Hydrogenation of Cyclic 1,3-Diones to Their 1,3-Diols Using Heterogeneous Catalysts: Toward a Facile, Robust, Scalable, and Potentially Bio-Based Route.

Cyclopentane-1,3-diol (4b) has gained renewed attention as a potential building block for polymers and fuels because its synthesis from hemicellulose-derived 4-hydroxycyclopent-2-enone (3) was recently disclosed. However, cyclopentane-1,3-dione (4), which is a constitutional isomer of 3, possesses a higher chemical stability and can therefore afford higher carbon mass balances and higher yields of 4b in the hydrogenation reaction under more concentrated conditions. In this work, the hydrogenation of 4 into 4b over a commercial Ru/C catalyst was systematically investigated on a bench scale through kinetic studies and variation of reaction conditions. Herein, the temperature, H2-pressure, and the solvent choice were found to have significant effects on the reaction rate and suppression of undesired dehydration of 4. The cis-trans ratio of 4b is naturally generated as 7:3 in these reactions. However, at elevated reaction temperatures, 4b epimerizes, yielding more trans products. This effect was also studied and rationalized from a thermodynamic perspective using DFT. The combined optimized reaction conditions provided 78% yield for 4b, and successful applications to 8-fold scaled up reactions (40 g) and a substrate scope of several 1,3-diones demonstrate the general applicability of this catalytic approach.

Introduction

The utilization of renewable bio-derived feedstock proves to be qualitatively successful for numerous chemical transformations toward essential products for the present human society.[1] Namely, through extensive scientific research, the development of various novel bio-based chemical building blocks,[2] polymeric materials,[3] fuels,[4] and their corresponding production processes has been established in pursuit of sustainable manufacturing strategies.

However, many of such bio-derived substances are also excessively functionalized. The low stability that results from this molecular complexity often negatively affects their chemical stability and selectivity in chemical processes. Therefore, more delicate reaction conditions are required.[5] As a consequence, significant challenges may emerge in terms of space–time yield and cost-efficacy, when industrial upscaling is anticipated.

One notable example within this context is the reductive conversion of hemicellulose-derived furfural (1) and its cyclopentane derivatives, which has drawn worldwide attention over the last decade. Originally, Hronec et al.(6) reported in 2012 the first aqueous-phase hydrogenation of 1 at high temperatures using a Pt/C catalyst. This resulted in a cascade transformation via selective aldehyde reduction to furfuryl alcohol (2), a water-catalyzed rearrangement of 2 into 4-hydroxycyclopent-2-enone (3), finally yielding cyclopentanone (4d) via a dehydration/hydrogenation mechanism (Scheme ). Prolonged reaction time would ultimately lead to further hydrogenation of 4d to cyclopentanol (4e). Numerous subsequent investigations on this reaction have led to commendable improvements in terms of product selectivity and catalyst expense; albeit an unavoidable drawback is the prerequisite of highly dilute conditions (<5 vol % substrate in water and 80 vol % overhead space in a batch reactor).[7] The reason for applying such conditions is the delicacy of the conversion of 2 into 3, which is also known as the “Piancatelli rearrangement”.[8]

Scheme 1

Conversion of Hemicellulose-Derived Furfural via Reductive Pathways

Combined aqueous-phase hydrogenation of furfural (1) at high temperature (>160 °C) inevitably leads to dehydration into cyclopentanone (4d) via a cascade process, while individual reaction steps under sophisticated conditions allow the formation of cyclopentane-1,3-diol (4b) from 4-hydroxycyclopent-2-enone (3) or cyclopentane-1,3-dione (4).

Compound 3 is a highly functionalized molecule with a high reactivity and is therefore quite susceptible to various side reactions.[9] For instance, subjecting compound 3 to high temperatures induces dehydration to yield unstable cyclopentadienone, which is prone to Diels–Alder-type polymerizations. Polymer accumulation onto the catalyst surface may cause a diminished chemoselectivity or even total catalyst deactivation.[10] Consequently, very low concentrations (<5 vol % substrate in a solvent)[8]b,c are required to suppress polymerizations. This leads to higher expenses and environmental impact in terms of negatively affected space–time yields, down-stream processing, and overall material and energy consumption.[11]

Alternative to the harsh reductive cascade transformation of 1, the mild hydrogenation of 1 at lower temperatures or in the absence of water only proceeds until formation of 2,[12] and exposure of an aqueous solution of 2 to non-hydrogenative conditions allows the selective Piancatelli rearrangement to obtain and isolate 3.[8] Importantly, this opens the possibility of producing bio-based cyclopentane-1,3-diol (4b)[13] (Scheme ). Currently, this compound is still manufactured from petrochemical cyclopentadiene by stoichiometric hydroboration.[14]

Cycloaliphatic diols such as 4b are interesting building blocks for novel jet fuels,[15] surfactants,[16] and particularly specialized polymers.[13,17] Their molecular structure is moderately rigid and consists of at least two diastereoisomers, namely, cis and trans (as primary classification). For related polyesters, it has been shown that the incorporation of larger relative portions of the cyclic trans-monomer generally leads to polymeric materials with higher crystallinity and glass-transition temperatures (Tg).[17,18] In the case of 4b, the molecular architecture of the cyclopentane ring exhibits a lower degree of symmetry compared to the more commonly used 1,4-cyclohexanediol and therefore might result in polyesters with moderate rigidity and crystallinity.[17,19] For these polyesters made from 4b, the cis–trans ratio of the cyclopentane ring units also affects the degradation temperature as the ester groups of cis-units are more susceptible to dehydrative decomposition than those of trans-units.[17]

Zhang et al. recently demonstrated the first successful catalytic conversion of bio-derived 3 to selectively obtain 4b in high yields and a potential application of 4b in polyurethane synthesis.[13] They employed the heterogeneous catalysts Ru/C and Raney Nickel for the hydrogenation of 3 at 160 °C under 50 bar H2 for 1 h. Key to their achievement was reported to be the use of tetrahydrofuran (THF) as the solvent. However, other highly influential factors were possibly a rather high catalyst-to-substrate loading (±14 wt %) and dilute conditions (1.75 wt % substrate-to-solvent). Samples of pure cis- and trans-diastereoisomers of 4b were obtained by fractional distillation of a large-scale batch, but curiously no details on the cis–trans ratio were reported for the crude hydrogenation output and neither with respect to the synthesized polyurethane.

Alternatively, 4b has also been synthesized by hydrogenation of cyclopentane-1,3-dione (4) using stoichiometric reducing agents[20] and with the homogeneous ruthenium Shvo catalyst.[21] To the best of our knowledge, the hydrogenation of 4 to 4b using supported metal catalysts has surprisingly not been explored yet, albeit procedures employing Raney Nickel onto alkyl-substituted variants of 4 have been reported.[22] Interestingly, an incidental discovery by Noyori et al.(23) revealed that 3 can be isomerized into 4 in the presence of a Rh-phosphine catalyst, which denotes a potentially sustainable route for producing 4.

In contrast to the selectivity issues with 3, substrate 4 possesses a significantly higher stability due to its tautomeric shift into the electronically conjugated enol structure.[24] This allows proper solvation of 4 in notably protic solvents to afford concentrated solutions, while no degradation takes place at temperatures up to its decomposition point of 150 °C.[25] Moreover, 4 is registered as a non-dangerous substance[26] and was stable during storage at room temperature under an aerobic atmosphere in our lab for years. Although the bio-based synthesis of 4bvia4 would impose an extra reaction step in the total process, the use of 4 in hydrogenation instead of 3 could render significant benefits to advocate for.

Therefore, in this work we present our findings on the hydrogenation of 4 in order to produce 4b using a commercially available heterogeneous metal catalyst. The aim of our research was to establish and optimize a scalable methodology for the synthesis of 4b using a substantially high substrate concentration (i.e., 10% m/v), in order to provide significantly improved space–time yields. Important targets were uniform reaction performance upon scale-up, determination and potential control over the cis–trans selectivity in 4b, facile product isolation and purification, and a generic applicability of this catalytic hydrogenation procedure to substituted 1,3-diones. Successful achievement of these practical goals adds to the techno-economic relevance of our approach, in particular in view of the potentially bio-based production of 4 from hemicellulose and the anticipated low-emission profile of our chemical reaction concept.

