Stereolithography 3D-Printed Catalytically Active Devices in Organic Synthesis

: This article describes the synthesis of stereolithography (SLA) 3D-printed catalyst-impregnated devices and their evaluation in the organocatalyzed Friedel–Crafts alkylation of N –Me–indole with trans - β -nitrostyrene. Using a low-cost SLA 3D printer and freeware design software, di ﬀ erent devices were designed and 3D-printed using a photopolymerizable resin containing a thiourea-based organocatalyst. The architectural control o ﬀ ered by the 3D-printing process allows a straightforward production of devices endowed with di ﬀ erent shapes and surface areas, with high reproducibility. The 3D-printed organocatalytic materials promoted the formation of the desired product up to a 79% yield, although with longer reaction times compared to reactions under homogeneous alkylation of N –Me–indole with trans - β -nitrostyrene. trans β -nitrostyrene promoted by embedded thiourea UV-polymerized resin.


Introduction
Three-dimensional (3D) printing, also known as additive manufacturing, refers to the process of producing 3D solid objects through the successive layering deposition of material. In the last few years, 3D printing has drawn attention in various fields due to its ability to create prototypical parts according to virtual concepts, and this technology has had very fast development in many scientific applications, such as in dentistry and odontology fields [1,2], medical implants [3], the aerospace and aircraft industries [4,5], jewelry making [6], clothes-manufacturing [7], food processing [8], and architecture [9].
Chemistry has also been drawn to 3D printing [10]; the technique represents an enabling tool in pharmaceutical and biological applications [11,12], as well as in organic synthesis [13], where sensors [14] and fluidic devices [15][16][17][18][19] were created. Three-dimensional printing applications range from the educational field, with the fabrication of molecular models [20] and cheap lab equipment [21], to the Active Pharmaceutical Ingredient (API) industry, where APIs such as Spritam are manufactured with a 3D-printing system [22].
Advantages of 3D-printing technology are related to its accessibility due to a thriving open-source community, to high customization freedom and cost-effectiveness (3D-printed objects cost less than those sold by supply companies), and to its sustainability in terms of employed materials and amount of generated waste.
Continuing our developments in the application of 3D-printing technology in organic synthesis [13,19], we investigated the design and the creation of stereolithography (SLA) 3D-printed catalytically active devices to be used as catalysts in synthetic transformations. SLA technology is the first patented 3D-printing technology [23], and the process works by focusing an ultraviolet (UV) light onto a vat of photopolymer resin. UV light is used to draw a preprogrammed design onto the surface of the photopolymer. Because photopolymers are photosensitive under ultraviolet light, the resin is solidified and forms a single layer of the desired 3D object. This process is repeated for each layer upon completion of the desired object.
The possibility to create a 3D-printed device containing an embedded organocatalyst is very attractive, since the catalyst could be immobilized on solid support without the need for any chemical modification of the catalyst itself. The supported catalytic species could easily be removed upon a completed reaction and, possibly, be reused in further reactions. Advantages of this approach are similar to those of immobilized species, such as easily completed isolation and purification procedure [24].
Only very few examples of this approach are known so far. Sotelo, Gil, and coworkers developed a 3D-printed woodpile structure composed of a 5 wt % catalytic copper species immobilized onto Al 2 O 3 support. Those devices showed good catalytic efficacy and good recyclability in different Ullmann reactions employed for the synthesis of imidazoles, benzimidazoles, and N-aryl amides [25]. In 2017, the same group reported that a 3D-printed woodpile that was made up of sintered Al 2 O 3 could act as a Lewis acid catalyst in the synthesis of biologically active 1,4-dihydropyridines and 3,4-dihydropyrimidin-2(1H)-ones under solventfree conditions with microwave irradiation [26]. In another example, Hilton filed a patent application disclosing the realization of 3D-printing impregnated plastics for chemical reactions [27]. Magnetic stirring-bar hosts were created by a stereolithographic technique; a p-toluenesulfonic acid catalyst was embedded in the photopolymer resin, and the "catalytic stirrer" was used to promote a Mannich reaction in good yields.
In order to further expand the classes of embedded catalysts in 3D-printed devices, we investigated the incorporation of different organocatalysts into photocurable resins, which were subjected to a 3D-printing stereolithographic process for the creation of functionalized devices.
For this, we selected thiourea (4) as the catalyst of choice for our preliminary investigations. This organocatalyst is robust, highly versatile, and, among other attributes, able to promote the Friedel-Crafts alkylation of N-Me-indole (1) with trans-β-nitrostyrene (2) to afford the 3-substituted indole derivative (3) in quantitative yields (Scheme 1) [28].
Catalysts 2019, 9, x FOR PEER REVIEW 2 of 9 light onto a vat of photopolymer resin. UV light is used to draw a preprogrammed design onto the surface of the photopolymer. Because photopolymers are photosensitive under ultraviolet light, the resin is solidified and forms a single layer of the desired 3D object. This process is repeated for each layer upon completion of the desired object. The possibility to create a 3D-printed device containing an embedded organocatalyst is very attractive, since the catalyst could be immobilized on solid support without the need for any chemical modification of the catalyst itself. The supported catalytic species could easily be removed upon a completed reaction and, possibly, be reused in further reactions. Advantages of this approach are similar to those of immobilized species, such as easily completed isolation and purification procedure [24].
Only very few examples of this approach are known so far. Sotelo, Gil, and coworkers developed a 3D-printed woodpile structure composed of a 5 wt % catalytic copper species immobilized onto Al2O3 support. Those devices showed good catalytic efficacy and good recyclability in different Ullmann reactions employed for the synthesis of imidazoles, benzimidazoles, and N-aryl amides [25]. In 2017, the same group reported that a 3D-printed woodpile that was made up of sintered Al2O3 could act as a Lewis acid catalyst in the synthesis of biologically active 1,4-dihydropyridines and 3,4dihydropyrimidin-2(1H)-ones under solventfree conditions with microwave irradiation [26]. In another example, Hilton filed a patent application disclosing the realization of 3D-printing impregnated plastics for chemical reactions [27]. Magnetic stirring-bar hosts were created by a stereolithographic technique; a p-toluenesulfonic acid catalyst was embedded in the photopolymer resin, and the "catalytic stirrer" was used to promote a Mannich reaction in good yields.
In order to further expand the classes of embedded catalysts in 3D-printed devices, we investigated the incorporation of different organocatalysts into photocurable resins, which were subjected to a 3D-printing stereolithographic process for the creation of functionalized devices.
For this, we selected thiourea (4) as the catalyst of choice for our preliminary investigations. This organocatalyst is robust, highly versatile, and, among other attributes, able to promote the Friedel-Crafts alkylation of N-Me-indole (1) with trans--nitrostyrene (2) to afford the 3-substituted indole derivative (3) in quantitative yields (Scheme 1) [28]. Some issues need to be addressed in the development of the embedded catalyst in 3D-printed devices: (i) resin compatibility towards used solvent and reactants; (ii) 3D printability of resin with modified composition; (iii) catalyst leaching phenomena during the chemical transformation; and (iv) identification of the optimal device shape to be 3D-printed.

