An Alternative Method for Preparing Methyl 2-Ferrocenyl-2-oxo-acetate
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript is well written and describes a 1 step low yield (6%) synthesis of methyl 2-ferrocenyl-2-oxo-acetate, a compound which has been previously reported and prepared by a 6 step synthesis.
The author claims that his low yield method is superior to the 6-step method. I am not convinced by the argument, other compounds along the route could also serve as precursors to other useful compounds. In truth, there is very little that is new to publish here. However, the manuscript does report previously unreported 1H and 13C NMR data and IR and MS data.
As it stands the manuscript is far too long (8 pages!) and in the introduction describes the 6-step process in great detail - perhaps this could be omitted, in any revised form.
Table 1 would need a footnote adding to help the reading understand the numbers and compounds e.g. I think KE4 had n=4 but it is not stated anywhere.
The synthetic work was done by Hugo Hapel. Since this is ‘synthetic paper’ I would expect to see Hugo as a co-author.
I cannot recommend acceptance of this for publication as it stands and I would expect major revision will be required.
Author Response
Comments1: The manuscript is well written and describes a 1 step low yield (6%) synthesis of methyl 2-ferrocenyl-2-oxo-acetate, a compound which has been previously reported and prepared by a 6 step synthesis.
The author claims that his low yield method is superior to the 6-step method. I am not convinced by the argument, other compounds along the route could also serve as precursors to other useful compounds. In truth, there is very little that is new to publish here. However, the manuscript does report previously unreported 1H and 13C NMR data and IR and MS data.
Answer1: Thank you for your comments.
Efforts were made to ensure that readers understand this method is not claimed to be superior in terms of yield, but it does offer certain advantages. For example, in the initial submission (retained in the updated version):
- In the abstract, it was just stated " Nevertheless, considering the time saved, simplicity, and the use of less hazardous and less expensive reagents, this method offers certain advantages for synthesizing this building block.".
- And in the conclusion " Although the yield (5.4%) is very low and does not surpass the overall yield of the six-step synthesis, our single-step synthesis uses inexpensive reagents like ferrocene, aluminum chloride, and methyl chlorooxoacetate in dichloromethane, without heating or cooling, and is incomparable in terms of time efficiency. ".
The last sentence of Introduction was changed to (slightly) softer the comments, " Nevertheless, it allows for the replacement of six steps with just one." was replaced by " Nevertheless, it offers chemists an alternative method to replace six steps with just one when time and simplicity are the primary criteria being sought.".
This alternative approach may be advantageous for chemists aiming to reduce time of preparation, as it requires just one day compared to several days with the former method, while also offering overall simplification. But now, thanks to the commercial availability of certain precursors, the former method is more time-efficient too, though possibly more expensive.
Comments2: As it stands the manuscript is far too long (8 pages!) and in the introduction describes the 6-step process in great detail - perhaps this could be omitted, in any revised form.
Aswer2: The text on the 6-step process was minimized. The yields, as requested by reviewer #2, were included in Scheme 1, allowing for the text reduction. I kept Scheme 1 in the main article to highlight the comparison of the two methods, which is the article's focus.
The replacement text is now: " We needed α-ketoester KE0, first published in 1964 [11], without further references, to prepare the shorter alcohol of this series. In accordance with the six steps beginning with ferrocene 1 (Scheme 1), it is necessary to first prepare amine 2, and subsequently the quaternary ammonium salt 3 [12]. This precursor, which is now conveniently available commercially, was utilized in our preparation of Fc-CH2-imide as well [13]. Salt 3 was utilized to synthesize nitrile 4, which was then converted to acid 5 [14]. This acid was subsequently transformed into its ester 6 and oxidized in KE0 [11], achieving an overall yield of approximately 13%.".
In the new text above, the part (that was inside the first submission, on another form)" … the quaternary ammonium salt 3 [12]. This precursor, which is now conveniently available commercially, was utilized in our preparation of Fc-CH2-imide as well [13]." agrees with your comment that other compounds along the route could also be precursors to useful compounds.
To further reduce, I condensed the short bibliography about KE0 - KE15 to Table 1, with minimal comments in the main text. I considered removing this section, but I believe this bibliography will be useful to readers. I considered placing it in the Supplementary Information, but since the references in the SI must also be cited within the main text, this approach would not be efficient due to the resulting repetitions.
Under Table 2, the text was simplified too.
Comments3: Table 1 would need a footnote adding to help the reading understand the numbers and compounds e.g. I think KE4 had n=4 but it is not stated anywhere.
Answer3: Done. The added footnote is " Naming of ketoesters: KEn, with n = the number of methylene groups. ".
Also in introduction: " Focusing on articles (excluding patents), most of the methyl ω-ferrocenyl-ω-keto esters series KEn (n ranging from 0 (KE0) to 15 (KE15)) have been documented (Table 1). "
Comments4: The synthetic work was done by Hugo Hapel. Since this is ‘synthetic paper’ I would expect to see Hugo as a co-author.
