Review Reports - Spontaneous Release of Metalloradicals and Coordinatively Unsaturated Species in Asymmetric Iridium Dimers to Promote C-N Bond Formation

Round 1

Reviewer 1 Report

In the present manuscript Chen et al report on synthesis of iridium dimer complex and its use in C-N bond forming reactions. The complex was characterized by X-ray, EPR and MS techniques. They proposed that dimer complex dissociates in solution to give catalytically active species, which are prone to couple primary alcohols and primary amines giving secondary amines. According to the isolated yields, the coupling reactions seem to work well, by simply mixing reactants and catalyst without solvent. The synthetic versatility of the reaction was nicely demonstrated by preparing a biologically active compound cyclizine. The entire experimental work is carefully done and supports their conclusions. Products are adequately characterized, and the structures supported by spectroscopic methods. However, the entire article has to be checked by an English expert. The proposed mechanistic pathway in Scheme 2 has to be carefully checked, as there are some inconsistencies regarding the intermediates. In my opinion, this work can be published in Inorganics only after careful revision.

Some remarks:

1.) Sheme 1: Which species is eliminating? ClO radical, anion?

2.) Scheme 2: formal charges have to be clearly presented (usually encircled) where appropriate, please check! in step VI, put the + charge on O! step V: how is radical-anion intermediate transforming into radical?

3.) in N-benzylaniline and analogues ‘’N’’ as well as p (para), n (n-hexane) etc. have to be italic

4.) Scheme 3: in reaction b) diphenylmethanamine is used, but in the text diphenylamine is mentioned

5.) experimental part: omit g/mol when MS is given

Author Response

Journal: Inorganics

Manuscript ID: inorganics-2033983

TITLE: Spontaneous Release of Metalloradicals and Coordinatively Unsaturated Species in Asymmetric Iridium Dimers to Promote C-N Bond Formation

Dear Editor:

Thank you for providing us an opportunity to revise the above-mentioned manuscript. We also thank you for your useful comments and suggestions on our manuscript. We have modified the manuscript accordingly, and the detailed corrections are listed below point by point. The changes in the text are marked in red.

REVIEWER REPORT(S):
Reviewer 1: In the present manuscript Chen et al report on synthesis of iridium dimer complex and its use in C-N bond forming reactions. The complex was characterized by X-ray, EPR and MS techniques. They proposed that dimer complex dissociates in solution to give catalytically active species, which are prone to couple primary alcohols and primary amines giving secondary amines. According to the isolated yields, the coupling reactions seem to work well, by simply mixing reactants and catalyst without solvent. The synthetic versatility of the reaction was nicely demonstrated by preparing a biologically active compound cyclizine. The entire experimental work is carefully done and supports their conclusions. Products are adequately characterized, and the structures supported by spectroscopic methods. However, the entire article has to be checked by an English expert. The proposed mechanistic pathway in Scheme 2 has to be carefully checked, as there are some inconsistencies regarding the intermediates. In my opinion, this work can be published in Inorganics only after careful revision.

Ans: We thank the reviewer’s valuable comment

Which species is eliminating? ClO radical, anion?

Ans: In this case, the chloride ion is most likely to combine with the oxygen atom to form a free radical, but it is difficult to detect.

Scheme 2: formal charges have to be clearly presented (usually encircled) where appropriate, please check! in step VI, put the + charge on O! step V: how is radical-anion intermediate transforming into radical?.

Ans: We thank the reviewers for their valuable comments. As suggested by the reviewers. Scheme 2 is rewritten as follows:

When an alcohol is used as an alkylating agent, the lone electron pair of the alcohol (Lewis base) combines with the vacant coordination site of 1b (Lewis acid) to form an alcohol-bound complex (step I). Then, β-hydride elimination of the alcohol-bound complex forms the iridium-hydride complex (step II). Then, the β-hydride elimination iridium-alkoxide of gives an aldehyde which undergoes dehydrative condensation with amine to give an imine intermediate (step III). Finally, imines are reduced to amines via hydride-transfer reduction of the iridium complex to complete the catalytic cycle (step IV). For the left cycle, the iridium radical (1a) traps alcohol in the first step (step V). Then, β-hydride elimination of the alcohol-bound radical complex forms the iridium-alkoxide radical with hydrido and oxyl ligand (step VI). Then, a second hydrogen atom is transferred from the α-hydrogen of alkoxide group of the radical intermediate to the oxy-group, leading to the formation of iridium complex with hydrido and hydroxido ligands and release aldehyde undergoes dehydrative condensation with amine to give imine intermediate (step VII). Finally, proton and hydride transfer from iridium-hydride and -hydroxide complex to imine yields N-alkylation product and recovered iridium complex 1a (step VIII).