Results and Discussion
Commercially available "clear" photopolymerizable resin, compatible with Formlabs Form 2 3D printer, was selected as the resin of choice. This methacrylate-based resin is commercially available at low cost and it has a good chemical resistance to solvents, as certified by the manufacturer [29]. Since no compatibility information has been reported with toluene, we replicated the swelling test of the manufacturer using this solvent (see Supporting Information (SI) for further details). Weight gain over 24 h for a printed and postcured (see SI) 1 × 1 × 1 cm cube immersed in toluene was less than 1%, and, after 3 months, no appreciable deformations were observed. This solvent was chosen as the preferred reaction medium for the addition of indoles to trans-β-nitrostyrene. Additional tests were Scheme 1. Organocatalyzed Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene.
Some issues need to be addressed in the development of the embedded catalyst in 3D-printed devices: (i) resin compatibility towards used solvent and reactants; (ii) 3D printability of resin with modified composition; (iii) catalyst leaching phenomena during the chemical transformation; and (iv) identification of the optimal device shape to be 3D-printed.

Results and Discussion
Commercially available "clear" photopolymerizable resin, compatible with Formlabs Form 2 3D printer, was selected as the resin of choice. This methacrylate-based resin is commercially available at low cost and it has a good chemical resistance to solvents, as certified by the manufacturer [29]. Since no compatibility information has been reported with toluene, we replicated the swelling test of the manufacturer using this solvent (see Supporting Information (SI) for further details). Weight gain over 24 h for a printed and postcured (see SI) 1 × 1 × 1 cm cube immersed in toluene was less than 1%, and, after 3 months, no appreciable deformations were observed. This solvent was chosen as the preferred reaction medium for the addition of indoles to trans-β-nitrostyrene. Additional tests were performed using a 0.15 M toluene solution of N-Me-indole, a 0.1 M toluene solution of trans-β-nitrostyrene, and a 0.1 M toluene solution of compound 3; in each case, no deformation was observed after one week. Having established the compatibility of "clear" resin with these mixtures, we focused our attention on the capability of resins loaded with a different weight % amount of thiourea 4 to undergo the photopolymerization process. Mixtures obtained by combination of clear resin and with the desired amount of catalyst 4 were subjected to ultrasound irradiation for 30 min, followed by orbital shake mixing (30 min, 400 rpm) in order to guarantee the homogeneity of the viscous mixture. Subsequently, a thin layer of resin was subjected to polymerization by irradiation with a UV lamp (365 nm) for 2 h. Results are reported in Table 1. According to this survey, in each of the cases studied, the polymerization process occurred positively. This thin solid cross-linked resin layer was then washed with isopropanol, sonicated for 15 min, air dried, and finally chipped into small flakes. These thiourea-embedded slivers were then used to catalyse the addition of N-Me-indole to trans-β-nitrostyrene. In a typical experiment, 1 mol/equiv of trans-β-nitrostyrene was reacted with 1.5 mol/equiv of N-Me-indole in a 0.1 M toluene solution and stirred by an orbital shaker (400 rpm) for 24 h at room temperature. Yields were determined by 1 H NMR using 1,3,5-trimethoxybenzene as internal standard and are reported in Table 2 [30]. Table 2. Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene promoted by embedded thiourea UV-polymerized resin. in each case, no deformation was observed after one week. Having established the compatibility of "clear" resin with these mixtures, we focused our attention on the capability of resins loaded with a different weight % amount of thiourea 4 to undergo the photopolymerization process. Mixtures obtained by combination of clear resin and with the desired amount of catalyst 4 were subjected to ultrasound irradiation for 30 min, followed by orbital shake mixing (30 min, 400 rpm) in order to guarantee the homogeneity of the viscous mixture. Subsequently, a thin layer of resin was subjected to polymerization by irradiation with a UV lamp (365 nm) for 2 h. Results are reported in Table 1. 389 Yes According to this survey, in each of the cases studied, the polymerization process occurred positively. This thin solid cross-linked resin layer was then washed with isopropanol, sonicated for 15 min, air dried, and finally chipped into small flakes. These thiourea-embedded slivers were then used to catalyse the addition of N-Me-indole to trans--nitrostyrene. In a typical experiment, 1 mol/equiv of trans--nitrostyrene was reacted with 1.5 mol/equiv of N-Me-indole in a 0.1 M toluene solution and stirred by an orbital shaker (400 rpm) for 24 h at room temperature. Yields were determined by 1 H NMR using 1,3,5-trimethoxybenzene as internal standard and are reported in Table  2 [30]. As shown, no product formation occurred when polymerized resin flakes without embedded thiourea 4 were used (Entry 1). Reactions performed in the presence of thiourea-embedded slivers with low catalyst loading or with low embedded-catalyst/substrate ratios gave no product or very poor results (Entries 2-9). However, when a 15 weight % thiourea-embedded resin was used in an equimolar ratio with the substrate, product 4 was formed in a 60% yield (Entry 10). Positive results were also obtained using resins with higher catalyst loading (Entries 14-15).
