2′,7′-Dimethyl-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one
, Aidan P. McKay, David B. Cordes, Iain L. J. Patterson, Nadiia Vladymyrova and Iain A. Smellie *Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsIn this manuscript, the authors reported the 1-step synthesis of 2’,7’-dimethyl-3H-spiro[isobenzofuran-1,9’-xanthen]-3-one with low yield (29%) from p-cresol and phthalic anhydride. The end product is known in the literature. The structures of the newly synthesized compounds have been convincingly characterized by 1H and 13C NMR spectroscopy, HRMS, IR, and X-ray crystallography. The manuscript is well written and easy to follow. However, only 2D NMR (COSY, HSQC, and HMBC), IR, and X-ray crystallography provide its novelty. Since the title compound is already known in the literature and has been adequately characterized in a recent (2024) article (ref. 7, yield: 81%) with 1H NMR, 13C NMR, and HRMS spectra, as well as the NMR assignment, I believe that this manuscript does not contain enough novelty to be published in Molbank. I do not consider the title compound to be of extraordinary general interest. Unfortunately, the novelty of the synthetic route is also low, as fluorene 2 was already prepared in the reaction between p-cresol and phthalic anhydride in the early 20th century. The milder conditions used (TfOH, 90 oC instead of ZnCl2 / 125 oC) are also not entirely original, since, for example, TfOH was also applied in ref. 7 (JOC, 2024, 89, 15931), only at a lower temperature.
Minor remarks:
1) The yields of the reactions should be shown. For example, Scheme 2(a) has a yield of 76%, Scheme 2(b) has a yield of 29%, and Scheme 3 has a yield of 81%.
2) In Scheme 2, the reaction was carried out in an N2 atmosphere.
3) In Scheme 3, the reaction was carried out at 25 oC and not at 0 oC.
4) Lines 49 and 55: instead of the name 4,4’-oxybis(methylbenzene), it would be better to use di-p-tolyl ether
5) Line 62: „this can be readily recrystallized” instead of „this is can readily be recrystallized”
6) Line 79: „Scheme 4” instead of „Scheme 3”
7) Line 121: duplicated "been"
8) Line 137: mmol should be given uniformly with one decimal place (2.0 mmol instead of 2 mmol), as in line 136 (3.3 mmol)
9) Line 138: How was the reaction monitored? If using TLC, then for the sake of reproducibility, the retention factor (Rf) data of the product should be provided.
10) Line 144: according to my calculations the yield is 27 or 28%, depending on rounding, and not 29%
11) Line 144: unlike the others, one IR data is specified to one decimal place (3016.8)
Author Response
In this manuscript, the authors reported the 1-step synthesis of 2’,7’-dimethyl-3H-spiro[isobenzofuran-1,9’-xanthen]-3-one with low yield (29%) from p-cresol and phthalic anhydride. The end product is known in the literature. The structures of the newly synthesized compounds have been convincingly characterized by 1H and 13C NMR spectroscopy, HRMS, IR, and X-ray crystallography. The manuscript is well written and easy to follow. However, only 2D NMR (COSY, HSQC, and HMBC), IR, and X-ray crystallography provide its novelty.
Since the title compound is already known in the literature and has been adequately characterized in a recent (2024) article (ref. 7, yield: 81%) with 1H NMR, 13C NMR, and HRMS spectra, as well as the NMR assignment, I believe that this manuscript does not contain enough novelty to be published in Molbank. I do not consider the title compound to be of extraordinary general interest. Unfortunately, the novelty of the synthetic route is also low, as fluorene 2 was already prepared in the reaction between p-cresol and phthalic anhydride in the early 20th century.
We are aware of the previous work and are not trying to claim the synthetic route described as novel or superior to any work published to date (the method described in ref 7 is the most efficient method we are aware of to date). Rather, the objective in this case was to determine whether the fluoran (2) or cresolphthalein isomer (3) was the product from the reaction of phthalic anhydride and 4-methylphenol in methanesulfonic acid (a reagent not in common use at the time of the original studies in the early 20th century). As was observed in older studies, the reaction in methanesulfonic acid also affords fluoran 2 rather than the cresolphthalein isomer 3. The yield of the reaction is also similar to the detailed study in 1920 (ref 3), in that case the isolated yield was 26%. In this work, fluoran 2 has been characterized by X-ray crystallography for the first time and submitted to the CCDC database, this is the intended main feature of the submission. For this reason, the submission was made to the “structure determination” section rather than the “organic synthesis and biosynthesis” section.