In N-benzylaniline and analogues ‘’N’’ as well as p (para), n (n-hexane) etc. have to be italic

Ans: All prefixes have been modified to italics.

Scheme 3: in reaction b) diphenylmethanamine is used, but in the text diphenylamine is mentioned

Ans: Diphenylamine is changed to diphenylmethylamine in the text.

experimental part: omit g/mol when MS is given

Ans: All this typing has been removed.

The revised manuscript has been submitted to your journal. We are looking forward to your positive response.

Sincerely

Tsun-Ren Chen

-----------------------

Tsun-Ren Chen

Professor

Department of Applied Chemistry

National Pingtung University

No.4-18, Minsheng Rd.,

Pingtung County 90003, Taiwan

Phone: 886-9-33261376
Email: trchen@mail.nptu.edu.tw

FAX: 886-8-723-0305

Author Response File: Author Response.pdf

Reviewer 2 Report

This manuscript written by Chen et al. describes a preparation and characterization of unusual dinuclear iridium complex which exhibited catalytic ability in N-alkylation of amines using alcohols as alkylating reagents. EPR analysis indicated an existence of an unpaired electron on the dinuclear iridium complex. Orbital analysis of the complex was performed by DFT calculation to indicate SOMO and LUMO. Oxidation states of the two iridium centers were discussed by using XPS analysis. The complex could be applied to a catalytic N-alkylation reaction of amines. These experimental and computational results are intriguing; however, a proposed mechanism for the catalytic N-alkylation reaction shown in scheme 2 has some controversial and unreasonable points to be improved. So, this work can be published in Inorganics after major revision on the reaction mechanism for the N-alkylation reaction. Concerns are as follows:

1) In scheme 2, right cycle, generation of 1b from fragmentation of dinuclear complex 1 is reasonable. But the catalytic cycle is unacceptable to general organometallic chemists. Coordination of an alcohol to 1b is possible; however, the following step is unlikely. Nucleophilic attack of amine to a carbon atom of the coordinating alcohol together with simultaneous hydride transfer from carbon to iridium is generally unbelievable. Typically accepted mechanism is the first β-hydride elimination of iridium-alkoxide complex formed via deprotonation of alcohol-bound complex. Then, the β-hydride elimination gives an aldehyde which undergoes dehydrative condensation with amine to give an imine intermediate. Finally, the imine is reduced to amine by hydride transfer from iridium complex to complete the catalytic cycle. If the authors propose the mechanism in the present form, some experimental evidence and literature references are required. The reviewer agrees to generally accepted mechanism of the typical N-alkylation reaction.

2) In scheme 2, left cycle, generation of 1a from fragmentation of dinuclear complex 1 is possible. But the following mechanism is unreliable. If hydrogen atom transfer from alcohol to 1a occurs, carbon radical intermediate and Ir-oxyl radical complex shold be generated. So, the anion center on the oxygen atom of the iridium complex is not true. Then, second hydrogen atom transfer from hydroxyl group of the radical intermediate to the oxyl center of the iridium complex occurs to give mere aldehyde and iridium complex having hydrido and hydroxido ligand, as shown in the present scheme 2. So, generation of aldehyde radical intermediate is less likely. The generated aldehyde undergoes dehydrative condensation with amine to give imine intermediate. Finally, proton and hydride transfer from iridium-hydride and -hydroxide complex to imine, otherwise, twice hydrogen atom transfers from the iridium complex to imine occurs to give N-alkylation product and recovered iridium complex 1a.

3) From illustration in Figure 3, SOMO of the complex looks like to be delocalized to 2 cpbo ligands bound to each iridium centers; however, in the main text, the authors insist delocalization to 4 cpbo ligands. Is it truly delocalized to 4 cpbo ligands?