Results and Discussion

In order to initiate our investigation toward a practical and efficient procedure for the hydrogenation of 4 toward the cyclopentane-1,3-diol monomers 4b, we arbitrarily defined a set of standard reaction conditions as follows. A concentrated reaction mixture consisting of about 10 wt % 4 in isopropanol as the solvent and a catalyst loading of about 5 wt % with respect to the substrate was selected to strive for a high space–time yield. For a pressure autoclave with 100 mL nominal volume, this translated into 4.90 g (50 mmol) of 4 and 250 mg of supported metal catalyst in 50 mL of isopropanol for facile calculation. Adequately firm reaction parameters featuring a temperature of 100 °C, 50 bar H2 pressure, a stirring rate of 750 rpm (i.e., the maximum for the used autoclave), and a reaction time of 7 h were selected to ensure complete conversion within a workable time period. Experiments were monitored over time via sampling and quantitative analysis by GC-FID. From this starting point, variations were systematically applied for optimization toward a scalable process.

Catalyst Screening

Using the selected set of standard reactions conditions, a few commercially available carbon-supported precious metal catalysts were tested (Table , entries 1–4). Among the four selected Ru, Rh, Pd, and Pt metals, Ru/C clearly rendered the best performance toward the desired products, displaying complete conversion with 69% yield of 4b and a nearly complete mass balance in just 2 h. In noteworthy contrast, the Rh/C, Pd/C and Pt/C catalysts strongly directed the reaction toward the dehydration products cyclopentanone and cyclopentanol, required longer reaction times, and suffered from a carbon mass loss in the range of 30–40%. The effect of the catalyst support was briefly inspected as well by testing Ru/Al2O3, which, however, appeared disadvantageous for the reaction rate (Table , entry 5).

Table 1

Summary of Kinetic Reaction Profiles Derived from Catalyst Screening Studies and the Effect of Olefinic Substrates Related to 4a

entry	catalyst	t (h)b	4b yield (%)	dehydration: 4c + 4d + 4e yield (%)	carbon mass balance (%)	cis–trans ratio 4b
1	Ru/C	2	69	27	96	71:29
2	Rh/C	4	11	61	72	77:23
3	Pd/C	4	0	69	69	N/A
4	Pt/C	7c	18	43	N/A	65:35
5	Ru/Al2O3	7c	46	27	N/A	75:25
6	Ru/Cd	7c	26	30	N/A	73:27
7	Ru/Ce	0.5	74	23	97	68:32
8f	Ru/C	0.75	40	1	42	65:35
9g	Ru/C	5c	33	16	51	67:33

Reaction conditions: 50 mmol of 4 and 5.1 wt % catalyst in 50 mL IPA, 100 °C, 50 bar H2.

Specific reaction time upon which complete conversion was observed via GC-FID.

No complete conversion was achieved after the stated reaction time. Carbon mass balance cannot be determined due to partial decomposition of 4 at T > 150 °C in GC.

Catalyst loading is 2.0 wt %.

Catalyst loading is 10.2 wt %.

Substrate = 4-hydroxycyclopent-2-enone (3).

Substrate = cyclopent-4-ene-1,3-dione (5).

The formation and subsequent depletion of intermediate species as is evident from the kinetic profile (Figure A) are in accordance with the reaction pathway depicted in Scheme . Substrate 4 is first mono-hydrogenated to 3-hydroxycyclopentanone (4a), which can be hydrogenated further into the desired product 4b. Alternatively, 4a can also undergo dehydration instead, in which 4a is converted into cyclopent-2-enone (4c), and is hydrogenated further into cyclopentanone (4d) and finally into cyclopentanol (4e). Furthermore, in all experiments, the diastereomeric ratio of the 4b product was dominated by the cis-diastereo-isomer (4b-cis), which is kinetically favored over the trans-diastereo-isomer (4b-trans) (vide infra). For clarification, 4b is defined as 4b-cis + 4b-trans (Scheme ). Finally, different catalyst loadings of the superior Ru/C were applied, namely, 100 and 500 mg (Table , entries 6 and 7). While a decrease of catalyst amount led to a significantly reduced reaction rate, it also notably decreased the selectivity toward 4b. The opposite effect was achieved by applying an increased amount of catalyst, which in addition shifted the isomeric ratio of the 4b product slowly to lower cis–trans ratios over the course of the extended reaction time (Figure S8). Although the higher loading of Ru/C (10 wt %) bears a slight advantage in catalytic performance, it was considered to be outweighed by the higher catalyst expenses. Hence, 250 mg of Ru/C was selected to proceed our research within further parameter optimizations.

Figure 1

Kinetic reaction profiles derived from hydrogenation of (A) substrate 4, (B) substrate 3, and (C) substrate 5, performed under reaction conditions of 50 mmol of substrate and 5.1 wt % Ru/C in 50 mL IPA, at 100 °C, under 50 bar H2.

Scheme 2

Generic Reaction Equation for the Hydrogenation of 4 and Its Products and Intermediate Species Observed in GC-FID

In order to validate the benefit of our catalytic concept to produce 4b from 4 compared to the aforementioned report by Zhang et al.,[13] we subjected the bio-based parent substrate 3 to our method. It should be noted that we were able to successfully reproduce their experiments under dilute conditions, but we observed deviating results for concentrated reaction mixtures. According to our findings, 3 reacts much faster than 4 and complete conversion was reached already within 1 h but yielded only 42% 4b at a substrate concentration of 10% (m/v) (Figure B). A high and rapid buildup of the intermediates was observed, which also depleted much faster than observed for 4, after which the formation of 4b ceased quite suddenly. Remarkably, this reaction produced no 4d or 4e, although the formation and depletion of dehydration intermediate 4c was detected. This typical reaction profile, the absence of the final dehydration products, and the incomplete mass balance are highly suggestive of side reactions between 3 and 4c (e.g., hetero-Diels–Alder or aldol condensations) toward polymeric materials,[9,27] which also build up on the catalyst surface and cause deactivation as such (vide infra).

In addition, the structurally related cyclopent-4-ene-1,3-dione (5) (see Scheme ), which does not show tautomeric behavior like 3 according to NMR (SI Figure S40 and S41) and DFT analysis, was tested as well. Compound 5 is hydrogenated significantly slower than 4, yielding only 33% 4b after 5 h, and renders a very low mass balance of 52% (Figure C). This outcome could be explained by the extended conjugated bond system of 5, which is less susceptible to hydrogenation but more reactive toward olefinic interactions.[28]

Scheme 3

Overview of the Hypothetical Interconnected Reaction Pathways of Substrates 3, 4, and 5 in Hydrogenationa

Reaction arrow with (a) a straight line indicate confirmed reaction pathways; (b) a red cross indicate disproven reaction pathways; and (c) a dashed line indicate uncertain reaction pathways.

Based on the observed kinetic plots of the hydrogenations of 3, 4, and 5, in conjunction with their chemoreactive properties, an overview of their most plausible reaction pathways is displayed in Scheme . A highly important aspect herein is that both 3 and 5 are prone to undergoing undesired (co)polymerization with itself and/or with 4c, while 4 does not. In the hydrogenation of 3, the in situ-generated 4c appears to be readily consumed by side reactions, instead of hydrogenating further into 4d and 4e. In contrast, the hydrogenation of 5 yields 16% 4e and is therefore more suggestive of a reaction path via4. However, in light of the very high reactivity of 3 under the applied reductive conditions, the absence of substantial detection of 3 in GC-FID cannot exclude a possible hydrogenation path of 5via3. Furthermore, the excellent carbon mass balance retrieved from 4 hydrogenation and the absence of 4 traces in the GC-FID analysis of the hydrogenation experiment of 3 are indicative that no significant rearrangement takes place between 4 and 3. Also no formation of cyclopent-4-ene-1,3-diol (4f) from 3 or 5 was observed, which confirms that 4b production always proceeds via4a.

