Oxidative N-Dealkylation of N,N-Dimethylanilines by Non-Heme Manganese Catalysts

Round 1

Reviewer 1 Report

The manuscript “Oxidative N-Dealkylation of N,N-dimethylanilines by Non-Heme Manganese Catalysts” reports oxidation of N,N-dimethylanilines to N-methylanilines (oxidative demethylation) and N-methyl-N-formylanilines by peroxides or air catalyzed by chelate pyridyl complexes of Mn(II) at almost room temperature. The selective catalytic oxidation of organic substrates at mild conditions is important ang challenging task. The understanding of catalytic mechanisms in this field is not so well-established compared to reductive and redox-neutral processes catalyzed by transition metal complexes. Thus mechanistic studies are very important for rational catalyst design. It should also be noted that the studied process can be considered as biologically relevant. The manuscript is well-written, interesting and scientifically novel. I recommend publication after revision:

1)     There must be a mistake in the abstract: “ Nonheme manganese(II) complexes, [(IndH)MnIICl2] (1) and [(N4Py*)FeII(CH3CN)](ClO4)2 (2)” – why Fe the complex 2?

2)     The phrase “resulting N-methylaniline (MA) as the predominant product with N-methylformanilide (MFA) as a result of a free-radical chain process under air” should be improved (grammar). From scientific point of view, not all processes proposed are radical chain processes (Scheme 2).

3)     “(1:100:100 for the catalyst:DMA:co-oxidant)” – why “co-oxidant”, not just “oxidant”?

4)     Why Mn(ClO4)2 is used as reference? In this salt it is very hard to oxidize Mn to higher oxidation states, therefore it demonstrated almost no redox-activity with peroxides. Mn(OAc)2 should be a better choice for higher chances of catalytic activity for simple salt.

5)     “The new intense absorption in the range of 650 nm indicates a complexation and charge-transfer (CT) type interaction between the oxidant and the substrate” – there is no absorption maximum on figure 8a, please, check the text. Regarding the assignment of some peak to the complex with starting substrate, one can expect its intensity to decrease due to reaction. But only peak 944 nm assigned to oxidant decreases. The similar situation with assignment of some peak to the intermediate – its intensity should increase with time, then decrease. But peaks 460 nm and 544 nm increase until the end of measurements, which is typical for some end products.

6)     I recommend Authors to use color in Figure 8.

7)     For some reason, some oxygen atoms in Scheme 2 are depicted as black blots.

8)     In Scheme 2, stage 1 to 2, check electron balance. It is two-electron oxidation of Mn(II), thus two ROOH molecules are needed or no O-radical should be formed (ROH instead of RO*). In the case of two ROOH molecules it may be not single mechanistic stage.

Author Response

Review 1

Comments and Suggestions for Authors

The manuscript “Oxidative N-Dealkylation of N,N-dimethylanilines by Non-Heme Manganese Catalysts” reports oxidation of N,N-dimethylanilines to N-methylanilines (oxidative demethylation) and N-methyl-N-formylanilines by peroxides or air catalyzed by chelate pyridyl complexes of Mn(II) at almost room temperature. The selective catalytic oxidation of organic substrates at mild conditions is important ang challenging task. The understanding of catalytic mechanisms in this field is not so well-established compared to reductive and redox-neutral processes catalyzed by transition metal complexes. Thus mechanistic studies are very important for rational catalyst design. It should also be noted that the studied process can be considered as biologically relevant. The manuscript is well-written, interesting and scientifically novel. I recommend publication after revision:

 

1)           There must be a mistake in the abstract: “ Nonheme manganese(II) complexes, [(IndH)MnIICl2] (1) and [(N4Py*)FeII(CH3CN)](ClO4)2 (2)” – why Fe the complex 2?

 

Thank you! Corrected.

 

2)     The phrase “resulting N-methylaniline (MA) as the predominant product with N-methylformanilide (MFA) as a result of a free-radical chain process under air” should be improved (grammar). From scientific point of view, not all processes proposed are radical chain processes (Scheme 2).

