Rhodium-catalyzed reductive carbonylation of aryl iodides to arylaldehydes with syngas

The reductive carbonylation of aryl iodides to aryl aldehydes possesses broad application prospects. We present an efficient and facile Rh-based catalytic system composed of the commercially available Rh salt RhCl3·3H2O, PPh3 as phosphine ligand, and Et3N as the base, for the synthesis of arylaldehydes via the reductive carbonylation of aryl iodides with CO and H2 under relatively mild conditions with a broad substrate range affording the products in good to excellent yields. Systematic investigations were carried out to study the experimental parameters. We explored the optimal ratio of Rh salt and PPh3 ligand, substrate scope, carbonyl source and hydrogen source, and the reaction mechanism. Particularly, a scaled-up experiment indicated that the catalytic method could find valuable applications in industrial productions. The low gas pressure, cheap ligand and low metal dosage could significantly improve the practicability in both chemical researches and industrial applications.


Introduction
The exploration of environmentally friendly and highly effective synthetic methods has been a significant goal of research [1][2][3][4][5]. In this aspect, effective catalytic systems and organometallic chemistry are suitable technologies to accomplish these goals. Carbonylation processes are important transformations in the refinement and reprocessing of readily available industrial raw materials into more functionalized products. These processes generally utilize carbon monoxide (CO), currently the most important C1 building block used in numerous industrial carbonylation processes [6][7][8] and widely applied in industrial productions [9][10][11][12]. Carbonylations are one of the industrial core technologies for transforming various bulk chemicals into useful products that are used in our daily life. Carbonylation reactions, together with polymerizations and oxidations, constitute the largest industrial applications in the field of homogeneous catalysis, and substantial value-added bulk and fine chemicals are available through this technology [13]. In spite of the existing plentiful progress in this conversion, the exploitation of advanced and more effective catalytic systems to the activity and to widen the range of substrates is crucial for new practical applications.
Syngas is a mixture of CO and H 2 , which is cheap, abundant and widely used in chemical industry productions [14][15][16]. In spite of its comprehensive utilization in industry, reactions involving CO are relatively seldom employed in fine chemicals syntheses. This could be due to the general difficulty of using gases as raw materials and the requirement of high-pressure equipment. In addition, relatively little attention has been paid to carbonylation chemistry using CO in academic research. Also, H 2 as representative clean energy source is far more environmentally friendly than other frequently used hydrogen sources like hydrosilanes [17], tributyltin hydride (Bu 3 SnH) (often used in natural product syntheses) [18][19][20] and hydroboranes [21][22][23], since the only byproduct is water. The production, storage and use of H 2 received much attention and plentiful achievements promoted the application of H 2 into more and more chemistry researches and industrial productions [24][25][26][27].
Aromatic aldehydes are highly valuable organic compounds that are widely employed as indispensable building blocks in numerous areas of chemistry, especially for the preparation of biologically active molecules or their intermediates [28,29]. Generally, aromatic aldehydes are synthesized by Reimer-Tiemann, Gattermann-Koch, Vielsmeier-Haag, or Duff reactions and so forth. Unfortunately, these reactions usually use auxiliary reagents and thus generate large amounts of industrial waste and other side products. Particularly, the reductive carbonylation of aryl iodides to produce arylaldehydes with CO and H 2 was seldom reported. Some homogeneous and heterogeneous catalytic systems based on palladium species using CO and H 2 to complete the reductive carbonylation of aryl halogens to arylaldehydes have been developed. The homogeneous systems included Pd(OAc) 2 with propyl di-tertbutylphosphinite ligand [30], Pd(acac) 2 with dppm ligand [31], Pd(OAc) 2 with CataCXium A ligand [32], and all of the three systems employed TMEDA as the base and toluene as the solvent. The heterogeneous systems contained: PdO/Co 3 O 4 with K 2 CO 3 [33], MCM-41-S-PdCl 2 [34], and MCM-41-2P-PdCl 2 [35]. However, the aforementioned systems often suffer from high toxicity of solvents, high pressure of gases or high reaction temperatures, which make these protocols inapplicable for large scale applications. Actually, in 2004, Eliseev et al. reported a catalytic system based on RhCl(CO)(PPh 3 ) 2 to achieve the conversion of iodobenzene to benzaldehyde in toluene using CO and H 2 [36]. We sought for a commercially available Rh salt for this conversion at lower cost and higher potential for practical application.
In this work, we established a catalytic system composed of RhCl 3 ·3H 2 O and PPh 3 , which allows the reductive carbonylation of aryl iodides using CO and H 2 in the presence of Et 3 N as the base at 90 °C. In addition, the reported catalytic system demonstrates high catalytic activity affording the arylaldehydes in good to excellent yields, displays high functional-group tolerance, and broad substrate scope. In particular, the catalytic system could be applied in a scaled-up experiment and thus has potential for applications in industrial productions. The reaction mechanism study revealed that RhCl 3 ·3H 2 O reacts with PPh 3 to form RhCl(PPh 3 ) 3 , which is able to activate C-I bonds in aryl iodides realizing the insertion of CO and hydrogenolysis with H 2 . The final trapping of HI by the base Et 3 N regenerates the catalyst to complete the reaction cycle. As far as we know, this is the first time that commercially available Rh salts with PPh 3 as the ligand were utilized to complete the conversion of aryl iodides into arylaldehydes using CO and H 2 with systematic researches. Considering the efficiency and generality, this catalytic system is expected to powerfully influence both laboratory research and chemical industry by offering a practical synthetic tool for the conversion of aryl iodides to arylaldehydes.

