# Synthesis of Leaf Alcohol using Lindlar Catalyst: From Batch to Continuous-Flow

Durand Hugo,[a] Vanoye Laurent,[a] Philippe Régis,[a] de Bellefon Claude,[a] Favre-Réguillon Alain*[a,b]

## Abstract

Leaf alcohol is typically produced through batch selective semi-hydrogenation of 3-hexyn-1-ol using Lindlar catalyst. While several catalysts have been described for this transformation, they are manufactured on a gram scale, posing challenges for industrialization. We decided to implement this process in flow. We show that, in the absence of quinoline, precise control of the reaction's progress is crucial for achieving high selectivity. To reduce the pressure drop, the catalyst was pelletized using CaCO₃ as binder. At 40°C, and under 1 bar of H₂, total conversion was obtained in less than 1 min. However, selectivity at high conversion is lower due to mass transfer limitations and a broad contact time distribution. Selectivity can be enhanced by increasing the liquid flow rate while high conversion can be attained by operating in a recirculating flow mode. Under this configuration, high selectivity at high conversion can be achieved in flow using commercial Lindlar catalyst.

<footnote>[a] Catalyse Polymérisation Procédés & Matériaux (CP2M), UMR 5128 CNRS-CPE Lyon-Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, F-69100 Villeurbanne, France.</footnote>

<footnote>[b] Conservatoire National des Arts et Métiers, Bâtiment Synergie, 10 rue de la Procession, F-93210 La Plaine Saint Denis, France.</footnote>
Introduction

Leaf alcohol, (Z)-3-hexen-1-ol 1, is naturally present in many fresh fruits and vegetables. 1 provides a fresh green grassy foliage note that is commonly utilized in the flavor and fragrance industry (apr. 400 tons annually, including esters).[1] Several synthetic methods have been explored since its first total synthesis in 1938 by Stoll and Rouvé,[2] who established the correct configuration. Among these methods recently reviewed,[3] only two pathways are used for the industrial production of 1 (Figure 1).

<figure><img src="image_1.png" /><figcaption>Figure 1. Processes used in the production of leaf alcohol 1 [3]</figcaption></figure>

The first pathway originates from the seminal work of Stoll and Rouvé.[2] The main intermediate is 3-hexyn-1-ol 2 (Figure 1) directly obtained from 1-butyne. Selective semi-hydrogenation of 2 using Lindlar catalyst provides the desired leaf alcohol 1 in high yield and selectivity (> 98%). The alternative pathway involves the ring opening of 6-methyl-3,6-dihydro-2H-pyran 3 obtained by the Diels-Alder reaction of 1,3-pentadiene and formaldehyde.[4] Reductive cleavage of 3 yields the leaf alcohol 1 in good yield, with high selectivity. However, the olfactory characteristics of the product obtained via the second method seem less appreciated.[3]

The selective semi-hydrogenation of hex-3-yn-1-ol 2 to (Z)-hex-3-en-1-ol 1 remains the most direct method, primarily utilizing the Lindlar catalyst[5] (Figure 2). Since its first report in 1952, the Lindlar catalyst[6] remains the industrial state of the art for selective alkyne semi-hydrogenations.[7] It typically consists of 5 wt% palladium supported on CaCO3, along with 1–5 wt% lead. The Lindlar catalyst enables the Z-selective semi-hydrogenation of alkynes in high yields and with high stereocontrol. Overall selectivity may be improved by adding competitive adsorbents[8], primarily quinoline (0.05–1 molar equiv.).[6] It is generally accepted that the selectivity of the Lindlar catalyst for alkene formation stems from control of the substrate adsorption on the Pd active site,[9] but the exact origins of this selectivity remain under debate.[8, 10] Once 1 is formed, different by-products can be obtained through consecutive over-hydrogenation (6) or isomerization (4 and 5). In the presence of Pd, isomerization products (4 and
5) can form, and their amount correlates with the reaction mixture's contact time with Pd (vide supra). Generally, a minimal amount of perhydrogenated product 6 is produced under those conditions.

<figure><img src="image_2.png" /></figure>

Figure 2. Catalytic pathway for the semi-hydrogenation of hex-3-yn-1-ol **2** to (Z)-hex-3-en-1-ol **1** using the Lindlar catalyst and H₂. The size of the arrows qualitatively illustrates the relative rates of the consecutive reactions.

The many drawbacks of the Lindlar catalyst have been extensively discussed, especially regarding the presence of Pb,[11] and using an excess of quinoline.[12] New catalysts[7b, 13] and procedures[14] have been proposed for the selective semi-hydrogenation of alkynols.[15] However, these methods require complex catalyst preparation methods or expensive types of equipment that are hardly available. In contrast, the Lindlar catalyst is commercially available, and previous publications have reported contradictory results about the selectivity of semi-hydrogenation of alkynols in flow using this catalyst.[16] Therefore, it may be worthwhile to reassess the potential of the commercial Lindlar catalyst for this important reaction and its implementation in flow. Furthermore, managing the fate of the solid catalyst is simpler in a flow reactor due to the confinement of the solid catalyst within the tubular reactor as pellets, as opposed to the use of micro powders (< 10 µm for Lindlar catalyst). This confinement has the potential to optimize catalyst application, enhance separation, and improve control over reactor and product contamination.

