Comment on “Dithiocarbamate-mediated thioamidation of arylglyoxylic acids by decarboxylative–decarbonylative C–C bond formation reactions” by D. Patra and A. Saha, Org. Chem. Front., 2023, 10, 1686

Abstract

The reported thioamidation reaction of phenylglyoxylic acid, PhCOCO₂H, gives only a 5% yield of thioamide product, and not the 96% yield reported in Org. Chem. Front., 2023, 10, 1686. The proposed Pd(II) catalyst plays no role in the reaction. Labelled phenylglyoxylic acid, Ph¹³COCO₂H, gave a thioamide product where the ¹³C label is retained. This rules out the suggested mechanism, which involves a phenyl radical derived from decarbonylation of benzoyl radical.

---

Introduction

This Comment concerns a paper by Debabrata Patra and Amit Saha that appeared in Org. Chem. Front., 2023, 10, 1686, in which a variety of thioamides are synthesized by a palladium catalyzed reaction of arylglyoxylic acids, dithiocarbamates, and ammonium persulfate (Scheme 1). Complex reactions that involve phenyl radicals are reported that give over 90% yields. Facile decarbonylation reactions of benzoyl radicals are reported, despite the lack of observation of decarbonylation in numerous literature reports on this well-studied radical. Elemental sulfur is isolated by simple filtration from a reaction mixture. For these and other reasons, attempts have been made to repeat some of the unexpected claims in this paper.

Scheme 1 Thioamide synthesis in Org. Chem. Front., 2023, 10, 1686.

Results and discussion

The main reaction described in this paper, i.e., the reaction of phenylglyoxylic acid, piperidine dithiocarbamate salt, and ammonium persulfate catalyzed by (dppf)PdCl₂ ¹ has been repeated using the conditions given in Org. Chem. Front., 2023, 10, 1686. The reaction turns black and gives a very complex mixture in which the major product is benzaldehyde. The ¹H NMR spectrum of the crude product is shown in Fig. 1. Only on very careful examination of the expanded spectrum can one see a trace of what could be the thioamide 3. This hardly represents a 96% yield of thioamide 3, as claimed by Patra and Saha. The reaction was then repeated using PdCl₂ as the putative catalyst, and the results are similar. Benzaldehyde is the major product. Again, careful examination of the expanded spectrum reveals a possible trace of the thioamide 3 (not 65% as claimed in the paper).

Fig. 1 ¹H NMR spectrum (CDCl₃; 600 MHz) of the crude products formed in the reaction of thiocarbamate salt 1, phenylglyoxylic acid, 2, ammonium persulfate, and (dppf)PdCl₂ in N-methyl-2-pyrrolidone at 70 °C.

The reaction can best be summarized in Scheme 2. For comparison purposes, and to aid in the detection of the expected product, the ¹H NMR spectrum of a pure sample of the thioamide 3 prepared by a known method² is shown in Fig. 2.

Scheme 2 Observed products from attempted thioamide synthesis.

Fig. 2 ¹H NMR spectrum (CDCl₃; 600 MHz) of an authentic sample of thioamide 3.

Next, the reaction was carried out a third time, but no Pd catalyst was added. The results mirror the reactions carried out with (dppf)PdCl₂ or with PdCl₂ added. In other words, the proposed palladium catalyst has no impact on the small amount of thioamide 3 that is produced. In this case, the product thioamide 3 was isolated by chromatography using silica gel. The actual yield of 3 is 5%. This result is summarized in Scheme 3 and in Fig. 3.

Scheme 3 Observed products from attempted thioamide synthesis with no Pd(II).

Fig. 3 ¹H NMR spectrum (CDCl₃; 600 MHz) of the crude products formed in the reaction of thiocarbamate salt 1, phenylglyoxylic acid, 2, and ammonium persulfate at 70 °C. No Pd catalyst was added.

In order to determine the origin of the small amount of thioamide 3, the ¹³C labelled phenylglyoxylic acid, 2* (99% ¹³C) was prepared.³ The reaction was then carried out using this labelled substrate 2*. The 5% thioamide product was then isolated by silica gel chromatography. ¹H and ¹³C NMR analyses (Fig. 4 and 5) show that the product is Ph¹³CSN(CH₂)₅, 3*, where the label has been retained in the product (Scheme 4). As summarized in Scheme 5, this completely rules out the mechanistic process claimed by the authors in Org. Chem. Front., 2023, 10, 1686. There is no phenyl radical involved in the reaction and neither is the potential palladium catalyst involved. While the origin of a product formed in only 5% yield is of some limited interest, clearly the product yields and mechanistic claims in this paper are incorrect. In fact, even without adding (NH₄)₂S₂O₈ or Pd(II), PhCOCO₂H, 2, reacts with salt 1 in NMP to form benzaldehyde and small amounts of thioamide 3.¹

Fig. 4 ¹H NMR spectrum (CDCl₃; 600 MHz) of the thioamide 3* isolated from the reaction of thiocarbamate salt 1, Ph¹³COCO₂H, 2*, and ammonium persulfate at 70 °C.

