A New Pd-Based Catalytic System for the Reductive Carbonylation of Nitrobenzene to Form N-(4-hydroxyphenyl)- acetamide Selectively in One Pot

: N-(4-hydroxyphenyl)acetamide (commonly named paracetamol or acetaminophen) is a target molecules for many industries that produce chemicals for pharmaceutical applications. The industrial processes, however, use multistep procedures with low overall yield and/or severe drawbacks and problems in terms of sustainability. In the present paper, a one-pot synthesis is proposed based on the reductive carbonylation of nitrobenzene catalyzed by Pd(II)-complexes. Usually, such a reaction leads to a mixture of different products, including aniline, 4-aminophenol and 1,3-diphenylurea. However, the selectivity towards the possible products strongly depends by the ligands on the Pd(II)-catalyst, but also by the nature of the solvent. According to this, we have found that when the reaction was carried out in dilute acetic acid as a solvent, the [PdCl 2 (dppb)] catalyst precursor leads in one pot to N-(4-hydroxyphenyl)acetamide. Under optimized reaction conditions, it was possible to produce N-(4-hydroxyphenyl)acetamide with a 85 mol % of selectivity in ca. 5 h.

In the present paper, the authors reported the synthesis of acetaminophen carried out in one pot, starting from nitrobenzene through the Pd-catalyzed reductive carbonylation of the nitro-group in water-acetic acid as a solvent.As pointed out in previous papers, the choice of the catalyst plays a key role in determining the selectivity of such reaction, but no less important is the influence of the solvent.For instance, the Pd-catalyzed reductive carbonylation of nitrobenzene can readily lead to aniline in high yield when methanol was used as a solvent, but the addition of a co-solvent can strongly influence the selectivity [57][58][59][60][61][62][63][64][65][66][67][68][69][70][71].According to this, we reported the selective synthesis of 1,3-diphenylurea in one pot by using an appropriate methanol-acetic acid mixture as a solvent [71].On the other hand, in the same reaction when H 2 O-acetic acid was used as a solvent, the selectivity moved again toward the aniline as the main products, even if traces of acetaminophen was also found in the by-products [72].This suggested to us the chance to obtain acetaminophen in one pot and in high yield.Therefore, the [PdCl 2 (dppb)] (dppb = 1,4 bis(diphenylphosphine)butane) complex has been selected to carry out the reaction (reaction 1) first, and the influence of some reaction parameters have been studied, with the aim of increasing the selectivity towards acetaminophen.
In the present paper, the authors reported the synthesis of acetaminophen carried out in one pot, starting from nitrobenzene through the Pd-catalyzed reductive carbonylation of the nitro-group in water-acetic acid as a solvent.As pointed out in previous papers, the choice of the catalyst plays a key role in determining the selectivity of such reaction, but no less important is the influence of the solvent.For instance, the Pd-catalyzed reductive carbonylation of nitrobenzene can readily lead to aniline in high yield when methanol was used as a solvent, but the addition of a co-solvent can strongly influence the selectivity [57][58][59][60][61][62][63][64][65][66][67][68][69][70][71].According to this, we reported the selective synthesis of 1,3-diphenylurea in one pot by using an appropriate methanol-acetic acid mixture as a solvent [71].On the other hand, in the same reaction when H2O-acetic acid was used as a solvent, the selectivity moved again toward the aniline as the main products, even if traces of acetaminophen was also found in the by-products [72].This suggested to us the chance to obtain acetaminophen in one pot and in high yield.Therefore, the [PdCl2(dppb)] (dppb = 1,4 bis(diphenylphosphine)butane) complex has been selected to carry out the reaction (reaction 1) first, and the influence of some reaction parameters have been studied, with the aim of increasing the selectivity towards acetaminophen.

Equipment and Characterization
The catalyst precursors have been weighted on a Sartorious Micro balance (precision 0.001 mg).High-performance liquid chromatography (HPLC) analyses were carried out by a Perkin Elmer 250 equipped with a diode array LC-235 detector and a Lichrosphere 100 (RP-18, 5 µm) column employing water acetonitrile mixtures as eluent; the concentrations of the reagent and products were calculated by calibration with standard solution.GC/MS analyses were performed on a MS Agilent apparatus 5975C Model, interfaced with an Agilent chromatograph 7890 A Model equipped with a HP1 column (30 m × 0.25 mm × 0.25 µm, oven: 45 • C (3 min) to 250 • C at 15 • C/min).Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Magna 750 instrument in KBr powder.All the NMR spectra were recorded on a Bruker Avance 300 spectrometer.