 

„The relatively low MA/MFA ratio indicates the presence of autoxidation process, which can be interpreted by the reaction of the DMA● (PhN(Me)CH2●) radical with di-oxygen, resulting in the formation of equimolar amount of PhN(Me)CH2OH and PhN(Me)CHO, and finally MA and CH2O via Russel-type termination mechanism (Scheme 2).”

 

Scheme 2. Proposed mechanism for the Russel-type termination mechanism.

 

3)     “(1:100:100 for the catalyst:DMA:co-oxidant)” – why “co-oxidant”, not just “oxidant”?

 

You are right, we wanted to make differences between the metal-based oxidant and so-called co-oxidant. Anyway, co-oxidant was changed to oxidant.

4)     Why Mn(ClO4)2 is used as reference? In this salt it is very hard to oxidize Mn to higher oxidation states, therefore it demonstrated almost no redox-activity with peroxides. Mn(OAc)2 should be a better choice for higher chances of catalytic activity for simple salt.

 

„In the first round, it can be established that the catalytic activity of the manganese salt (Mn^II(ClO₄)₂), and the in situ formed Mn^II(OAc)₂  and Mn^II(mCBA)₂ derivatives in the presence of PAA/AA and mCPBA/mCBA, respectively, is negligible.”

 

5)     “The new intense absorption in the range of 650 nm indicates a complexation and charge-transfer (CT) type interaction between the oxidant and the substrate” – there is no absorption maximum on figure 8a, please, check the text. Regarding the assignment of some peak to the complex with starting substrate, one can expect its intensity to decrease due to reaction. But only peak 944 nm assigned to oxidant decreases. The similar situation with assignment of some peak to the intermediate – its intensity should increase with time, then decrease. But peaks 460 nm and 544 nm increase until the end of measurements, which is typical for some end products.

 

This part was rewrite:

„In contrast to the iron-containing system, the reaction of the in situ formed oxoman-ganese(IV) with p-Me-DMA resulted in the immediate generation of a transient ab-sorption band at max = 460 nm (Figure 8a), which can be assigned to the formation of the transient radical cation intermediate, p-Me-DMA+• [32]. This band disappeared immediately and merged into another intense band (544 nm). The formation/decay of the characteristic band at 460 nm is accompanied by a decrease in the absorption band at 944 nm, which band can be assigned to the oxomanganese(IV) (3) species [34, 55-59]. The new intense absorption in the range of 544 nm indicates a complexation and charge-transfer (CT) type interaction between the oxidant and the substrate, albeit its nature is not known. Based on these results the reaction can be described by a fast electron-transfer (ET) from DMA to 2, followed by slower proton transfer (PT) step from p-Me-DMA+• to [(N4Py*)MnIII(O)]+ (Scheme 2), similarly to the [(Bn-TPEN)MnIV(O)]2+/p-Me-DMA system [32].

Finally, the UV-Vis experiments in the presence of p-Me-DMA under catalytic conditions (1/m-CPBA/p-Me-DMA = 1:10:30) has also confirmed the formation of MnIV(O) species (max = 764 nm), and that the substrate, DMA affects its decay (Figure 8b). The max value is similar to that was observed for [(Bn-TPEN)MnIV(O)]2+ (max = 725 nm) [32]. Unfortunately, due to the intense absorptions appearing in the range of 400-500 nm, in this case, we did not find evidence for the formation of the p-Me-DMA+• radical here.”

 

6)     For some reason, some oxygen atoms in Scheme 2 are depicted as black blots.

Yes, to show the origine of the oxygen (oxo-manganese(IV) versus dioxygen).

 

7)     In Scheme 2, stage 1 to 2, check electron balance. It is two-electron oxidation of Mn(II), thus two ROOH molecules are needed or no O-radical should be formed (ROH instead of RO*). In the case of two ROOH molecules it may be not single mechanistic stage.

 

Yes. In case of mCPBA and PAA oxene-transfer, while in case of TBHP radical route is proposed.