# Results and discussion

## Reduction in batch

The catalytic semi-hydrogenation of 3-hexyn-1-ol **2** by the commercial Lindlar catalyst was first evaluated in a batch reactor using toluene at 40°C under 10 bar of H₂ with 0.2 mol% of Pd. Toluene was selected due to the ability of aprotic solvents to enhance selectivity.[7a] Under these conditions, total conversion was obtained in less than 10 min (Figure 3).
<figure><img src="image_3.png" /><figcaption>Figure 3. Composition of the solution as a function of time for the hydrogenation of 3-hexyn-1-ol **2** in a batch reactor with toluene using the Lindlar catalyst. Reaction conditions: **2** in 100 mL toluene (0.25 M), H₂ 10 bar, 40°C, Lindlar catalyst 0.1 g (0.2 mol% Pd). The concentrations were determined by GC/FID through internal calibration. Lines serve as guides to the eye.</figcaption></figure>

In a batch reactor, without quinoline, a maximum selectivity of up to 97.7% toward (Z)-hex-3-en-1-ol **1** was obtained just below total conversion (9.7 min, conversion 99.8%), comparable to best new design catalysts.[13a, 17] However, from this point onward, a relatively rapid decrease in selectivity as a function of time is noted (Figure 3). At 10.7 min, the selectivity dropped to 95%. As described in the literature (Figure 2),[18] the major by-product formed was the E-isomer **4** (3.2%), with less than 1% of the fully saturated alcohol **6** and some other unsaturated isomers **5** (Figure S1). A time-related change in composition was then observed, i.e., up to 14% of E-isomer **4** was produced with less than 4% of **6** after 45 min (Figure 3).

The influence of quinoline in the batch reactor was then evaluated under the same experimental conditions (Figure 4). Adding 10 mol% of quinoline only slightly decreased the apparent hydrogenation rate of **2** from 26 without quinoline to 22 mmol.g<sub>cat</sub><sup>-1</sup>.min<sup>-1</sup>. Meanwhile, the observed maximum selectivity for **1** was marginally increased, from 97.7% to 98.3% without and with quinoline, respectively.
<figure><img src="image_4.png" /><figcaption>Figure 4. Composition of the solution as a function of time for the hydrogenation of 3-hexyn-1-ol **2** in toluene using the Lindlar catalyst with quinoline as a modifier. Reaction conditions: **2** in 100 mL toluene (0.25 M), H₂ 10 bar, 40°C, Lindlar catalyst 0.1 g (0.2 mol% Pd), 320 mg of quinoline (10 mol%). The concentrations were determined by GC/FID through internal calibration. Lines serve as guides to the eye.</figcaption></figure>

However, the main difference is that (Z)-hex-3-en-1-ol **1** was significantly less reactive in the presence of quinoline after the complete conversion of **2**. The apparent transformation rate of **1**, i.e., hydrogenation to **6** and isomerization to **4** and **5** (Figure 2), was only 0.4 mmol.g<sub>cat</sub><sup>-1</sup>.min<sup>-1</sup> compared to 1.2 mmol.g<sub>cat</sub><sup>-1</sup>.min<sup>-1</sup> without quinoline. Therefore, the selectivity towards **1** decreased more slowly as quinoline was added to the reaction mixture. In fact, 30 min after complete conversion, the selectivity towards **1** remained above 93% with quinoline (Figure 4), compared to 83% without it (Figure 3). The lack of quinoline's influence on selectivity is further illustrated by Figure 5, which displays the selectivity towards the (Z)-alkene **1** as a function of alkyne **2** conversion.
<figure><img src="image_5.png" /><figcaption>Figure 5. Evolution of the selectivity toward (Z)-hex-3-en-1-ol **1** as a function of the conversion of 3-hexyn-1-ol **2** in a batch reactor. Reaction conditions: **2** 0.25 M in toluene, H₂ 10 bar, 40°C, Pd 0.2 mol% Lindlar catalyst, no quinoline or 10 mol% of quinoline. The insert shows selectivity between 98% and 100% conversion. Data were extracted from Figure 3 and Figure 4. The selectivity toward **1** was calculated using the following equation: Selectivity **1** (%) = (|[**1**]ᵢ| / |[**2**]₀ - |[**2**]ᵢ|) × 100. Lines serve as guides to the eye.</figcaption></figure>

In both experiments, until 98.5% of conversion, the selectivity for (Z)-hex-3-en-1-ol **1** remains constant, i.e., at a mean value of 98.8% (Figure 5). From this point onwards, a rapid decrease in the selectivity can be observed without quinoline (Figure 5, insert), although the selectivity remains high with quinoline until 99.9% conversion. This highlights the advantage of using a classic modifier such as quinoline for the semi-reduction of 3-hexyn-1-ol **1** in a batch process. Quinoline minimally impacts the chemical rate and selectivity of the alkyne **2** reduction. Quinoline, on the other hand, effectively reduces the rate of both isomerization and hydrogenation of (Z)-alkene **1** into by-products, including (E)-alkene **4**, isomers **5** and perhydrogenated compounds **6** (Figure 2).[19] Therefore, precise control of the reaction and, by extension, residence time is crucial to prevent isomerization and hydrogenation in the absence of a homogeneous modifier, like quinoline. The high sensitivity of selectivity to reaction conditions may account for the deceiving results and significant variability observed when using the Lindlar catalyst without quinoline.[13a, 20] In batch reactors, achieving this control is challenging due to the difficulty of monitoring concentrations in real-time (ex-situ analysis) and the process's inertia (quenching and cooling times).
Reduction in flow

Flow chemistry is of considerable current interest, as it offers numerous advantages over conventional batch processes, including enhanced safety, superior mass and heat transfer, and unprecedented control over critical reaction conditions, such as reaction time. However, in the presence of a catalyst, defining reaction time becomes less straightforward, even in batch reactors. To compare flow experiments performed at different liquid flow rates, the concept of contact time was used. The contact time is defined as the mass of the catalytic bed divided by the feed rate of 3-hexyn-1-ol 2, as stated in Eq. 1. Weight hourly space velocity (WHSV) and Contact time are inversely related.

$$ \text{Contact time (min)} = \frac{\text{Mass of catalyst (g)}}{\underline{2 \text{ feed rate (g·min}^{-1})}} = \frac{1}{\text{WHSV}} \qquad \text{Eq. 1} $$

It should be noted that the contact time, as defined in Eq. 1, does not account for other factors that can significantly affect reactor performance, such as reactor size, catalyst type, and liquid and gas flow. However, contact time may still be useful for comparing different reaction conditions.