Catalytic Reactions
The catalysis has been carried out in a batch reactor of ca.60 mL provided with a magnetic stirrer.In a typical experiment, 2.48 × 10 −3 mmol of Pd(II) complex (for instance 1.50 mg of [PdCl 2 (dppb)]), together with 0.5 mL (0.600 g, 4.87 mmol) of nitrobenzene, were added to 11.5 mL of solvent (H 2 O-AcOH).In order to avoid catalyst deactivation due to the presence of air, the reactor was carefully flushed with CO at room temperature with stirring and then pressurized with 0.5 MPa of CO and heated up to 373 K in ca. 10 min without stirring.The pressure was then adjusted to the desired value (typically 5.0 MPa of total pressure) and, while stirring, maintained constant throughout the experiment (3 h) by continuously supplying the carbon monoxide from a reservoir.At the end of each experiment, the reactor was quickly cooled and carefully depressurized.
The reaction products were detected and quantified by the HPLC and GC-MS analysis.All the experiments were repeated at least twice, and the error analysis confirmed the reproducibility of the data within an error of ±1%.

Preliminary Experiments
Table 1 shows the results of the preliminary experiments carried out by using some Pd(II) complexes as catalyst precursors in H 2 O-acetic acid as a solvent.The reaction conditions adopted in such tests were typically used in a previous paper to produce 1,3-diphenylurea [71].Among the complexes tested, the [PdCl 2 (dppb)] led to the best conversion (60 mol %, TON = 1178 mol/mol, entry 3), forming, under reaction conditions adopted, aniline (33%), and acetanilide (25%), together with 4-aminophenol (19%) and acetaminophen (8%), whereas only a trace amount of 1,3-diphenylurea was detected.The experiments have been limited to such complexes because they are stable, easily handled at room temperature Pd(II) and effective in several carbonylation reactions, including the reductive carbonylation of nitrobenzene to 1,3-diphenylurea carried out in methanol as a solvent [71,72].In addition, they are interesting from an industrial point of view, being readily synthesized from commercially available reagents and are very soluble in several solvents (e.g., alcoholic solvents or in H 2 O-acetic acid mixture, as in the present case).The results in Table 1 suggest that both catalytic activity and selectivity are strongly influenced by the electronic and steric characteristics of the chelating di-phosphine ligands, according to the studies reported in literature [71,73].
Furthermore, the Table 1 shows also that the nature of ionic ligand have poor influence on the conversion and selectivity under the reaction conditions.This could be ascribed to the nature of the solvent mixture used, in which the amount of acetic acid determinates the solubility of the complexes, whereas H 2 O has a key role to form the desired products (see mechanism), but also in determining the dielectric constant of the reaction medium.The latter could favor the solvation and the displacement of ionic ligands from the coordination site of the metal center.In such a way, it is plausible to suppose that such sites become more available for the coordination of the reagents, regardless of the coordinating ability of the ionic ligands.
On the basis of such preliminary results, the [PdCl 2 (dppb)] complex has been used as catalyst precursor in all the following experiments.

