutions [28,[31][32][33][34].
In our previous studies, we have developed a family of C3-symmetry binaphthylbased monophosphites [35], whose rhodium complexes provided highly active and regioselective catalysts for the hydroformylation of aryl and alkyl olefins [36,37], including substituted and internal C=C double bonds of long-chain methyl esters, terpene and steroid derivatives. As a part of our continuous research in this field, in this paper we report the synthesis and characterisation of four stereoisomeric BINOL-menthol bulky monophosphite ligands, which have axial chirality provided by the binaphthyl backbone and central chirality provided by the menthol moiety. The Tolman's steric (cone angles) and electronic parameters were calculated using the B97D3 density functional method. In addition, 31 P NMR spectroscopy studies in solution were performed for Rh/phosphite complexes to assess their coordination ability. Finally, their evaluation in Rh-catalysed hydroformylation of styrene and two disubstituted aryl olefins is described.

Synthesis and Characterisation of Monophosphites
The synthesis of tris-BINOL-menthol-based phosphites consisted of a two-step procedure that involved the monoprotection of enantiomerically pure (S)-or (R)-BINOL with (+)-or (−)-menthol, followed by PCl3 phosphorylation, in the presence of a base (Scheme 1). The introduction of menthyloxy substituents at the 2-position of the 1,1'-binaphthyl backbone was intended to incorporate steric bulkiness, expecting that the three modified binaphthyloxy units at phosphorus would be "fixed" into a screw-like alignment and that this would subsequently induce helicity in order to obtain a single diastereomeric conformer for each monophosphite [27]. In addition, besides the axial chirality of (R)-or (S)-BINOL, both (+)-and (−)-menthol chiral enantiomers were used in order to obtain four different stereoisomers. The first step of the synthesis consisted of the monoetherification of axially chiral (R)or (S)-BINOL with (+)-or (−)-menthol, in presence of triphenylphosphine and diisopropyl azodicarboxylate (DIAD), using THF as solvent (Scheme 2), following an optimised procedure of the Mitsunobu reaction [38,39]. The progress of the reaction was controlled by TLC, Molecules 2022, 27,1989 3 of 16 until full consumption of triphenylphosphine was observed. At the end, the reaction was quenched with water and successively worked up through standard procedures. Finally, the crude mixtures were purified by flash chromatography to afford the desired monoethers 1-4 in isolated yields of ca. 30% for all stereoisomers. It should be highlighted that, upon etherification, the absolute configurations of carbon atoms C2 and C5 in menthol fragment remained unchanged, but the absolute configuration of carbon C1 underwent inversion of configuration as a result of the Mitsunobu reaction S N 2 mechanism [38], which resulted in the formation of BINOL-neomenthol stereoisomers. azodicarboxylate (DIAD), using THF as solvent (Scheme 2), following an optimised procedure of the Mitsunobu reaction [38,39]. The progress of the reaction was controlled by TLC, until full consumption of triphenylphosphine was observed. At the end, the reaction was quenched with water and successively worked up through standard procedures. Finally, the crude mixtures were purified by flash chromatography to afford the desired monoethers 1-4 in isolated yields of ca. 30% for all stereoisomers. It should be highlighted that, upon etherification, the absolute configurations of carbon atoms C2 and C5 in menthol fragment remained unchanged, but the absolute configuration of carbon C1 underwent inversion of configuration as a result of the Mitsunobu reaction SN2 mechanism [38], which resulted in the formation of BINOL-neomenthol stereoisomers. The low reaction rate and moderate yields of the optimised etherification were attributed to the high steric hindrance of menthol, similarly to that previously observed for the Mitsunobu reaction with other secondary or tertiary alcohols [36,39]. After chromatographic purification, the unreacted BINOL was recovered and used in a subsequent monoetherification reaction. All the synthesised BINOL ether derivatives were characterised by 1 H and 13 C NMR spectroscopy (Figures S1-S9, Supplementary Materials), and the full assignment of the NMR signals was performed for 3 (Table S1, Supplementary Materials), using two-dimensional techniques (COSY, HMBC, HSQC) and DEPT 135 (Figures S10-S13, Supplementary Materials).
Single-crystals of the BINOL-neomenthol stereoisomers 1-4 were obtained from a diethyl ether/n-hexane (1:1) solution (5 mg mL −1 ), by slow evaporation of the solvent at 25 The low reaction rate and moderate yields of the optimised etherification were attributed to the high steric hindrance of menthol, similarly to that previously observed for the Mitsunobu reaction with other secondary or tertiary alcohols [36,39]. After chromatographic purification, the unreacted BINOL was recovered and used in a subsequent monoetherification reaction. All the synthesised BINOL ether derivatives were characterised by 1 H and 13 C NMR spectroscopy (Figures S1-S9, Supplementary Materials), and the full assignment of the NMR signals was performed for 3 (Table S1, Supplementary Materials), using two-dimensional techniques (COSY, HMBC, HSQC) and DEPT 135 (Figures S10-S13, Supplementary Materials).