In order to confirm that the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene was catalyzed by heterogeneous thiourea-embedded flakes and not promoted by homogeneous catalyst 4 released from the resin in solution, we evaluated the leaching of the catalyst using different procedures. At first, 10 weight % thiourea slivers were refluxed with chloroform in a Soxhlet apparatus for 24 h. Since "clear" resin is not stable under chlorinated solvents (see Supporting Information), further sliver fragmentation was observed. After solvent evaporation, the resulting solid material was analyzed by NMR; only signals belonging to the polymer material were detected, with no evidence of catalyst signals in the crude form.
In an additional test, the crude reaction mixtures of Entries 7 and 11 in Table 2 were analyzed by 19 F NMR in order to verify the absence/presence of a thiourea 4 fluorine signal. Only very minor traces of the catalyst were detected in the solution. In order to quantitatively analyze the catalyst leaching of the slivers loaded with different amounts of catalyst 4, 19 F NMR analysis was performed using a 0.017 M solution of hexafluorobenzene in toluene as 19 F NMR internal standard. Results are reported in Figure 1. As shown, no product formation occurred when polymerized resin flakes without embedded thiourea 4 were used (Entry 1). Reactions performed in the presence of thiourea-embedded slivers with low catalyst loading or with low embedded-catalyst/substrate ratios gave no product or very poor results (Entries 2-9). However, when a 15 weight % thiourea-embedded resin was used in an equimolar ratio with the substrate, product 4 was formed in a 60% yield (Entry 10). Positive results were also obtained using resins with higher catalyst loading (Entries 14-15).
In order to confirm that the Friedel-Crafts alkylation of N-Me-indole with trans--nitrostyrene was catalyzed by heterogeneous thiourea-embedded flakes and not promoted by homogeneous catalyst 4 released from the resin in solution, we evaluated the leaching of the catalyst using different procedures. At first, 10 weight % thiourea slivers were refluxed with chloroform in a Soxhlet apparatus for 24 h. Since "clear" resin is not stable under chlorinated solvents (see Supporting Information), further sliver fragmentation was observed. After solvent evaporation, the resulting solid material was analyzed by NMR; only signals belonging to the polymer material were detected, with no evidence of catalyst signals in the crude form.
In an additional test, the crude reaction mixtures of Entries 7 and 11 in Table 2 were analyzed by 19 F NMR in order to verify the absence/presence of a thiourea 4 fluorine signal. Only very minor traces of the catalyst were detected in the solution. In order to quantitatively analyze the catalyst leaching of the slivers loaded with different amounts of catalyst 4, 19 F NMR analysis was performed using a 0.017 M solution of hexafluorobenzene in toluene as 19 F NMR internal standard. Results are reported in Graphic 1. As shown, 10 wt % thiourea-embedded material showed a catalyst leaching of 0.25 wt % after 24 h, and 1.3 wt % after 10 days of continuous shaking at 400 rpm. In addition, 15 and 20 wt % thiourea-embedded flakes showed comparable negligible leaching after 24 h (0.27% and 0.33%, respectively); after 10 days, the first showed catalyst leaching of 2.5%, while 8.2 wt % leaching was detected for the second.
Therefore, we selected 15 wt % resin as a good compromise between efficiency and (re)usability. However, the observed catalyst leaching (0.27 wt %) was not sufficient to promote Friedel-Crafts alkylation. Indeed, after 24 h reaction between N-Me-indole and trans--nitrostyrene (60% yield, Entry 7, Table 2), thiourea-embedded slivers were removed, and the reaction was shaken for 24 h  As shown, 10 wt % thiourea-embedded material showed a catalyst leaching of 0.25 wt % after 24 h, and 1.3 wt % after 10 days of continuous shaking at 400 rpm. In addition, 15 and 20 wt % thiourea-embedded flakes showed comparable negligible leaching after 24 h (0.27% and 0.33%, respectively); after 10 days, the first showed catalyst leaching of 2.5%, while 8.2 wt % leaching was detected for the second.
Therefore, we selected 15 wt % resin as a good compromise between efficiency and (re)usability. However, the observed catalyst leaching (0.27 wt %) was not sufficient to promote Friedel-Crafts alkylation. Indeed, after 24 h reaction between N-Me-indole and trans-β-nitrostyrene (60% yield, Entry 7, Table 2), thiourea-embedded slivers were removed, and the reaction was shaken for 24 h more. After this period, no yield increase was observed, confirming that the small amount of catalyst leached during the reaction was not able to promote the reaction by itself.
On the basis of these positive preliminary results using thiourea-embedded flakes of methacrylate-based resin as a catalyst in organocatalytic Friedel-Crafts alkylation, we focused our attention on the creation of devices with a well-defined shape that could be manufactured using an SLA 3D-printing process. Considering that the higher performance of catalysts could be related to increased exposed surface areas (as for a typical heterogeneous process), we designed four different devices characterized by the presence of many grooves. Autodesk 123d design freeware CAD software [31] was used to design and generate the corresponding Surface Tessellation Language (.stl) files. The rendering of these devices is reported in Figure 2.
leached during the reaction was not able to promote the reaction by itself.
On the basis of these positive preliminary results using thiourea-embedded flakes of methacrylate-based resin as a catalyst in organocatalytic Friedel-Crafts alkylation, we focused our attention on the creation of devices with a well-defined shape that could be manufactured using an SLA 3D-printing process. Considering that the higher performance of catalysts could be related to increased exposed surface areas (as for a typical heterogeneous process), we designed four different devices characterized by the presence of many grooves. Autodesk 123d design freeware CAD software [31] was used to design and generate the corresponding Surface Tessellation Language (.stl) files. The rendering of these devices is reported in Figure 1.