Answer4: Done. Hugo was added as co-author.
Comments5: I cannot recommend acceptance of this for publication as it stands and I would expect major revision will be required.
Answer5: The text was reduced by about one page. I hope it suffices to focus more on the novelty.
Thank you for your helpful feedback.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript submitted by Pigeon describes the one-step synthesis of methyl 2-ferrocenyl-2-oxo-acetate from ferrocene and methyl chlolooxoacetate. Although methyl 2-ferrocenyl-2-oxo-acetate is a known compound reported in reference 15, the current synthesis provides rapid access to the title compound (5% yield in just one step), while the literature procedure requires six synthetic steps (13% overall yield). In addition, ferrocene compounds have attracted increased attention owing to their interesting features such as anticancer activities, logic gates, and flame retardants. This synthetic approach will allow short access to ferrocene compounds. Therefore, I recommend that the manuscript be published in Molbank after addressing the following minor remarks.
- Table 2: Table 2 clearly shows low yields (1–5%) of this synthesis. What are the other side products? Please mention it.
- P4–P5: The author mentioned that “They found that the best results (yield 40-60%) were obtained at -78°C for 6 h, demonstrating that Friedel-Crafts coupling reactions of acyl chlorides on ferrocene can be successful at very low temperatures. However, our setup (immersion cooler + ethanol bath + flask) could not reach temperatures lower than -68°C. We conducted the run at this temperature (entry 9), and although degradation was reduced, the yield was still low, despite the slightly higher temperature and the reaction time being four times longer than in Turbitt and Watts' experiment.”. However, I think Turbitt and Watts used dry ice/acetone bath to set up the reaction at –78 °C. Therefore, please mention it if dry ice is difficult to be available in the author’s institute. Otherwise, the reason why the author did not perform the reaction at –78 °C is not appropriate.
- Scheme 1: Please add the yields at each step for easier comparison.
- Table 2: Please consider moving Table 2 to the top of Table 2 because the general scheme is missing in Table 2. In addition, what is T.A. in Table 2? Please explain this abbreviation.
- SI, Fig S1–S4: Please insert MHz frequencies for each page.
- SI, Fig S3–S4: Please describe the solvents for NMR.
Other points:
- Abstract, L6: The compound name “methyl-2-ferrocenyl-2-oxoacetate” is different from the title. Please correct.
- Table 1, Scheme 1,2: Please insert two coordinating bonds between the iron atom and cyclopentadienyl anions.
- Table 2: Insert a space between numbers and “°C”.
- MS data in section 3.2: Italicize “m/z”. Also at the end of page 6.
- Reference 2: Please correct the comma to period at the end of the publication title.
- Reference 10: Please correct “Ed. Int.” to “Int. Ed.”.
- Reference 14: Remove “and” between “Curhy, R. J.” and “Sokol. P. E.”
- Reference 15: The abbreviation of the journal title seems to be “J. Chem. Eng. Data”.
Author Response
The manuscript submitted by Pigeon describes the one-step synthesis of methyl 2-ferrocenyl-2-oxo-acetate from ferrocene and methyl chlolooxoacetate. Although methyl 2-ferrocenyl-2-oxo-acetate is a known compound reported in b 15, the current synthesis provides rapid access to the title compound (5% yield in just one step), while the literature procedure requires six synthetic steps (13% overall yield). In addition, ferrocene compounds have attracted increased attention owing to their interesting features such as anticancer activities, logic gates, and flame retardants. This synthetic approach will allow short access to ferrocene compounds. Therefore, I recommend that the manuscript be published in Molbank after addressing the following minor remarks.
Comments 1: Table 2: Table 2 clearly shows low yields (1–5%) of this synthesis. What are the other side products? Please mention it.
Response 1: The flash chromatography of the black residue obtained after filtration on silica gel (to remove a part of the black degradation product) showed only three orange bands + a very large black band migrating very slowly in the column eluting with dichloromethane.
This black band was assumed to not be an identifiable compound but degradation because of the color and polarity and stayed at the beginning of the column during the run (from 0 to 1/3 of its length max, thus, was not recovered). Even cleaning the column (to reuse it) with a very polar solvent (THF) took time, thus, there is no doubt about its nature of degradation compounds (polymer-like probably).
The first orange band to go out was unreacted ferrocene (this was expected, since an excess (1.5 equiv.) was used).