Single-crystals of the BINOL-neomenthol stereoisomers 1-4 were obtained from a diethyl ether/n-hexane (1:1) solution (5 mg mL −1 ), by slow evaporation of the solvent at 25 • C. Then, X-ray diffraction data were collected using Mo-Kα radiation (λ = 0.71073 Å), with ϕ/ω scans at 296(2) K. Direct methods were applied to obtain an initial structure model which was then refined with the least-squares method. The bond lengths and angles found are in agreement with related previously reported structures [40,41]. Chiralityrepresentative moieties found in the asymmetric units of 1-4 are shown in Figure 1. °C. Then, X-ray diffraction data were collected using Mo-Kα radiation (λ = 0.71073 Å), with φ/ω scans at 296(2) K. Direct methods were applied to obtain an initial structure model which was then refined with the least-squares method. The bond lengths and angles found are in agreement with related previously reported structures [40,41]. Chiralityrepresentative moieties found in the asymmetric units of 1-4 are shown in Figure 1.  The obtained crystal structures clearly show the structural differences between the four stereoisomers, generated by chirality of both the menthol moiety and the BINOL backbone. From the images, we can observe the same stereoconfiguration of the binaphthyl scaffold in diastereomers 1 and 3, both synthesised from (S)-BINOL (Figure 1a,c). On the other hand, as expected, the crystal structures obtained for enantiomers 1 and 2 are the perfect mirror images of each other (Figure 1a,b). Furthermore, the crystal structures The obtained crystal structures clearly show the structural differences between the four stereoisomers, generated by chirality of both the menthol moiety and the BINOL backbone. From the images, we can observe the same stereoconfiguration of the binaphthyl scaffold in diastereomers 1 and 3, both synthesised from (S)-BINOL (Figure 1a,c). On the other hand, as expected, the crystal structures obtained for enantiomers 1 and 2 are the perfect mirror images of each other (Figure 1a,b). Furthermore, the crystal structures corroborate the differences observed in the 1 H NMR chemical shifts of the two diastereotopic methyl groups of the isopropyl moiety for each pair of diastereomers, which result from their slightly different chemical environment due to molecular asymmetry. As illustrated in Figure 2, in stereoisomer 3, the more shielded methyl protons B, which are above the aromatic ring current ( Figure 2) give rise to a NMR signal with lower chemical shift (δ = 0.40 ppm), while the methyl group A, which is out of the shielding cone (Figure 2), produce a lower field signal with a slightly higher chemical shift (δ = 0.55 ppm).
Molecules 2022, 27, x FOR PEER REVIEW 5 of 17 corroborate the differences observed in the 1 H NMR chemical shifts of the two diastereotopic methyl groups of the isopropyl moiety for each pair of diastereomers, which result from their slightly different chemical environment due to molecular asymmetry. As illustrated in Figure 2, in stereoisomer 3, the more shielded methyl protons B, which are above the aromatic ring current ( Figure 2) give rise to a NMR signal with lower chemical shift (δ = 0.40 ppm), while the methyl group A, which is out of the shielding cone ( Figure 2), produce a lower field signal with a slightly higher chemical shift (δ = 0.55 ppm). The second step of the monophosphite synthesis comprised the phosphorylation of monohydroxylated BINOL derivatives 1-4 with PCl3, using triethylamine (Et3N) simultaneously as a base and reaction solvent (Scheme 3). The reaction progress was followed by TLC analysis and 31 P NMR spectroscopy from aliquots taken from the reaction mixture. After 5 h, the emergence of a 31 P NMR signal at ca. δ = 136 ppm, concomitantly with the disappearance of the signal at δ = 219 ppm, confirmed the full consumption of PCl3 and the formation of P(OR)3 species. Then, the remaining Et3N was evaporated and the residues were purified by flash chromatography, which allowed the isolation of the desired monophosphites L1-L4 in yields ranging from 65 to 68%. These were fully characterised by 31   The second step of the monophosphite synthesis comprised the phosphorylation of monohydroxylated BINOL derivatives 1-4 with PCl 3 , using triethylamine (Et 3 N) simultaneously as a base and reaction solvent (Scheme 3). The reaction progress was followed by TLC analysis and 31 P NMR spectroscopy from aliquots taken from the reaction mixture. After 5 h, the emergence of a 31 P NMR signal at ca. δ = 136 ppm, concomitantly with the disappearance of the signal at δ = 219 ppm, confirmed the full consumption of PCl 3 and the formation of P(OR) 3 species. Then, the remaining Et 3 N was evaporated and the residues were purified by flash chromatography, which allowed the isolation of the desired monophosphites L1-L4 in yields ranging from 65 to 68%. These were fully characterised by 31 P, 1 H and 13 C NMR spectroscopy and HRMS (Figures S17-S28, Supplementary Materials).

