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Published in final edited form as: J Am Chem Soc. 2021 Oct 4;143(40):16709–16717. doi: 10.1021/jacs.1c07857

Understanding Halide Counterion Effects in Enantioselective Ruthenium-Catalyzed Carbonyl (α-Aryl)allylation: Alkynes as Latent Allenes and TFE-Enhanced Turnover in The Conversion of Ethanol to Higher Alcohols via Hydrogen Auto-Transfer

Eliezer Ortiz †, Jonathan Z Shezaf †, Yu-Hsiang Chang †, Théo P Gonçalves ‡, Kuo-Wei Huang ‡, Michael J Krische †
PMCID: PMC8749865  NIHMSID: NIHMS1767392  PMID: 34606271

Abstract

Crystallographic characterization of RuX(CO)(η3-C3H5)(JOSIPHOS), where X = Cl, Br, I, reveals a halide-dependent diastereomeric preference that defines metal-centered stereogenicity and, therefrom, the enantioselectivity of C-C coupling in ruthenium-catalyzed anti-diastereo- and enantioselective C-C couplings of primary alcohols with 1-aryl-1-propynes to form products of carbonyl anti-(α-aryl)allylation. Computational studies reveal a non-classical hydrogen bond between iodide and the aldehyde formyl CH bond stabilizes the favored transition state for carbonyl addition. An improved catalytic system enabling previously unattainable transformations was developed that employs an iodide-containing precatalyst RuI(CO)3(η3-C3H5) in combination with trifluoroethanol (TFE), as illustrated by the first enantioselective ruthenium-catalyzed C-C couplings of ethanol to form higher alcohols.

Introduction

The development of atom-efficient catalytic methods for the valorization of renewable feedstocks is a longstanding goal of chemical research.1 To this end, our laboratory has introduced a family of hydrogen auto-transfer (“borrowing hydrogen”) processes that convert lower alcohols to higher alcohols.2,3 These reactions affect carbinol C-H functionalization and, hence, differ from Guerbet-type reactions of alcohols, which result in hydroxyl substitution.3,4,5 This work encompasses the first catalytic enantioselective C-C couplings of methanol6b,c (>30 M tons/year) and ethanol7 (>80 M tons/year). Specifically, using iridium-catalysts, methanol was coupled to dienes6b and allenes6c to form primary neopentyl alcohols, and ethanol was coupled to allylic acetates7 to form branched secondary homoallylic alcohols. As reflected by annual production rates, ruthenium (30 tons/yr) is more abundant than iridium (3 tons/yr),8 yet use of ruthenium catalysts in asymmetric conversion of methanol or ethanol to higher alcohols is unknown.9 Recent advances in our laboratory on ruthenium-catalyzed alkyne-alcohol carbonyl reductive coupling via hydrogen auto-transfer support the feasibility of converting ethanol and 1-aryl-1-propynes to higher enantiomerically enriched alcohols.10,11e,i However, our previously reported catalytic system was inefficient, requiring high loadings of ruthenium (10 mol%).11i

Here, by understanding halide counterion effectss12,13 and exploiting trifluoroethanol (TFE)-enhanced turnover,14 we report an improved catalytic system for alkyne-alcohol C-C coupling, as illustrated by the regio- and enantioselective conversion of ethanol (the most abundant renewable small molecule carbon source)15 to enantiomerically enriched homoallylic alcohols (Figure 1). Specifically, using a ruthenium catalyst modified by JOSIPHOS16 in the presence of TFE, diverse 1-aryl-1-propynes react with ethanol to form branched secondary homoallylic alcohols through a tandem catalytic cycle in which alkyne-to-allene internal redox isomerization10 is followed by allene-aldehyde reductive coupling via hydrogen auto-transfer.17,18,19 As corroborated by DFT calculations and crystallographic characterization of a series of halide-bound complexes RuX(CO)(η3-C3H5)(JOSIPHOS), where X = Cl, Br, I, there exists a halide-dependent diastereomeric preference that defines metal-centered stereogenicity and, therefrom, the absolute stereochemical course of C-C coupling. Whereas the chloride- and bromide-bound catalysts exist as stereoisomeric mixtures, the iodide-bound catalyst exists as a single stereoisomer, enforcing superior levels of enantioselectivity. These insights have led to a simplified catalyst system that exploits an iodide-containing precatalyst, RuI(CO)3(η3-C3H5) that operates at lower catalyst loadings and enables previously unattainable 1-aryl-1-propyne-mediated carbonyl anti-(α-aryl)allylations of alcohol reactants.20,21

Figure 1.

