Atom Exchange Radical Cyclization: A Sustainable Synthetic Approach towards New Functionalized Targets
, Andrea Severini 1, Camilla Ferrari 2, Claudio Fontanesi 2,3, Vittorio Ascari 1,†, Niccolò Braidi 1 and Fabrizio Roncaglia 1,3,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript by Roncaglia and coworkers presents the study of the reactivity of -N-allyl-N-phenyl-2,2-dihalopropanamides in a Cu catalyzed radical cyclization reaction where two halogens are present. This work takes advantage of the observed halogen exchange that the reacting intermediates undergo along the reaction. The presented transformation, after the evaluation of the variables that improve its efficiency, represents an atom economic method for accessing dihalogenated (and trihalogenated( cyclic gamma-lactams.
In Figure 3, compound 2 is illustrated as a N-benzylamide. Please, check if it is correct.
The introduction covers adequately the precedents and the challenge that the authors aim to tackle. The experimental procedures are appropriately presented, as the obtained results, which lead to the conclusions drawn by the authors.
For these reasons, it is recommended to proceed to address the aforementioned minor issues prior to final acceptance of the manuscript.
Author Response
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Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript presented by Anderlini and coworkers titled “Atom Exchange Radical Cyclization: A Sustainable Synthetic Approach Towards New Functionalized Targets” presents a novel Atom Exchange Radical Cyclization (AERC) technique that integrates traditional Atom Transfer Radical Cyclization with a halogen exchange process. This method is significant in synthetic chemistry as it promises enhanced atom economy and could potentially lead to more sustainable chemical processes.
Nonetheless, there are minor issues that need to be addressed before the manuscript can be accepted.
1. The discussion section primarily focuses on the methodology and immediate results. It could be expanded to include broader implications of the findings, comparisons with other methods, and potential applications in various industries, which provide a deeper understanding of the method’s importance.
2. While the paper does a good job of optimizing the copper-based catalyst system, it might benefit from exploring or discussing alternative catalysts that further enhance the sustainability or efficiency of the process.
3. The figures included (mechanisms and synthetic applications) are informative but could be improved in clarity and detail. Enhanced graphical representations could make the paper more accessible to readers unfamiliar with radical cyclization.
4. The paper proposes mechanistic pathways for the AERC process; however, more detailed kinetic studies or computational models could be presented to substantiate these proposed mechanisms robustly.
5. In table 2 the authors do not indicate in the discussion how the polarity of the cosolvent affects the conversion. Do the authors have any clue?
Regarding the edition of the manuscript, some points also need attention:
1. Incorrect or inconsistent hyphenation in compound names and scientific terms should be standardized according to the IUPAC guidelines or journal-specific style manuals.
2. In several places, articles ("a", "an", "the") are missing or used incorrectly, which affects the readability and professional quality of the text.
3. Ensure consistent terminology, especially with abbreviations. For instance, if "AERC" is used as an abbreviation for "Atom Exchange Radical Cyclization," it should be used consistently throughout the document after the first full mention.
4. Check the consistency of units and numerical data presentation. For example, ensure that all percentages are accompanied by the "%" symbol and that there is no space between the number and the percentage sign.
5. Some sentences are overly complex or run-on. Breaking these into simpler sentences can improve clarity and understanding.
6. Comma usage is inconsistent, particularly in lists and compound sentences. Standardizing comma use can improve readability.
7. Ensure proper use of semicolons and colons for lists and explanatory statements.
8. Inconsistent capitalization of chemical names, techniques, and generic terms should be addressed. For example, "Atom Exchange Radical Cyclization" should either always be capitalized when used as a defined term or not, depending on style guidelines.
Here are some specific Corrections:
Introduction section
1. Catalytic amount: Corrected "the use of catalytic amount" to "the use of a catalytic amount" for grammatical accuracy.