NMR Studies on Complex Formation in Solution
To get an insight about the coordination ability of the tris-BINOL-neomenthol monophosphite ligands, NMR studies were carried out to investigate complex formation in solution. Thus, equimolar amounts of monophosphite L2 and Rh(CO) 2 (acac) were dissolved in toluene-d8 under an argon atmosphere at 25 • C and stirred for 1 h. Then, 31 P NMR spectra of the mixture were acquired at variable temperatures ( Figure 3b). We clearly observe a signal at δ = 138 ppm (ca. 6%, Figure S29, Supplementary Materials), assigned to the non-coordinated phosphite and the emergence of a doublet at δ = 122-124 ppm, with a 1 J( 103 Rh-31 P) coupling constant of ca. 290 Hz, typical of direct rhodium-phosphorus coordination [36], which confirmed the Rh-phosphite complex formation. The signal broadening, observed in the temperature range 10-50 • C, was attributed to the existence of rotational isomerism, and slow rotation in solution with consequent enhanced relaxation. At 80 • C, the 31 P NMR shows a sharper doublet, probably due to higher motion with increasing temperatures. On the other hand, the 31 P NMR acquired at −3 • C also presented a welldefined signal for the Rh-P complex, which was attributed to the restricted rotation at low temperature, leading to the prevalence of a single major species in solution. It should be noted that, when using a twofold excess of phosphite, no additional signals were observed in the 31 P NMR spectra, which points towards the formation of a single Rh-P species containing only one phosphite ligand.

NMR Studies on Complex Formation in Solution
To get an insight about the coordination ability of the tris-BINOL-neomenthol monophosphite ligands, NMR studies were carried out to investigate complex formation in solution. Thus, equimolar amounts of monophosphite L2 and Rh(CO)2(acac) were dissolved in toluene-d8 under an argon atmosphere at 25 °C and stirred for 1 h. Then, 31 P NMR Scheme 3. Synthesis of monophosphites L1-L4. 80 °C, the 31 P NMR shows a sharper doublet, probably due to higher motion with increasing temperatures. On the other hand, the 31 P NMR acquired at −3 °C also presented a welldefined signal for the Rh-P complex, which was attributed to the restricted rotation at low temperature, leading to the prevalence of a single major species in solution. It should be noted that, when using a twofold excess of phosphite, no additional signals were observed in the 31 P NMR spectra, which points towards the formation of a single Rh-P species containing only one phosphite ligand.