Following points are minor concerns.

4) Details on the computational studies are lacked. Information on the basis sets, solvation effects, and coordinates for the optimized structure are required. Comparison of the optimized structure with the X-ray structure around the iridium centers would be beneficial for discussing validity of the computational method.

5) Catalyst loading ratios should be described in molar ratios mmol/mmol, not in g/mmol.

Author Response

Journal: Inorganics

Manuscript ID: inorganics-2033983

TITLE: Spontaneous Release of Metalloradicals and Coordinatively Unsaturated Species in Asymmetric Iridium Dimers to Promote C-N Bond Formation

Dear Editor:

REVIEWER REPORT(S):
Reviewer 2: This manuscript written by Chen et al. describes a preparation and characterization of unusual dinuclear iridium complex which exhibited catalytic ability in N-alkylation of amines using alcohols as alkylating reagents. EPR analysis indicated an existence of an unpaired electron on the dinuclear iridium complex. Orbital analysis of the complex was performed by DFT calculation to indicate SOMO and LUMO. Oxidation states of the two iridium centers were discussed by using XPS analysis. The complex could be applied to a catalytic N-alkylation reaction of amines. These experimental and computational results are intriguing; however, a proposed mechanism for the catalytic N-alkylation reaction shown in scheme 2 has some controversial and unreasonable points to be improved. So, this work can be published in Inorganics after major revision on the reaction mechanism for the N-alkylation reaction. Concerns are as follows:

Ans: We thank the reviewer’s valuable comment

In scheme 2, right cycle, generation of 1b from fragmentation of dinuclear complex 1 is reasonable. But the catalytic cycle is unacceptable to general organometallic chemists. Coordination of an alcohol to 1b is possible; however, the following step is unlikely. Nucleophilic attack of amine to a carbon atom of the coordinating alcohol together with simultaneous hydride transfer from carbon to iridium is generally unbelievable. Typically accepted mechanism is the first β-hydride elimination of iridium-alkoxide complex formed via deprotonation of alcohol-bound complex. Then, the β-hydride elimination gives an aldehyde which undergoes dehydrative condensation with amine to give an imine intermediate. Finally, the imine is reduced to amine by hydride transfer from iridium complex to complete the catalytic cycle. If the authors propose the mechanism in the present form, some experimental evidence and literature references are required. The reviewer agrees to generally accepted mechanism of the typical N-alkylation reaction.

Ans: We thank the reviewers for their valuable comments. As suggested by the reviewers. Scheme 2 is rewritten as follows:

In scheme 2, left cycle, generation of 1a from fragmentation of dinuclear complex 1 is possible. But the following mechanism is unreliable. If hydrogen atom transfer from alcohol to 1a occurs, carbon radical intermediate and Ir-oxyl radical complex shold be generated. So, the anion center on the oxygen atom of the iridium complex is not true. Then, second hydrogen atom transfer from hydroxyl group of the radical intermediate to the oxyl center of the iridium complex occurs to give mere aldehyde and iridium complex having hydrido and hydroxido ligand, as shown in the present scheme 2. So, generation of aldehyde radical intermediate is less likely. The generated aldehyde undergoes dehydrative condensation with amine to give imine intermediate. Finally, proton and hydride transfer from iridium-hydride and -hydroxide complex to imine, otherwise, twice hydrogen atom transfers from the iridium complex to imine occurs to give N-alkylation product and recovered iridium complex 1a.

Ans: We thank the reviewers for their valuable comments. Answer combined with answer from comment 1.

From illustration in Figure 3, SOMO of the complex looks like to be delocalized to 2 cpbo ligands bound to each iridium centers; however, in the main text, the authors insist delocalization to 4 cpbo ligands. Is it truly delocalized to 4 cpbo ligands?

Ans: We thank the reviewer for the valuable comments. The statement has been revised to "two 4-cpbo ligands".

Details on the computational studies are lacked. Information on the basis sets, solvation effects, and coordinates for the optimized structure are required. Comparison of the optimized structure with the X-ray structure around the iridium centers would be beneficial for discussing validity of the computational method.

Ans: The information from the computational studies has been verified and a comparison of the optimized structure with the X-ray structure around the iridium center has been added as Table 2. The coordinates of the optimized structures are shown in Table S1.