Device 1 consisted of a 6 mm diameter sphere with two circular channels (diameter = 1 mm) and was characterized by 0.07 cm 3 volume and 1.57 cm 2 surface area. Device 2 was a "gear wheel" of 6 mm diameter and 3 mm height (0.05 cm 3 volume, 2.06 cm 2 surface area); Device 3 was a cubic woodpile structure (6 × 6 × 6 mm, 0.11 cm 3 volume, and 3.78 cm 2 surface area); and Device 4 was a cube with nine channels for each face (6 × 6 × 6 mm, 0.10 cm 3 , 4.36 cm 2 surface area). Then, 150 ml of 10 wt % and 150 ml of 15 wt % thiourea (4)-embedded resin were prepared (with 0.300 and 0.199 mmol/g catalyst loading, respectively) and loaded into a Formlabs Form 2 stereolithography (SLA) 3D printer. The 3D-printing process was performed with 50 μm layer thickness, and supports were added in order to facilitate the process. Multiple copies of the devices were simultaneously printed on the same build plate to provide a good number of catalytically active devices to be employed in Friedel-Crafts alkylation ( Figure 2). Device 1 consisted of a 6 mm diameter sphere with two circular channels (diameter = 1 mm) and was characterized by 0.07 cm 3 volume and 1.57 cm 2 surface area. Device 2 was a "gear wheel" of 6 mm diameter and 3 mm height (0.05 cm 3 volume, 2.06 cm 2 surface area); Device 3 was a cubic woodpile structure (6 × 6 × 6 mm, 0.11 cm 3 volume, and 3.78 cm 2 surface area); and Device 4 was a cube with nine channels for each face (6 × 6 × 6 mm, 0.10 cm 3 , 4.36 cm 2 surface area).
Then, 150 mL of 10 wt % and 150 mL of 15 wt % thiourea (4)-embedded resin were prepared (with 0.300 and 0.199 mmol/g catalyst loading, respectively) and loaded into a Formlabs Form 2 stereolithography (SLA) 3D printer. The 3D-printing process was performed with 50 µm layer thickness, and supports were added in order to facilitate the process. Multiple copies of the devices were simultaneously printed on the same build plate to provide a good number of catalytically active devices to be employed in Friedel-Crafts alkylation ( Figure 3). more. After this period, no yield increase was observed, confirming that the small amount of catalyst leached during the reaction was not able to promote the reaction by itself.
On the basis of these positive preliminary results using thiourea-embedded flakes of methacrylate-based resin as a catalyst in organocatalytic Friedel-Crafts alkylation, we focused our attention on the creation of devices with a well-defined shape that could be manufactured using an SLA 3D-printing process. Considering that the higher performance of catalysts could be related to increased exposed surface areas (as for a typical heterogeneous process), we designed four different devices characterized by the presence of many grooves. Autodesk 123d design freeware CAD software [31] was used to design and generate the corresponding Surface Tessellation Language (.stl) files. The rendering of these devices is reported in Figure 1.
Device 1 consisted of a 6 mm diameter sphere with two circular channels (diameter = 1 mm) and was characterized by 0.07 cm 3 volume and 1.57 cm 2 surface area. Device 2 was a "gear wheel" of 6 mm diameter and 3 mm height (0.05 cm 3 volume, 2.06 cm 2 surface area); Device 3 was a cubic woodpile structure (6 × 6 × 6 mm, 0.11 cm 3 volume, and 3.78 cm 2 surface area); and Device 4 was a cube with nine channels for each face (6 × 6 × 6 mm, 0.10 cm 3 , 4.36 cm 2 surface area). Then, 150 ml of 10 wt % and 150 ml of 15 wt % thiourea (4)-embedded resin were prepared (with 0.300 and 0.199 mmol/g catalyst loading, respectively) and loaded into a Formlabs Form 2 stereolithography (SLA) 3D printer. The 3D-printing process was performed with 50 μm layer thickness, and supports were added in order to facilitate the process. Multiple copies of the devices were simultaneously printed on the same build plate to provide a good number of catalytically active devices to be employed in Friedel-Crafts alkylation ( Figure 2). Freshly printed objects need to be carefully cleaned before use to remove any residue of unpolymerized material. For this purpose, crude 3D-printed devices were sonicated in an iPrOH bath for 20 min, and the same operation was repeated twice with toluene until lost weight was lower than 1%. After this washing process, the solvent was removed, and devices were air-dried prior to postcuring for 20 min under a UV lamp. Their efficiency as organocatalysts was then investigated in the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene. Reactions were performed with different catalyst/substrate ratios (mol/mol) considering the required catalyst amount as the global amount of catalyst present into the entire device (the catalyst that is really accessible and interacts with the reactants is much less). Results are reported in Table 3. Table 3. Friedel-Crafts alkylation promoted by stereolithography (SLA) 3D-printed devices. Freshly printed objects need to be carefully cleaned before use to remove any residue of unpolymerized material. For this purpose, crude 3D-printed devices were sonicated in an iPrOH bath for 20 min, and the same operation was repeated twice with toluene until lost weight was lower than 1%. After this washing process, the solvent was removed, and devices were air-dried prior to postcuring for 20 min under a UV lamp. Their efficiency as organocatalysts was then investigated in the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene. Reactions were performed with different catalyst/substrate ratios (mol/mol) considering the required catalyst amount as the global amount of catalyst present into the entire device (the catalyst that is really accessible and interacts with the reactants is much less). Results are reported in Table 3. Table 3. Friedel-Crafts alkylation promoted by stereolithography (SLA) 3D-printed devices.