Computational Studies: Determination of Electronic and Steric Parameters
The electronic (νA) and steric parameters (θ) of the new tris-binaphthyl phosphite ligands were computed for ligand L1 within the framework of the DFT methodology (see Section 3.5). The cone angles were determined, using a program developed by us, according to Tolman's standard definition [44], in which the most stable conformer for L1 was found to preserve the C3 symmetry. In contrast to the former alkoxy-substituted monophosphites [36], which had a cone angle in the range of 239-271 degrees, the larger steric bulkiness of the menthol substituents enforced an extremely large cone angle (345°). However, upon coordination with the metal atom, the repulsion of the spectator ligands resulted in a decrease in the cone angle, as shown for Ni(CO)3L1, whose structure was computed ( Figure 4), with the cone angle decreasing to 265°. For comparison, the geometries of the rhodium(I) complexes cis-and trans-HRh(CO)2L1, considered as the hydroformylation active catalytic species, were also determined and the constrained cone angle was found to be 263°, and 264°, respectively. Therefore, the constrained cone angle showed almost negligible dependence upon the metal containing fragment.

Computational Studies: Determination of Electronic and Steric Parameters
The electronic (ν A ) and steric parameters (θ) of the new tris-binaphthyl phosphite ligands were computed for ligand L1 within the framework of the DFT methodology (see Section 3.5). The cone angles were determined, using a program developed by us, according to Tolman's standard definition [44], in which the most stable conformer for L1 was found to preserve the C 3 symmetry. In contrast to the former alkoxy-substituted monophosphites [36], which had a cone angle in the range of 239-271 degrees, the larger steric bulkiness of the menthol substituents enforced an extremely large cone angle (345 • ). However, upon coordination with the metal atom, the repulsion of the spectator ligands resulted in a decrease in the cone angle, as shown for Ni(CO) 3 L1, whose structure was computed ( Figure 4), with the cone angle decreasing to 265 • . For comparison, the geometries of the rhodium(I) complexes cisand trans-HRh(CO) 2 L1, considered as the hydroformylation active catalytic species, were also determined and the constrained cone angle was found to be 263 • , and 264 • , respectively. Therefore, the constrained cone angle showed almost negligible dependence upon the metal containing fragment.
Moreover, the computed electronic parameter (CEP), that is the total symmetric (A) carbonyl stretching frequency in the Ni(CO) 3 L complex type, was calculated for ligand L1 (Figure 4). The obtained value was ν A = 2083.2 cm −1 , which is in between the CEPs of triphenyl phosphite (ν A = 2085.3 cm −1 ) and trimethyl phosphite (ν A = 2079.5 cm −1 ), calculated at the same level of theory [45]. Since this parameter is a generally accepted measure for the Lewis basicity of P-donor ligands, we concluded that the new tris-BINOLneomenthol monophosphites are expected to present a stronger Lewis base character compared with that of triphenyl phosphite. carbonyl stretching frequency in the Ni(CO)3L complex type, was calculated for ligand L1 (Figure 4). The obtained value was νA = 2083.2 cm −1 , which is in between the CEPs of triphenyl phosphite (νA = 2085.3 cm −1 ) and trimethyl phosphite (νA = 2079.5 cm −1 ), calculated at the same level of theory [45]. Since this parameter is a generally accepted measure for the Lewis basicity of P-donor ligands, we concluded that the new tris-BINOL-neomenthol monophosphites are expected to present a stronger Lewis base character compared with that of triphenyl phosphite.