We acknowledge that the objective is not as clear as it could be in the original manuscript, so a revised version has been prepared, we have updated the introduction to include the following paragraph to clarify the objectives further.
“In this work, we describe a short study to examine whether 2’,7’-Dimethyl-3H-spiro[isobenzofuran-1,9’-xanthen]-3-one (2) or 3,3-bis(2-hydroxy-5-methylphenyl)isobenzofuran-1(3H)-one (3) is the isolable product from the reaction of phthalic anhydride and 4-methylphenol under milder conditions than reported previously.[3,4] Our findings align with the outcome of related reactions from the earlier 20th century, fluoran 2 was isolated (Scheme 3) and the structure of this product has been determined using X-ray crystallography for the first time.”
Additional text has also been added to section 2.1 “synthesis and spectroscopy”.
The text now also includes “The isolated yield (28%) in this case is very similar to the study by Copisarow in 1920 (26%), so it is apparent that heating the reagents in methanesulfonic acid does not offer a significant improvement in terms of % yield.”
The milder conditions used (TfOH, 90 oC instead of ZnCl2 / 125 oC) are also not entirely original, since, for example, TfOH was also applied in ref. 7 (JOC, 2024, 89, 15931), only at a lower temperature.
In the manuscript submitted, methanesulfonic acid has been used as the reagent. In contrast, trifluoromethanesulfonic acid is the reagent reported in reference 7.
Minor remarks:
1) The yields of the reactions should be shown. For example, Scheme 2(a) has a yield of 76%, Scheme 2(b) has a yield of 29%, and Scheme 3 has a yield of 81%.
The scheme numbers have been updated as a result of the changes to the text, however yields have now been included as requested.
2) In Scheme 2, the reaction was carried out in an N2 atmosphere.
This has been updated.
3) In Scheme 3, the reaction was carried out at 25 oC and not at 0 oC.
This has been updated.
4) Lines 49 and 55: instead of the name 4,4’-oxybis(methylbenzene), it would be better to use di-p-tolyl ether
We have used the IUPAC name but have now also included “di-p-tolyl ether” in brackets
5) Line 62: „this can be readily recrystallized” instead of „this is can readily be recrystallized”
This has now been corrected.
6) Line 79: „Scheme 4” instead of „Scheme 3”
This has now been corrected.
7) Line 121: duplicated "been"
This has now been corrected.
8) Line 137: mmol should be given uniformly with one decimal place (2.0 mmol instead of 2 mmol), as in line 136 (3.3 mmol)
This has been updated.
9) Line 138: How was the reaction monitored? If using TLC, then for the sake of reproducibility, the retention factor (Rf) data of the product should be provided.
In this case the reaction has not been monitored by thin-layer chromatography, we have followed similar protocols for the synthesis of phenolphthalein and cresolphthalein, the reaction time is typically 4-6 hours.
10) Line 144: according to my calculations the yield is 27 or 28%, depending on rounding, and not 29%
Agreed, we have recalculated and round to 28%. Thank you for identifying this error.
11) Line 144: unlike the others, one IR data is specified to one decimal place (3016.8)
The data has now been amended to show consistency in the number of decimal places.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors described an alternative method to the existing ones for the synthesis of 2’,7’-dimethyl-3H-spiro[isobenzofuran-1,9’-xanthen]-3-one. With respect to the existing literature data the structure determination has been enriched by Xray analysis and full assignment of the structure by 2D NMR techniques and ATR-IR analysis. Some minor indications to improve the quality of the paper are given below.
Page 1 line 20: study has also shown should be “study which has also showed”
(Scheme 2(a)) should be (Scheme 2a)
(Scheme 2(a)) should be (Scheme 2a)
“Scheme 3” is not mentioned in the text
Page 3 line 62: The crude material is usually obtained as a tan coloured solid, however this is can readily be recrystallized from hot acetone.
The crude material is usually obtained as a tan coloured solid, however it can readily be recrystallized from hot acetone.
Line 79: Scheme 3 should be Scheme 4
Page 4 line 91: Crystals of 2, number “2” should be bold
Page 6 line 120: for 1H and 13C NMR, use superscript
The title compound has been obtained in 29% yield, the authors should be add in the scheme this information. Moreover, a comment on the comparison between the yield herein obtained with those of the previously published methodologies should be added.
Could the author explain the reasons for the low yield obtained with their method? What are the side products that are obtained? Or is there still starting material? This information should be added to the text and to the experimental section.
Reaction yields should be added also in the Scheme 1-3
Author Response
Thank you for your helpful comments, these are addressed below.
Page 1 line 20: study has also shown should be “study which has also showed”
The wording has now been changed.