Entry
Device Shape After completing the reactions, the catalytic devices were easily removed from the reaction mixture. All 3D-printed thiourea-embedded devices could promote the synthesis of compound 3, but longer reaction times were required. From a general point of view, devices realized with 10 wt % thiourea-embedded resin were characterized by less chemical efficiency in promoting the reaction compared to the same device realized at 15 wt % thiourea-embedded resin. However, spherical devices led to the formation of the desired compound in 60% yield when a 1:1 catalyst/substrate ratio was employed (Table 3, Entry 4). Comparable results were also obtained using holed-cube Device 4, which presented the highest exposed surface, while other device shapes seemed to be less effective in promoting the Friedel-Crafts alkylation of N-Me-indole with trans--nitrostyrene.
Preliminary recycling studies were also carried out using the described general procedures (1:1 catalyst/substrate ratio). The 3D-printed 15 wt % thiourea-embedded devices were used; although devices changed in color from yellow to pale orange, the reused devices were effective for a second run without significant loss of yield, but showed clear drop in efficiency in the third run (first run, 40%; second run, 37%; third run, 11%).

Entry
Device Shape  Freshly printed objects need to be carefully cleaned before use to remove any residue of unpolymerized material. For this purpose, crude 3D-printed devices were sonicated in an iPrOH bath for 20 min, and the same operation was repeated twice with toluene until lost weight was lower than 1%. After this washing process, the solvent was removed, and devices were air-dried prior to postcuring for 20 min under a UV lamp. Their efficiency as organocatalysts was then investigated in the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene. Reactions were performed with different catalyst/substrate ratios (mol/mol) considering the required catalyst amount as the global amount of catalyst present into the entire device (the catalyst that is really accessible and interacts with the reactants is much less). Results are reported in Table 3. Table 3. Friedel-Crafts alkylation promoted by stereolithography (SLA) 3D-printed devices.