Evaluation in Rh-catalysed Hydroformylation
The synthesised bulky tris-BINOL-neomenthol monophosphite ligands L1-L4 were then evaluated in rhodium-catalysed hydroformylation of styrene and disubstituted styrene derivatives, such as (E)-prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene, using Rh(CO)2(acac) as a catalytic precursor in toluene. To appraise the effect of the ligand structure on the catalytic activity and selectivity, the phosphites L1-L4 were first evaluated in the Rh-catalysed hydroformylation of styrene. The results are presented in Table 1.
A control experiment was carried out in the absence of phosphite ligand, at 80 °C, using a total syngas pressure of 10 bar (CO/H2 1:1), which led to 96% conversion in 4 h, 100% chemoselectivity for aldehydes and 50% regioselectivity (Table 1, entry 1). The catalyst Rh/L3 was then tested under the same conditions and almost full conversion (99%) was obtained in 4 h, with a higher regioselectivity (61%) for the branched aldehyde (Table  1, entry 2). When using its enantiomeric monophosphite L4 as ligand, similar results were obtained in terms of activity, chemo-and regioselectivity (Table 1, entry 3). As observed, similar conversion was achieved with the rhodium precursor in the absence of any phosphite ligand when using 10 bar syngas pressure at 80 °C. However, the considerably higher regioselectivity obtained with the Rh/L3 and Rh/L4 catalytic systems suggests that, when bulky tris-BINOL-neomenthol phosphites are used as rhodium ligands, the hydroformylation of styrene, under these conditions, can be simultaneously catalysed either by Rh-carbonyl and Rh-phosphite species. By increasing the syngas pressure to 20 bar or 25 bar H2/CO (1:1), at the same temperature (80 °C), the catalyst Rh/L4 also obtained full conversion in 4 h but no significant changes were observed on the reaction's regioselectivity (

Evaluation in Rh-Catalysed Hydroformylation
The synthesised bulky tris-BINOL-neomenthol monophosphite ligands L1-L4 were then evaluated in rhodium-catalysed hydroformylation of styrene and disubstituted styrene derivatives, such as (E)-prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene, using Rh(CO) 2 (acac) as a catalytic precursor in toluene. To appraise the effect of the ligand structure on the catalytic activity and selectivity, the phosphites L1-L4 were first evaluated in the Rh-catalysed hydroformylation of styrene. The results are presented in Table 1. tivity for the branched aldehyde, independently from the syngas pressure used. The tiomeric excesses, determined by GC after derivatisation of the aldehyde mixtures corresponding carboxylic acids, were ca. 12% in all cases. Although it is well estab that highly enantioselective hydroformylation reactions [46] require the use of bid P ligands, such as bisphosphites [47], P-chiral diphosphines [48] or hybrid phos phosphite ligands [49], we hypothesised that the oxygen atom of the neomentho moiety could interact with the rhodium centre through hemilabile bonds and th could result in enantiodiscrimination. On the other hand, we also expected to obs matching/mismatching effect of the combination of both BINOL and menthol m chirality on the reaction's enantioselectivity. However, to our regret, neither of th sumptions were confirmed. Nevertheless, the high regioselectivity obtained with th Rh/phosphite catalysts is in agreement with those previously obtained with r Rh/monodentate phosphite catalysts [36,50].

Entry
Ligand The reaction's scope was further expanded to disubstituted aryl olefins, such prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene, performed at 80 °C, using a pressure of 25 bar (Table 2). Table 2. Results of catalytic hydroformylation of (E)-prop-1-en-1-ylbenzene and prop-1-en-2 zene using Rh/L2 catalyst a . A control experiment was carried out in the absence of phosphite ligand, at 80 • C, using a total syngas pressure of 10 bar (CO/H 2 1:1), which led to 96% conversion in 4 h, 100% chemoselectivity for aldehydes and 50% regioselectivity (Table 1, entry 1). The catalyst Rh/L3 was then tested under the same conditions and almost full conversion (99%) was obtained in 4 h, with a higher regioselectivity (61%) for the branched aldehyde (Table 1, entry 2). When using its enantiomeric monophosphite L4 as ligand, similar results were obtained in terms of activity, chemo-and regioselectivity (Table 1, entry 3). As observed, similar conversion was achieved with the rhodium precursor in the absence of any phosphite ligand when using 10 bar syngas pressure at 80 • C. However, the considerably higher regioselectivity obtained with the Rh/L3 and Rh/L4 catalytic systems suggests that, when bulky tris-BINOL-neomenthol phosphites are used as rhodium ligands, the hydroformylation of styrene, under these conditions, can be simultaneously catalysed either by Rh-carbonyl and Rh-phosphite species. By increasing the syngas pressure to 20 bar or 25 bar H 2 /CO (1:1), at the same temperature (80 • C), the catalyst Rh/L4 also obtained full conversion in 4 h but no significant changes were observed on the reaction's regioselectivity (Table 1, entries 4 and 5). Finally, the hydroformylation of styrene was conducted at 50 • C, either using a CO/H 2 pressure of 20 bar (Table 1, entry 6) or 25 bar (Table 1, entries 7-9). Under these mild conditions, all catalysts Rh/L4, Rh/L1 and Rh/L2 led to close to full conversions in 4 h, with 100% chemoselectivity for aldehydes and up to 96% regioselectivity for the branched aldehyde, independently from the syngas pressure used. The enantiomeric excesses, determined by GC after derivatisation of the aldehyde mixtures to the corresponding carboxylic acids, were ca. 12% in all cases. Although it is well established that highly enantioselective hydroformylation reactions [46] require the use of bidentate P ligands, such as bisphosphites [47], P-chiral diphosphines [48] or hybrid phosphine-phosphite ligands [49], we hypothesised that the oxygen atom of the neomenthol ether moiety could interact with the rhodium centre through hemilabile bonds and that this could result in enantiodiscrimination. On the other hand, we also expected to observe a matching/mismatching effect of the combination of both BINOL and menthol moieties chirality on the reaction's enantioselectivity. However, to our regret, neither of these assumptions were confirmed. Nevertheless, the high regioselectivity obtained with the new Rh/phosphite catalysts is in agreement with those previously obtained with related Rh/monodentate phosphite catalysts [36,50].