One advantage of continuous flow reactors is their remarkable control over contact time. This precise control of contact time can be applied for the semi-hydrogenation of 3-hexyn-1-ol 2, eliminating the need for quinoline. This led us to further investigate the selective semi-hydrogenation of alkynols in flow using Lindlar catalysts. Such reactions have already been described, but deceptive selectivities towards 1 (<40%) were obtained at high conversions (Table 1, entry 1)[16a] or for another alkynol at low conversion (Table 1, entry 2).[21] More recently, interesting selectivities were achieved in flow for alkynols (Table 1, entries 3 and 4) using catalytic static mixers coated with commercial Lindlar catalysts, albeit under harsh conditions.[16b] These results prompted us to reevaluate the Lindlar catalyst.
<table><caption>Table 1. Semi-hydrogenation of alkynols in flow using Lindlar catalyst</caption><thead><tr><th>Entry</th><th>Reaction studied and conditions</th><th>Conv. (%)<sup>a)</sup></th><th>Select. (%)<sup>a)</sup></th><th>Ref.</th></tr></thead><tbody><tr><td>1</td><td><img src="image_0_0.png" alt="Chemical structure of 2-ethylhexylphenol"></td><td>99.2</td><td>40</td><td>[16a]</td></tr><tr><td>2</td><td><img src="image_0_1.png" alt="Chemical structure of 2-ethylhexylphenol"></td><td>&lt; 35%</td><td>85</td><td>[21]</td></tr><tr><td>3</td><td><img src="image_0_2.png" alt="Chemical structure of 2-ethylhexylphenol"></td><td>97</td><td>73</td><td>[16b]</td></tr><tr><td>4</td><td><img src="image_0_3.png" alt="Chemical structure of 2-ethylhexylphenol"></td><td>100</td><td>87</td><td>[16b]</td></tr></tbody></table>

<sup>a)</sup> Highest selectivity at the highest conversion mentioned in the references

Commercial Lindlar catalyst appears as a micro powder (particle size < 10 µm), and prohibitive pressure drops are expected when using such powder. Our group has developed catalyst immobilization on metallic open-cell foams (OCF) over several years to operate Pd-supported catalysts in continuous flow mode with a low-pressure drop (Pd/Al₂O₃[22] or Pd/C[23]). However, the coating procedure must be adapted for each support[24], and a coating procedure for CaCO₃ has not yet been settled.

We therefore decided to shape the Lindlar catalyst by pelletization using CaCO₃ as a support and binder.[25] Pelletization allows for a higher catalyst content per reactor volume, which is a significant advantage when the reaction is relatively slow and occurs in a chemical regime.

After various trials, cylindrical tablets (10 x 2 mm) were produced from a commercial catalyst (Strem, 5 wt% Pd) under a pressure of 15 tons, following a five-fold dilution with CaCO₃ (on a mass basis). The press used was a hydraulic lab press commonly found in laboratories for making KBr pellets for IR analysis of solid samples. The resulting pellets were then crushed and sieved to 180-250 µm (Figure S2). Considering the dilution, a Pd loading of 1 wt% could thus be estimated for the pelletized catalyst. Compared to traditional Pd-supported catalysts, commercial Pd-supported CaCO₃ catalysts are characterized by a very low surface area (5-10 m²/g). Based on the pristine Lindlar catalyst, we hypothesized that the pelletization did not change this trend.

The sieved pelletized Lindlar catalysts (155 mg) were housed in a 1/8" PFA tubing (6 cm long, 1.55 mm internal diameter). The catalyst bed was packed between two layers of glass wool. Catalytic experiments were performed by connecting the filled PFA tubing to PEEK tees and adapters from IDEX (see experimental section).
The packed bed reactor was then evaluated for the semi-reduction of **2** under continuous flow conditions. First, the hydrogenation of **2** in flow was performed under the same conditions as the batch (40°C, 0.25 M in toluene) but using 1 bar H₂.[16a] The liquid flow rate was adjusted from 0.05 to 0.5 mL.min⁻¹ with a large excess of hydrogen (H₂ flow rate 200 NmL.min⁻¹). Under these conditions, the pressure drop generated by the reactor was less than 0.1 bar in all cases. Reproducible selectivity and conversion results were obtained.

The composition and selectivity changes with varying contact time are shown in Figure 6 and Figure 7, respectively. The conversion of **2** increased with increasing contact time, and total conversion was obtained for a contact time higher than 0.22 min using 1 bar of H₂ at 40°C (Figure 6). As expected from the batch results, an increase in contact time increased the concentration of by-products. (E)-3-hexen-1-ol **4** was the main by-product until total conversion was achieved. Then, the concentrations of other by-products (**4**, fully saturated product **6**, and others unsaturated isomers **5**) rises steeply with increasing contact time.

<figure><img src="image_6.png" /></figure>

Figure 6. Composition of the solution at the reactor outlet as a function of contact time for the semi-hydrogenation of **2** in flow. Reaction conditions: **2** 0.25 M in toluene; 40 °C, H₂ 1 bar; 155 mg of pelletized Lindlar catalyst 1 wt% Pd; Liquid flow rate 0.05 – 0.5 mL.min⁻¹, H₂ flow range 200 NmL.min⁻¹. The concentrations were determined by GC/FID using internal calibration. Lines serve as guides to the eye.
A comparison of the evolution of batch and flow selectivity for **1** as a function of the conversion of **2** is shown in Figure 7. As expected from the batch reactor, without quinoline, a selectivity for **1** higher than 97% was observed in flow at a conversion of 35% (i.e., contact time 0.31 min). However, unlike with the batch reactor, a steady selectivity was not observed as the conversion increased (Figure 7). Despite this decrease in selectivity at higher conversion, a selectivity for **1** of up to 93% was obtained for a conversion of 90%. However, the selectivity for **1** dropped to 83% for a conversion of 99% (contact time 1.1 min).