Effect of Temperature

Using the selected catalytic conditions of 5.1 wt % Ru/C to 4, the reaction temperature was optimized by means of variation from 80 to 160 °C with intervals of 20 °C. As expected, elevating the reaction temperature causes higher conversion rates for each step, and therefore the effective reaction time to full conversion decreases (Table , entries 1–5). However, disadvantages of a higher temperature are a significant decrease in the yield of 4b and a lower carbon mass balance. These observations could be rationalized by the facts that the increased temperature promotes undesired side reactions of 4c in the presence of the metal catalyst[27] and that 4 decomposes at temperatures higher than 150 °C.[25] A remarkable and useful observation is that from 120 °C or higher, the epimeric equilibrium slowly shifts in favor of 4b-trans during the extended reaction time after complete conversion is achieved. The epimerization rate increases with elevated temperature, and ultimately an equilibrium was reached at 160 °C, corresponding to a cis–trans ratio of 48:52 (Figure A). While this epimerization of in situ-generated 4b was initiated in a 65:35 cis-trans ratio, we also confirmed epimerization of a commercial 4b sample with a 15:85 cis-trans ratio to reach the same equilibrium position under identical reaction conditions (see Figure S35). Importantly, additional experiments revealed that the presence of the Ru/C catalyst is a prerequisite for epimerization and was also found to induce dehydration when no hydrogenative conditions were applied.

Table 2

Summary of Kinetic Reaction Profiles Derived from Temperature and Pressure Screening Studiesa

entry	T (°C)	PH2 (bar)	t (h)b	4b yield (%)	dehydration: 4c + 4d + 4e yield (%)	carbon mass balance (%)	cis–trans ratio 4b
1	80	50	3	70	26	96	71:29
2	100	50	2	69	27	96	71:29
3	120	50	1.5	70	25	95	67:33
4	140	50	1	62	26	88	66:34
5	160	50	0.75	53	29	82	65:35
6	100	20	7c	56	31	N/A	68:32
7	100	80	1	74	22	96	69:31

Reaction conditions: 50 mmol of 4 and 5.1 wt % Ru/C in IPA.

Specific reaction time upon which complete conversion was observed via GC-FID.

Complete conversion was not achieved at the stated reaction time. Carbon mass balance cannot be determined due to partial decomposition of 4 at T > 150 °C in the GC analysis.

Figure 2

Kinetic reaction profiles derived from hydrogenation of 50 mmol of substrate 4 and 5.1 wt % catalyst in 50 mL solvent at (A) 160 °C and 50 bar H2 in IPA; (B) 100 °C and 80 bar H2 in IPA; (C) 100 °C and 50 bar H2 in tBuOH.

Effect of H2 Pressure

Significant effects upon the overall reaction performance were found by varying the applied H2 pressure (Table , entries 1, 6, and 7). Notably, when only 20 bar H2 is applied, the reaction rate is severely inhibited, and a relatively high dehydration yield is obtained. Conversely, under 80 bar H2, the reaction proceeds faster (Figure B), but the difference in the product distribution of 4b versus 4e is less pronounced compared to the application of 50 bar H2. Hence, a related trend is observed with respect to the product output, where a higher pressure gratifyingly suppresses the undesired dehydration step and thus enhances the yield of 4b.

Although these results on itself could suggest a pressure-related equilibrium (i.e., Le Chatelier’s principle), we attribute the inhibition of dehydration predominantly to the increased hydrogenative reaction rates of the corresponding experiments, in light of other observations in this work. The dehydration of 4a to yield 4c is readily accomplished upon slight heating and can proceed without an acid- or metal-based catalyst.[29,30] Since a higher reaction rate reduces the residence time of 4a, this intermediate gains a higher probability to undergo hydrogenation to 4b, rather than to dehydrate. Our experiments conducted under isobaric conditions of 50 bar H2 but with different catalyst loadings (Table , entries 1, 6, and 7) support this hypothesis. At higher temperatures, both the hydrogenation and dehydration are promoted, as the dehydration products rendered are 25–29% in all cases.

Since the product output is virtually equal for reactions run at temperatures in the range of 80–120 °C, we selected the median of 100 °C as the most desirable temperature. In addition, the experimentally obtained trend regarding the H2 pressure indicates that maximizing this parameter is favorable in order to suppress the undesired dehydration most effectively. Nevertheless, the dehydrative reaction pathway is also dependent on matrix effects.

Effect of Solvent

As reported by Zhang et al., the hydrogenation of 3 toward 4b was tremendously improved by selecting tetrahydrofuran as the solvent instead of water or methanol.[13] This fact prompted us to spend close attention to the effect of different solvents for the hydrogenation of 4 to 4b. Initial solubility tests at room temperature show that 4 rapidly dissolves in water and several small-chain alcohols but is clearly less soluble in more apolar organic solvents. In order to fine-tune this trend in terms of reaction performance, we selected water and all isomers of C1- to C4-alcohols as solvents for detailed kinetic investigation using the standard reaction conditions (Table ). In an aqueous medium, the reaction was already completed after 30 min, affording only 49% 4b and 40% 4e. When alcoholic solvents were applied instead, the selectivity of the reaction favored 4b production but at the cost of the conversion rate. This effect could be amplified in general by introducing higher alcohols, following the trend from smaller to larger carbon chains, as well as their degree of branching, although n-butanol poses an exception to this rule. Hence, the best result was obtained with tert-butanol, which rendered 74% 4b.

Table 3

Summary of Kinetic Reaction Profiles Derived from Solvent Screening Studiesa

entry	solvent	t (h)b	4b yield (%)	dehydration: 4c + 4d + 4e yield (%)	carbon mass balance (%)	cis–trans ratio 4b
1	water	0.5	49	40	89	64:36
2	MeOH	0.75	46	34	80	65:35
3	EtOH	0.75	56	36	92	67:33
4	n-PrOH	1.5	61	28	89	67:33
5	i-PrOH	2	69	27	96	71:29
6	n-BuOH	1	36	53	89	69:33
7	i-BuOH	3	61	25	86	68:32
8	s-BuOH	3	72	22	94	67:33
9	t-BuOH	3	74	21	95	67:33
10	EtOAc	4	62	37	99	69:31
11	CPME	2	62	36	98	69:31
12	THF	7	65	31	96	71:29
13	dioxane	2	69	29	98	68:32
14c	toluene	7	26	73	99	71:29
15c	heptane	7	29	69	98	52:48

Reaction conditions: 50 mmol of 4 and 5.1 wt % Ru/C, 100 °C, 50 bar H2.

Specific reaction time upon which complete conversion was observed via GC-FID.

The reaction was run for 7 h without collection of kinetic samples. Since the diol products emulsified out of the solvent, the entire reaction mixture was dissolved in acetonitrile for GC analysis.

Meanwhile, finalized reaction profiles with a decent selectivity toward 4b were also observed using aprotic solvents bearing moderate polarity, such as ethyl acetate, cyclopentyl methyl ether (CPME), and 1,4-dioxane. The experiment performed in tetrahydrofuran proceeded rather slowly, which could be attributed to the poor solubility of 4 in this solvent. In the cases of toluene and heptane, the 4b product was quantified after a reaction time of 7 h without sampling because the insolubility of 4b in these solvents rendered the earlier acquired kinetic reaction profiles thereof non-representative. As a result, these solvents were found to induce a poor selectivity for 4b.

The total outcome of this solvent screening in terms of reaction rate and product selectivity induced by the applied solvent is not completely understood at present time, as no distinct trends with respect to the (a)protic nature; polarity; water miscibility; or substrate, product, and H2 solubility can be assigned. Reported computational studies on Ru-catalyzed carbonyl hydrogenations, however, suggest that protic solvents could facilitate enhanced catalytic activity via solvent chemisorption, thereby altering the hydrogen transfer mechanism and lowering the energetic transition barrier.[31] Nevertheless, multiple solvents were shown to be reasonably compatible for this chemical transformation, among which tert-butanol (Figure C) induces the highest selectivity toward 4b. However, for desirable practicality (i.e., liquid state at room temperature) in industrial setups, sec-butanol and isopropanol are the most suitable alternatives as the solvent in terms of reaction performance.