Entry Substrate Time (h) Conversion (%) Major Product (Regioselectivity, %)
1 P ligands, such as bisphosphites [47], P-chiral diphosphines [48] or hybrid phosphinephosphite ligands [49], we hypothesised that the oxygen atom of the neomenthol ether moiety could interact with the rhodium centre through hemilabile bonds and that this could result in enantiodiscrimination. On the other hand, we also expected to observe a matching/mismatching effect of the combination of both BINOL and menthol moieties chirality on the reaction's enantioselectivity. However, to our regret, neither of these assumptions were confirmed. Nevertheless, the high regioselectivity obtained with the new Rh/phosphite catalysts is in agreement with those previously obtained with related Rh/monodentate phosphite catalysts [36,50].

Entry
Ligand The reaction's scope was further expanded to disubstituted aryl olefins, such as (E)prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene, performed at 80 °C, using a syngas pressure of 25 bar (Table 2). Table 2. Results of catalytic hydroformylation of (E)-prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene using Rh/L2 catalyst a . P ligands, such as bisphosphites [47], P-chiral diphosphines [48] or hybrid phosphinephosphite ligands [49], we hypothesised that the oxygen atom of the neomenthol ether moiety could interact with the rhodium centre through hemilabile bonds and that this could result in enantiodiscrimination. On the other hand, we also expected to observe a matching/mismatching effect of the combination of both BINOL and menthol moieties chirality on the reaction's enantioselectivity. However, to our regret, neither of these assumptions were confirmed. Nevertheless, the high regioselectivity obtained with the new Rh/phosphite catalysts is in agreement with those previously obtained with related Rh/monodentate phosphite catalysts [36,50].  The reaction's scope was further expanded to disubstituted aryl olefins, such as (E)prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene, performed at 80 °C, using a syngas pressure of 25 bar (Table 2). Table 2. Results of catalytic hydroformylation of (E)-prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene using Rh/L2 catalyst a . P ligands, such as bisphosphites [47], P-chiral diphosphines [48] or hybrid phosphinephosphite ligands [49], we hypothesised that the oxygen atom of the neomenthol ether moiety could interact with the rhodium centre through hemilabile bonds and that this could result in enantiodiscrimination. On the other hand, we also expected to observe a matching/mismatching effect of the combination of both BINOL and menthol moieties chirality on the reaction's enantioselectivity. However, to our regret, neither of these assumptions were confirmed. Nevertheless, the high regioselectivity obtained with the new Rh/phosphite catalysts is in agreement with those previously obtained with related Rh/monodentate phosphite catalysts [36,50].  The reaction's scope was further expanded to disubstituted aryl olefins, such as (E)prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene, performed at 80 °C, using a syngas pressure of 25 bar (Table 2). Table 2. Results of catalytic hydroformylation of (E)-prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene using Rh/L2 catalyst a . P ligands, such as bisphosphites [47], P-chiral diphosphines [48] or hybrid phosphinephosphite ligands [49], we hypothesised that the oxygen atom of the neomenthol ether moiety could interact with the rhodium centre through hemilabile bonds and that this could result in enantiodiscrimination. On the other hand, we also expected to observe a matching/mismatching effect of the combination of both BINOL and menthol moieties chirality on the reaction's enantioselectivity. However, to our regret, neither of these assumptions were confirmed. Nevertheless, the high regioselectivity obtained with the new Rh/phosphite catalysts is in agreement with those previously obtained with related Rh/monodentate phosphite catalysts [36,50].  The reaction's scope was further expanded to disubstituted aryl olefins, such as (E)prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene, performed at 80 °C, using a syngas pressure of 25 bar (Table 2). Table 2. Results of catalytic hydroformylation of (E)-prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene using Rh/L2 catalyst a . Remarkably, in the hydroformylation of (E)-prop-1-en-1-ylbenzene, the catalytic system Rh/L2 provided 73% conversion in 4 h, along with 100% chemoselectivity for aldehydes and 80% regioselectivity for 2-phenylbutanal ( Table 2, entry 1). The same catalyst was even active in the hydroformylation of less reactive 1,1-disubstituted olefin, prop-1-en-2ylbenzene, providing 75% conversion in 18 h ( Table 2, entry 2). The catalytic activity and selectivity obtained in the hydroformylation of these disubstituted olefins were within the same magnitude of those previously achieved with former C 3 -symmetry binaphthyl-based monophosphites [36]. In the latter case, it is also worth mentioning that complete chemoselectivity for aldehydes was reached, along with a substrate-controlled regioselectivity (99% to the linear aldehyde, 2-phenylbutanal) due to the preferential insertion of the carbonyl ligand at the less substituted carbon atom of the rhodium-alkyl intermediate [51].