Entry
Device Shape After completing the reactions, the catalytic devices were easily removed from the reaction mixture. All 3D-printed thiourea-embedded devices could promote the synthesis of compound 3, but longer reaction times were required. From a general point of view, devices realized with 10 wt % thiourea-embedded resin were characterized by less chemical efficiency in promoting the reaction compared to the same device realized at 15 wt % thiourea-embedded resin. However, spherical devices led to the formation of the desired compound in 60% yield when a 1:1 catalyst/substrate ratio was employed (Table 3, Entry 4). Comparable results were also obtained using holed-cube Device 4, which presented the highest exposed surface, while other device shapes seemed to be less effective in promoting the Friedel-Crafts alkylation of N-Me-indole with trans--nitrostyrene.
Preliminary recycling studies were also carried out using the described general procedures (1:1 catalyst/substrate ratio). The 3D-printed 15 wt % thiourea-embedded devices were used; although devices changed in color from yellow to pale orange, the reused devices were effective for a second run without significant loss of yield, but showed clear drop in efficiency in the third run (first run, 40%; second run, 37%; third run, 11%). Freshly printed objects need to be carefully cleaned before use to remove any residue of unpolymerized material. For this purpose, crude 3D-printed devices were sonicated in an iPrOH bath for 20 min, and the same operation was repeated twice with toluene until lost weight was lower than 1%. After this washing process, the solvent was removed, and devices were air-dried prior to postcuring for 20 min under a UV lamp. Their efficiency as organocatalysts was then investigated in the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene. Reactions were performed with different catalyst/substrate ratios (mol/mol) considering the required catalyst amount as the global amount of catalyst present into the entire device (the catalyst that is really accessible and interacts with the reactants is much less). Results are reported in Table 3. After completing the reactions, the catalytic devices were easily removed from the reaction mixture. All 3D-printed thiourea-embedded devices could promote the synthesis of compound 3, but longer reaction times were required. From a general point of view, devices realized with 10 wt % thiourea-embedded resin were characterized by less chemical efficiency in promoting the reaction compared to the same device realized at 15 wt % thiourea-embedded resin. However, spherical devices led to the formation of the desired compound in 60% yield when a 1:1 catalyst/substrate ratio was employed (Table 3, Entry 4). Comparable results were also obtained using holed-cube Device 4, which presented the highest exposed surface, while other device shapes seemed to be less effective in promoting the Friedel-Crafts alkylation of N-Me-indole with trans--nitrostyrene.

Materials and Methods
Preliminary recycling studies were also carried out using the described general procedures (1:1 catalyst/substrate ratio). The 3D-printed 15 wt % thiourea-embedded devices were used; although devices changed in color from yellow to pale orange, the reused devices were effective for a second run without significant loss of yield, but showed clear drop in efficiency in the third run (first run, 40%; second run, 37%; third run, 11%). Freshly printed objects need to be carefully cleaned before use to remove any residue of unpolymerized material. For this purpose, crude 3D-printed devices were sonicated in an iPrOH bath for 20 min, and the same operation was repeated twice with toluene until lost weight was lower than 1%. After this washing process, the solvent was removed, and devices were air-dried prior to postcuring for 20 min under a UV lamp. Their efficiency as organocatalysts was then investigated in the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene. Reactions were performed with different catalyst/substrate ratios (mol/mol) considering the required catalyst amount as the global amount of catalyst present into the entire device (the catalyst that is really accessible and interacts with the reactants is much less). Results are reported in Table 3. After completing the reactions, the catalytic devices were easily removed from the reaction mixture. All 3D-printed thiourea-embedded devices could promote the synthesis of compound 3, but longer reaction times were required. From a general point of view, devices realized with 10 wt % thiourea-embedded resin were characterized by less chemical efficiency in promoting the reaction compared to the same device realized at 15 wt % thiourea-embedded resin. However, spherical devices led to the formation of the desired compound in 60% yield when a 1:1 catalyst/substrate ratio was employed (Table 3, Entry 4). Comparable results were also obtained using holed-cube Device 4, which presented the highest exposed surface, while other device shapes seemed to be less effective in promoting the Friedel-Crafts alkylation of N-Me-indole with trans--nitrostyrene.

Materials and Methods
Preliminary recycling studies were also carried out using the described general procedures (1:1 catalyst/substrate ratio). The 3D-printed 15 wt % thiourea-embedded devices were used; although devices changed in color from yellow to pale orange, the reused devices were effective for a second run without significant loss of yield, but showed clear drop in efficiency in the third run (first run, 40%; second run, 37%; third run, 11%). Freshly printed objects need to be carefully cleaned before use to remove any residue of unpolymerized material. For this purpose, crude 3D-printed devices were sonicated in an iPrOH bath for 20 min, and the same operation was repeated twice with toluene until lost weight was lower than 1%. After this washing process, the solvent was removed, and devices were air-dried prior to postcuring for 20 min under a UV lamp. Their efficiency as organocatalysts was then investigated in the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene. Reactions were performed with different catalyst/substrate ratios (mol/mol) considering the required catalyst amount as the global amount of catalyst present into the entire device (the catalyst that is really accessible and interacts with the reactants is much less). Results are reported in Table 3. After completing the reactions, the catalytic devices were easily removed from the reaction mixture. All 3D-printed thiourea-embedded devices could promote the synthesis of compound 3, but longer reaction times were required. From a general point of view, devices realized with 10 wt % thiourea-embedded resin were characterized by less chemical efficiency in promoting the reaction compared to the same device realized at 15 wt % thiourea-embedded resin. However, spherical devices led to the formation of the desired compound in 60% yield when a 1:1 catalyst/substrate ratio was employed (Table 3, Entry 4). Comparable results were also obtained using holed-cube Device 4, which presented the highest exposed surface, while other device shapes seemed to be less effective in promoting the Friedel-Crafts alkylation of N-Me-indole with trans--nitrostyrene.