Fig. 5 ¹³C NMR spectrum (CDCl₃; 150 MHz) of the thioamide 3* isolated from the reaction of thiocarbamate salt 1, Ph¹³COCO₂H, 2*, and ammonium persulfate at 70 °C.

Scheme 4 Observed products from attempted thioamide synthesis with Ph¹³COCO₂H.

Scheme 5 Mechanistic proposal disproved by labelling study.

Benzoyl radical dearbonylation

A crucial step in the mechanism proposed in this paper is the decarbonylation of benzoyl radical 4 to generate the phenyl radical 5. The labelling study described above shows that this process is not involved in the formation of the 5% thioamide 3. It is informative to address this potential reaction, which, at first glance, might seem reasonable. The following computational studies shed light on why such a decarbonylation should be a difficult process, even if benzoyl radicals were actually generated. The decarbonylation of benzoyl radical 4 ⁴ was evaluated at the M062X/6-311+G** level of theory. Fig. 6 shows the calculated ΔG° energy values for decarbonylation of benzoyl radical 4, while Fig. 7 shows ΔH values. Fig. 6 and Scheme 6 show that decarbonylation of benzoyl radical 4 is quite endergonic, i.e., unfavorable thermodynamically. Indeed, it accounts for the fact that benzoyl radical can readily be generated by the reverse reaction, i.e., reaction of carbon monoxide with phenyl radical.^4,5 Additionally, the free energy of activation for decarbonylation is 22.3 kcal mol⁻¹ and the enthalpy of activation is 24.3 kcal mol⁻¹. These values indicate slow rates of decarbonylation of benzoyl radical 4 at room temperature. In other words, other potential reactions of 4 are far more likely to occur before decarbonylation occurs.

Fig. 6 M062X/6-311+G** free energy diagram for decarbonylation.

Fig. 7 M062X/6-311+G** calculated enthalpy diagram for decarbonylation.

Scheme 6 M062X/6-311+G** calculated free energy for decarbonylation of benzoyl radical 4.

These energy diagrams account for the fact that numerous reactions involving benzoyl radicals 4 give no decarbonylation.⁶ Typical reactions include the autooxidation of benzaldehyde to benzoic acid, which gives no decarbonylation.⁷ Benzaldehyde is readily converted to PhCON₃ via benzoyl radicals and no decarbonylation is observed.⁸ Benzoyl radicals, when generated by other methods, add readily to electron deficient alkenes without decarbonylation.⁹ Can benzoyl radicals ever undergo decarbonylation? In 1971 rates of decarbonylation were measured.¹⁰ However, the temperature was in the 341–394 °C range, consistent with Fig. 6 and 7. Only recently has it been reported¹¹ that decarbonylation of benzoyl radical 4 can occur when generated from PhCOCHO in dichloroethane at 120 °C. Under these conditions it was suggested that decarbonylation generates the phenyl radical, which then adds to coumarin. Yet when benzoyl radical 4 is generated from PhCOCO₂H in dichloroethane, there is no decarbonylation before 4 adds to coumarin. These findings are quite inconsistent and suggest that the mechanism for formation of 3-phenylcoumarin needs to be reevaluated.¹²

Decarbonylation of benzoyl radical 4 contrasts with decarboxylation of benzoyloxy radical 8. Results of computational studies are shown in Scheme 7.¹³ Computationally, decarboxylation of 8 is very exergonic (ΔG° = −14.8 kcal mol⁻¹). This accounts for the fact that decarboxylation of 8 is a well-known experimental phenomenon. The intrinsic stability of CO₂ is undoubtedly the reason for the differing behaviors of 4 and 8.

Scheme 7 M062X/6-311+G** calculated free energy for decarboxylation of benzoyloxy radical 8.