Instrumentation
NMR spectra were recorded on a Bruker Avance III 400 spectrometer (Wissembourg, France). The 1 H and 13 C chemical shifts (δ) are expressed in ppm relatively to chloroform residual peaks in CDCl 3 (7.26 and 77.16 ppm for 1 H and 13 C, respectively) or to a tetramethylsilane (TMS) internal standard. For 31 P NMR, δ are expressed relative to a phosphoric acid solution (85%) external standard. High-resolution mass spectrometry analysis was carried out on a Bruker Microtof apparatus (Billerica, MA, United States), equipped with selective ESI or MALDI detector. GC analysis was performed with an Agilent-7820A GC System (Ratingen, Germany) equipped with a non-polar capillary HP-5 column (5% diphenyl and 95% dimethylpolysiloxane), with 30 m length and 0.32 mm inside diameter equipped with an FID detector, and an Agilent-6890 (Ratingen, Germany) apparatus equipped with a chiral capillary column Supelco β-Dex 120 (20% β-cyclodextrins) with 30 m length and 0.25 mm of inside diameter, equipped with FID detector. GC-MS analysis was performed in an Agilent 7820A GC System (Ratingen, Germany), equipped with a HP-5 MS column, coupled to an Agilent 5975 MSD System Technologies spectrometer (Ratingen, Germany), using EI detector (70 eV) and helium as carrier gas. X-ray diffraction data were collected with a Bruker APEXII diffractometer (Delft, The Netherlands) (Mo-Kα radiation, λ = 0.71073 Å, graphite monochromator, using ϕ and ω scans at 296(2) K. Data integration and scaling were performed with SAINT [53,54], and SADABS [55] was used for empirical absorption correction. All structures were solved by direct methods using SHELXT-2014/5 [56], and full-matrix least-squares refinement on F2 of the structural model was performed by SHELXL-2016/4 [56]. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed at calculated idealised positions and refined as a riding model using SHELXL-2016/4 default values. The specific rotation [α] was measured in an electrical Optical Activity AA-5 polarimeter (Huntingdon, UK).
After solvent removal under reduced pressure, monoethers 1-4 were isolated by flash chromatography using silica gel as stationary phase, and CH 2 Cl 2 /n-hexane 1:2 as eluent.  13