<figure><img src="image_7.png" /><figcaption>Figure 7. Evolution of the selectivity toward (Z)-hex-3-en-1-ol **1** as a function of 3-hexyn-1-ol **2** conversion in flow. Data were obtained from Figure 3 (batch reactor) and Figure 6 (flow reactor). The selectivity toward **1** was calculated using the equation:</figcaption></figure>

$$ \text{Selectivity } \mathbf{1} \text{ (\%)} = \left( \frac{\left[ \frac{\mathbf{1}}{\mathbf{t}} \right]}{\left[ \mathbf{2} \right]_0 - \left[ \mathbf{2} \right]_t} \right) \times 100. \text{ Lines serve as guides to the eye.} $$

Although the performance of product selectivity in flow stands behind that of batch reactor (i.e., 83% vs. 97% at 99% conversion of **2** respectively), the selectivity obtained with pelletized commercially available Lindlar catalyst (Table 2, entry 1) is comparable to the best-reported catalysts for this reaction in flow (Table 2). These included packed-bed systems with commercial catalysts (Table 2, entries 2-4), immobilized Pd nanoparticles catalysts (Table 2, entry 5), monolith systems (Table 2, entries 6-9), as well as wall-coated reactors (Table 2, entry 10). The data were obtained using a typical plug flow reactor
with non-optimized contact time distribution and mass transfer limitations.[26] To further enhance these results, significant work on reactor optimization is necessary. Foam or wall coating of the catalyst would greatly improve mass transfer, as was already demonstrated by Kreutzer et al. with Pd/γ-Al₂O₃,[27] but this improvement could come at the expense of reactor productivity.

<table><caption>Table 2. Selectivity for (Z)-hex-3-en-1-ol **1** obtained under continuous flow semi-hydrogenation of 3-hexyn-1-ol **2**.</caption><thead><tr><th>Entry</th><th>Catalyst</th><th>Experimental conditions</th><th>Conv. (%) <sup>a)</sup></th><th>Select. (%) <sup>a)</sup></th><th>Ref.</th></tr></thead><tbody><tr><td>1</td><td>Pd Lindlar pelletized</td><td>0.25 M toluene, 40°C, 1 bar H<sub>2</sub></td><td>99</td><td>83</td><td>This work</td></tr><tr><td>2</td><td>Pd Lindlar</td><td>0.1 M MeOH, r.t., 1.2 bar H<sub>2</sub></td><td>99</td><td>40</td><td>[16a]</td></tr><tr><td rowspan="2">4</td><td>Pd/C</td><td>0.2 M MeOH, r.t., 2.4 bar H<sub>2</sub></td><td>94</td><td>17</td><td rowspan="2">[28]</td></tr><tr><td>Pd/C</td><td>0.1 M MeOH, r.t., 1.2 bar H<sub>2</sub></td><td>20</td><td>70</td></tr><tr><td>3</td><td>Pd/SiO<sub>2</sub></td><td>0.1 M MeOH, r.t., 1.15 bar H<sub>2</sub></td><td>85</td><td>38</td><td>[12]</td></tr><tr><td>5</td><td>Pd/titanate nanotubes</td><td>0.2 M MeOH, r.t., 2.4 bar H<sub>2</sub></td><td>88</td><td>88</td><td>[28]</td></tr><tr><td>6</td><td>Pd/silica monolith</td><td>0.2 M MeOH, r.t., 2.8 bar H<sub>2</sub></td><td>85</td><td>80</td><td>[29]</td></tr><tr><td>7</td><td>Pd/borate monolith</td><td>0.1 M MeOH, r.t., 1.2 bar H<sub>2</sub></td><td>99</td><td>87</td><td>[16a]</td></tr><tr><td>8</td><td>Pd/sulfonated silica monolith</td><td>0.1 M MeOH, r.t., 1.15 bar H<sub>2</sub></td><td>94</td><td>85</td><td>[12]</td></tr><tr><td>9</td><td>Pd/grafted porous silica monolith</td><td>0.2 M MeOH, 40°C, 1.2 bar H<sub>2</sub></td><td>80</td><td>70</td><td>[30]</td></tr><tr><td>10</td><td>Pd/ZrO<sub>2</sub>/PVA wall reactors</td><td>0.03 M MeOH, r.t., 2 bar H<sub>2</sub></td><td>70</td><td>65</td><td>[31]</td></tr></tbody></table>

To achieve higher selectivity in flow, additional experiments were conducted to optimize the performance of the catalytic system (Table 3). The temperature (Table 3, entries 1 to 3) was shown to influence the different reaction rates to a similar extent and, within the studied range, has a limited effect on selectivity. The concentration of 3-hexyn-1-ol **2** (Table 3, entries 3 to 6) has a minor impact on selectivity towards **1**. Concentration has a significant impact on the time required to achieve total conversion. For a concentration of 2 mol.L⁻¹, a conversion of 80% was obtained for a contact time of up to 12 min (Table 3, entry 6) using the same experimental setup, whereas only 1 min was necessary to

<footnote><sup>a)</sup> Highest selectivity at the highest conversion mentioned in the references</footnote>
achieve total conversion for a concentration of 0.25 M (Figure 6). An increase in hydrogen pressure (Table 3, entries 7-9) enhanced the hydrogenation rate of alkyne **2** while significantly reducing the selectivity toward **1**. Different solvents were also studied (Table 3, entries 10-14). For the selective semi-hydrogenation of **2**, protic solvents (Table 3, entries 13-14) provide lower selectivity (see Supporting Information, Figures S3 to S20 for details and comparison).