Combined Optimum, Scale-Up, and Isolation of 4b

Ultimately, based on the results of each individual parameter optimization for the hydrogenation of 4, a final experiment was conducted in tBuOH, catalyzed by 5 wt % Ru/C, at 100 °C, and under 100 bar H2 pressure, in order to accumulate their benign effects to a combined optimum. Indeed, an improved 4b yield of 78% in a 67:33 cis–trans ratio and a suppressed dehydration of 18% are achieved, while the acquired kinetic reaction profile reveals complete conversion after only 60 min (Figure ), corresponding to an appreciable conversion rate of about 100 g/L/h and a turnover frequency (TOF) of 400 h–1 by mol Ru.

Figure 3

Kinetic reaction profile for the fully optimized hydrogenation of 4.

For comparison, various modern ketone reduction processes[32] catalyzed by carbonyl reductase enzymes typically tolerate substrate concentrations of 50 to >100 g/L but require reaction times of several hours to days until complete conversion is achieved. Conversely, numerous organometallic complexes are known to excel in homogeneously catalyzed transfer and pressure hydrogenations, rendering TOFs in the orders of 104–106 h–1.[33] However, their application in a large scale is often encumbered with difficult separation and recycling.

Encouraged by this outcome, the corresponding reaction conditions were applied for 8-fold scaled-up experiments by administering 40 g of 4 into a 600 mL autoclave reactor. The first batch was run for 1 h to replicate the shortened time required for complete conversion, as extrapolated from the small-scale kinetic reaction profile (Figure ). Indeed, GC analysis of the crude mixture displayed a 4b yield of 79 and 99% carbon mass balance. After facile recovery of the catalyst by Büchner filtration and removal of the solvent and 4e by rotavaporization, 4b was isolated in a 7:3 cis–trans ratio (Figure a) by vacuum distillation. The five obtained distillation fractions displayed a gradient of the 4b diastereoisomers, ranging from 91% pure cis-isomer (Figure b) to a 4:6 cis–trans ratio. The difficulty to obtain the trans-isomer in appreciable purity was presumably caused by the fact that the crude product naturally has a rather low trans-content of about 33%.

Figure 4

1H-NMR spectra (300 MHz) of isolated products: (a) 4b with a cis–trans ratio of 7:3; (b) 4b-cis (91% pure); (c) 4b-trans (92% pure).

In order to obtain the isolated trans-isomer in higher purity, we set out to establish a crude 4b mixture with a 1:1 cis–trans ratio for fractionated vacuum distillation. Such a mixture could be obtained by reproducing the observed epimerization at elevated reaction temperature (Figure A). Hence, a second scaled-up batch was carried out at 160 °C for 5 h, affording a crude yield of 62% 4b and 73% carbon mass balance. Interestingly, the recovered Ru/C catalyst from the first scaled-up batch was successfully recycled in this second batch. After workup, vacuum distillation was applied to harvest the trans-isomer in 92% purity in the last of five fractions in 29% yield (Figure c).

Substrate Screening

In light of the commonly observed product characteristics of the hydrogenation of 4, in particular the dehydrative side-reaction and the standard cis-trans ratio of 7:3, our curiosity was sparked to test the hydrogenation of various substituted 1,3-diones using our optimized catalytic procedure. Hence, a scope of 1,3-dione compounds with different substitution patterns and ring sizes was composed (Table ), featuring 2-methylcyclopentane-1,3-dione (6), 2,2-dimethylcyclopentane-1,3-dione (7), indane-1,3-dione (8), acetylacetone (9), cyclohexane-1,3-dione (10), dimedone (11), and 2,2,4,4-tetramethylcyclobutane-1,3-dione (12). Although substrates 4, 6, 9, 10, and 11 usually shift into their enol tautomer, they are represented as their diketone tautomers for conformity and clarity. It is noteworthy to mention that substrates 6 and 7 are potentially semi-biobased as procedures for their syntheses by methylation of 4 are known.[34] After hydrogenation for 2 h using our optimized protocol for the hydrogenation of 4, their conversions and crude product distributions were initially assessed using GC-FID. However, the isolation and spectroscopic characterization of the attained products was required to accurately determine their identity and diastereomeric ratio. Purification of the diols was performed by column chromatography, through which moderate to excellent separation of the cis- and trans-diastereoisomers could be achieved in the cases of 4, 6, 7, and 11.

Table 4

Application of the Optimized Reaction Protocol to Various Cyclic and Substituted 1,3-Dionesa

Reaction conditions: 50 mmol substrate and 5.1 wt % Ru/C in tBuOH, 100 °C, 100 bar H2.

Product contains three diastereoisomers according to 1H- and 13C-NMR: meso-cis-syn, meso-cis-anti, and d,l-trans.

N/A = not applicable.

N/D = not determined. However, traces of the corresponding product were detected by GC-FID.

Isolated by crystallization.

A mixture of the corresponding keto-alcohol (11a), alkenone (11d), ketone (11e), and alcohol (11e) was isolated.

Compared to the results of the hydrogenation of 4, the reduction of 6 is accompanied by significantly more dehydration. This can be rationalized by the increased electronic stability by the methyl substituent on the methine carbon to allow facile carbocation formation. Nevertheless, an isolated yield of 39% for the 2-methylcyclopentane-1,3-diols (6b) was obtained, of which the vast majority is the two cis-diol diastereoisomers, as tentatively assigned on the basis of NMR analysis.

The hydrogenation of 7 proceeded in a surprisingly difficult way, since the reaction temperature had to be arduously increased to 180 °C, before active conversion was finally observed by the decrease of H2 pressure. Even then, analysis of the isolated products revealed incomplete conversion but a grateful 40% isolated yield of 2,2-dimethylcyclopentane-1,3-diols (7b). As expected, the presence of the quaternary carbon on the 2-position prevents dehydration via the hypothetical alk-2-en-1-one intermediate. With regard to the notably high content of the cis-diastereo-isomer (7b-cis), this structural feature may also play a role in the apparent absence of epimerization at the exceptionally high temperature that was applied.

In the case of 8, highly selective monohydrogenation to 3-hydroxy-indanone (8a) was achieved at 100 °C. Further elevation of the temperature to 150 °C allowed the slow production of the desired diol compounds, while the formation of unidentified side products was also observed. Through isolation by column chromatography, indane-1,3-diol (8b) was obtained in a 68:32 cis–trans ratio. However, the isolated product from a third experiment was allowed to crystallize from refluxing ethyl acetate, as reported by Clerici et al.,[35] leading to the facile isolation of cis-indane-1,3-diol (8b-cis) in 99% purity.

Subjecting the substrates 9, 10, and 11 to the optimized reaction conditions for the hydrogenation of 4 provided good to excellent diol yields, accompanied by mere trace amounts of dehydration products. We suspect that the carbon skeletons of these linear- and six-membered ring structures allow more conformational degrees of freedom than that of cyclopentane-1,3-diol (4b).[36] Therefore, less alignment of the atomic π orbitals of the carbon atoms is invoked, which would otherwise promote olefinic bond formation to facilitate the dehydration via an elimination mechanism. Furthermore, the 5,5-disubstitution of 11 gives more conformational strain compared to 10, which inhibits the conversion rate and also affects the cis–trans ratio of the corresponding diol product (11b) significantly.

Substrate 12 was hydrogenated in excellent yield and chemoselectivity toward the desired diol product (12b) as its permethylated structure excludes dehydration via the elimination mechanism. However, separation of the corresponding cis–trans isomers by column chromatography failed because both diastereoisomers tend to precipitate rapidly from various solvents at room temperature.