Conclusions

Given all of the findings described in this Comment, I now conclude that there are numerous issues in Org. Chem. Front., 2023, 10, 1686 that need to be addressed. The product yield of 3 in the reaction of phenylglyoxylic acid is only about 5% (not 96%). Without adding any Pd catalyst, the 5% yield of 3 suggests that the palladium species is not involved in the formation of this trace amount of product. The mechanism for formation of 3 does not involve phenyl radical, as shown by a labelling study, and there is no evidence of decarbonylation. This suggests that the putative mechanism given in Scheme 5 of Org. Chem. Front., 2023, 10, 1686 is incorrect. Finally, the reaction turns very dark (black) at the end and there is no formation of elemental sulfur as shown in Fig. 1 of the paper.

As a final remark, reaction mechanisms are never absolutely proven and hence can often be up for debate. However, factual experimental results are not open for debate or interpretation. Since the reagents used in the experiments are available in most organic laboratories, or commercially available, others are encouraged to verify the experimental facts concerning the reactions discussed.

Conflicts of interest

There are no conflicts of interest to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: experimental procedures and computational details. See DOI: https://doi.org/10.1039/d4qo00393d.

References

1. Full experimental details are given as SI.
2. A. D. Kale, Y. A. Tayade, S. D. Mahale, R. D. Patil and D. S. Dalal, Willgerodt-Kindler reaction at room temperature: Synthesis of thioamides from aromatic aldehydes and secondary amines, Tetrahedron, 2019, 75, 130575–130586.
3. A. R. Lippert, K. Keshari, J. Kurhanewicz and C. J. Chang, A Hydrogen Peroxide-Responsive Hyperpolarized ¹³C MRI Contrast Agent, J. Am. Chem. Soc., 2011, 133, 3776–3779 . For an alternative synthesis of Ph¹³COCO₂H used in this study, see the SI.
4. For an earlier theoretical study, see: G.-J. Nam, W. Xia, J. Park and M. C. Lin, The Reaction of C₆H₅ with CO: Kinetic Measurement and Theoretical Correlation with the Reverse Process, J. Phys. Chem. A, 2000, 104(6), 1233–1239.
5. S.-Y. Lin and Y.-P. Lee, Infrared Absorption of Gaseous Benzoyl Radical C₆H₅CO Recorded with a Step-Scan Fourier-Transform Spectrometer, J. Phys. Chem. A, 2012, 116(24), 6366–6374.
6. For numerous examples, see: C. Chatgilialoglu, D. Crich, M. Komatsu and I. Ryu, Chemistry of Acyl Radicals, Chem. Rev., 1999, 99, 1991–2069.
7. M. Sankar, E. Nowika, E. Carter, D. M. Murphy, D. W. Knight, D. Bethell and G. J. Hutchings, The benzaldehyde oxidation paradox explained by the interception of peroxy radical by benzyl alcohol, Nat. Commun., 2014, 5, 3332.
8. D.-J. Chen and Z.-C. Chen, Hypervalent iodine in synthesis. Part 54: One-step conversion of aryl aldehydes to aroyl azides using a combined reagent of (diacetoxyiodo)benzene with sodium azide, Tetrahedron Lett., 2000, 41, 7361–7366.
9. E. de Pedro Beato, D. Mazzarella, M. Balletti and P. Melchiorre, Photochemical generation of acyl and carbamoyl radicals using a nucleophilic organic catalyst: applications and mechanism thereof, Chem. Sci., 2020, 11, 6312–6324.
10. R. K. Solly and S. W. Benson, Kinetics of gas-phase unimolecular decomposition of benzoyl radical, J. Am. Chem. Soc., 1971, 93, 2127.
11. A. Moazzam, M. Khodadadi, F. Jafarpour and M. Ghandi, Dual Role of Oxoaldehydes: Divergent Synthesis of 3-Aryl- and 3-Aroylcoumarins, J. Org. Chem., 2022, 87, 3630–3737.
12. Since submission of this paper, ref. 11 has been retracted since the reported procedures do not form the reported products. See: A. Moazzam, M. Khodadadi, F. Jafarpour and M. Ghandi, Retraction of “Dual Role of Oxoaldehydes: Divergent Synthesis of 3-Aryl- and 3-Aroylcoumarins”, J. Org. Chem., 2025, 90, 9672.
13. For earlier computational and experimental studies, see: B. Abel, J. Assmann, P. Botschwina, M. Buback, M. Kling, R. Oswald, S. Schmatz, J. Schroeder and T. Witte, Experimental and Theoretical Investigations of the Ultrafast Photoinduced Decomposition of Organic Peroxides in Solution: Formation and Decarboxylation of Benzoyloxy Radicals, J. Phys. Chem. A, 2003, 107(26), 5157–5167.

---