<table><caption>Table 3. Optimization of the experimental conditions for the semi-hydrogenation of **2** in flow.</caption><thead><tr><th>Entry</th><th>Solvent</th><th>Conc. (mol.L<sup>-1</sup>)</th><th>H<sub>2</sub> (bar)</th><th>Temp. (°C)</th><th>Conv. (%)</th><th>Selec. (%)<sup>[a]</sup></th></tr></thead><tbody><tr><td>1</td><td>Toluene</td><td>0.25</td><td>1</td><td><strong>40</strong></td><td>99<sup>[b]</sup></td><td>83<sup>[b]</sup></td></tr><tr><td>2</td><td>Toluene</td><td>0.25</td><td>1</td><td><strong>60</strong></td><td>98</td><td>88</td></tr><tr><td>3</td><td><strong>Toluene</strong></td><td><strong>0.25</strong></td><td>1</td><td><strong>30</strong></td><td>98</td><td>84</td></tr><tr><td>4</td><td>Toluene</td><td><strong>0.5</strong></td><td>1</td><td>25</td><td>97</td><td>89</td></tr><tr><td>5</td><td>Toluene</td><td><strong>1</strong></td><td>1</td><td>25</td><td>93</td><td>88</td></tr><tr><td>6</td><td>Toluene</td><td><strong>2</strong></td><td>1</td><td>25</td><td>99<sup>[d]</sup></td><td>78<sup>[d]</sup></td></tr><tr><td>7</td><td>Toluene</td><td>0.25</td><td><strong>2</strong></td><td>25</td><td>78</td><td>71</td></tr><tr><td>8</td><td>Toluene</td><td>0.25</td><td><strong>4</strong></td><td>25</td><td>76</td><td>68</td></tr><tr><td>9</td><td>Toluene</td><td>0.25</td><td><strong>8</strong></td><td>25</td><td>74</td><td>62</td></tr><tr><td>10</td><td><strong>Acetonitrile</strong></td><td>0.25</td><td>1</td><td>25</td><td>98</td><td>85</td></tr><tr><td>11</td><td><strong>Ethylacetate</strong></td><td>0.25</td><td>1</td><td>25</td><td>94</td><td>85</td></tr><tr><td>12</td><td><strong>Heptane</strong></td><td>0.25</td><td>1</td><td>25</td><td>99</td><td>88</td></tr><tr><td>13</td><td><strong>Ethanol</strong></td><td>0.25</td><td>1</td><td>25</td><td>94</td><td>82</td></tr><tr><td>14</td><td><strong>Isopropanol</strong></td><td>0.25</td><td>1</td><td>25</td><td>87</td><td>76</td></tr></tbody></table>

Next, we tried to enhance the selectivity by modifying the hydrodynamic conditions of the experiments. The decline in selectivity against batch (Figure 7) represents one of the well-known limitations of a non-ideal mini plug flow reactor operating at low flow rates. The reduction in selectivity under external mass transfer limitations has already been documented for the semi-hydrogenation of 2-methyl-3-butyn-2-ol.[26] Mass transfer limitations also contributed to explaining the decrease in selectivity at constant conversion during the semi-hydrogenation of 2-butyne-1,4-diol in a monolithic reactor.[32] Both non-ideal plug flow deviation and mass transfer limitations were invoked to account for the lower selectivity and apparent reaction rate observed in a milli-packed-bed reactor compared to a wall-coated tube reactor during the semi-hydrogenation of 2-methyl-3-butyn-2-ol.[33]

<footnote>[a] Maximum selectivity for **1** observed for maximum conversion of **2**. The composition of the solution at the reactor outlet as the function of contact time for each experiment could be found in the supplementary material. [b] Initial condition, see Figure 6 and Figure 7. [d] Contact time up to 12 min.</footnote>
These limitations can be partially offset by increasing the liquid flow rate, specifically the superficial liquid velocity, under the same experimental conditions (toluene, 0.25 M, 1 bar H₂, 40°C). The liquid flow rate was raised to 0.8 and 1.0 mL.min⁻¹ while the previously studied flow rates ranged from 0.05 to 0.4 mL.min⁻¹ (Figure 6). As a result, at a liquid flow rate of 0.8 mL.min⁻¹, the conversion drops to 40%, but, as expected due to the low residence time, the selectivity for **1** remains unchanged (Table 4, entry 2). Higher selectivity could be achieved by increasing the liquid flow rate to 1.0 mL.min⁻¹ (Table 4, entry 6). The resulting reaction mixture can be reinjected into the same continuous reactor to increase the conversion (Figure 8). Consequently, conversion gradually increases as a function of the number of reinjections, with only a limited drop in selectivity (Table 4). This is illustrated in Figure 9, which shows the yield of (Z)-3-hexen-1-ol **1** as a function of the conversion of 3-hexyn-1-ol **2**.