Throughout this substrate scope performed under the rather forcing hydrogenation conditions (e.g., 100 bar H2), some remarkable differences in reactivity were observed. Notably substrates 7 and 8 showed difficulty in conversion even at significantly elevated reaction temperatures. A plausible rationale for this observation relies on the fully diketonic nature of 7 and 8, in contrast to the other substrates. For instance, 4 is an enolic substrate, of which the olefinic bond is hydrogenated prior to the carbonylic bond, forming 4a as the intermediate instead of 4f. This reaction pathway was always observed in the kinetic studies of this work, and the identities of the intermediates were confirmed by NMR analysis (Figure S116 and S117). According to the experimental work supported by computational findings of Davis et al., catalytic Ru(0001) surfaces indeed hydrogenate olefinic bonds more easily than carbonylic bonds.[37] While this selectivity is on the one hand influenced by the desirably mild Ru–C interaction compared to the stronger Ru–O bonding, the steric properties of the substrate were also found to affect the rate of catalysis significantly in terms of adsorbing and desorbing on/from the catalyst surface.

In this context, the hydrogenation of 12 is a particularly interesting example, whereas its conversion is achieved facilely, despite its diketonic nature. Excessively bulky substrates are often associated with a diminished reactivity due to steric hindrance. However, in the case of 12, this steric repulsion with the catalyst surface may inflict a weakening of the Ru–carbonyl bonding interaction, which is energetically favorable for the catalysis to proceed. Nevertheless, the higher ring strain of the cyclobutane structure may also induce more activation of the ketone groups to promote the hydrogenation of 12 as such.

Furthermore, from most of the tested substrates, the cis-diol is produced as the major diastereo-isomer. However, upon prolonged reaction times at elevated temperatures (i.e., T ≥ 120 °C), the products derived from hydrogenation of 4 epimerized to a 1:1 ratio. In order to rationalize these outcomes from a thermodynamic perspective, several possible conformations of these diols and their precursors were considered and computationally optimized with density functional theory (DFT), using the hybrid B3LYP function[38] and the 6-31G core potential.[39]

While cyclohexane rings are well known for their ability to toggle between the chair and boat conformation via ring-flipping, cyclopentane rings possess only a moderate degree of ring bending. Importantly, for both 5- and 6-membered rings, this can affect the orientation of their substituting groups. In the case of cyclic cis-1,3-diols, we identified two local minima, in which the hydroxyl substituents are in either an axial-axial orientation or in an equatorial-equatorial orientation. In the cyclic trans-1,3-diols, the hydroxyl substituents always converged to an axial-equatorial orientation (Figure ).

Figure 5

Optimized structures of (a) 4b-cis, (b) 4b-cis with a hydrogen bridge between the hydroxyl groups, and (c) 4b-trans, derived from DFT calculations.

By comparison of their calculated Gibbs free energy values (ΔG) (Figure ), it is deduced that the cyclic cis-isomers in vacuo are thermodynamically more stable than the trans-isomers in the case of 4b, 6b, 7b, 8b, 10b, and 11b due to their ability to form intramolecular hydrogen bridges between the hydroxyl groups,[22] when these adopt an axial-axial orientation. An exception to this trend are 9b because its linear structure also allows intramolecular hydrogen bridge formation in its trans-isomer, and 12b because its rigid cyclobutane ring structure does not allow any intramolecular hydrogen bridge formation at all.

Figure 6

Gibbs Free Energy values for the optimized molecular 1,3-diol products calculated by DFT. The corresponding 1,3-dione structures are normalized to 0.0 kcal/mol. 6b* refers to the diols derived from ketol 6a-cis (i.e., 6b-cis-syn and 6b-trans); 6b** refers to the diols derived from ketol 6a-trans (i.e., 6b-cis-anti and 6b-trans).

The formation of the intramolecular hydrogen bridge for cis-1,3-diols is a kinetically favored step that proceeds directly after furnishing the cis-diol in situ. However, the observed epimerization of 4b in isopropanol demonstrates that such internal hydrogen bridges can be broken as well at sufficiently high temperatures,[40] allowing a thermodynamically favored equilibrium to be reached. In protic solvents, the hydroxyl groups of 4b can interact in both a hydrogen-donating and a hydrogen-accepting mode. To explore these possibilities, several hydrogen-bonding modes of 4b-cis and 4b-trans with up to four methanol molecules were calculated as well (Figure ). Although the epimerization reactions were conducted in isopropanol, methanol was selected for the DFT calculations as simplification to reduce calculation time.

Figure 7

Gibbs free energy values for the optimized molecular structures of 4b in various H-bonding modes with one, two, three, and four methanol molecules, calculated by DFT. The corresponding structure of 4 is normalized to 0.0 kcal/mol. Post-scripts indicate the bonding mode (e.g., {1a,2d} means: ‘MeOH1 accepts proton of 4b hydroxyl 1; MeOH[2] donates proton to 4b hydroxyl 2).

The corresponding ΔG values of these molecular systems indicate a trend that the interaction of 4b with increasingly more methanol molecules generates the thermodynamically most favorable situation, because more hydrogen bridges are formed. In some cases where 4b interacts with only one or two methanol molecules, the computational optimization converged to a structure in which an extra hydrogen bond was established by a methanol bridging between the hydroxyl groups of 4b-cis exclusively (indicated with *). However, when maximal protic interactions of 4b with methanol are established, ΔG values of 4b-cis and 4b-trans are approximately equal.

In a physical sample at elevated temperature, a fluxional ensemble of 4b, interacting with methanol (or any other protic/functionalized/heteroatomic solvent) in various modes and orientations, is anticipated. Therefore, the ΔG values of the total populations of 4b-cis and 4b-trans in a solvent can be regarded as equal, and the thermodynamic 4b product will strive toward an equal 1:1 cis–trans ratio. Of course, the presence of a suitable catalyst (e.g., Ru/C) is a prerequisite for allowing this diastereomeric equilibrium to be reached. The interpretations of these computational findings are supported by the observed epimerization curves. Nevertheless, it should also be kept in mind that the preferred formation of one diastereo-isomer over another is possibly affected by a number of other factors as well, such as the possible modes of substrate binding to the catalyst and unequal transition energies for the formation of different diastereoisomers.

Overall, the substrate scope demonstrates a generic compatibility of this straightforward catalytic hydrogenation procedure of 1,3-diones to afford their corresponding 1,3-diols. The fact that many of such substrates exhibit little to no susceptibility for engaging dehydrative pathways compared to certain tested cyclopentane-1,3-diones (i.e., 4 and 6) creates a reason to impose lower H2 pressures in these cases. In addition, we believe that further detailed reaction optimization through kinetic studies for various 1,3-diones individually, as performed for 4 in this work, is an essential tool for finding the ideal reaction metrics toward their scale-up to production processes.

Conclusions

In this work, we report the successful hydrogenation of cyclopentane-1,3-dione (4) to cyclopentane-1,3-diol (4b) using a commercial Ru/C catalyst. he acquisition of kinetic reaction profiles from all bench-scale screening experiments was key to our thorough understanding of the chemical reaction, as well as to understand how changes in several reaction conditions affect the reaction rate and product distribution. The conversion of 4 proceeds in two reduction steps via 3-hydroxycyclopentanone (4a) to 4b; however, a competitive dehydration pathway originating from 4a, to finally yield cyclopentanol (4e), also takes place.

Importantly, the use of 4 as the substrate in this reaction generally leads to an excellent carbon mass balance, while subjecting its structurally related olefinic compounds 3 and 5 to the relatively concentrated conditions applied displays significant untraceable product losses. The optimal reaction temperature is about 100 °C in terms of 4b yield and carbon mass balance. However, prolonged exposure to 120–160 °C ultimately epimerizes the diastereomeric 4b mixture from a naturally generated cis–trans ratio of 7:3 to an epimerized ratio of 1:1. The yield of 4b was found to increase significantly by applying a higher H2 pressure up to 100 bar and also by delicately selecting the solvent, preferably tert-butanol. As such, an isolated yield of 78% of 4b was achieved within 2 h under the optimized conditions. These results appeared to be perfectly reproducible in an 8-fold scaled-up reaction, and vacuum-distillation provided isolated fractions for each of the cis- and trans-diastereo-isomer in >90% purity.

