Synthesis and Characterization of New Monosubstituted Pillar[5]arene with Terminal Carboxyl Group
Laurent Bischoff
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis paper describes a further functionalization of pillar[5]arenes, via the acylation of the terminal amino group of a hexamethylene diamine.
One new compound is described in this manuscript, however the supplementary information file lacks clear NMR characterization of this compound.
As they did in a previous paper (New J. Chem. 2022), the authors should provide assignment of the different protons on the NMR spectra, indicating which portion of the hexamethylene linker lies inside the cavity. Even if the amine compound (2) was already described, it should appear in the supp info to provide comparison with the newly-formed amide. In particular, the disappearance of the CH2 adjacent to the amino group (probably at 2 ppm on their previous paper, as a triplet, however attributed to the amino group itself), could be shown by comparing both spectra (2 and 3). As these compounds give broad NMR signals, only the mass spectrum provides a clear analytical proof for this molecule. Maybe if possible, the authors could also record the 1H NMR spectrum in DMSO with adding a drop of TFA in order to shift the water peak and see if there is no signal below.
In the manuscript, the authors may also explain the choice of this anhydride, instead of classical symmetrical anhydrides such as succinic or glutaric anhydrides.
In addition, concerning the preparation of diglycolic anhydride (1,3-dioxolan-4-one), the authors should state why they chose this protocol, instead of already-published methods such as in Tetrahedron Letters (2017), 58(32), 3160-3163 for instance. Then, if the protocol is new, describe it shortly.
My recommendation for this manuscript is to be published in Molbank after these minor revisions.
Author Response
Comments 1: One new compound is described in this manuscript, however the supplementary information file lacks clear NMR characterization of this compound.
As they did in a previous paper (New J. Chem. 2022), the authors should provide assignment of the different protons on the NMR spectra, indicating which portion of the hexamethylene linker lies inside the cavity. Even if the amine compound (2) was already described, it should appear in the supp info to provide comparison with the newly-formed amide. In particular, the disappearance of the CH2 adjacent to the amino group (probably at 2 ppm on their previous paper, as a triplet, however attributed to the amino group itself), could be shown by comparing both spectra (2 and 3). As these compounds give broad NMR signals, only the mass spectrum provides a clear analytical proof for this molecule. Maybe if possible, the authors could also record the 1H NMR spectrum in DMSO with adding a drop of TFA in order to shift the water peak and see if there is no signal below.
Response 1:
Earlier, Wang et al. showed the formation of an intramolecular hydrogen bond NH∙∙∙OCH2 and inclusion of an alkylamide fragment into the macrocyclic cavity by X-ray diffraction for compounds with a similar structure [10.1080/10610278.2017.1287367]. In our previous works we showed that macrocycle 2 tend to form self-inclusion complex in CDCl3 as well as in DMSO because of this intramolecular NH∙∙∙OCH2 hydrogen bond. (6’-Amino)hexamethyleneamide fragment was included in the macrocyclic cavity up to the 4th carbon atom, while the amino group remained outside the macrocyclic cavity. The same behaviour was observed for compound 3 described in the current manuscript. There are significant upfield shifts (-2.11 and -1.77 ppm, respectively) of the methylene proton (H6 and H7) signals of the alkyl fragment of 3 in the 1H NMR spectrum. H8 and H9 methylene proton signals were also observed in the upfield (-0.72 and -0.33 ppm, respectively). This fact unambiguously indicates inclusion of the alkyl substituent in the pillar[5]arene cavity (Figure S1).
Figure S1. 1H NMR spectrum of 4-(2-[6-(2-[carbomethoxy]acetamido)hexylamino]-2-oxoethoxo)- 8,14,18,23,26,28,31,32,35- nonamethoxy-pillar[5]arene (3), CDCl3, 298 K, 400 MHz.
A narrow intense band at 3405 cm–1 in the IR spectra (Fig. S4, ESI) of pillar[5]arene 3 is also indicated the formation of a strong hydrogen bond between the NH-protons and oxygen of the methoxyl fragment. We assumed that the presence of such a strong hydrogen bond is possible only for the self-inclusion complex characterized for compound 3.
The following comparison of 1H NMR spectra of compounds 2 and 3 has also confirmed inclusion of (6’-amino)hexamethyleneamide fragment in the macrocyclic cavity up to the 4th carbon atom (Figure S6, ESI).