<figure><img src="image_8.png" /><figcaption>Figure 8. Comparison of the experimental setup for the semi-hydrogenation of 2 in flow. a) one pass process with low liquid flow, which ensures high conversion but relatively low selectivity; b) a recirculation process using the same catalytic bed with a high liquid flow rate, that, after several passes, achieves high conversion while maintaining high selectivity. Reaction conditions: **2** 0.25 M in toluene; 40 °C, H₂ 1 bar; 155 mg of pelletized Lindlar catalyst 1 wt% Pd.</figcaption></figure>
<table><caption>Table 4. Conversion of 3 and selectivity for 1 as the function of contact time. Reaction conditions: 2 0.25 M in toluene; 40 °C, H₂ 1 bar; 155 mg of pelletized Lindlar catalyst 1 wt% Pd; Liquid flow rate 0.2 to 1 mL.min⁻¹, H₂ flow range 200 NmL.min⁻¹ (H₂ in large excess). The concentrations were determined by GC/FID using internal calibration.</caption><thead><tr><th>Entry</th><th>Recirculation</th><th>Liquid flow (mL.min<sup>-1</sup>)</th><th>Contact time (min)</th><th>Cumulative contact time (min)<sup>a)</sup></th><th>Conv. (%)</th><th>Selec. (%)</th></tr></thead><tbody><tr><td>1</td><td>—</td><td>0.2</td><td>0.55</td><td>—</td><td>90</td><td>83</td></tr><tr><td>2</td><td>—</td><td>0.8</td><td>0.14</td><td>—</td><td>40</td><td>92</td></tr><tr><td>3</td><td>1<sup>st</sup> 🌶️</td><td>0.8</td><td>0.14</td><td>0.28</td><td>82</td><td>91</td></tr><tr><td>4</td><td>2<sup>nd</sup> 🌶️</td><td>0.8</td><td>0.14</td><td>0.42</td><td>97</td><td>91</td></tr><tr><td>5</td><td>3<sup>rd</sup> 🌶️</td><td>0.8</td><td>0.14</td><td>0.56</td><td>99</td><td>89</td></tr><tr><td>6</td><td>—</td><td>1.0</td><td>0.11</td><td>—</td><td>32</td><td>95</td></tr><tr><td>7</td><td>1<sup>st</sup> 🌶️</td><td>1.0</td><td>0.11</td><td>0.22</td><td>59</td><td>94</td></tr><tr><td>8</td><td>2<sup>nd</sup> 🌶️</td><td>1.0</td><td>0.11</td><td>0.33</td><td>94</td><td>93</td></tr><tr><td>9</td><td>3<sup>rd</sup> 🌶️</td><td>1.0</td><td>0.11</td><td>0.44</td><td>99</td><td>93</td></tr></tbody></table>

<figure><img src="image_9.png" /><figcaption>Figure 9. Comparison of (Z)-hex-3-en-1-ol 1 yield as a function of 3-hexyn-1-ol 2 conversion in batch, flow, and recirculating flow experiments. Reaction conditions: 2 0.25 M in toluene; 40 °C, H₂ 1 bar. Batch reactor: 100mg of Lindlar catalyst (Pd 0.2 mol%) see Figure 3 for data; Flow: 155 mg of pelletized Lindlar catalyst; Liquid flow rate 0.05 – 0.4 mL.min⁻¹, H₂ flow range 200 NmL.min⁻¹; Recirculating flow reactor. 155 mg of pelletized Lindlar catalyst; Liquid flow rate 0.8 or 1.0 mL.min⁻¹, H₂ flow range 200 NmL.min⁻¹; see Figure 8 for setup and Supplementary Materials for data. Lines serve as a guide for the eye.</figcaption></figure>

<footnote>a) The liquid phase at the reactor outlet was analyzed and reinjected into the continuous reactor under the same experimental conditions.</footnote>
High selectivity at high conversion (93% selectivity for 99% conversion) can be achieved in four passes with a flow rate of 1.0 mL.min⁻¹ (Table 4, entries 6 to 9). The effect of liquid flow rate on the selectivity of this transformation was demonstrated, and the results obtained after the 4th pass are comparable to the results obtained in batch (Figure 9). These results suggest that it is feasible to selectively reduce 3-hexyn-1-ol **2** into (Z)-3-hexen-1-ol **1** in a continuous reactor using the pelletized commercial Lindlar catalyst, achieving similar performances to the batch reactor with a simple fixed bed flow reactor and a suitable liquid flow rate.

Conclusion

This paper studied the evolution of selectivity in the semi-hydrogenation of 3-hexyn-1-ol **2** into (Z)-3-hexen-1-ol **1**, an important flavor and fragrance compound, with regards to conversion using a commercial Lindlar catalyst. It was demonstrated that the large excess of quinoline, typically used in this process, only slows the formation rate of the primary by-product, i.e., (E)-3-hexen-1-ol **4**. In a batch reactor, quinoline is necessary to maintain high selectivity at high conversion because precisely determining the endpoint is not trivial. Under flow conditions, pinpointing precise endpoints is easier. Therefore, it was stated that high selectivity should be achievable in the absence of quinoline using a continuous flow microreactor. We have demonstrated that the commercial Lindlar catalyst can be pelletized with CaCO₃ as a support and binder, and the resulting sieved particles can be used in a flow process.

Nevertheless, the selectivity observed in flow using pelletized commercial Lindlar catalyst was lower than in batch processes due to mass transfer and broad contact time distribution issues. In order to tackle these challenges, experiments conducted in recirculating flow mode and with a shorter contact time clearly demonstrate an increase in selectivity at high conversion, matching the best results achieved in batch. The operation of pelletized commercial Lindlar catalyst in continuous flow reactors remains impressive for the complex selective semi-hydrogenation reaction of 3-hexyn-1-ol **2**. These results encourage us to develop new reactor designs with a thin coating and improved contact time distribution.
# Materials and methods

## General

All substrates, solvents, and reactants were purchased from Sigma-Aldrich and used as received. The Lindlar catalyst was acquired from Strem (Ref. 46-2020, Pd 5 wt%, surface area 5-10 m²/g, pore volume 0.38 cc/g). Hydrogen (99.999%) was provided by Air Liquide.

The analyses were performed using a Shimadzu GC2030 equipped with an Agilent DB-heavy wax column (20m*0.1mm*0.1µm) and FID detector. Side products were characterized using the same method with a Shimadzu GC-MS QP2010SE. The products were unequivocally identified by comparing the GC retention times and mass spectra of authentic specimens. The concentrations were determined by GC/FID using internal calibration with hexadecane (I.S.).

## Reduction in batch

Batch experiments were performed using a Top industry 200 mL pressure vessel equipped with a Rushton turbine (1200 rpm) under constant hydrogen pressure. Typically, 100 mL of liquid (0.25 M) was introduced in the presence of 0.1 g of Lindlar catalyst (0.2 mol%). Regularly, 100 µL samples were taken for analysis.