Table 2 Comparison of selected bond lengths (Å) and angles (^o) of 1 from crystallography and DFT calculation

	Ir-Cl	Ir-O	Ir-N	Ir-C
X-Ray	2.457(3)	2.153(5)	2.157(7)	2.035(9)
	2.402(3)	2.093(5)	2.069(8)	2.022(10)
			2.049(7)	2.021(9)
			2.037(7)	2.011(9)
DFT	2.454	2.150	2.154	2.031
	2.309	2.090	2.065	2.017
			2.045	2.016
			2.033	2.008

Catalyst loading ratios should be described in molar ratios mmol/mmol, not in g/mmol.

Ans: Catalyst loading ratios was changed from g/mmol to molar ratios mmol/mmol.

The revised manuscript has been submitted to your journal. We are looking forward to your positive response.

Sincerely

Tsun-Ren Chen

-----------------------

Tsun-Ren Chen

Professor

Department of Applied Chemistry

National Pingtung University

No.4-18, Minsheng Rd.,

Pingtung County 90003, Taiwan

Phone: 886-9-33261376
Email: trchen@mail.nptu.edu.tw

FAX: 886-8-723-0305

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

the authors redraw the proposed mechanism. Again, I recommend to check it carefully (charges!). also check the corresponding text.

Author Response

Journal: Inorganics

Manuscript ID: inorganics-2033983

TITLE: Spontaneous Release of Metalloradicals and Coordinatively Unsaturated Species in Asymmetric Iridium Dimers to Promote C-N Bond Formation

Dear Editor:

REVIEWER REPORT(S):
Reviewer 1: the authors redraw the proposed mechanism. Again, I recommend to check it carefully (charges!). also check the corresponding text.

Ans: We thank the reviewer’s valuable comment. According to the reviewer's suggestion, the proposed mechanism was redrawn, and formal charges was presented.

The alcohol binds to the vacant coordination site of 1b and is then deprotonated by the extra amine, resulting in the dissociation of ammonium chloride to give the coordinatively unsaturated Ir-alkoxide complex I (step a). Then, β-hydride elimination occurs to give an Ir(III)-hydride complex II and an aldehyde (step b). Dehydration condensation of aldehydes and amines yields imine intermediate, which is attacked by Ir-hydrides to yield Ir-amide intermediates III (step c). Finally, protonation by ammonium chloride furnishes the catalytic cycle to generate alkylated amines and recovered Ir catalyst (step d). For the left cycle, the iridium radical (1a) traps alcohol in the first step (step e). Then, proton transfer from bound alcohol to oxido ligand, resulting in iridium complex VI with hydroxido and alkoxido ligands (step f). Then, β-hydride elimination occurs to give an iridium complex VII with hydrido and hydroxido ligands and releases aldehyde undergoes dehydrative condensation with amine to give imine intermediate (step g). Finally, proton and hydride transfer from iridium-hydride and -hydroxide complex to imine yields N-alkylation product and recovered iridium complex 1a (step h).

Sincerely

Tsun-Ren Chen

-----------------------

Tsun-Ren Chen

Professor

Department of Applied Chemistry

National Pingtung University

No.4-18, Minsheng Rd.,

Pingtung County 90003, Taiwan

Phone: 886-9-33261376
Email: trchen@mail.nptu.edu.tw

FAX: 886-8-723-0305

Author Response File: Author Response.pdf

Reviewer 2 Report

The reaction mechanism for N-alkylation of amine in Scheme 2 requires further improvement.

For right cycle: step I is OK, but step II should be wrong. The revised step II here is a formal oxidative addition of O-H bond to Ir(III), affording Ir(V) complex. This is unlikely process. So, more plausible mechanism is deprotonation by extra amine resulting in dissociation of ammonium chloride to give a coordinatively unsaturated Ir-alkoxide complex. Then, β-hydride elimination occurs to give an Ir(III)-hydride complex and an aldehyde. The aldehyde undergoes dehydrative condensation with amine to give imine intermediate, which is attacked by Ir-hydride to give Ir-amide intermediate. Finally, protonation by ammonium chloride furnishes the catalytic cycle to generate alkylated amine and recovered Ir catalyst. Please see an attached pdf file.