(Scheme 2(a)) should be (Scheme 2a)
(Scheme 2(a)) should be (Scheme 2a)
This has now been changed.
“Scheme 3” is not mentioned in the text
This has now been updated.
Page 3 line 62: The crude material is usually obtained as a tan coloured solid, however this is can readily be recrystallized from hot acetone.
The crude material is usually obtained as a tan coloured solid, however it can readily be recrystallized from hot acetone.
The wording has now been changed.
Line 79: Scheme 3 should be Scheme 4
This has now been changed.
Page 4 line 91: Crystals of 2, number “2” should be bold
This has now been changed.
Page 6 line 120: for 1H and 13C NMR, use superscript
This has now been changed.
The title compound has been obtained in 29% yield, the authors should be add in the scheme this information. Moreover, a comment on the comparison between the yield herein obtained with those of the previously published methodologies should be added.
In light of one of the other reviewer comments, some additional information has been provided to provide context.
Could the author explain the reasons for the low yield obtained with their method? What are the side products that are obtained? Or is there still starting material? This information should be added to the text and to the experimental section.
There some possible explanations, no starting material was recovered in this case. It is possible that some of the cresolphthalein (3) was formed and then washed out during the purification process. It is also known that under strongly acidic conditions that hydroquinone products can also be formed (in this case none were isolated after purification).
Reaction yields should be added also in the Scheme 1-3
These have been added.
Reviewer 3 Report
Comments and Suggestions for AuthorsThis paper describes the synthesis, characterization, and crystal structure of the title compound. Although the title compound was first reported almost 100 years ago, this paper presents its full NMR characterization and crystal structure for the first time. This is a carefully done study, and the findings are useful for the related studies. Thus, this paper is worth publishing in Molbank as a present form.
Author Response
Thank you very much for taking the time to read the manuscript and providing your comments.
Reviewer 4 Report
Comments and Suggestions for Authors
Brian A. Chalmers with Iain A. Smellie and coauthors submitted the short notes paper that updates the synthetic route to 2’,7’-dimethyl-3H-spiro[isobenzofuran-1,9’-xanthen]-3-one, referred to in the paper as fluoran 2. The authors complemented previous research by providing a complete NMR assignment of fluoran 2 and conducted X-ray crystallography to characterize the compound. In my opinion, the paper is suitable for publishing after the following corrections:
Minor corrections:
Line 120 : “ been” appears twice please correct it
Line 62: “this is can readily be recrystallized from” please correct it
Line 41 : “fluoran 4”- the number should be bolded
The compound: 3,3-bis(4-hydroxy-3-methylphenyl)isobenzofuran-1(3H)-one was initially numbered as 1 in the introduction; however, it is not renumbered in the body text. I believe it would be better to consistently follow the numbering of compound with(1) as they appears in the paper.
Author Response
Thank you for your comments, the suggested corrections (copied below) have now been completed.
Minor corrections:
Line 120 : “ been” appears twice please correct it.
Line 62: “this is can readily be recrystallized from” please correct it
Line 41 : “fluoran 4”- the number should be bolded
The compound: 3,3-bis(4-hydroxy-3-methylphenyl)isobenzofuran-1(3H)-one was initially numbered as 1 in the introduction; however, it is not renumbered in the body text. I believe it would be better to consistently follow the numbering of compound with(1) as they appears in the paper.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsAlthough the quality of the revised manuscript has improved, I still have some doubts concerning the synthetic utility of the presented procedure. To the best of the reviewer's knowledge, Molbank focuses primarily on the publication of reports of the preparation and characterization of novel compounds. In some cases, alternative syntheses of known compounds are publishable, but in those cases, the route needs to be novel and the compound needs to be of extraordinary general interest. I do not consider the title compound (fluoran 2) to be of extraordinary general interest. Moreover, it appears that the one-step synthesis is based on a combination of several previous methods, and the yield (28%) is poor. The mentioned methods are correctly cited in the MS, but the synthetic novelty is still small. The two reaction partners (phthalic anhydride and p-cresol) and the reagent (mesylic acid) are also known in the literature for this type of reaction. The reviewer is pleased to see that the product was subjected to 2D NMR, IR, and X-ray crystallography measurements in this project in addition to the previously published 1H NMR and 13C NMR dpectra (and NMR assignment too), and HRMS, but I am not sure whether this is sufficient for publication in Molbank. If the editor deems the MS suitable for the journal despite the aforementioned comments, the reviewer does not intend to prevent acceptance.
Comments on the Quality of English LanguageI am not qualified enough to judge the quality of the english language.