Author Response File: Author Response.pdf

Reviewer 2 Report

In this manuscript, the authors prepared two Mn(II) complexes 1 and 2 and studied their catalytic activities toward the oxidative demethylation of N,N-dimethylanilines. They compared the preformance of different catalysts (1, 2 and Mn(CLO4)2) and different oxidants on the oxidative demethylation of N,N-dimethylanilines. In combination with the Hammett plot and some spectroscopic researches, they proposed an eletrophilic mechanism of the catalytically active species with the substrates, which potentially supported the oxidative transformaitons of many biologically degradation catalyzed by non-heme enzymes.

Overall, this work seems significant and deserves publishing on the journal.

Some corrections should be noticed before its acceptance, which involves:

1) abstract: [(N4Py*)FeII(CH3CN)](ClO4)2 (2)  should be [(N4Py*)MnII(CH3CN)](ClO4)2 (2);

2) Figure 1: Mn 1/PAA, the overall yield is unequal to the sum of the two yields of the two products；

3）Scheme 2: in the mechanism, the authors proposed that N-formalaniline products were produced under the interaction of O2 (in air), so the question is that if the authors did the reaction under the conditions that the O2 was rigorously excluded? and what is the result?

Author Response

 

 

Review 2

Comments and Suggestions for Authors

In this manuscript, the authors prepared two Mn(II) complexes 1 and 2 and studied their catalytic activities toward the oxidative demethylation of N,N-dimethylanilines. They compared the preformance of different catalysts (1, 2 and Mn(CLO4)2) and different oxidants on the oxidative demethylation of N,N-dimethylanilines. In combination with the Hammett plot and some spectroscopic researches, they proposed an eletrophilic mechanism of the catalytically active species with the substrates, which potentially supported the oxidative transformaitons of many biologically degradation catalyzed by non-heme enzymes.

 

Overall, this work seems significant and deserves publishing on the journal.

 

Some corrections should be noticed before its acceptance, which involves:

1) abstract: [(N4Py*)FeII(CH3CN)](ClO4)2 (2)  should be [(N4Py*)MnII(CH3CN)](ClO4)2 (2);

Corrected.

 

2) Figure 1: Mn 1/PAA, the overall yield is unequal to the sum of the two yields of the two products；

Corrected.

 

3）Scheme 2: in the mechanism, the authors proposed that N-formalaniline products were produced under the interaction of O2 (in air), so the question is that if the authors did the reaction under the conditions that the O2 was rigorously excluded? and what is the result?

 

When the reaction was carried out under argon, the catalytic activity was moderate, but it proved to be selective, producing only MA as a product. However, when the reaction was carried out under air, in addition to the main product MA, the formation of MFA was also detected.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Dear Authors,

please, pay careful attention to these few remarks:

1) The statement “In contrast to the iron-containing system, the reaction of the in situ formed oxomanganese(IV) with p-Me-DMA resulted in the immediate generation of a transient absorption band at max = 460 nm (Figure 8a), which can be assigned to the formation of the transient radical cation intermediate, p-Me-DMA+• [32]. This band disappeared immediately and merged into another intense band (544 nm).” Is not consistent with Scheme 8a. Please, look at graph inside spectral box, intensity of 460 mn band vs Time (round dots) – it does not disappear. In addition, why color is not used for spectral lines? All of them are black and it is not convenient. Why color is not used in Figure 8?

2) The statement “In the first round, it can be established that the catalytic activity of the manganese salt (MnII(ClO4)2), and the in situ formed MnII(OAc)2  and MnII(mCBA)2 derivatives in the presence of PAA/AA and mCPBA/mCBA, respectively, is negligible.” is not clear without reference to the specific entry of Table 1. I also should note that results of experiments with Mn(ClO4)2 and, for example, Mn(OAc)2 as catalysts both dissolved in AcOH can be dramatically different. Anion always plays an important role in such simple salts.

3) The remark of the reviewer “ In Scheme 2, stage 1 to 2, check electron balance. It is two-electron oxidation of Mn(II), thus two ROOH molecules are needed or no O-radical should be formed (ROH instead of RO*). In the case of two ROOH molecules it may be not single mechanistic stage.” was not answered and no correctios were made. I mean “Yes. In case of mCPBA and PAA oxene-transfer, while in case of TBHP radical route is proposed.” – is not the answer to the question. Electron balance is not ok.