For left cycle: similar to the revised right cycle, formal oxidative addition of O-H bond is involved in step VI. This is unlikely. Proton transfer from bound alcohol to oxido or oxyl ligand is more likely. Please see the attached pdf file for an illustration of the mechanism.

The reviewer felt that the other parts of the manuscript was appropriately improved. So, please re-consider the reaction mechanism in Scheme 2.

Comments for author File: Comments.pdf

Author Response

Journal: Inorganics

Manuscript ID: inorganics-2033983

TITLE: Spontaneous Release of Metalloradicals and Coordinatively Unsaturated Species in Asymmetric Iridium Dimers to Promote C-N Bond Formation

Dear Editor:

REVIEWER REPORT(S):
Reviewer 2: For right cycle: step I is OK, but step II should be wrong. The revised step II here is a formal oxidative addition of O-H bond to Ir(III), affording Ir(V) complex. This is unlikely process. So, more plausible mechanism is deprotonation by extra amine resulting in dissociation of ammonium chloride to give a coordinatively unsaturated Ir-alkoxide complex. Then, β-hydride elimination occurs to give an Ir(III)-hydride complex and an aldehyde. The aldehyde undergoes dehydrative condensation with amine to give imine intermediate, which is attacked by Ir-hydride to give Ir-amide intermediate. Finally, protonation by ammonium chloride furnishes the catalytic cycle to generate alkylated amine and recovered Ir catalyst. Please see an attached pdf file. For left cycle: similar to the revised right cycle, formal oxidative addition of O-H bond is involved in step VI. This is unlikely. Proton transfer from bound alcohol to oxido or oxyl ligand is more likely. Please see the attached pdf file for an illustration of the mechanism. The reviewer felt that the other parts of the manuscript was appropriately improved. So, please re-consider the reaction mechanism in Scheme 2.:

Ans: We thank the reviewers for their valuable comments. As suggested by the reviewers. Scheme 2 is rewritten as follows:

Sincerely

Tsun-Ren Chen

-----------------------

Tsun-Ren Chen

Professor

Department of Applied Chemistry

National Pingtung University

No.4-18, Minsheng Rd.,

Pingtung County 90003, Taiwan

Phone: 886-9-33261376
Email: trchen@mail.nptu.edu.tw

FAX: 886-8-723-0305

Author Response File: Author Response.pdf

Round 3

Reviewer 2 Report

The modified mechanism in Scheme 2 is almost acceptable. Minor mistakes are still left on the structures of Ir complex I and imine intermediates. A proton on the O atom of coordinated alcohol in complex I should be removed. Similarly, a proton on the N atom of the imine intermediate should be removed, otherwise the structure means an iminium cation. Points to be corrected in Scheme 2 is shown in an attached pdf file.

The reviewer believes that this manuscript can be published just after this subtle correction.

Comments for author File: Comments.pdf

Author Response

Journal: Inorganics

Manuscript ID: inorganics-2033983

TITLE: Spontaneous Release of Metalloradicals and Coordinatively Unsaturated Species in Asymmetric Iridium Dimers to Promote C-N Bond Formation

Dear Editor:

REVIEWER REPORT(S):
The modified mechanism in Scheme 2 is almost acceptable. Minor mistakes are still left on the structures of Ir complex I and imine intermediates. A proton on the O atom of coordinated alcohol in complex I should be removed. Similarly, a proton on the N atom of the imine intermediate should be removed, otherwise the structure means an iminium cation. Points to be corrected in Scheme 2 is shown in an attached pdf file.

Ans: We thank the reviewer’s valuable comment. According to the reviewer's suggestion, the proposed mechanism was redrawn. The proton on the O atom of coordinated alcohol in complex I, and on the N atom of the imine intermediate were removed.

The revised manuscript has been submitted to your journal. We are looking forward to your positive response.

Sincerely

Tsun-Ren Chen

-----------------------

Tsun-Ren Chen

Professor

Department of Applied Chemistry

National Pingtung University

No.4-18, Minsheng Rd.,

Pingtung County 90003, Taiwan

Phone: 886-9-33261376
Email: trchen@mail.nptu.edu.tw

FAX: 886-8-723-0305

Author Response File: Author Response.pdf