One-Pot Synthesis of Acetaminophen in H 2 O-Acetic Acid as a Solvent
Figure 1 and Table 2 show that the solvent composition strongly influences the conversion and the selectivity to acetaminophen.In fact, the conversion of nitrobenzene increases by increasing the amount of H 2 O in the reaction medium, reaching ca. 100 mol % at H 2 O 60 mol % (H 2 O/acetic acid 60/40 mol/mol).At H 2 O higher than 65 mol %, the conversion sharply decreases (it was ca.22 mol % at H 2 O = 80 mol %), probably due to the separation of two liquid phases (nitrobenzene and water) observed at the end of such an experiment.methanol as a solvent [71,72].In addition, they are interesting from an industrial point of view, being readily synthesized from commercially available reagents and are very soluble in several solvents (e.g., alcoholic solvents or in H2O-acetic acid mixture, as in the present case).The results in Table 1 suggest that both catalytic activity and selectivity are strongly influenced by the electronic and steric characteristics of the chelating di-phosphine ligands, according to the studies reported in literature [71,73].
Furthermore, the Table 1 shows also that the nature of ionic ligand have poor influence on the conversion and selectivity under the reaction conditions.This could be ascribed to the nature of the solvent mixture used, in which the amount of acetic acid determinates the solubility of the complexes, whereas H2O has a key role to form the desired products (see mechanism), but also in determining the dielectric constant of the reaction medium.The latter could favor the solvation and the displacement of ionic ligands from the coordination site of the metal center.In such a way, it is plausible to suppose that such sites become more available for the coordination of the reagents, regardless of the coordinating ability of the ionic ligands.
On the basis of such preliminary results, the [PdCl2(dppb)] complex has been used as catalyst precursor in all the following experiments.
As schematized in Scheme 1, in order to simplify the discussion, we have indicated the molar sum of 4-aminophenol and its acetylated derivative with A, the molar sum of aniline and its acetylated derivative with B, and the molar sum of 2-aminophenol and its acetylated derivative with C. D indicates the molar sum of some compounds that, under the experimental conditions adopted, were each formed in concentration < 5 mol % (by-products), such as 1,3-diphenylurea, nitrosobenzene, N,N -azobenzene, etc.
Reactions 2023, 4, FOR PEER REVIEW 5 As schematized in Scheme 1, in order to simplify the discussion, we have indicated the molar sum of 4-aminophenol and its acetylated derivative with A, the molar sum of aniline and its acetylated derivative with B, and the molar sum of 2-aminophenol and its acetylated derivative with C. D indicates the molar sum of some compounds that, under the experimental conditions adopted, were each formed in concentration < 5 mol % (byproducts), such as 1,3-diphenylurea, nitrosobenzene, N,N'-azobenzene, etc. Scheme 1. Scheme of the possible products formed during the reductive carbonylation of nitrobenzene in H2O-AcOH as a solvent.
The acid concentration, however, also influences the yield of acetylation.For instance, the percent of acetaminophen in A was 1 mol % when AcOH in H2O was 40 mol % (Table 3, entry 1; for conversion 99 mol %, see Table 2, entry 5), whereas it was 72 mol % when AcOH in H2O was 93 mol % (Table 3, entry 5; for conversion 39 mol %, see Table 2, Regarding the selectivity to A, it increases with the amount of H 2 O in the solvent, reaching 40 mol % when H 2 O was ca.60 mol % (see Table 2, entry 5).
The acid concentration, however, also influences the yield of acetylation.For instance, the percent of acetaminophen in A was 1 mol % when AcOH in H 2 O was 40 mol % (Table 3, entry 1; for conversion 99 mol %, see Table 2, entry 5), whereas it was 72 mol % when AcOH in H 2 O was 93 mol % (Table 3, entry 5; for conversion 39 mol %, see Table 2, entry 1).The same trend was observed for aniline and acetanilide in B composition (see Table 3).Run conditions: * see Table 2.
In light of such results, and with the aim to increase the conversion and the selectivity to acetaminophen at the same time, we have carried out the following experiments by using a solvent dilution such as H 2 O/acetic acid = 50/50 (mol/mol).

Influence of Pressure and Temperature on Conversion and Selectivity
The conversion of nitrobenzene linearly increases with the pressure of carbon monoxide in the range 0-6.0 MPa (Table 4), whereas under 5.0 MPa of CO, the conversion reaches its maximum (100%) between 393 K and 403 K (Table 5).The decrease of conversion observed at temperatures higher than 410 K could be ascribed to the progressive thermal decomposition of the Pd(II) complex, which leads to a loss of catalytic activity [71].Focusing on the reaction at 403 K, it can be observed that nitrobenzene was fully converted with 85 mol % of selectivity towards A, which contains ca.95 molar % of acetaminophen (see Figure 2).However, under the last conditions but with an increasing reaction time (e.g., 5 h), it was possible to obtain a selectivity of 85 mol % towards A, containing 100% acetaminophen.

On the Reaction Mechanism
The catalytic reductive carbonylation of nitrobenzene (or nitro-arenes), to form aniline, 1,3-diphenylurea, N-phenylisocyanates, or carbamate (in alcoholic solvents), has been extensively studied by several authors, who generally have proposed a reaction mechanism starting from a Pd (0) species, usually formed in situ from a Pd(II) precursor [69][70][71][72].Such a species can activate the reaction of nitrobenzene with CO to form a complex which eliminates CO 2 to lead to the Pd(II)-nitroso species 1 (see Scheme 2, reaction a).As schematized, following the reaction pathway b -d , the species 4 can form which, in turn, can lead to aniline (reaction e , together with azo-benzene), 1,3-diphenylurea (reaction e ) and/or N-phenylisocyanates (reaction e , together with carbamate in alcoholic solvents) [71].
with an increasing reaction time (e.g., 5 h), it was possible to obtain a selectivity of 85 mol % towards A, containing 100% acetaminophen.

