This manuscript is the extension of a previous work entitled;” Gas‐phase fragmentation reactions of protonated benzofuranand dihydrobenzofuran‐type neolignans investigated by accurate‐mass electrospray ionization tandem mass spectrometry” published by the same research group in J Mass Spectrom. 2019; 54:35–46.

In this manuscript, the authors have analyzed by ESI-MS (-ion mode) with a QTOF-MS hybrid instrument a series of pure eight synthesized benzofuran- and dibenzofuran-neolignans. After measuring the low-energy CID-MS/MS analysis of the deprotonated molecules, the authors proposed the gas-phase fragmentation pathways of the benzofuran-neolignans 6 and 8 and dihydrobenzofuran-neolignans 1–5 and 7 on the basis of accurate-mass data and MSn experiments.

Furthermore, they also measured the thermochemical data by the B3LYP/6-31+G(d, p) level of theory (computational quantum) to estimate the gas-phase acidity (GA) of the sites that were the most susceptible to deprotonation (benzylic or α-carbonyl positions and phenolic hydroxyl) in the structures of neolignan compounds 1–8

The authors reported that the CID-MS/MS analyses revealed that it was possible to differentiate between the benzofuran 6 and 8 from the dihydrobenzofuran neolignans 1–5 and 7, on the basis of the [M ‒ H ‒ C2H3O2•]‒ product ions.
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Moreover, the direct [C2H3O2•] elimination from the precursor ion was only observed for the BNs and helped in distinguishing these compounds from the DBNs. These types of radical eliminations were not observed in the product ion spectrum of protonated compounds 1–8. They also noted that the intensities of the product ions [M ‒H-CH3OH] ‒ obtained in the CID-MS/MS strongly depended on the specific structural features of the different precursor deprotonated molecules. They also found that the majority of these diagnostic product ions were formed by radical eliminations.

Comparison between the ESI-MS/MS data of neolignans 1–8 in the positive and negative ion modes demonstrated that the ESI-MS in the negative ion mode allowed to obtain much more information (at least one diagnostic product ion emerged for all the analyzed compounds.

This manuscript is well written, and the MS science presented which include experiments, results, and conclusions is beyond any reproach.

Nevertheless, there are perhaps some minor mistakes that needs to be corrected.

1. In Table 1, you have chosen to define your precursor ion as for eg. A ([M – H]-) which produces the product ion B (A – CH3OH).
   QUERY: In this table as we move to the next production ion C is formed from product ion [B-CO]-This gives the impression that all your fragmentations are sequential? Is it the case!

Have you considered the notion that low energy CID-QTOF-MS/MS is not identical to IT-MS/MS?

Perhaps you should compare one example of your CID-MS/MS analyses recorded with your QTOF-MS with that measured with the IT MS instrument.

1. I really like the efficient and simplistic way you described all of your MS/MS analyses. However, why not use the MS/MS nomenclature proposed by Morreel at al. “ Mass Spectrometry-Based Fragmentation as an Identification Tool in Lignomics” Mass Spectrometry-Based Fragmentation as an Identification Tool in Lignomics”.October 2010, Analytical Chemistry 82(19):8095-105