## Pelletizing

1 g of Lindlar catalyst was added to 4 g of calcium carbonate. The resulting powder is thoroughly mixed in an agate mortar. A portion of the powder is then compressed into cylinder tablets (10 x 2 mm) under 15 tons of pressure (2 min). The resulting pellets were then crushed and sieved to 180-250 µm.

## Reduction in flow

The PFA tubing, PEEK Tess, and PEEK adapters are sourced from IDEX Health & Science. The reactor is composed of 1/8" PFA tubing (6 cm long) with a 1.55 mm internal diameter. It holds 155 mg of catalyst powder for a reactive volume of 0.11 mL (Figure 10).
<figure><img src="image_10.png" /><figcaption>Figure 10. Reactor setup. The liquid and gas phases (H2) mix in a PEEK Tee at the reactor inlet. A K-type thermocouple monitored the reaction mixture's temperature at the reactor outlet. The insert shows a close-up of the catalytic bed inside the PFA tubing.</figcaption></figure>

A Shimadzu LC20AD was used for pumping the liquid phase, while a Bronkhorst El-flow was used to deliver hydrogen gas. The H₂ flow rate was kept constant at 200 NmL.min⁻¹, ensuring that hydrogen was always in large excess. Outlet pressure was controlled using an Equilibar pressure regulator. The liquid flow rate ranged from 0.05 to 0.5 mL.min⁻¹. The equilibration time before sampling was set at a liquid delivery of 5 reactor volumes (~ 0.5 mL).

## Acknowledgments

This work was supported by the France Relance program of the Agence Nationale de la Recherche (ANR-21-PRRD-0064), which is gratefully acknowledged. M2i Life Sciences is also greatly appreciated for its funding of D.H.'s grant.

## Conflict of Interests

The authors declare no conflict of interest.

## Data Availability Statement

The data supporting the findings of this study are available in the Supporting Information of this article.

[1] L. P. Somogyi, *Chem. Ind. 1996*, *4 March*, 170-173.

[2] M. Stoll, A. Rouvé, *Helv. Chim. Acta* **1938**, *21*, 1542-1547.

[3] W. Ou, H. Liu, R. Wang, *Curr. Org. Chem. 2022*, *27*, 1512-1529.

[4] T. Kobayashi, H. Tsuruta, *Synthesis* **1980**, *1980*, 492-493.

[5] a) H. Bönnemann, W. Brijoux, A. S. Tilling, K. Siepen, *Top. Catal. 1997*, *4*, 217-227; b) M. Endou, Patent WO 2014156781 **2014**, Process for producing cis-3-hexen-1-ol, (2014-10-02).

[6] H. Lindlar, *Helv. Chim. Acta* **1952**, *35*, 446-450.

[7] a) Z. Wang, in *Comprehensive Organic Name Reactions and Reagents*, John Wiley & Sons, Inc., **2010**, pp. 1758-1762; b) C. Oger, L. Balas, T. Durand, J. M. Galano, *Chem. Rev. 2013*, **113**, 1313-1338.
1350; c) M. Crespo-Quesada, F. Cárdenas-Lizana, A.-L. Dessimoz, L. Kiwi-Minsker, ACS Catal. **2012**, *2*, 1773-1786.

[8] S. Asano, S. J. Adams, Y. Tsuji, K. Yoshizawa, A. Tahara, J.-i. Hayashi, N. Cherkasov, *React. Chem. Eng.* **2022**, *7*, 1818-1826.

[9] a) M. García-Mota, J. Gómez-Díaz, G. Novell-Leruth, C. Vargas-Fuentes, L. Bellarosa, B. Bridier, J. Pérez-Ramírez, N. López, *Theor. Chem. Acc.* **2010**, *128*, 663-673; b) G. A. Attard, J. A. Bennett, I. Mikheenko, P. Jenkins, S. Guan, L. E. Macaskie, J. Wood, A. J. Wain, *Faraday Discuss.* **2013**, *162*, 57-75.

[10] a) J. G. Ulan, E. Kuo, W. F. Maier, R. S. Rai, G. Thomas, *J. Org. Chem.* **1987**, *52*, 3126-3132; b) N. Cherkasov, D. Y. Murzin, C. R. A. Catlow, A. Chutia, *Catal. Sci. Technol.* **2021**, *11*, 6205-6216; c) Z. Wang, Q. Luo, S. Mao, C. Wang, J. Xiong, Z. Chen, Y. Wang, *Nano Res.* **2022**, *15*, 10044-10062.

[11] a) P. McNeice, M.-A. Müller, J. Medlock, W. Bonrath, N. Rockstroh, S. Bartling, H. Lund, K. Junge, M. Beller, *ACS Sustainable Chem. Eng.* **2022**, *10*, 9787-9797; b) P. McNeice, M.-A. Müller, J. Medlock, W. Bonrath, N. Rockstroh, S. Bartling, H. Lund, K. Junge, M. Beller, *Green Chem.* **2022**, *24*, 6912-6922; c) J. Ballesteros-Soberanas, J. C. Hernández-Garrido, J. P. Cerón-Carrasco, A. Leyva-Pérez, *J. Catal.* **2022**, *408*, 43-55.

[12] F. Liguori, P. Barbaro, B. Said, A. Galarneau, V. D. Santo, E. Passaglia, A. Feis, *ChemCatChem* **2017**, *9*, 3245-3258.