Figure 1.

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Halide effects in enantioselective ruthenium-catalyzed conversion of ethanol to higher alcohols.

Results and Discussion

In prior work on enantioselective ruthenium-JOSIPHOS-catalyzed couplings of alcohols and sec-alkyl-substituted propynes to form branched products of carbonyl allylation,11e iodide counterions were found to enforce high levels of enantioselectivity and suppress competing formation of (Z)-homoallylic alcohols that arise via allene-carbonyl oxidative coupling (for catalytic cycle, see Scheme 2).11c The iodide-bound ruthenium catalysts are generated in situ through an acid-base reaction of a ruthenium dihydride with an arylsulfonic acid followed by substitution of the resulting sulfonate counterion by iodide (eq. 1).22 The selectivity and productivity of the catalytic system is highly dependent upon the efficiency with which the iodide counterion is introduced. As illustrated in related reactions of 1-aryl-1-propynes,11i replacement of 2,4,6-(iPr)3PhSO3H with 4-NO2PhSO3H resulted in >50% increase in isolated yield, yet high catalyst loadings (10 mol%) remained necessary.

Scheme 2.

Scheme 2.

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Proposed catalytic cycle and stereochemical model for the ruthenium-catalyzed C-C coupling of 1-aryl-1-propynes with ethanol to form products of carbonyl anti-(α-aryl)allylation.

graphic file with name nihms-1767392-f0006.jpg (eq.1)

Given the low turnover numbers associated with the previously developed catalytic system additional optimization experiments were undertaken using 1-(4-CF3-phenyl)-1-propyne 1a (150 mol%) and ethanol 2a (100 mol%) (Table 1). Consistent with our previous observations,11i low conversion to the product of carbonyl anti-(α-aryl)allylation 3a is observed upon omission of halide additives or introduction of lower halides (Table 1, entries 1-3). Using the iodide-bound catalyst, adduct 3a is formed in 68% yield with a 91% enantiomeric enrichment (Table 1, entries 4). Extending reaction time to 48 hours, the yield of adduct 3a was increased to 87% (Table 1, entry 5). However, at 5 mol% loadings of RuH2(CO)(PPh3)3, SL-J009-1 and 4-NO2PhSO3H under otherwise identical conditions, the yield of 3a was substantially decreased. Low turnover was attributed to inefficient release of the homoallylic ruthenium alkoxide derived upon carbonyl addition. It was posited that TFE might facilitate exchange of the homoallylic ruthenium alkoxide with the primary alcohol reactant via protonolytic cleavage of the former species, or perhaps facilitate carbonyl addition via hydrogen bonding to the carbonyl ligand23 to enhance Lewis acidity at ruthenium. In the event, using TFE as an additive led to a pronounced increase in the yield of 3a without changing the degree of asymmetric induction (Table 1, entries 8-9). At optimal loadings of TFE (300 mol%), 3a was generated in 82% yield and 91% enantiomeric enrichment (Table 1, entry 8).

Table 1.