On the Reaction Mechanism
The catalytic reductive carbonylation of nitrobenzene (or nitro-arenes), to form aniline, 1,3-diphenylurea, N-phenylisocyanates, or carbamate (in alcoholic solvents), has been extensively studied by several authors, who generally have proposed a reaction mechanism starting from a Pd (0) species, usually formed in situ from a Pd(II) precursor [69][70][71][72].Such a species can activate the reaction of nitrobenzene with CO to form a complex which eliminates CO2 to lead to the Pd(II)-nitroso species 1 (see Scheme 2, reaction a).As schematized, following the reaction pathway b′-d′, the species 4′ can form which, in turn, can lead to aniline (reaction e′, together with azo-benzene), 1,3-diphenylurea (reaction e″) and/or N-phenylisocyanates (reaction e‴, together with carbamate in alcoholic solvents) [71].
However, when the reaction has been carried out in H2O-acetic acid as a solvent, 4aminophenol together with aniline and the corresponding acetylated products (not included in the scheme) are mainly formed whereas azo-benzene and 1,3-diphenylurea are detected only in trace amounts (<5 mol %).
Since aniline, azo-benzene and 1,3-diphenylurea were formed even under the experimental conditions of the present work, we can assume the mechanism proposed in the literature is still effective.However, to also include the formation of 4-aminophenol, it is necessary to suppose the presence of parallel reaction pathways.For instance, we can suggest two hypotheses: (i) 4-aminophenol could form from N-phenylhydroxylamine, which in turn forms through reactions b-c″, and/or (ii) 4-aminophenol could form through reactions b-d.Since, in all experiments of the present work, we never detected N-phenylhydroxylamine in the reaction medium, we assumed that it reacted quickly during the reaction.As a matter of fact, it is reported that some metal catalysts (usually Pd/C, Pt/C, or Ru/C, but it could be possible also the Pd(0) species active in the present work) catalyze the fast Scheme 2. Proposed reaction mechanism.
However, when the reaction has been carried out in H 2 O-acetic acid as a solvent, 4-aminophenol together with aniline and the corresponding acetylated products (not included in the scheme) are mainly formed whereas azo-benzene and 1,3-diphenylurea are detected only in trace amounts (<5 mol %).
Since aniline, azo-benzene and 1,3-diphenylurea were formed even under the experimental conditions of the present work, we can assume the mechanism proposed in the literature is still effective.However, to also include the formation of 4-aminophenol, it is necessary to suppose the presence of parallel reaction pathways.For instance, we can suggest two hypotheses: (i) 4-aminophenol could form from N-phenylhydroxylamine, which in turn forms through reactions b-c , and/or (ii) 4-aminophenol could form through reactions b-d.
Since, in all experiments of the present work, we never detected N-phenylhydroxylamine in the reaction medium, we assumed that it reacted quickly during the reaction.As a matter of fact, it is reported that some metal catalysts (usually Pd/C, Pt/C, or Ru/C, but it could be possible also the Pd(0) species active in the present work) catalyze the fast reaction of N-phenylhydroxylamine with hydrogen to form aniline together with the 4-aminophenol, via the Bamberger's rearrangement (Scheme 3, [50,52,74-78]).By considering that it is plausible also the formation in situ of hydrogen from CO and H 2 O, through the Pd(II)catalyzed water gas shift reaction [79][80][81], we have carried out some additional experiments to test such a pathway.

Conclusions
The reductive carbonylation of nitrobenzene, by using the [PdCl2(dppb)] complex as a catalyst precursor, leads to a mixture of acetaminophen and N-phenylacetamide in one pot when carried out in dilute acetic acid as a solvent.Although both products are interesting targets for the pharmaceutical industry, we can produce acetaminophen in one pot, choosing the most suitable reaction conditions (for instance, in H2O/AcOH = 50/50 mol/mol and at 403 K, 5 h of reaction it has been obtained acetaminophen, with 85% selectivity and 100% conversion of nitrobenzene).
We have pointed out that the selectivity towards A (4-aminophenol and acetaminophen) increases by increasing the amount of H2O but, on the other hand, the high percent of H2O favors 4-aminophenol rather than acetaminophen.Moreover, by increasing the temperature and the reaction time, it is possible to favor both the selectivity towards A and the acetylation to acetaminophen (100% at 5 h).

Scheme 1 .
Scheme 1. Scheme of the possible products formed during the reductive carbonylation of nitrobenzene in H 2 O-AcOH as a solvent.

Table 2 .
Influence of solvent composition on conversion and selectivity.

Table 2 .
Influence of solvent composition on conversion and selectivity.

Table 3 .
Influence of the solvent on composition of A and B.

Table 5 .
Influence of the temperature on the conversion and selectivity.