Ultimately, the optimized hydrogenation procedure was also applied to various other 1,3-diones and successfully afforded substantial amounts of the desired diol products in most cases. Our study revealed that the largest formations of undesired dehydration products are inherent to five-membered cyclic substrates with a hydrogen-appended 2-position (i.e., 4 and 6) and that cyclic substrates are prone to predominantly affording cis-diols. The latter observation accords with thermodynamic insights derived from computational structure optimizations using DFT, suggesting that various cyclic cis-1,3-diols are kinetically favored due to intramolecular hydrogen bonding of the hydroxyl groups. However, modeled interaction with methanol as the solvent suggests that 4b-cis and 4b-trans are thermodynamically favored equally, which is in line with the observed epimerization.

The straightforward catalytic hydrogenation procedure along with its ecological advantages and the acquired experimental knowledge is very relevant for the development of large-scale processes of several bio-based fine-chemicals.

Experimental Section

All reagents, catalysts, and solvents were purchased from various commercial suppliers and used without further purification, unless stated otherwise. NMR spectra were recorded on a Bruker Avance-300 Ultra Shield spectrometer, with 300 MHz for 1H-NMR and 75 MHz for 13C-NMR. Infrared spectra were recorded on a Shimadzu Miracle 10 FT-IR spectrometer in the range of 400–4000 cm–1. GC-FID analyses were performed using a Shimadzu GC-2010 Plus gas chromatograph equipped with a Supelco SLB-5 capillary column (length = 30 m, inner diameter = 0.25 mm, film thickness = 0.25 μm) and a flame ionization detector (FID). The heating program was 2 min isothermal at 40 °C; 5 °C min–1 to 80 °C; 6 min isothermal at 80 °C, then 30 °C min–1 to 300 °C; and finally 5 min isothermal at 300 °C. Thin-layer chromatography was conducted using aluminum TLC plates coated with 60 μm mesh normal phase silica. Typical eluent gradients were ethylacetate/hexane (50:50 v/v) to 100% ethylacetate.

Purification of Cyclopentane-1,3-dione (4)

The quality of the substrate was of great importance to the success of the hydrogenation reactions because small quantities of impurities were found to poison the Ru/C catalyst. In our case, purification of 4 was performed as follows. In a 5 L round-bottom flask, 500 g of a yellow-brown batch of 4 was dissolved in 4 L of isopropanol under vigorous mechanical stirring for 1 h followed by filtration to remove undissolved solid impurities, and the filtrate was rotavaporized to retrieve 4. Subsequently, the resulting 4 was suspended in 4.0 L of THF and dissolved by refluxing for 4 h under vigorous stirring. Slow cooling allowed 4 to crystallize overnight, which was collected via Buchner filtration over a glass frit. Drying in vacuo yielded 330 g (66%) of light-brown powder of 4 with >99% purity, as determined by 1H-NMR in DMSO-d6.

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 12.18 (br, 1H, OH), 5.07 (s, 1H, CH), 2.36 (s, 4H, CHCH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 197.78, 105.02, 31.36 ppm. FTIR: 2365, 1869, 1558, 1420, 1395, 1346, 1306, 1236, 1234, 1171, 999, 905, 843, 633 cm–1.

Synthesis of 4-Hydroxycyclopent-2-enone (3)

Freshly distilled furfuryl alcohol (2, 11.0 g) was dissolved in demineralized water to a total of 500 mL. The solution was divided in portions of 20.0 mL over 25 microwave vials with a size of 25 mL. The vials were sealed under aerobic conditions using aluminum crimp caps fitted with a PTFE septum. Each vial was irradiated using a Biotage Initiator+ microwave. The applied heating program contains a heating ramp to reach 200 °C within 100 s, then remains at 200 °C for 10 min, and is finally cooled down to room temperature within 5 min by means of a pressurized air flow. After the heating procedure, the reaction liquids had become orange-brown, and a suspension of a small amount of dark-brown solids had formed. The 25 reaction mixtures were combined and centrifuged for 15 min at 15000 rpm, in order to trap all solids in a pellet. The light-orange liquids were then decanted carefully, while the solid pellets were discarded. The liquid mixture was rotavaporized to give an orange oil (10.92 g crude yield). Finally, this oil was vacuum-distilled at 83 °C and 6 × 10–2 mbar (oil bath at 115 °C, vigreux = 8 cm long) to furnish 7.98 g (64.5%) of pure (99%) light-yellow product. A trace amount of levulinic acid impurity was observed in NMR.

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 7.64 (dd, J1 = 5.6; J2 = 2.3 Hz, 1H, vinyl), 6.15 (dd, J1 = 5.6; J2 = 1.0 Hz, 1H, vinyl), 5.46 (d, J = 3.9 Hz, 1H, OH), 4.83 (s, 1H, methine), 2.63 (dd, J1 = 18.2; J2 = 6.0 Hz, 1H, CHH), 2.03 (dd, J1 = 18.2, J2 = 2.1 Hz, 1H, CHH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 207.39, 166.37, 133. 94, 69.49, 44.62 ppm. FTIR: 3381, 2920, 1703, 1585, 1400, 1341, 1314, 1265, 1233, 1184, 1151, 1101, 1038, 945, 854, 831, 793, 731, 656 cm–1.

Hydrogenation Reactions

In a typical experiment, a 100 mL stainless steel autoclave (Parr 5500 reactor) was loaded with 50 mmol of substrate, 250 mg of catalyst, and 50 mL of solvent, unless stated otherwise. Subsequently, the reactor was sealed and purged five times with 3 bar N2 and then three times with 10 bar H2, and finally the reactor was charged with a substantial H2 pressure (i.e., 10–20 bar less at room temperature, compared to the desired pressure at elevated temperature). Mechanical stirring at 750 rpm was initiated, and the reaction mixture was heated to the desired temperature within 10 min. Upon reaching the desired temperature, a continuous H2 feed was allowed by opening the gas valve at the desired pressure. Optionally, kinetic samples were collected at delicate time intervals of (5, 10), 15, 30, 45, 60, 90, 120, 180, 240, 300, (360, 420) min. Afterward, the heating mantle of the autoclave was removed, and an ice water bath was used for cooling. When a temperature below 40 °C was reached, the remaining H2 pressure was carefully released. The autoclave was further neutralized by purging three times with 3 bar N2 and finally opened to retrieve the reaction mixture. Aliquots (16.3 μL) of the kinetic samples were dissolved in 1.00 mL of stock solution of 0.100 wt % naphthalene in acetonitrile.

Isolation of 1,3-Diol Products

Crude product mixtures from the hydrogenation reactions were filtered over 3 g of Celite to remove the heterogeneous catalyst. The filtrate was rotavaporized to remove the solvent and dehydrated mono-alcoholic side products as well if possible. Typically, the diol products were isolated and purified using silica gel column chromatography, using an eluent gradient of hexane/ethyl acetate (1:1 v/v) → 100% ethylacetate. In the case of 4b, both the cis- and the trans-isomers could be separated and isolated completely.

cis-Cyclopentane-1,3-diol (4b-cis)

Appearance: colorless thixotropic substance (20 °C).

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.45 (d, J = 4.7 Hz, 2H, OH), 3.98 (m, 2H, CHOH), 2.01 (dt, J1= 13.4; J2= 6.8 Hz, 1H, CHH), 1.62 (m, 2H, CHH-CHH), 1.55 (m, 2H, CHH-CHH), 1.33 (dt, J1= 13.4; J2= 6.8 Hz, 1H, CHH) ppm.

13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 70.60, 44.32, 33.14 ppm.

1H-NMR (300 MHz), 25 °C, CDCl3 (7.26 ppm): δ = 4.25 (m, 2H, CHOH), 2.35 (d, J = 5.3 Hz, 1H, CHH), 1.90 (br, 4H, CHH-CHH), 1.89 (d, J = 5.3 Hz, 1H, CHH) ppm.

13C-NMR (75 MHz), 25 °C, CDCl3 (77.16 ppm): δ = 74.19, 44.33, 34.15 ppm.

1H-NMR (300 MHz), 25 °C, D2O (4.79 ppm): δ = 4.38 (m, 2H, CHOH), 2.26 (dt, J1= 13.8; J2= 6.8 Hz, 1H, CHH), 1.88 (m, 2H, CHH-CHH), 1.69 (m, 2H, CHH-CHH), 1.49 (dt, J1= 13.8; J2= 6.8 Hz, 1H, CHH) ppm.