Top: Selected optimization experiments illustrating the influence of TFE and halide counterion in the enantioselective transfer hydrogenative coupling of alkyne 1a and ethanol 2a to form the product of carbonyl anti-(α-aryl)allylation 3a. Bottom: Effect of TFE on the ruthenium-JOSIPHOS catalyzed C-C coupling of alkynes 1b-1e with alcohols 2b-2e to form adducts 4a-4d.a

graphic file with name nihms-1767392-t0009.jpg
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a

Yields of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase HPLC analysis. Diastereoselectivities were determined by 1H NMR analysis of crude reaction mixtures.

b

Entries 1-5: H2Ru(CO)(PPh3)3 (10 mol%), SL-J009-1 (10 mol%), Bu4NI (20 mol%) and 4-NO2PhSO3H (10 mol%).

c

Entries 6-9, H2Ru(CO)(PPh3)3 (5 mol%), SL-J009-1 (5 mol%), Bu4NI (10 mol%) and 4-NO2PhSO3H (5 mol%).

Use of the iodide-containing precatalyst, RuI(CO)3(η3-C3H5),24 should preclude the need for 4-NO2PhSO3H and Bu4NI, potentially simplifying the catalytic system. A series of experiments were conducted in which 1-(4-CF3-phenyl)-1-propyne 1a and ethanol 2a were exposed to RuI(CO)3(η3-C3H5) (5 mol%) and SL-J009-1 (5 mol%) in the presence of variable quantities of TFE (Table 1, entries 10-13). To our delight, reactions run for 48 hours using TFE (400 mol%) delivered adduct 3a in 92% yield and 91% enantiomeric enrichment (Table 1, entry 12). In the absence of TFE, a 5% yield of 3a was obtained (Table 1, entry 14). The increased sensitivity of reactions involving the iodide-bound precatalyst toward TFE may be due to the fact that 4-NO2PhSO3H is absent and an acid in the medium may be required to catalyze alkoxide exchange at the metal center. While it is possible that TFE initiates entry into the catalytic cycle through protonation of the π-allylruthenium precatalyst, a reaction conducted in the presence propanal (which can remove the π-allyl via carbonyl allylation) produced 3a in only 4% yield (Table 1, entry 15). Interestingly, in the presence propanal catalytic activity is not fully restored upon reintroduction of TFE (Table 1, entry 16). As will be discussed (vide infra), it appears pairwise generation of the aldehyde and π-allylruthenium intermediates is required for high catalytic turnover. Using the chloride- and bromide- bound precatalysts RuX(CO)3(η3-C3H5), X = Cl, Br, significantly lower yields and Reactions conducted using hexafluoroisopropanol HFIP in place of TFE (400 mol%) led to no conversion, however, lower loadings of HFIP were not explored.

To assess the generality of TFE-enhanced turnover in ruthenium-JOSIPHOS catalyzed C-C couplings beyond ethanol, alkynes 1b-1e were exposed to alcohols 2b-2e under the two optimal conditions identified for the formation of 3a in the presence and absence of TFE (Table 1). Specifically, “Conditions A” (Table 1, entry 8) utilizing the RuH2(CO)(PPh3)3 precatalyst in combination with 4-NO2PhSO3H and Bu4NI, and “Conditions B” (Table 1, entry 12) using the RuI(CO)3(η3-C3H5) precatalyst in the absence of 4-NO2PhSO3H and Bu4NI were employed. The products of carbonyl anti-(α-aryl)allylation 4a-4d were formed in substantially higher yields in the presence of TFE. Roughly equivalent enantioselectivities were obtained using either Conditions A or B. As demonstrated in the formation of 4a-4d (and in couplings to ethanol vide infra, Table 2), the superiority of Conditions A or B is case dependent and differences in yield typically do not diverge more than 10-20%.

Table 2.