[13] a) T. Montsch, M. Heuchel, Y. Traa, E. Klemm, C. Stubenrauch, *Appl. Catal., A* **2017**, *539*, 19-28; b) W. Oberhauser, M. Frediani, I. Mohammadi Dehcheshmeh, C. Evangelisti, L. Poggini, L. Capozzoli, P. Najafi Moghadam, *ChemCatChem* **2022**, *14*, e202101910; c) K. Liu, L. Jiang, W. Huang, G. Zhu, Y. J. Zhang, C. Xu, R. Qin, P. Liu, C. Hu, J. Wang, J. F. Li, F. Yang, G. Fu, N. Zheng, *Nat. Commun.* **2022**, *13*, 2597; d) B. J. Gregori, M.-O. W. S. Schmotz, A. Jacobi von Wangelin, *ChemCatChem* **2022**, *14*, e202200886; e) J. Audevard, J. Navarro-Ruiz, V. Bernardin, Y. Tison, A. Corrias, I. Del Rosal, A. Favre-Réguillon, R. Philippe, I. C. Gerber, P. Serp, *ChemCatChem* **2023**, *15*, e202300036.

[14] a) S. A. Jagtap, B. M. Bhanage, *Mol. Catal.* **2018**, *460*, 1-6; b) M. Fukui, Y. Omori, S.-y. Kitagawa, A. Tanaka, K. Hashimoto, H. Kominami, *J. Catal.* **2019**, *374*, 36-42; c) A. Fukazawa, J. Minoshima, K. Tanaka, Y. Hashimoto, Y. Kobori, Y. Sato, M. Atobe, *ACS Sustainable Chem. Eng.* **2019**, *7*, 11050-11055; d) J. Bu, S. Chang, J. Li, S. Yang, W. Ma, Z. Liu, S. An, Y. Wang, Z. Li, J. Zhang, *Nat. Commun.* **2023**, *14*, 1533.

[15] X. Chen, C. Shi, C. Liang, *Chinese J. Catal.* **2021**, *42*, 2105-2121.

[16] a) F. Liguori, P. Barbaro, *J. Catal.* **2014**, *311*, 212-220; b) M. Kundra, B. Bin Mohamad Sultan, D. Ng, Y. Wang, D. L. J. Alexander, X. Nguyen, Z. Xie, C. H. Hornung, *Chem. Eng. Process.* **2020**, *154*, 108018.

[17] a) T. Mitsudome, T. Urayama, K. Yamazaki, Y. Maehara, J. Yamasaki, K. Gohara, Z. Maeno, T. Mizugaki, K. Jitsukawa, K. Kaneda, *ACS Catal.* **2016**, *6*, 666-670; b) S. Paganelli, A. Angi, N. Pajer, O. Piccolo, *Catalysts* **2021**, *11*, 14.

[18] A. Steenhoek, B. H. van Wijngaarden, H. J. J. Pabon, *Recl. Trav. Chim. Pays-Bas* **1971**, *90*, 961-973.

[19] G. Vilé, D. Albani, N. Almora-Barrios, N. López, J. Pérez-Ramírez, *ChemCatChem* **2016**, *8*, 21-33.

[20] D. A. Lomeli-Rosales, J. A. Delgado, M. Diaz de Los Bernardos, S. Perez-Rodriguez, A. Gual, C. Claver, C. Godard, *Chem. Eur. J.* **2019**, *25*, 8321-8331.

[21] G. Vile, N. Almora-Barrios, S. Mitchell, N. Lopez, J. Perez-Ramirez, *Chem. Eur. J.* **2014**, *20*, 5926-5937.

[22] a) J.-N. Tourvieille, R. Philippe, C. de Bellefon, *Chem. Eng. J.* **2015**, *267*, 332-346; b) J. Lévêque, R. Philippe, M.-L. Zanota, V. Meille, F. Sarrazin, L. Baussaron, C. de Bellefon, *Chem. Eng. Res. Des.* **2016**, *109*, 686-697.

[23] a) L. Vanoye, B. Guicheret, C. Rivera-Cárcamo, R. Castro Contreras, C. de Bellefon, V. Meille, P. Serp, R. Philippe, A. Favre-Réguillon, *Chem. Eng. J.* **2022**, *441*, 135951; b) B. Guicheret, L. Vanoye, C. Rivera-Cárcamo, C. de Bellefon, P. Serp, R. Philippe, A. Favre-Reguillon, *ChemSusChem* **2022**, *15*, e202200916.
[24] V. Meille, *Appl. Catal., A* **2006**, *315*, 1-17.

[25] J. T. García-Sánchez, V. G. Baldovino-Medrano, *Ind. Eng. Chem. Res.* **2023**, *62*, 7769-7838.

[26] A. Bruehwiler, N. Semagina, M. Grasemann, A. Renken, L. Kiwi-Minsker, A. Saaler, H. Lehmann, W. Bonrath, F. Roessler, *Ind. Eng. Chem. Res.* **2008**, *47*, 6862-6869.

[27] J. J. W. Bakker, M. M. P. Zieverink, R. W. E. G. Reintjens, F. Kapteijn, J. A. Moulijn, M. T. Kreutzer, *ChemCatChem* **2011**, *3*, 1155-1157.

[28] N. Linares, C. Moreno-Marrodan, P. Barbaro, *ChemCatChem* **2016**, *8*, 1001-1011.

[29] A. Sachse, N. Linares, P. Barbaro, F. Fajula, A. Galarneau, *Dalton Trans.* **2013**, *42*, 1378-1384.

[30] C.-H. Pélisson, T. Nakanishi, Y. Zhu, K. Morisato, T. Kamei, A. Maeno, H. Kaji, S. Muroyama, M. Tafu, K. Kanamori, T. Shimada, K. Nakanishi, *ACS Appl. Mater. Interfaces* **2017**, *9*, 406-412.

[31] C. Moreno-Marrodan, F. Liguori, P. Barbaro, H. Sawa, *Appl. Catal., A* **2018**, *558*, 34-43.

[32] J. M. Winterbottom, H. Marwan, E. H. Stitt, R. Natividad, *Catal. Today* **2003**, *79-80*, 391-399.

[33] N. Cherkasov, P. Denissenko, S. Deshmukh, E. V. Rebrov, *Chem. Eng. J.* **2020**, *379*, 1222-1229.