Materials and Methods
Preliminary recycling studies were also carried out using the described general procedures (1:1 catalyst/substrate ratio). The 3D-printed 15 wt % thiourea-embedded devices were used; although devices changed in color from yellow to pale orange, the reused devices were effective for a second run without significant loss of yield, but showed clear drop in efficiency in the third run (first run, 40%; second run, 37%; third run, 11%). Freshly printed objects need to be carefully cleaned before use to remove any residue of unpolymerized material. For this purpose, crude 3D-printed devices were sonicated in an iPrOH bath for 20 min, and the same operation was repeated twice with toluene until lost weight was lower than 1%. After this washing process, the solvent was removed, and devices were air-dried prior to postcuring for 20 min under a UV lamp. Their efficiency as organocatalysts was then investigated in the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene. Reactions were performed with different catalyst/substrate ratios (mol/mol) considering the required catalyst amount as the global amount of catalyst present into the entire device (the catalyst that is really accessible and interacts with the reactants is much less). Results are reported in Table 3. After completing the reactions, the catalytic devices were easily removed from the reaction mixture. All 3D-printed thiourea-embedded devices could promote the synthesis of compound 3, but longer reaction times were required. From a general point of view, devices realized with 10 wt % thiourea-embedded resin were characterized by less chemical efficiency in promoting the reaction compared to the same device realized at 15 wt % thiourea-embedded resin. However, spherical devices led to the formation of the desired compound in 60% yield when a 1:1 catalyst/substrate ratio was employed (Table 3, Entry 4). Comparable results were also obtained using holed-cube Device 4, which presented the highest exposed surface, while other device shapes seemed to be less effective in promoting the Friedel-Crafts alkylation of N-Me-indole with trans--nitrostyrene.

Materials and Methods
Preliminary recycling studies were also carried out using the described general procedures (1:1 catalyst/substrate ratio). The 3D-printed 15 wt % thiourea-embedded devices were used; although devices changed in color from yellow to pale orange, the reused devices were effective for a second run without significant loss of yield, but showed clear drop in efficiency in the third run (first run, 40%; second run, 37%; third run, 11%). Freshly printed objects need to be carefully cleaned before use to remove any residue of unpolymerized material. For this purpose, crude 3D-printed devices were sonicated in an iPrOH bath for 20 min, and the same operation was repeated twice with toluene until lost weight was lower than 1%. After this washing process, the solvent was removed, and devices were air-dried prior to postcuring for 20 min under a UV lamp. Their efficiency as organocatalysts was then investigated in the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene. Reactions were performed with different catalyst/substrate ratios (mol/mol) considering the required catalyst amount as the global amount of catalyst present into the entire device (the catalyst that is really accessible and interacts with the reactants is much less). Results are reported in Table 3. Table 3. Friedel-Crafts alkylation promoted by stereolithography (SLA) 3D-printed devices.

Entry
Device Shape After completing the reactions, the catalytic devices were easily removed from the reaction mixture. All 3D-printed thiourea-embedded devices could promote the synthesis of compound 3, but longer reaction times were required. From a general point of view, devices realized with 10 wt % thiourea-embedded resin were characterized by less chemical efficiency in promoting the reaction compared to the same device realized at 15 wt % thiourea-embedded resin. However, spherical devices led to the formation of the desired compound in 60% yield when a 1:1 catalyst/substrate ratio was employed (Table 3, Entry 4). Comparable results were also obtained using holed-cube Device 4, which presented the highest exposed surface, while other device shapes seemed to be less effective in promoting the Friedel-Crafts alkylation of N-Me-indole with trans--nitrostyrene.
Preliminary recycling studies were also carried out using the described general procedures (1:1 catalyst/substrate ratio). The 3D-printed 15 wt % thiourea-embedded devices were used; although devices changed in color from yellow to pale orange, the reused devices were effective for a second run without significant loss of yield, but showed clear drop in efficiency in the third run (first run, 40%; second run, 37%; third run, 11%). Freshly printed objects need to be carefully cleaned before use to remove any residue of unpolymerized material. For this purpose, crude 3D-printed devices were sonicated in an iPrOH bath for 20 min, and the same operation was repeated twice with toluene until lost weight was lower than 1%. After this washing process, the solvent was removed, and devices were air-dried prior to postcuring for 20 min under a UV lamp. Their efficiency as organocatalysts was then investigated in the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene. Reactions were performed with different catalyst/substrate ratios (mol/mol) considering the required catalyst amount as the global amount of catalyst present into the entire device (the catalyst that is really accessible and interacts with the reactants is much less). Results are reported in Table 3. After completing the reactions, the catalytic devices were easily removed from the reaction mixture. All 3D-printed thiourea-embedded devices could promote the synthesis of compound 3, but longer reaction times were required. From a general point of view, devices realized with 10 wt % thiourea-embedded resin were characterized by less chemical efficiency in promoting the reaction compared to the same device realized at 15 wt % thiourea-embedded resin. However, spherical devices led to the formation of the desired compound in 60% yield when a 1:1 catalyst/substrate ratio was employed (Table 3, Entry 4). Comparable results were also obtained using holed-cube Device 4, which presented the highest exposed surface, while other device shapes seemed to be less effective in promoting the Friedel-Crafts alkylation of N-Me-indole with trans--nitrostyrene.