Ruthenium-catalyzed coupling of 1-aryl-1-propynes 1a, 1c, 1d, 1f-1t with ethanol 2a to form enantiomerically enriched homoallylic alcohols 3a-3r.a

graphic file with name nihms-1767392-t0010.jpg
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a

Yields of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase HPLC analysis. Diastereoselectivities were determined via 1H NMR analysis of crude reaction mixtures.

b

DME (0.25 M). See Supporting Information for further experimental details.

graphic file with name nihms-1767392-f0007.jpg (eq.2)
graphic file with name nihms-1767392-f0008.jpg (eq.3)

To gain insight into the pronounced effect of halide counterion on productivity and enantioselectivity in the present ruthenium-catalyzed (α-aryl)allylations, the complexes RuX(CO)(JOSIPHOS)(η3-C3H5), where X = Cl, Br, I, were prepared as shown (eq. 2, 3) and their solid state structures were characterized by single crystal X-ray diffraction (Figure 2). Comparison of these crystal structures reveals a halide-dependent selectivity for occupancy of the axial coordination sites to define metal-centered stereogenicity. For the chloride complex, a 3:1 ratio of isomers is observed with chloride predominantly occupying the “northern” coordination site. For bromide, a 1:1 ratio of isomers is observed. For iodide, the “southern” coordination site is exclusively occupied. An analogous trend is observed in relation to the degree of disorder the π-allyl moiety. For the chloride complex, there exists a 1:1 ratio of conformers in which the π-allyl is “up vs down.” For the bromide complex, the π-allyl is less disordered and simply tilts a small amount (a 3:1 ratio of conformers is observed). For the iodide complex, there is no discernable disorder associated with the π-allyl. We posit that steric interactions between the southern tert-butyl group guide site-occupancy. Although iodide has the largest Van der Waals radius (Cl = 1.75 Å, Br = 1.85 Å, I = 1.98 Å), the exceptionally long ruthenium-iodine bond (Ru-X, Cl = 2.57 Å, Br = 2.66 Å, I = 2.85 Å) alleviates steric interactions between iodide and the tert-butyl group relative to chloride, bromide and the carbonyl ligand. The long ruthenium-iodine bond also appears to mitigiate π-backbonding to the carbonyl ligand, as the C≡O bond length is shortest in the iodide complex. As will be discussed, diminished π-backbonding increases charge density on the iodide counterion, facilitating its role as a non-classical hydrogen-bond acceptor to the aldehyde formyl CH bond in the transition state for carbonyl addition (vide infra).

Figure 2.

Figure 2.

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Solid state structures of RuX(CO)(JOSIPHOS)(η3-C3H5), where X = Cl, Br, I, as determined by single crystal X-ray diffraction and selected bond distances. Disorder due to incomplete axial site selectivity between the CO ligand and halide counterion is evident for the complexes containing chloride and bromide but not iodide. Displacement ellipsoids are scaled to the 50% probability level. Hydrogen atoms have been omitted for clarity.a

a See Supporting Information for complete crystallographic data

To gain deeper insight into how the iodide counterion influences the transition state for enantioselective C-C bond formation, density functional theory (DFT) calculations were undertaken (Scheme 1).25 Based on the crystallographic data, these studies focused on complexes in which the iodide counterion resides in the “southern” coordination site. The JOSIPHOS ligand has one of the t-butyl groups positioned nearly on the P-Ru-P plane (with a P-Ru-P-C dihedral angle of 159°), which may introduce greater steric interactions with the allyl moiety to disfavor TS3 and TS4. Unlike TS2, TS1 has the iodide positioned in close proximity to the formyl C-H bond of acetaldehyde with an I···HCO distance of 2.845 Å, suggesting the existence of a non-classical hydrogen bond.26 Quantum theory of atoms in molecules (QTAIM)27 analysis identified the bond critical point (BCP) between the I···H region, which is in alignment with natural bond orbital (NBO)28 analysis (Figure 3 and SI). The fuzzy bond order (FBO)29 of 0.069 was computed, accounting for an overall stabilization energy of 4.44 kcal/mol (E(2)-NBO) in TS1 through the iodide’s three electron lone pairs with the σ* orbital of the formyl CH bond as determined by second-order perturbation treatments in NBO (See supporting information). In sharp contrast, no BCP was observed between the CO ligand and acetaldehyde in TS2 and E(2)-NBO from the overlap of the π orbitals of CO and the σ* of the CH group were found to be much smaller (0.53 kcal/mol). These results indicate that beyond steric effects, the formyl hydrogen bond to iodide contributes a critical stabilizing interaction in the carbonyl addition by way of TS1. Hence, TS1 is calculated to be more stable than TS2 and TS3 by 1.38 and 1.35 kcal/mol, respectively.