13C-NMR (75 MHz), 25 °C, D2O (uncorrected): δ = 71.78, 42.66, 32.13 ppm.

FTIR: 3287, 2961, 2936, 2866, 1653, 1425, 1341, 1296, 1236, 1206, 1161, 1067, 997, 957, 660 cm–1.

{d,l-trans}-Cyclopentane-1,3-diol (4b-trans)

Appearance: colorless solid.

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.37 (d, J = 3.9 Hz, 2H, OH), 4.18 (m, 2H, CHOH), 1.85 (m, 2H, CHH-CHH), 1.60 (t, J = 5.3 Hz, 2H, CH), 1.35 (m, 2H, CHH-CHH) ppm.

13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 70.60, 45.08, 33.19 ppm.

1H-NMR (300 MHz), 25 °C, CDCl3 (7.26 ppm): δ = 4.43 (m, 2H, CHOH), 2.10 (m, 2H, CHH-CHH), 1.82–1.63 (m, 2H, CH), 1.58 (m, 2H, CHH-CHH) ppm.

13C-NMR (75 MHz), 25 °C, CDCl3 (77.16 ppm): δ = 72.77, 45.50, 33.71 ppm.

1H-NMR (300 MHz), 25 °C, D2O (4.79 ppm): δ = 4.50 (m, 2H, CHOH), 2.05 (m, 2H, CHH-CHH), 1.87 (t, J = 5.3 Hz, 2H, CH), 1.57 (m, 2H, CHH-CHH) ppm.

13C-NMR (75 MHz), 25 °C, D2O (uncorrected): δ = 71.99, 43.07, 32.06 ppm.

FTIR: 3391, 1653, 1034, 1022, 995, 824, 762, 660 cm–1.

Scaled-up Hydrogenation of 4 and Isolation of 4b

A 600 mL Stainless steel autoclave (Parr 4560 reactor) was loaded with 39.3 g (400 mmol) of substrate 4, 2.00 g of Ru/C, and 400 mL of tert-butanol. Subsequently, the reactor was sealed and purged five times with 3 bar N2 and then three times with 10 bar H2, and finally the reactor was charged with 80 bar H2. The reaction mixture was heated to (a) 100 °C or (b) 160 °C for 2 h effectively while stirring at 750 rpm. A continuous feed of 100 bar H2 was maintained throughout the reaction. Afterward, the heating mantle of the autoclave was removed, and an ice water bath was used for cooling. When a temperature below 40 °C was reached, the remaining H2 pressure was carefully released. The autoclave was further neutralized by purging three times with 3 bar N2 and finally opened to retrieve the reaction mixture. The crude reaction mixture was filtered over a glass frit to recover the catalyst for reuse. The light-yellow filtrate was rotavaporized to remove the solvent. Next, the crude product was vacuum-distilled (vigreux = 30 cm long) in two steps to first remove cyclopentanol (4e) (62 °C; 45 mbar) and then 4b in five fractions (92–114 °C; 1 mbar). These fractions featured a gradual decrease of the cis/trans ratio upon increased distillation temperature.

Analysis of Products Derived from the Substrate Scope

{meso-cis-syn}-2-Methylcyclopentane-1,3-diol (6b-cis-syn)

Appearance: colorless viscous liquid. 1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.17 (d, J = 5.9 Hz, 2H, OH), 3.89 (m, 2H, methine), 1.8–1.5 (m, 5H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 73.49, 43.05, 32.08, 8.41 ppm. FTIR: 3296, 2957, 2932, 1420, 1339, 1300, 1159, 1065, 1007, 667 cm–1.

2-Methylcyclopentane-1,3-diol (Mixture of Isomers) (6b-cis-anti + 6b-trans)

Appearance: colorless viscous liquid. FTIR: 3292, 2957, 2928, 2870, 2359, 2334, 1456, 1327, 1175, 1146, 1069, 1028, 986, 951, 885, 669 cm–1.

{meso-cis-anti}-2-Methylcyclopentane-1,3-diol (6b-cis-anti)

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.56 (d, J = 5.3 Hz, 2H, OH), 3.39 (m, 2H, CHOH), 1.71 (m, 2H, CHH), 1.57–1.20 (m, 3H, CHH; CHMe), 0.95 (d, J = 6.8, 3H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 76.28, 50.04, 31.41, 15.62 ppm.

{d,l-trans}-2-Methylcyclopentane-1,3-diol (6b-trans)

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.44 (d, J = 4.4 Hz, 1H, OH), 4.24 (d, J = 4.4 Hz, 1H, OH), 3.91 (m, 1H, CHOH), 3.62 (m, 1H, CHOH), 2.00–1.80 (m, 2H, CH), 1.58–1.20 (m, 3H, CH), 0.89 (d, J = 7.0, 3H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 76.58, 72.41, 47.08, 31.72, 11.70 ppm.

2,2-Dimethyl-3-hydroxycyclopentanone (7a)

Appearance: colorless liquid. 1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.95 (d, J = 4.2 Hz, 1H, OH), 3.83 (q, J = 5.3, 1H, CHOH), 2.35–1.95 (m, 3H, CH), 1.81–1.63 (m, 1H, CH), 0.90 (s, 3H, CH), 0.85 (s, 3H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 220.93, 76.25, 49.34, 33.80, 27.35, 21.81, 16.97 ppm. FTIR: 3420, 2967, 2934, 2872, 2361, 2340, 1724, 1456, 1404, 1379, 1362, 1339, 1261, 1254, 1215, 1169, 1101, 1076, 1059, 1015, 968, 966, 935, 887, 868, 800, 797 cm–1.

cis-2,2-Dimethylcyclopentane-1,3-diol (7b-cis) (Extrapolated from Mixtures with 7a and 7b-trans)

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.39 (d, J = 5.4, 2H, OH), 3.43 (d, J = 5.3, 2H, CHO), 1.72 (m 2H, CHH), 1.40 (m, 2H, CHH), 0.86 (s, 3H, CH), 0.66 (s, 3H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 77.00, 43.94, 28.92, 24.82, 13.83 ppm.

{d,l-trans}-2,2-Dimethylcyclopentane-1,3-diol (7b-trans)

Appearance: white solid. 1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.31 (d, J = 4.9 Hz, 2H, OH), 3.62 (dd, J = 10.4; J2 = 5.3 Hz, 2H, CHO), 2.00–1.80 (m, 2H, CHH), 1.40–1.20 (m, 2H, CHH), 0.78 (s, 6H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 77.45, 44.83, 29.67, 20.28 ppm. FTIR: 3375, 3312, 3281, 2959, 2934, 2884, 2359, 2160, 2008, 1967, 1472, 1465, 1441, 1420, 1339, 1304, 1234, 1200, 1119, 1065, 1028, 989, 972, 947, 887, 729, 669 cm–1.

3-Hydroxy-indane-1-one (8a)

Appearance: brown viscous liquid. 1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 7.73 (d, J = 3.8 Hz, 2H, Ar), 7.63 (d, J = 7.6 Hz, 1H, Ar), 7.50 (dt, J1 = 7.8; J2 = 4.0 Hz, 1H, Ar), 5.25 (dd, J1 = 6.8; J2 = 3.0 Hz, 1H, CHO), 3.02 (dd, J1 = 18.6; J2 = 6.8 Hz, 1H, CHH), 2.42 (dd, J1 = 18.6; J2 = 3.0 Hz, 1H, CHH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 203.45, 156.86, 135.89, 134.97, 128.81, 126.34, 122.17, 66.95, 46.81 ppm. FTIR: 3385, 2920, 2359, 2158, 2033, 1967, 1701, 1603, 1464, 1395, 1331, 1277, 1240, 1211, 1155, 1069, 1043, 758 cm–1.

cis-Indane-1,3-diol (8b-cis)

Appearance: colorless solid. 1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 7.29 (dm, J = 14.5 Hz, 4H, Ar), 5.37 (d, J = 6.4, 2H, OH), 4.81 (q, J = 7.0 Hz, 2H, CHO), 2.74 (dt, J1 = 12.1 ; J2 = 6.8 Hz, 1H, CHH), 1.59 (dt, J1 = 12.0; J2 = 8.4 Hz, 1H, CHH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 145.37, 127.19, 123.53, 70.33, 46.79 ppm. FTIR: 3292, 3244, 2361, 2160, 2008, 1684, 1653, 1558, 1506, 1472, 1429, 1323, 1290, 1215, 1167, 1105, 1069, 1051, 1032, 964, 945, 766, 743, 667, 604 cm–1.

