Concatenated Batch and Continuous Flow Procedures for the Upgrading of Glycerol-Derived Aminodiols via N-Acetylation and Acetalization Reactions
Round 1
Reviewer 1 Report
The manuscript ‘Concatenated batch and continuous flow procedures for the upgrading of glycerol-derived aminodiols via amidation and acetalization reactions’ submitted to catalysts by Rigo et al. (catalysts-1042043) describes a two-step procedure combining a batch and continuous flow setup for the upgrading of two aminodiol regioisomers.
While I do not doubt that the results and the protocol development are of interest to the scientific community, I wonder why the authors have chosen catalysts to disseminate their work. The first reaction (N-acetylation) is catalyst free. The second reaction is catalyzed by a solid acid catalyst. But the authors admit that ‘In line with previous studies on the acetalization of glycerol, this study confirms that acid organic resins, specifically Amberlyst (A15) shows a far better performance than other solid catalysts’. The manuscript does not add anything new in this regard and the catalytic part does not attempt a rationalization in any way. Solely table 2 shows a catalytic comparison.
Let me be more specific here. As the performance of the various catalysts was known from the literature, why have AF and HY been tested to begin with (the expectation must have been that they perform worse). The manuscript could very well survive without mentioning these results at all. Indeed, the focus in this work is on the protocol development.
Therefore, I cannot see how this manuscript fits into the scope of catalysts and furthers the understanding of catalytic reactions in any way. I recommend rejection of the manuscript. I want to re-iterate that I do not doubt that the manuscript has scientific value though and would recommend submission to a journal more specialized on process development like processes.
Author Response
We thank Reviewer 1 for underlining the scientific merit of the manuscript, and we understand his objection to publication on “Catalysts”. Our reply is that the development of a reaction protocol that relies on the use of catalysis in one or more of its steps – as is the case of this manuscript – represents itself a step forward in the diversified general field of the use of catalysis / catalysts. We have a longstanding interest in the implementation of more efficient and greener reaction protocols, and we try to approach this issue from a multiplicity of facets, one being catalysis. The rationale is that it is insufficient to address and improve single problems in a reaction scheme. Rather it is important to consider as many of the aspects that contribute to efficiency and greenness in order to truly improve the global system. We therefore believe that integration of different steps/procedures that involve catalysis is intrinsically of interest for a wide audience of scientists that operate in the field of catalysis. On a final note, regarding the objection on the significance of our comparison with catalysts such as AF and HY that show poorer performance, we believe that full understanding of all the variables and of the mechanism implies explanation of why one type of catalyst works better than the another. Otherwise research papers run the risk of becoming merely descriptive and phenomenological.
Reviewer 2 Report
This paper describes a useful protocol for synthesis of two N-acylated cyclic acetals from amino-glycerol derivatives in two step reaction. The authors checked different techniques, batch and catalytic continuous flow methods, for these reactions. They investigated an influence of various factors, such as, reaction temperature and time, solvent, catalysts, ration of reagents, on yields of target compounds. The most optimal conditions were found. This is an important work in a view of use of bio-based molecules for synthesis of novel materials. In this particular study, the starting compounds, amino derivatives, were obtained from glycerol, which is considered as a bio-based platform chemical, derived from renewable plant resources (vegetable oils, for instance).
There is one comment on this paper. The authors use the term “amidation”, even in the title of the paper. But, in fact, this is “N-acylation”. Perhaps, it would be better to use the term “N-acylation”, instead of “amidation”.
Author Response
In the current literature, amidation is a commonly used definition for amide-bond forming reactions even when referred to the straightforward reactions of esters and amine (as in the present paper): see for example, (a) A. S. Santos, A. M. S. Silva, M. M. B. Marques Eur. J. Org. Chem. 2020, 2501–2516; (b) S. Karthik, R. Sreedharan, T. Gandhi ChemistrySelect 2019, 4, 175 –180. That is the reason why – albeit amidation refers to the chemical structure of final product, and N-acylation to the reaction - we deem the two terms interchangeable. However, in response to comment of the Reviewer, we agree to replace “amidation” using the more appropriate “N-acetylation” rather than the generic “N-acylation”, throughout the revised text.
Reviewer 3 Report
The manuscript entitled “Concatenated batch and continuous flow procedures for the upgrading of glycerol-derived aminodiols via amidation and acetalization reactions” by Selva and coworkers explores the preparation of aminodiol regioisomers3-amino-1,2-propanediol and 2-amino-1,3-propanediolderived from glycerol using two step sequence using batch and continuous flow processes. In batch process amidation was achieved utilizing isopropenyl acetate (iPAc) while in second step acetalization was achieved using acid resin Amberlyst 15. The authors have carefully optimized conditions to achieve these transformations chemoselectively with excellent yield. Moreover, authors have realized solvent1,4-dioxane is better over DMSO and for acetal formation resin Amberlyst 15 is better choice over other studied solid catalysts HY and AlF3•3H2O. In continuous flow synthesis authors have studied effect of temperature, pressure, different solvents and flow rate etc. on conversion and selectivity to design efficient synthetic protocol.The described protocol would be helpful to prepare these chemicals on large scale and capable for industrial application. The construction of the paper is professional; it is clear and understandable; I think it is suited for the publication in the journal Catalysts.
I would like to recommend the acceptance of this article for the publication in the journal in its present form while addressing a minor typo.
- Line 200: the conversion of 1a did not exceed 76 and 79% at 150 °C using AF and HY, respectively. (Entries 4 and 6 are mismatched).
Author Response
We thank Reviewer 3 for the positive comments and for catching the typo (on line 200) that has been corrected in the revised version of the ms