Materials and Methods
Preliminary recycling studies were also carried out using the described general procedures (1:1 catalyst/substrate ratio). The 3D-printed 15 wt % thiourea-embedded devices were used; although devices changed in color from yellow to pale orange, the reused devices were effective for a second run without significant loss of yield, but showed clear drop in efficiency in the third run (first run, 40%; second run, 37%; third run, 11%). Freshly printed objects need to be carefully cleaned before use to remove any residue of unpolymerized material. For this purpose, crude 3D-printed devices were sonicated in an iPrOH bath for 20 min, and the same operation was repeated twice with toluene until lost weight was lower than 1%. After this washing process, the solvent was removed, and devices were air-dried prior to postcuring for 20 min under a UV lamp. Their efficiency as organocatalysts was then investigated in the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene. Reactions were performed with different catalyst/substrate ratios (mol/mol) considering the required catalyst amount as the global amount of catalyst present into the entire device (the catalyst that is really accessible and interacts with the reactants is much less). Results are reported in Table 3. Table 3. Friedel-Crafts alkylation promoted by stereolithography (SLA) 3D-printed devices.

Entry
Device Shape After completing the reactions, the catalytic devices were easily removed from the reaction mixture. All 3D-printed thiourea-embedded devices could promote the synthesis of compound 3, but longer reaction times were required. From a general point of view, devices realized with 10 wt % thiourea-embedded resin were characterized by less chemical efficiency in promoting the reaction compared to the same device realized at 15 wt % thiourea-embedded resin. However, spherical devices led to the formation of the desired compound in 60% yield when a 1:1 catalyst/substrate ratio was employed (Table 3, Entry 4). Comparable results were also obtained using holed-cube Device 4, which presented the highest exposed surface, while other device shapes seemed to be less effective in promoting the Friedel-Crafts alkylation of N-Me-indole with trans--nitrostyrene.
Preliminary recycling studies were also carried out using the described general procedures (1:1 catalyst/substrate ratio). The 3D-printed 15 wt % thiourea-embedded devices were used; although devices changed in color from yellow to pale orange, the reused devices were effective for a second run without significant loss of yield, but showed clear drop in efficiency in the third run (first run, 40%; second run, 37%; third run, 11%). Freshly printed objects need to be carefully cleaned before use to remove any residue of unpolymerized material. For this purpose, crude 3D-printed devices were sonicated in an iPrOH bath for 20 min, and the same operation was repeated twice with toluene until lost weight was lower than 1%. After this washing process, the solvent was removed, and devices were air-dried prior to postcuring for 20 min under a UV lamp. Their efficiency as organocatalysts was then investigated in the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene. Reactions were performed with different catalyst/substrate ratios (mol/mol) considering the required catalyst amount as the global amount of catalyst present into the entire device (the catalyst that is really accessible and interacts with the reactants is much less). Results are reported in Table 3. Table 3. Friedel-Crafts alkylation promoted by stereolithography (SLA) 3D-printed devices.

Entry
Device Shape After completing the reactions, the catalytic devices were easily removed from the reaction mixture. All 3D-printed thiourea-embedded devices could promote the synthesis of compound 3, but longer reaction times were required. From a general point of view, devices realized with 10 wt % thiourea-embedded resin were characterized by less chemical efficiency in promoting the reaction compared to the same device realized at 15 wt % thiourea-embedded resin. However, spherical devices led to the formation of the desired compound in 60% yield when a 1:1 catalyst/substrate ratio was employed (Table 3, Entry 4). Comparable results were also obtained using holed-cube Device 4, which presented the highest exposed surface, while other device shapes seemed to be less effective in promoting the Friedel-Crafts alkylation of N-Me-indole with trans--nitrostyrene.
Preliminary recycling studies were also carried out using the described general procedures (1:1 catalyst/substrate ratio). The 3D-printed 15 wt % thiourea-embedded devices were used; although devices changed in color from yellow to pale orange, the reused devices were effective for a second run without significant loss of yield, but showed clear drop in efficiency in the third run (first run, 40%; second run, 37%; third run, 11%). After completing the reactions, the catalytic devices were easily removed from the reaction mixture. All 3D-printed thiourea-embedded devices could promote the synthesis of compound 3, but longer reaction times were required. From a general point of view, devices realized with 10 wt % thiourea-embedded resin were characterized by less chemical efficiency in promoting the reaction compared to the same device realized at 15 wt % thiourea-embedded resin. However, spherical devices led to the formation of the desired compound in 60% yield when a 1:1 catalyst/substrate ratio was employed (Table 3, Entry 4). Comparable results were also obtained using holed-cube Device 4, which presented the highest exposed surface, while other device shapes seemed to be less effective in promoting the Friedel-Crafts alkylation of N-Me-indole with trans-β-nitrostyrene.

Materials and Methods
Preliminary recycling studies were also carried out using the described general procedures (1:1 catalyst/substrate ratio). The 3D-printed 15 wt % thiourea-embedded devices were used; although devices changed in color from yellow to pale orange, the reused devices were effective for a second run without significant loss of yield, but showed clear drop in efficiency in the third run (first run, 40%; second run, 37%; third run, 11%).