{d,l-trans}-Indane-1,3-diol (8b-trans) (Extrapolated from a Mixture with 8b-cis)

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 7.29 (dm, J = 14.5 Hz, 4H, Ar), 5.25 (d, J = 6.4, 2H, OH), 5.16 (t, J = 6.4 Hz, 2H, CHO), 2.09 (t, J = 5.3 Hz, 2H, CH2) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 146.77, 127.68, 124.40, 72.33, 45.83 ppm.

Pentane-2,4-diol (9b)

Appearance: colorless mixture. FTIR: 3304, 2967, 2928, 2359, 2160, 1558, 1506, 1456, 1373, 1319, 1211, 1155, 1119, 1043, 1003, 959, 918, 885, 827 cm–1.

cis-Pentane-2,4-diol (9b-cis)

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.45 (d, J = 4.1 Hz, 2H, OH), 3.75 (m, 2H, CHO), 1.48 (dt, J1 = 13.5; J2 = 7.9 Hz, 1H, CHH), 1.25 (dt, J1 = 8.4; J2 = 5.1 Hz, 1H, CHH), 1.04 (d, J = 6.2 Hz, 6H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 64.64, 48.15, 23.88 ppm.

{d,l-trans}-Pentane-2,4-diol (9b-trans)

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.29 (d, J = 4.8 Hz, 2H, OH), 3.75 (m, 2H, CHO), 1.32 (t, J = 6.0, 2H, CH), 1.03 (d, J = 6.2 Hz, 6H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 63.07, 48.54, 24.33 ppm.

Cyclohexane-1,3-diol (10b)

Appearance: colorless viscous liquid. FTIR: 3294, 2932, 2857, 2160, 2008, 1456, 1362, 1339, 1260, 1248, 1192, 1125, 1080, 1063, 1032, 1011, 978 cm–1.

cis-Cyclohexane-1,3-diol (10b-cis)

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.51 (d, J = 4.5 Hz, 2H, OH), 3.33 (m, 2H, CHO), 2.01 (d, J = 11.5 Hz, 1H, CH), 1.71 (d, J = 13.0 Hz, 2H, CH), 1.59 (dm, J = 13.0 Hz, 1H, CH), 1.21–0.87 (m, 5H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 67.42, 45.43, 34.78, 20.55 ppm.

{d,l-trans}-Cyclohexane-1,3-diol (10b-trans)

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.29 (d, J = 3.9 Hz, 2H, OH), 3.82 (m, 2H, CHO), 1.51 (d, 2H, CH), 1.49 (d, J = 5.0 Hz, 2H, CH), 1.35–1.22 (m, 2H, CH2), 1.21–0.87 (m, 2H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 64.94, 42.32, 33.83, 18.77 ppm.

Mixture of 3-Hydroxy-5,5-dimethylcyclohexan-1-one (11a) and cis-5,5-Dimethylcyclohexane-1,3-diol (11b-cis)

Appearance: pale yellow viscous liquid. FTIR: 2957, 2872, 2158, 2018, 1701, 1670, 1653, 1558, 1506, 1456, 1418, 1387, 1368, 1339, 1261, 1244, 1231, 1165, 1051, 1018, 980, 901, 733 cm–1.

3-Hydroxy-5,5-Dimethylcyclohexan-1-One (Extrapolated from a Mixture with 11b-cis)

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.93 (d, J = 4.1 Hz, 1H, OH), 3.86 (td, J1 = 10.0; J2 = 5.1, 1H, CHOH), 2.48–2.36 (m, 1H, CO-CHH-COH), 2.30–2.15 (m, 2H, CMe2-CH-CO), 1.90 (dd, J1 = 13.4; J2 = 1.8 Hz, 1H, CO-CHH-COH), 1.82–1.70 (m, 1H, COH-CHH-CMe2), 1.51, (dd, J1 = 12.8; J2 = 10.5 Hz, 1H, COH-CHH-CMe2), 1.00 (d, J = 11.9 Hz, 6H, CMe2 ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 209.21, 65.75, 53.38, 50.34, 46.61, 32.62, 31.26, 26.59 ppm.

cis-5,5-Dimethylcyclohexane-1,3-diol (11b-cis)

Appearance: white solid. 1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.41 (d, J = 4.8 Hz, 2H, OH), 3.50 (tq, J1 = 11.3; J2 = 4.5 Hz, 2H, CHO), 2.03 (dd, J1 = 6.9 ; J = 4.5 Hz, 1H, CHH), 1.48 (dm, J = 12.5 Hz, 2H, CH), 0.89 (s, 3H, CH), 0.88 (t, J = 11.4 Hz, 1H, CHH), 0.82 (s, 3H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 64.48, 47.92, 45.77, 33.12, 30.89, 25.92 ppm. FTIR: 3210, 2951, 2928, 2849, 2158, 2008, 1456, 1368, 1339, 1279, 1248, 1163, 1123, 1074, 1013, 941, 908, 860, 725 cm–1.

{d,l-trans}-5,5-Dimethylcyclohexane-1,3-diol (11-trans)

Appearance: white crystalline solid. 1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.28 (s, 2H, OH), 3.93 (m, 2H, CH-OH), 1.49 (t, J = 5.4 Hz, 2H, CH), 1.34 (dd, J1 = 13.1 ; J2 = 3.7 Hz, 2H, CHH), 1.18 (dd, J1 = 13.0 ; J2 = 6.9 Hz, 2H, CHH), 0.94 (s, 6H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 64.22, 46.43, 42.37, 31.69, 31.15 ppm. FTIR: 3275, 2990, 2940, 2920, 2862, 2160, 2018, 1456, 1364, 1337, 1296, 1288, 1227, 1221, 1171, 1128, 1069, 1055, 1024, 982, 924, 903, 866, 826, 779, 660 cm–1.

2,2,4,4-Tetramethylcyclobutane-1,3-diol (12b)

Appearance: white solid. FTIR: 3298, 2963, 2951, 2914, 2862, 2361, 2160, 2021, 1977, 1468, 1341, 1219, 1200, 1123, 1038, 993, 976, 851 cm–1.

cis-2,2,4,4-Tetramethylcyclobutane-1,3-diol (12b-cis)

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.52 (d, J = 5.2 Hz, 2H, OH), 3.28 (d, J = 4.8 Hz, 2H, CHO), 0.98 (s, 6H, CH), 0.83 (s, 6H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 76.90, 42.19, 29.41, 16.10 ppm.

{d,l-trans}-2,2,4,4-Tetramethylcyclobutane-1,3-diol (12b-trans)

1H-NMR (300 MHz), 25 °C, DMSO-d6 (2.50 ppm): δ = 4.50 (d, J = 5.5 Hz, 2H, OH), 3.14 (d, J = 4.9 Hz, 2H, CHO), 0.90 (s, 12H, CH) ppm. 13C-NMR (75 MHz), 25 °C, DMSO-d6 (39.50 ppm): δ = 78.33, 40.33, 23.12 ppm.

DFT Calculations

Computational calculations for all chemical geometries were performed using the ORCA software package (version 2.8.0). Optimizations were performed at the level of DFT by means of the hybrid B3LYP functional, and the basis set 6-31G was employed for all elements (i.e., C, H, O). All calculated structures were obtained without using redundant coordinates, and with an energy change precision of 1.0 × 10–8 au (i.e., TightSCF convergence criteria, which is default for geometry optimizations). Vibrational frequency calculations were performed for all stationary points at the same level to identify the minimum energy states (zero imaginary frequencies) and to provide the Gibbs free energy values at 298.15 K and 1.0 atm.