Figure S6. 1H NMR spectrum (CDCl3, 298 K, 400 MHz) of: (A) 4-(2-[6-(2-[carbomethoxy]acetamido)hexylamino]-2-oxoethoxo)- 8,14,18,23,26,28,31,32,35- nonamethoxy-pillar[5]arene (3); (B) 4-[(N-{6’-aminohexyl}-amino)-carbomoylmthoxy]-8,14,18,23,26,28,31,32,35-nonamethoxypillar[5]arene (2).
Comments 2: In the manuscript, the authors may also explain the choice of this anhydride, instead of classical symmetrical anhydrides such as succinic or glutaric anhydrides.
Response 2: Syntheses with other anhydrides have been conducted and some results have been published. In particular, the results of the reaction of amines with succinic anhydride are presented in the works (1) Nazarova, A.; Yakimova, L.; Filimonova, D.; Stoikov, I. Surfactant effect on the physicochemical characteristics of solid lipid nanoparticles based on pillar[5]arenes. Int. J. Mol. Sci. 2022, 23(2), 779. (2) Nazarova, A.; Yakimova, L.; Stoikov, I. Solid Lipid Nanoparticles Based on Monosubstituted Pillar[5]arenes: Chemoselective Synthesis of Macrocycles and Their Supramolecular Self-Assembly. Nanomaterials 2022, 12(23), 4266.
Comments 3: In addition, concerning the preparation of diglycolic anhydride (1,3-dioxolan-4-one), the authors should state why they chose this protocol, instead of already-published methods such as in Tetrahedron Letters (2017), 58(32), 3160-3163 for instance. Then, if the protocol is new, describe it shortly.
Response 3: In the work, we used reagents available to us, which also provided a quantitative yield of the anhydride. The protocol is not new (Anschuetz [Justus Liebigs Annalen der Chemie, 1890, vol. 259, p. 190]).
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsIn this paper, the authors report a new approach for the synthesis of monosubstituted pillar[5]arene with anionic carboxylic group. The compound has a terminal carboxylic acid group and two amide groups, achieving a high yield of 71% of the target compounds. The chemical structure of the product obtained was established based on 1H and 13C NMR, IR spectroscopy, MALDI TOF mass spectrometry, and elemental analysis. Notably, significant upfield shifts of the alkyl chains in the 1HNMR spectrum (-1.94 and -0.48 ppm), indicating inclusion of the alkyl substituent in the pillar[5]arene cavity. Therefore, I like to recommend this manuscript to be accepted in Molbank after a major overhaul with the following recommendations.
(1) The synthesis of intermediates 1 and 2 is cited in the literature, but it is not stated whether the reaction conditions have been optimized in this paper. If improvements have been made, the datas can be compared or analyzed. If followed exactly, the description should be streamlined so that the innovative and challenges of the latter step can be highlighted.
(2) The article mentions that the compounds will be used in drug-carrier systems, but no datas or studies are provided. In recent years, there have been some developments regarding the application of monosubstituted pillar[5]arene in drug-carrier systems. Summarize the novelty of this paper in terms of synthesis or structure of compounds.
(3) This paper deals with amide preparation and the authors are advised to cite the latest literature on the synthesis of amides. (Nat. Commun., 2025, 16, 993.)
Author Response
Comments 1: The synthesis of intermediates 1 and 2 is cited in the literature, but it is not stated whether the reaction conditions have been optimized in this paper. If improvements have been made, the datas can be compared or analyzed. If followed exactly, the description should be streamlined so that the innovative and challenges of the latter step can be highlighted.
Response 1: Yes, intermediates 1 and 2 was synthesized according to the literature without optimization.
Comments 2: The article mentions that the compounds will be used in drug-carrier systems, but no datas or studies are provided. In recent years, there have been some developments regarding the application of monosubstituted pillar[5]arene in drug-carrier systems. Summarize the novelty of this paper in terms of synthesis or structure of compounds.
Response 2: Agree. We modified Introduction section.
Comments 3: This paper deals with amide preparation and the authors are advised to cite the latest literature on the synthesis of amides. (Nat. Commun., 2025, 16, 993.).
Response 3: We cited this paper (ref. 19): Wang, Z.-Y.; Wang, S.; Dai, N.-N.; Xiao, Y.; Zhou, Y.; Tian, W.-C.; Sun, D.; Li, Q.; Wang, Y.; Wei, W.-T. Carbon-carbon triple bond cleavage and reconstitution to achieve aryl amidation using nitrous acid esters. Nature Commun. 2025, 16, 993.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe comments have been carefully addressed in the revised paper. New experiments have been performed allowing a better evaluation of the paper. So, I recommend publication of the revised manuscript in its current form.