Scheme 1.

Scheme 1.

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Chair-like transition structures leading to enantiomeric products of carbonyl anti-(α-aryl)allylation (ΔΔG‡ in kcal/mol at ωB97X-V).24

Figure 3.

Figure 3.

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Gradient trajectories mapped on a total electron density plot in the Ru-I-HCO plane showing bond critical points (BCP, blue circles).

Based on these data, a catalytic cycle for the ruthenium-catalyzed C-C coupling of 1-aryl-1-propynes with ethanol has been proposed in which stereogenicity at ruthenium is defined (Scheme 2). β-Hydride elimination from the indicated ethoxyruthenium species generates a ruthenium hydride with concomitant release of acetaldehyde. Hydrometalation of the allene,30 which is generated via alkyne isomerization, forms a π-allylruthenium complex that engages acetaldehyde in carbonyl addition by way of TS1 to form the indicated homoallylic ruthenium alkoxide. TFE-catalyzed exchange of the homoallylic alkoxide with ethanol liberates the product 3 and regenerates the ethoxyruthenium complex to close the catalytic cycle. Dehydrogenation of TFE vs ethanol are not competitive processes, as TFE dehydrogenation is prohibitively endothermic due to inductive destabilization of the transition state for hydride transfer to ruthenium.31

Conclusions

In summary, halide effects in transition metal catalysis are frequently observed, yet seldom understood.12 Here, we illuminate the origins of halide effects in ruthenium-JOSIPHOS-catalyzed anti-diastereo- and enantioselective C-C couplings of primary alcohols with 1-aryl-1-propynes through DFT calculations and crystallographic characterization of RuX(CO)(η3-C3H5)(JOSIPHOS), where X = Cl, Br, I. Notably, a “halide-dependent diastereomeric preference that defines metal-centered stereogenicity is observed. Whereas incomplete axial site-selectivity is observed for lower halides (Cl, Br), the iodide counterion exclusively occupies a single coordinate site. Additionally, the iodide counterion contributes a key stabilizing interaction, a non-classical CH···I hydrogen bond,26 in the preferred transition state for carbonyl addition. In this way, halide-directed metal-centered stereogenicity defines absolute stereochemical course of carbonyl addition. Based on these insights and exploiting trifluoroethanol (TFE)-enhanced turnover, a simplified catalyst system using an iodide-containing precatalyst, RuI(CO)3(η3-C3H5), that functions efficiently at lower catalyst loadings was designed that enables previously unattainable 1-aryl-1-propyne-mediated carbonyl anti-(α-aryl)allylations of alcohol reactants. Finally, the utility of this improved second-generation catalyst system was demonstrated in the first enantioselective ruthenium-catalyzed C-C couplings of ethanol, the most abundant renewable small molecule feedstock.15 These studies contribute to a growing class of hydrogen auto-transfer processes for catalytic carbonyl addition beyond premetalated reagents.1

Supplementary Material

Supporting Info

ACKNOWLEDGMENT

The Robert A. Welch Foundation (F-0038) and the NIH-NIGMS (RO1-GM069445) are acknowledged for partial support of this research. We are grateful for the assistance of Dr. Vincent Lynch for the acquisition and analysis of X-ray diffraction data. The service of Ibex, Shaheen 2 High Performance Computing Facilities was provided by King Abdullah University of Science and Technology (KAUST).

Footnotes

Supporting Information. Experimental procedures and spectroscopic data for all new compounds (1H NMR, 13C NMR, IR, HRMS), including images of NMR spectra and HPLC traces for racemic and enantiomerically enriched compounds. Single crystal X-ray diffraction data for RuX(CO)(JOSIPHOS)(η3-C3H5), where X = Cl, Br, I and compound 3e.

The authors declare no competing financial interest.

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