The second one was an unknown compound, difficult to separate from band one and three (as could be seen in Figure S4 representing NMR of KE0 contaminated by this compound). Its NMR consists of a group of peaks in the ferrocene area and can be seen on Figure S4 from 3.8 to 4.3 ppm. Despite its NMR peaks being in the ferrocene area, it seems there is no Cp peak (singlet, 5H, very easy to find even in crowded spectra, but maybe hidden into a big peak of KE0) that could prove it to be a ferrocenic compound (except its color, but it is not relevant since it is contaminated with ferrocene). A compound with its two Cp rings substituted cannot be excluded to explain the possible absence of the 5H singlet of Cp. Anyway, this compound is in small quantity (about the same quantity as for KE0!) and cannot explain into what most of the starting compound transformed.
The third band is KE0 (also in small quantity, unfortunately).
In conclusion, most of the starting reagents followed the degradation path at room temperature.
Comments 2: P4–P5: The author mentioned that “They found that the best results (yield 40-60%) were obtained at -78°C for 6 h, demonstrating that Friedel-Crafts coupling reactions of acyl chlorides on ferrocene can be successful at very low temperatures. However, our setup (immersion cooler + ethanol bath + flask) could not reach temperatures lower than -68°C. We conducted the run at this temperature (entry 9), and although degradation was reduced, the yield was still low, despite the slightly higher temperature and the reaction time being four times longer than in Turbitt and Watts' experiment.”. However, I think Turbitt and Watts used dry ice/acetone bath to set up the reaction at –78 °C. Therefore, please mention it if dry ice is difficult to be available in the author’s institute. Otherwise, the reason why the author did not perform the reaction at –78 °C is not appropriate.
Response 2: Turbitt and Watts conducted the reaction for 6 hours, allowing them to regulate the temperature by intermittently adding dry ice, although this detail was not mentioned in their article. In our case, the duration was extended to 24 hours, and due to university safety regulations prohibiting overnight stays in the laboratory (and to be alone!), an automatic cooler was utilized instead. Moreover, there is no special reason to be exactly at -78 °C here. Also, we rarely order dry ice because of its bad conservation (we have liquid nitrogen in place of dry ice, but it is less convenient).
I changed the main text like this: " …can be successful at very low temperatures. We set the reaction time to 24 hours, which does not allow the use of dry ice, so an immersion cooler was mandatory. However, our setup (immersion cooler + ethanol bath + flask) could not reach temperatures lower than -68°C. ".
Comments 3: Scheme 1: Please add the yields at each step for easier comparison.
Response 3: Done. The other reviewer asked me to shorten the article, especially this part. I kept Scheme 1 (I hesitated to move it in SI but I thought it would be a waste because it is better to keep it for comparison between the two methods in one sight) but reduced the text to the minimum. Fortunately, since the yields now appear in Scheme 1, it permitted me to shorten the text without losing information. It was helpful, thank you.
Comments 4: Table 2: Please consider moving Table 2 to the top of Table 2 because the general scheme is missing in Table 2.
Response 4: I guess you meant Scheme 2.
This reaction scheme was also shown in red in Scheme 1, but this proves that it is not so easy to see it, even being drawn in red (and because it is inside the Introduction, not in "2. Results and Discussion"). Scheme 2 was moved just above Table 2 as asked for.
Comments 5: In addition, what is T.A. in Table 2? Please explain this abbreviation.
Response 5: You meant Scheme 2. This means "Temperature ambiante" (room temperature) in French but this mistake was corrected now (replaced by 20 °C, to be more precise than r.t.). Thank you for noticing it.
Comments 6: SI, Fig S1–S4: Please insert MHz frequencies for each page.
Response 6: Done in SI file (summary + caption). Titles updated in "Supplementary Materials" section of main text too.
Comments 7: SI, Fig S3–S4: Please describe the solvents for NMR.
Response 7: Done (CDCl3).
Other points:
Comments 8: Abstract, L6: The compound name “methyl-2-ferrocenyl-2-oxoacetate” is different from the title. Please correct.
Response 8: Done. The first "-" was removed, it was an error.
Comments 9: Table 1, Scheme 1,2: Please insert two coordinating bonds between the iron atom and cyclopentadienyl anions.
Response 9: Done.
Comments 10: Table 2: Insert a space between numbers and “°C”.
Response 10: Done, for Table 2, its caption, and other places in the text.
Comments 11: MS data in section 3.2: Italicize “m/z”. Also at the end of page 6.
Response 11: Done for both.
Comments12: Reference 2: Please correct the comma to period at the end of the publication title.
Response 12: Done. It was not easy to see this error! Thank you!
Comments13: Reference 10: Please correct “Ed. Int.” to “Int. Ed.”.
Response 13: Done. Thank you!
Comments 14: Reference 14: Remove “and” between “Curhy, R. J.” and “Sokol. P. E.”
Response 14: This reference was deleted, due to the demand of reviewer#1 to simplify the text.
Comments 15: Reference 15: The abbreviation of the journal title seems to be “J. Chem. Eng. Data”.
Response 15: Done. Thank you for finding it.
Thank you for all your helpful comments on improving the article.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsNothing additional.
Comments on the Quality of English LanguageNothing additional