Effects of Rh species
Rhodium salts coordinated with proper ligands have been reported to be able to realize the activation of CO and H 2 and thus might achieve the reductive carbonylation of aryl iodides to afford aromatic aldehydes [37][38][39][40]. Rh salts generally play vital roles in the catalytic results. Therefore, we tested 20 different Rh salts and the results are summarized in Table 1. The initial reaction conditions were set as PhI (1 mmol), Rh species (2.5 mol %), PPh 3 (10 mol %), Et 3 N (1.2 mmol), DMA (2 mL), CO/H 2 (5 bar:5 bar), 90 °C and 12 h. As can be seen from  low yield (Table 1, entries [17][18][19][20]. This strongly implied that not only the valence state of Rh and the species of anions were crucial for the conversion (even if all with halogen anions), but also structural differences (e.g., crystal water, RhCl 3 vs RhCl 3 ·3H 2 O) of analogous Rh salts played an important role in the catalytic synthesis of benzaldehyde. Among all tested rhodium salts, RhCl 3 ·3H 2 O afforded benzaldehyde in the highest yield and was chosen as the most suitable Rh salt for the conversion. In addition, in spite of low yields, Rh species with valence states of 0, +1, +2 or +3 all promoted the reaction at least to some extent. It is worth noting that as a good leaving group, I − tends to leave in an alkaline environment, and dehalogenation and direct coupling products (namely, benzene and biphenyl) were detected as the main byproducts by GC-MS. This observation also explains why the conversions were always higher than the yields.

Effects of ligands
Ligands play a decisive role in adjusting the catalytic ability of metal cations [12,13,[41][42][43][44][45][46][47][48][49][50][51]. Different ligands coordinating with the same metal cations could make a difference between full conversion with nearly quantitative yields and no reactions. To obtain the optimized conditions, 13 kinds of ligands were tested and their structures are included in Table 2. In accordance with the expectations, only PPh 3 was effective and afforded benzaldehyde in 97% yield, whereas the majority of the other ligands did not afford any product (Table 2). Therefore, PPh 3 was selected as the proper ligand employed in the subsequent reactions.

Effects of bases
As explored in the mechanism study, the acid HI is produced during the reaction process, since H + and I − were generated from the reaction system. In order to make the reaction proceed continuously, HI produced needs to be removed effectively and in time. Five different bases were examined to assess their ability to bind HI. All of them were found suitable for the reaction and provided benzaldehyde with yields higher than 70%, except for TMEDA (53%, Figure 1a). The best results were obtained with Et 3 N, which was selected as the most appropriate base.
The optimized base concentration was explored next and the results are shown in Figure 1b. Since the base held the post of absorber for acids produced during the reaction, sufficient amounts are necessary to ensure high yields. As shown in Figure 1b, amounts of Et 3 N less than 1 mmol led to lower yields of 33% for 0.5 mmol Et 3 N and 61% for 0.8 mmol Et 3 N, respectively. However, a slight excess of Et 3 N (1.2 mmol) allowed the reaction to be completed with a product yield of 97%. In addition, further increasing the amount of the base was not beneficial for the yield of benzaldehyde (1.5 mmol Et 3 N, 95% yield; 2 mmol Et 3 N, 92% yield; 3 mmol Et 3 N, 89% yield). Thus, the appropriate amount of Et 3 N was set at 1.2 mmol.

Effect of solvents
Solvents act as the reaction media and strongly influence the catalytic reactions [52,53]. We screened nine representative solvents in the catalytic reaction and the results are summarized in Figure 1c. Apparently, protic solvents like EtOH or MeOH and nonpolar solvents like THF or toluene were inappropriate for the reaction leading to yields lower than 10%. Medium polar solvents like MeCN or 1,4-dioxane afforded slightly higher yields but still below 15%. To our delight, polar solvents with high boiling points, NMP, DMI or DMA proved to be more suitable, and afforded benzaldehyde in 32%, 54% and 97% yield, respectively, likely owing to the high boiling point and better CO and H 2 dissolution ability, highlighting a strong sol-vent dependency of the system [54,55]. Therefore, DMA was selected as the most suitable solvent for the reaction.