2. ATRP stands out: Added "stands" to "ATRP stand out" for grammatical agreement.
3. Comma after i.e.: Added a comma after "i.e." for correct punctuation.
4. Polydispersity: Ensured consistency in terminology and description.
5. Transition metal-catalyzed ATRC: Clarified the descriptor for better readability and technical accuracy.
6. Halogen atom: Consistency in chemical terminology, ensuring that the description matches the standard scientific nomenclature.
7. tris(2-pyridylmethyl)amine: Corrected to "tris(2-pyridylmethyl)amine" from "tris(2-pyridilmethyl)amine" to fix the typographical error in the chemical name.
Material and methods section
Original: "were weighed ascorbic acid..."
Corrected: "ascorbic acid was weighed..."
Original: "...once the substrate was fully solubilized – a 0.04 mol/L solution of CuCl2/TPMA in absolute ethanol (EtOH, 1 mL) were added..."
Corrected: "...once the substrate was fully solubilized, a 0.04 mol/L solution of CuCl2/TPMA in absolute ethanol (EtOH, 1 mL) was added..."
Original: "...previously rinsed with a 10% aqueous NH4OH and water in sequence..."
Corrected: "...previously rinsed with 10% aqueous NH4OH and water in sequence..."
Check for consistent representation of chemical compounds and formulations, e.g., "CuCl2" should consistently appear without spaces in the molecular formula. Also, it's crucial to maintain consistency in the way chemical names are written, particularly when transitioning from abbreviations to full names, e.g., "ethyl acetate (AcOEt, 3 mL)" should be formatted consistently when referred to by its abbreviation or full name throughout the text.
"In the ARGET-ATRC process towards compound 2, an oven-dried Schlenk tube, previously rinsed with 10% aqueous NH4OH and water, was used. Ascorbic acid (0.2 mmol, 35.2 mg), Na2CO3 (0.4 mmol, 42.4 mg), and amide 1 (8 mmol, 2.065 g) were accurately weighed. After three cycles of vacuum and argon (approximately 10 minutes each), ethyl acetate (3 mL) was added. Once the substrate had fully solubilized, a 0.04 mol/L solution of CuCl2/TPMA in absolute ethanol (1 mL) was introduced under an argon atmosphere. The reaction mixture was then heated at 35°C and stirred at 700 rpm for 8 hours."
Results and discussion section
Original: "A higher concentration of Cu(II)Br·L was potentially associ-ated with a dominant AERC..."
Corrected: "A higher concentration of Cu(II)Br·L would potentially be associated with dominant AERC..."
Original: "The inclusion of increasing amounts of NaBr within the reaction mixture, was then expected to bring the formation of increasing amounts of bro-minated compounds..."
Corrected: "The inclusion of increasing amounts of NaBr within the reaction mixture was then expected to lead to the formation of increasing amounts of brominated compounds..."
Original: "The formation of dibromide 3b from the AERC product 3 may also follow the same substitution mechanism."
Corrected: "The same substitution mechanism may also apply to the formation of dibromide 3b from the AERC product 3."
Original: "The limited operativity of the radical substitution mechanisms affording 3a or 3b, in the AERC reaction conditions, was then ascertained."
Corrected: "The limited effectiveness of the radical substitution mechanisms that produce 3a or 3b under AERC reaction conditions was then confirmed."
Original: "This new compound featured higher retention in GC-MS (r.t. ~ 13.95 min) compared to 2 (GC r.t. ~ 12.90 min) and is characterized by a MS pattern compatible with a bromo-chloro lactam."
Corrected: "This new compound, which featured higher retention in GC-MS (r.t. ~ 13.95 min) compared to compound 2 (GC r.t. ~ 12.90 min), was characterized by an MS pattern compatible with a bromo-chloro lactam."
Original: "The greater selectivity observed at higher EtOH concentrations suggests that salt sol-ubility might play a significant role in the outcome of the reaction."
Corrected: "The greater selectivity observed at higher EtOH concentrations suggests that salt solubility might play a significant role in determining the reaction's outcome."
