Upgrading Renewable Phenols to Functional Benzyl Chlorides and Formamides: Versatile Building Blocks for the Chemical Industry

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript by Porcelli et al. reports a sustainable synthetic approach for the transformation of bio-derived phenols into mono-, di-, and tri-functional benzyl chlorides via a Blanc–Quelet-type chloromethylation reaction. The resulting benzyl chlorides are subsequently converted to benzyl formamides through an amidation process. The authors demonstrate that, through careful process optimization, many of these transformations can be conducted under “on-water” conditions, significantly reducing the use of organic solvents. Control over the degree of substitution (mono-, di-, or tri-chloromethylation) is achieved by adjusting the stoichiometry of the reagents and the reaction conditions.

This manuscript is interesting and can be acceptable to the Journal. There are  few comments and suggestions to the authors.

(1) The manuscript demonstrates excellent selectivity, particularly for piceol, where mono- and di-chloromethylation products are obtained in a controlled manner. A more detailed discussion on the reaction kinetics would greatly enhance the mechanistic understanding of why substrates such as piceol exhibit better selectivity compared to more activated substrates like guaiacol or eugenol.

(2) For eugenol and guaiacol, a drop in selectivity and the formation of complex mixtures are noted, requiring the use of DCM to homogenize the reaction medium. The authors may consider exploring the use of mild protective groups (e.g., silyl ethers) for phenolic hydroxyl groups, particularly where acyl protecting groups are unstable under aqueous acidic conditions.

(3) In line with the manuscript’s sustainability focus, the authors could discuss the potential use of phase-transfer catalysis strategies. Such approaches would facilitate selective mono- or di-chloromethylation of phenolic compounds without relying on hazardous solvents like DCM.

(4) Under acidic aqueous formaldehyde conditions, phenols are prone to polymerization, leading to the formation of phenol-formaldehyde resins. While the manuscript reports clean product formation, it does not address whether oligomeric byproducts are observed or how resin formation is suppressed. A discussion of this potential side reaction and the strategies employed to minimize or avoid it is needed.

(5) It is known that benzyl chlorides bearing electron-donating groups can react more slowly or undergo side reactions during amidation with formamide under reflux. The manuscript reports clean conversions for all substrates. It, however, would be useful for the authors to comment on whether electron-donating substituents have any measurable impact on reaction rates, yields, or purification challenges.

(6) As the manuscript emphasizes the sustainable nature of the synthetic route, it would be beneficial for the authors to explicitly compare the environmental metrics (e.g., E-factor, process mass intensity (PMI)) of their method against traditional chloromethylation protocols. Such a comparison would better substantiate the claims of improved environmental performance.

 

Author Response

Please, see the attached file

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript presents an interesting and well-structured study focused on upgrading bio-based phenolic compounds via chloromethylation and subsequent amidation processes, providing valuable building blocks for chemical and material sciences. The research is timely, innovative, and fits well within the scope of Applied Sciences. Also, the experimental work is solid and supports the proposed applications.

The introduction is well-organized and offers a comprehensive overview of the relevance of bio-based phenolics, their chemical properties, and their potential applications. It provides a clear rationale for selecting the Blanc-Quelet reaction for chloromethylation processes. Additionally, recent literature is appropriately cited, although I suggest briefly mentioning more recent sustainable advances in lignin valorization, which could strengthen the introduction even further.

Also, include a short paragraph highlighting recent green chemistry trends regarding biomass-derived building blocks and a concise clarification could be added to better explain why the amidation of chloromethylated phenols represents a strategic route compared to other valorization methods.

Moreover, the methodology is adequately detailed, ensuring reproducibility. The description of the synthetic routes, choice of reagents, reaction conditions, and analytical methods (NMR, elemental analysis) is appropriate and clear. However, a minor suggestion is to briefly justify why THF was preferred for amidation reactions instead of other solvents from a green chemistry perspective, aligning with the sustainability focus highlighted in the introduction.

Furthermore, the results are systematically presented for each bio-based phenol studied where tables and reaction schemes are clear and facilitate understanding. The discussion provides meaningful insights into reaction conditions, selectivity, and substrate behavior, with a logical progression from experimental results to conclusions.
One minor point for improvement: it is important to consider briefly discussing possible limitations or scalability aspects of the chloromethylation process under your described conditions.

Finally, the conclusions are coherent and accurately reflect the findings. The authors emphasize the green chemistry aspects and the synthetic versatility of the obtained compounds appropriately.

Author Response

Please, see the attached file

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The authors presented the conversion of phenols to benzyl chlorides and formamides. The work is moderately interesting and the presentation adequate. The compounds presented appear to be novel.
However, the products are not fully characterised therefore I suggest that the paper is rejected.
The paper can only be reconsidered if the comments below are corrected.

Further comments:
-The products are not fully characterised. 13C NMR, mp, IR and Mass spectrommetry data are missing. All these neeed to be added.
-Figure 3. The starting material (formamide) is missing from the reaction scheme.
-Figure 4. Please add the yields of each reaction. The same applies to all figures.
-The supporting information file is of poor quality. The spectra show that the products are not clean. Please provide clean spectra. Also have one spectrum per page in a landscape configuration so that the peaks are more clear.

Author Response

Please, see the atteched file

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript entitled “Upgrading Renewable Phenols to Functional Benzyl Chlorides and Formamides: Versatile Building Blocks for the Chemical Industry” by N. Porcelli et al. presents a synthetic method for upgrading bio-based phenols into benzyl chlorides and their subsequent conversion to N-formylamides, positioning these compounds as potential building blocks for polymers and specialty chemicals. The study leverages the Blanc-Quelet reaction, a well-established process, and applies it to a selection of bio-based phenols, which is a commendable effort toward sustainable chemistry. The manuscript may be of general interest to the researchers of this field. However, the manuscript suffers from several evidential and logical shortcomings that undermine its scientific rigor and claims. Specific concerns are outlined below and recommendations for addressing them are provided. Therefore, I recommend major revisions, including additional experiments and data analysis.

1. The abstract must be rewritten to align with the journal’s guidelines. The current abstract is overly brief and lacks specificity about the carried-out research.
2. The authors’ assertion of "quantitative yields" for amidation (Section 2.3, p. 4) is not supported by the supplementary NMR spectra. These impurities suggest that yields are not truly 100%, as losses during purification or side products are likely. The authors should revise these claims to reflect actual isolated yields, provide purification details, and include purity assessments (e.g., HPLC) to validate product quality (LC-MS analysis).
3. ¹³C NMR should be added for the compounds, as they were mentioned at the beginning of the experimental section.
4. Melting points of the compounds should be added to the experimental part.
5. To ensure clarity and compliance with chemical nomenclature standards, IUPAC names should be provided for all compounds in the experimental part.

Author Response

Please, see the attache file

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript has been sufficiently improved and can now be accepted for publication.

Reviewer 4 Report

Comments and Suggestions for Authors

 Thank you for your response to my suggestions. I agree with your answers.