Effects of temperature and time
To further optimize the performance of the catalytic system, the effect of the reaction temperature was screened in the range of 50 °C to 100 °C. The results revealed that the reaction temperature had an important influence on the catalytic process and the product yield increased with increasing temperature. At low temperature the reaction did not proceed at all, however, at 90 °C or higher, a nearly quantitative yield of benzaldehyde was obtained ( Figure 1d). Next, parallel experiments were conducted at three selected temperatures (80 °C, 90 °C, and 100 °C) to study the yields at different reaction times. The results revealed that equally high yields were obtained at 90 °C and 100 °, but the reaction was much faster at 100 °C than at 90 °C (Figure 1e). On the other hand, when performing the reaction at 80 °C, the product yield was lower and required longer times to be reached.

Effects of pressure of CO and H 2
The influence of the pressures of CO and H 2 was explored next. As expected, a low pressure of both, CO (1 atm) and H 2 (1 atm), resulted in a lower yield of benzaldehyde (24% yield, Table 3, entry 1). When the pressures of both gases were increased to 2, 3, 4, or 5 bar, the yield of benzaldehyde accordingly increased to 51%, 62% 81%, and 97%, respectively (Table 3, entries 2-5). However, further increasing the pressures did not lead to higher yields (Table 3, entries 6 and 7). After that, we examined the proportions of the syngas components on the reaction and it was found that the optimized proportions of syngas were 5 bar CO and 5 bar H 2 (1:1, (

Scaled-up experiment
Noteworthy, when conducting the reaction at a larger scale (10 mmol), benzaldehyde was obtained with a high yield of 93%, indicating that our system could be suitable for industrial application (Scheme 1).

Optimal ratio of Rh salt and PPh 3 ligand and active species participating in the catalytic process
In order to ascertain the optimized ratio of RhCl 3 ·3H 2 O and the PPh 3 ligand, a series of experiments with different concentrations and ratios of RhCl 3 ·3H 2 O and PPh 3 were conducted. At first, the concentration of RhCl 3 ·3H 2 O was fixed at 1 mol %. When changing the amount of PPh 3 from 2 mol % to 5 mol %, the yield gradually increased reaching a maximum yield of 74% at 4 mol % PPh 3 . Further increasing the amount of the ligand resulted in a decrease of the product yield (Table 4, entries   3 Cl although they share the identical metal center and ligand (Scheme 2c and 2d). This indicated that the anion plays an important role in the catalytic process.

Substrate scope
Next, the scope of the reductive carbonylation reaction was explored (shown in Scheme 3), after having identified the optimized conditions for benzaldehyde synthesis from iodobenzene. The results showed that electronic effects had little impact on the reaction. Both, substrates with electron-withdrawing or electron-donating groups afforded similar yields. However, steric effects played an important role in the catalytic process, i.e., the yields were influenced by the substituent group positions following the order of ortho < meta < para. The obtained isolated yields were slightly lower than the NMR yields owing to a loss of products during the workup process. Iodobenzene with no substituent group provided benzaldehyde (1) with 93% yield. For iodobenzene derivatives with electron-donating groups (Me, OMe), 83-95% yield of aldehydes 2-7 were obtained. As expected, the yields increased in the order of ortho < meta < para-substituted compounds. As for aryl iodides with halide substituents (F, Cl, Br), these were also compatible with the reaction system, affording 79−89% yields of the halogenated aromatic aldehydes 8-16. Iodobenzene derivatives with phenyl or tert-butyl groups displaying larger steric hindrance in the para-position still provided the corresponding aldehydes 17 and 18 in relatively high yields (85% and 81%, respectively). 2-Iodonaphthalene with smaller steric hindrance performed a little better than 1-iodonaphthalene (19, 84% and 20, 77%). However, starting iodides having methyl substituents in both ortho-positions afforded the corresponding aldehydes in much lower yields (21 61% and 22 60%). Also, iodobenzenes with an acetyl group in either ortho, meta, or para-position gave the products in satisfactory yields (23 79%, 24 81% and 25 87%). 1-Iodo-3,4-methylenedioxybenzene performed well providing aldehyde 26 with 92% yield. Aryl iodide with an acetamido group in the para-position gave a medium yield (27 82%). Aryl iodides containing one or two trifluoromethyl groups in their structure worked slightly less efficient producing arylaldehydes 28-30 with yields of 72-79%. It is worth noticing that a cyano group in the substrate stayed intact in the catalytic process giving aldehyde 31 with 77% yield. Also substrates comprising two halogen substituents performed well offering access to dihalogenated aldehydes 32-35 with yields between 76-81%.
In addition, heterocyclic iodides were also amenable to the reductive carbonylation reaction and the corresponding aldehydes 36-42 were isolated with yields of 65−73%.