I strongly recommend that the authors have the manuscript revised by a native English speaker or writer.
After making the necessary corrections to address all the issues, the document should be re-evaluated to ensure that all changes preserve the scientific accuracy and integrity of the work. I recommend acceptance pending minor changes.
Comments on the Quality of English Language
I detect several grammatical errors in the whole document, I strongly recommend that the authors have the manuscript revised by a native speaker/writer of English.
Author Response
Please, see the attache pdf file
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsIn this manuscript is detailed a novel atom exchange radical cyclization (AERC) of allyldichloroamides to access functionalized pyrrolidinones. The more classical atom transfer racial cyclization (ATRC) pathway to form dichlorinated products is bypassed through the formation of CuBrL as an intermediate of the catalyst through the use of added bromide as NaBr. Furthermore, the AERC/ATRC ratio is shown to be sensitive to solvent with AERC being favored in protic solvents. Tricholoracetamides were also shown to be competent substrates for the AERC method with similar solvent dependencies. Overall, the developed method should be valuable and the study was expertly executed. Only minor points/concerns are addressed below.
- line 192-193. Should it be Cu(I)BrL or BrCu(II)ClL?
- The role of the protic solvent was not fully addressed. One possibility to consider is that protic solvents will help drive the halide exchange equilibrium to favor Br-CuCl-L by solvating the ionized Cl-, as Cl- is more strongly solvated in protic solvents than Br-, which will favor AERC.
Author Response
Please, see the attached pdf file
Author Response File: Author Response.pdf
Reviewer 4 Report
Comments and Suggestions for Authors
The manuscript submitted by Roncaglia and co-workers describes the facile synthesis of dihalo-gamma-lactams using the Atom Exchange Radical Cyclization (AERC) method. The synthesis was performed on a gram scale under mild conditions, using commonly used reagents. In addition, cyclization precursors are readily accessible by simple operation, which would be beneficial for further substrate scope. Therefore, I recommend that the manuscript be published in Applied Sciences after addressing the following minor remarks.
1) LL48–52: Although the authors explained the importance of the N-substituent of the cyclization precursor, different N-substituents were used, a phenyl group for 1 and a benzyl group for 4. The authors should explain the reason why different substituents were used.
2) L323: The amount of minor product 5 was estimated to be ~15 mol% (“mol” should be removed). However, the authors described “~9% GC of 5” in the Materials and Methods section (L179). Since Figure S2 shows 1H NMR analysis of the reaction of 4 to 6 (major) and 5 (minor), “~15 mol%” in L323 should be changed to “15% based on 1H NMR”.
3) From the viewpoint of further transformation of the synthesized lactam, please mention the possibility of deprotection of the phenyl group from 3 or the benzyl group from 6.
4) L168, L188: In addition to elemental analysis data, I would like to request the mass spectral data of compounds 3 and 6 as proof of the presence of bromide atoms.
5) L31–L32: Insert appropriate references for ATRP.
Other points:
6) L115: Capitalize “d” of “2,2-dichloropropanoyl”.
7) L143: Since the abbreviation “SARA” appears first here, the formal name of SARA should be described here rather than L235.
8) LL341–348: Specify author contributions.
9) L356, L361, L409: G(gamma) should be lowercase.
10) L363: Italicize “H” of “2H-1-Benzopyrans”
11) L376: The numbers of “(Ph3P)3RuCl2” should be subscripts.
12) L376: Italicize “N” of “N-Tosyl”
13) L382: The numbers of “H2O2” should be subscripts.
14) L385: The numbers of “H2O2” and “AlCl3” should be subscripts.
15) LL399, 400: Italicize “N”s of “N-Allyl-N-Benzyl”.
16) L400: The “0” of “Fe0” should be superscript while the “3” of “FeCl3” should be subscript.
17) L409: “B” of “B(beta)- and G(gamma)-Lactams” should be lowercase.
Author Response
Please, see the attached pdf file
Author Response File: Author Response.pdf