 

Author Response

Dear Editor,

Dear Reviwer,

Enclosed I send you our revised paper.

Best regards,

József Kaizer

 

Review 1

• The statement “In contrast to the iron-containing system, the reaction of the in situ formed oxomanganese(IV) with p-Me-DMA resulted in the immediate generation of a transient absorption band at lmax = 460 nm (Figure 8a), which can be assigned to the formation of the transient radical cation intermediate, p-Me-DMA+• [32]. This band disappeared immediately and merged into another intense band (544 nm).” Is not consistent with Scheme 8a. Please, look at graph inside spectral box, intensity of 460 mn band vs Time (round dots) – it does not disappear. In addition, why color is not used for spectral lines? All of them are black and it is not convenient. Why color is not used in Figure 8?

Rewrited and new figure included.

In contrast to the iron-containing system, the reaction of the in situ formed oxomanganese(IV) with p-Me-DMA resulted in the immediate generation of a transient absorption band at l_max = 460 nm (Figure 8a), which can be assigned to the formation of the transient radical cation intermediate, p-Me-DMA^+• [32]. This band shows a spontaneous increase for 8-10 s, then merges into a new, intense band (540 nm). The formation of the characteristic band at 460 nm is accompanied by a decrease in the absorption band at 944 nm, which band can be assigned to the oxomanganese(IV) (3) species [34, 55-59]. The new intense absorption in the range of 544 nm indicates a complexation and charge-transfer (CT) type interaction between the oxidant and the substrate, albeit its nature is not known.

• The statement “In the first round, it can be established that the catalytic activity of the manganese salt (MnII(ClO4)2), and the in situ formed MnII(OAc)2  and MnII(mCBA)2 derivatives in the presence of PAA/AA and mCPBA/mCBA, respectively, is negligible.” is not clear without reference to the specific entry of Table 1. I also should note that results of experiments with Mn(ClO4)2 and, for example, Mn(OAc)2 as catalysts both dissolved in AcOH can be dramatically different. Anion always plays an important role in such simple salts.

In the first round, it can be established that the catalytic activity of the manganese salt, Mn^II(ClO₄)₂ is negligible. Regardless of the oxidant used, only few amounts of products were observed (overall yields (the sum of both MA and MFA) are from 0.7 to 2.8%). A somewhat larger but not significant increase in activity was found for Mn(OAc)₂ with 14% yield.

Catalyst1	Co-oxidant	Substrate 4R-DMA	Yield (%)3 4R-MA	Yield (%)3 4R-MFA	MA/MFA	SYield (%)3	TON2
Mn(ClO4)2	PAA/Air	-H	1.6	0.6	2.67	2.2	2.2
Mn(OAc)2	PAA/Air	-H	9.9	4.3	2.30	14.2	14.2

 

3) The remark of the reviewer “ In Scheme 2, stage 1 to 2, check electron balance. It is twoelectron oxidation of Mn(II), thus two ROOH molecules are needed or no O-radical should be formed (ROH instead of RO*). In the case of two ROOH molecules it may be not single mechanistic stage.” was not answered and no correctios were made. I mean “Yes. In case of mCPBA and PAA oxene-transfer, while in case of TBHP radical route is proposed.” – is not the answer to the question. Electron balance is not ok.

New Scheme 3 was included.

The relatively low MA/MFA ratio indicates the presence of autoxidation process, which can be interpreted by the reaction of the DMA● (PhN(Me)CH2●) radical with dioxygen, resulting in the formation of equimolar amount of PhN(Me)CH2OH and PhN(Me)CHO, and finally MA and CH2O via Russel-type termination mechanism (Scheme 2 and Route 1 in Scheme 3).

Moreover, the reaction of the cage-escaped radical with dioxygen is also conceivable, which also leads to MFA (Scheme 2 and Route 1 in Scheme 3). Repeating the reaction in the presence of 2 under argon, we did not observe a formation of MFA, which is consistent with our hypothesis above (Route 2 in Scheme 3). Same behavior has been observed for the [(N4Py*)FeII(CH3CN)](ClO4)2-catalysed oxidation of DMAs under similar conditions [27].

Author Response File: Author Response.pdf