Isotope labeling experiments
Isotope labeling experiments were conducted to study the mechanism of the reductive carbonylation of aryl iodide with CO and H 2 under our optimized conditions, using 13 CO and D 2 instead of CO and H 2 , respectively, as the sources of the carbonyl group and hydrogen in the formyl group. C 6 H 5 13 CHO, Reaction mechanism and role of each component Based on the results from the labeling experiments a reaction mechanism for the reductive carbonylation of aryl iodides was proposed, as shown in Scheme 5 [57]. First, RhCl 3 ·3H 2 O reacted with PPh 3 to form Rh(PPh 3 ) 3 Cl (A), followed by an oxidative addition of Rh(PPh 3 ) 3 Cl (A) to the aryl iodide, producing the corresponding arylrhodium complex (B). Then, the coordination and insertion of CO led to the formation of benzoylrhodium complex (C). Next, metathesis with H 2 afforded the aldehyde product. The base, Et 3 N neutralized the proton in the rhodium hydroiodide complex (D) and regenerated the active Rh species [11].
Scheme 5: Proposed reaction mechanism for the Rh-catalyzed reductive carbonylation of aryl iodides using CO and H 2 .
In the catalytic system, CO and H 2 (or syngas) were used as the carbonyl and hydrogen sources, respectively. The catalyst RhCl 3 ·3H 2 O and PPh 3 reacted via a redox reaction to form Rh(PPh 3 ) 3 Cl, which is the active catalytic species able to activate C-I bonds in the aryl iodides for the insertion of CO in the next step. The base Et 3 N neutralized the proton in the intermediate rhodium hydroiodide (D) complex and regenerated the active Rh species completing the catalytic cycle.

Conclusion
An efficient and facile Rh-based catalytic system composed of a commercially available Rh salt, RhCl 3 ·3H 2 O, a phosphine ligand PPh 3 , and a base Et 3 N, was evaluated for the synthesis of arylaldehydes via the reductive carbonylation of aryl iodides using CO as carbonyl source and H 2 as hydrogen source under relatively mild conditions with a broad substrate range. The low gas pressure, cost-effective ligand and low metal dosage significantly improved the practicability of the system for industrial productions. Another advantage of the method includes the use of cheap and abundant syngas (mixtures of CO and H 2 ) in the catalytic system as an effective and convenient formyl source at relatively low pressures, which further enhanced the possibility of practical application of the proposed system.

Experimental
Materials Instrumentation 1 H NMR spectra in solution were recorded in CDCl 3 using the residual CHCl 3 as internal reference (7.26 ppm) on a Bruker 400 spectrometer. 1 H NMR peaks were labeled as singlet (s), doublet (d), triplet (t), and multiplet (m). The coupling constants, J, are reported in hertz (Hz). 13 C NMR spectra in solution were recorded at 101 MHz in CDCl 3 using the solvent as internal reference (77.0 ppm). GC analysis was performed on Agilent 4890D with a FID detector and a nonpolar capillary column (DB-5) (30 m × 0.25 mm × 0.25 μm). The column oven was temperature-programmed with a 2 min initial hold at 50 °C, followed by heating to 265 °C at a rate of 10 °C /min and kept at 265 °C for 10 min. High purity nitrogen was used as the carrier gas.
General procedure for reductive carbonylation of aryl iodides with CO and H 2 All reactions were carried out in an 80 mL Teflon-lined stainless steel reactor equipped with a magnetic stirring bar. Typically, in a glovebox, the aryl iodides (1.0 mmol), RhI 3 (0.025 mmol), PPh 3 (0.1 mmol), Et 3 N (1.2 mmol), and DMA (2 mL) were loaded into the reactor. Then, the autoclave was screwed up, charged with CO and H 2 to a total pressure of 10 bar (1:1) and transferred to an oil bath preheated at 90 °C, which was controlled by a Haake-D3 temperature controller. After completion of the reaction, the reactor was cooled in iced water and the gas carefully vented. The conversion and yield of the aryl iodides and arylaldehydes were determined by GC analysis using dodecane as an internal standard. For yield determination of the other products, the reaction mixture was first analyzed by GC-MS to determine the structures of the aromatic aldehyde products. Then, CH 2 Cl 2 (5 mL) was added to the reaction mixture, after which deionized water (10 mL) was added to extract the solvent DMA for 5 times. The organic layer was dried over anhydrous Na 2 SO 4 , concentrated by rotary evaporation and finally purified by column chromatography on silica gel using n-hexane/ethyl acetate as eluent to obtain the pure products and isolated yields.