Synthesis and Characterisation of Monophosphites L1-L4
General procedure: A dried Schlenk flask was charged with the BINOL monoether 1-4 (1.5 g, 3.5 mmol), which was azeotropically dried with toluene, then placed under argon atmosphere and dissolved in dry triethylamine (7 mL). The solution was cooled to 0 • C and PCl 3 (0.1 mL, 1.1 mmol) was slowly added with stirring. After 5 h, Et 3 N was evaporated un-der reduced pressure. Then, the residue was dissolved in dichloromethane/n-hexane (1:1) and filtered through a silica plug. The monophosphite ligands L1-L4 were further purified by flash chromatography using silica gel as stationary phase and dichloromethane/nhexane (1:1) as eluent.  13 13

Rh(I)/Monophosphite Complex Formation in Solution
A dried Schlenk tube was charged with Rh(CO) 2 (acac) (2.6 mg,0.01 mmol) and the monophosphite ligand L2 (0.01 mmol), under an argon atmosphere. The solids were dissolved in CDCl 3 (0.5 mL), and the mixture was stirred for 1 h, at 25 • C. Then, variable temperature 31 P NMR spectra of the resulting solution were registered, ranging from −3 • C to 80 • C.

DFT Computational Studies
The electronic (CEP) and steric parameters (θ) were computed within the framework of the DFT methodology after obtaining its global minimum via Monte Carlo simulations using the OPLS-AA force field [57,58], within the TINKER suite of programs [59], followed by geometry optimisations at the B97D3 functional [60] in combination with the def2-SVP basis set [61], utilising the Gaussian 16 software package [62].

Catalytic Hydroformylation Procedure
A 60 mL autoclave was charged with the monophosphite ligand L1-L4 (0.030 mmol) and the system was purged by three cycles of CO/H 2 (1:1) and vacuum. Then, a solution of [Rh(CO) 2 (acac)] (1.5 mg, 0.006 mmol) in toluene (3 mL) was introduced via cannula, under vacuum. After 1 h incubation at 80 • C and 40 bar of syngas, the substrate (2.32 mmol), previously passed through an aluminium oxide (grade I) column, was dissolved in toluene (4 mL) and subsequently introduced through the inlet cannula. Then, the temperature and syngas pressure were set to the desired values (see Tables 1 and 2) and the reaction was conducted under magnetic stirring for the selected time with constant syngas pressure. The conversion, chemo-and regioselectivity were determined by GC analysis of the reaction mixture.

Conclusions
We have efficiently synthesised four stereoisomeric BINOL-neomenthol monoethers, which were characterised by NMR and X-ray crystallography, and the corresponding tris-monophosphite ligands. Complex formation studies, performed by 31 P NMR spectroscopy in solution, using monophosphite L2 and Rh(CO) 2 (acac), pointed toward the formation of a single Rh(I)-carbonyl-phosphite complex, as demonstrated by a broad doublet at δ = 120 ppm, with a 1 J( 103 Rh-31 P) coupling constant of 290 Hz, typical of direct Rh-P coordination. The signal broadening was attributed to the existence of rotational isomerism in solution as demonstrated by variable temperature 31 P NMR experiments. DFT computational studies allowed us to calculate an exceptionally large cone angle of 345 • (decreasing to 265 • upon coordination with a metal atom), and an electronic parameter (CEP) of 2083.2 cm −1 , a value in between those calculated for triphenyl phosphite and trimethyl phosphite, suggesting that the BINOL-menthol monophosphites have an intermediate Lewis-base character. The monophosphites were efficiently applied as ligands in rhodium-catalysed hydroformylation of styrene and two disubstituted aryl olefins, (E)-prop-1-en-1-ylbenzene and prop-1-en-2-ylbenzene, leading to active, chemo-and regioselective catalytic systems. The combination of the axial chirality of the BINOL backbone with the central chirality of the menthol moiety might be promising for the development of other asymmetric catalytic reactions, where the presence of the hemilabile ether oxygen atoms and/or the matching-mismatching effect of the chiral scaffolds can be crucial to achieve high diastereo-or enantioselectivity, such as hydrogenation, allylic substitution and hydrovinylation.