This manuscript describes an effort to estimate the sensitivity of an extractive electrospray ionization TOF-MS to multifunctional organic compounds produced from the oxidation of 1,3,5-trimethylbenzene, d-limonene and o-cresol. The authors use the semi-quantitative response of a Vocus-PTR instrument to the same compounds (or molecular formulas) measured in the gas phase to estimate the sensitivity of the EESI-ToF-MS to those molecular formulas in the particle phase. The authors find a very wide range in EESI response factors, largely driven by molecular size/volume and degree of oxidation or functionalization. Further, comparison of summed EESI signals with total organic content from an aerosol mass spectrometer indicates promise for bulk quantification. 

This is an interesting analysis that I believe should be published in AMT, given that the following comments and suggestions can be adequately addressed.

Major Comments:

(1) As the authors state in their abstract, these results demonstrate that some level of quantification with the EESI-ToF-MS is possible without standards; however, this analysis includes a series of logical leaps that lead to significant uncertainty in resulting EESI response factors. The authors state that the Vocus-PTR -based EESI response factors range from 10^3 to 10^6 ions/s/ppb, with an geometric mean of 10^4.5 ions/s/ppb. For a given EESI RF for a specific compound, what is the associated uncertainty? (e.g., determined by propagating the uncertainty in calculated k_MH applied to Vocus data, described in L125-127 to become "more uncertain" as parameterizations are applied to more oxygenated species, through to the resultant EESI response factor). Related to this, how are the error bars in Figure 3a generated?

(2) Estimation of EESI response factors for specific molecular formulas in this work hinges on quantification of Vocus signals using k_MH calculated according to Sekimoto et al., 2017 (in addition to assumptions about gas-particle partitioning). Under the fIMR conditions given in L 135-136 (i.e., 59 Td), is Vocus sensitivity linear with k_MH for compounds that can be calibrated? At 59 Td, water clusters should dominate the reagent ion distribution over H3O+, potentially producing a regime where sensitivity is not linear with k_MH. The authors should show that their sensitivity is linear with k_MH (as an SI figure), thus demonstrating that they can apply k_MH for these unknown compounds. If the Vocus sensitivity is not linear with k_MH under these conditions, the authors should demonstrate how this impacts their use of Vocus signals to constrain EESI response.

(3) A statement prominent in the conclusions section is that the EESI-ToF-MS responds quantitatively to organic aerosol concentrations even with significant inorganic aerosol present. This seems a rather important conclusion of this paper, but the exact origin of this conclusion is somewhat unclear. Please make explcit whether this conclusions arises directly from the linear relationship between summed EESI signals and AMS OA, or some other specific result.

(4) This manuscript contains a large number of symbols and acronyms. A glossary of terms might be useful as an appendix to this paper so the reader can reference it easily.

Specific Comments:

L21: Inorganic coating or inorganic seed particles?

L48: The authors may also wish to cite https://pubs.acs.org/doi/10.1021/acsearthspacechem.9b00312 in this context

L70: What additional differences can be contributed by "operators" beyond the instrument parameters already listed?

L85-101: Please state clearly whether the seed aerosol was polydisperse or monodisperse

L180-185 (an in conclusions): Can these different factors contributing to EESI RF_x be separated? Some discussion on how these could be separated, if at all, would be useful here.

L39-391: Both larger molecules/higher molar volume and higher solubility in water are somewhat opposing features. Is it clear from this analysis which features are dominant?

L481: "law of averages" -- please be more specific

This manuscript describes the use of PTR-MS and AMS to constrain the response factors of EESI-TOF. The authors oxidized VOCs in a flow tube, varied the seed aerosol concentrations (and thereby the condensational sink), and compared the reduction in gas-phase concentrations of organic compounds measured by Vocus PTR-MS to the increase in aerosol-phase signal measured by EESI-TOF. This dataset provides the most comprehensive attempt to constrain EESI-TOF response factors to date and will be valuable to the continued development of EESI-TOF as a technique for studying atmospheric aerosol. I recommend that this manuscript be published in AMT after the following comments are addressed:

1) I agree completely with Referee #1’s comment that the authors must expand discussion of how the uncertainty in the Sekimoto et al. 2017 parameterization propagates through to the calculated RF*x in this work. The error bars from the fit uncertainty shown in Fig. 3 suggest to me that the authors’ methods produced good fits between the EESI-TOF and Vocus signals, and so the 50% uncertainty from the PTR parameterization is going to be a major contributor to the overall uncertainty.

2) The authors’ assumption that there is no fragmentation in the Vocus PTR-MS does not seem consistent with the literature on PTR fragmentation, especially for monoterpenes. See for example the recent GC-Vocus work from Claflin et al. 2021 AMT which documents limonene fragmentation of 50% (Table 3). While the extent of fragmentation will vary significantly with drift tube conditions, the oxidation products of limonene (e.g. alcohols, peroxides) typically show fragmentation of 70% or more (Pagonis et al. 2019). I am a coauthor on both of these papers and so I don’t insist that the authors cite either one. In my opinion, fully constraining the fragmentation patterns of the compounds in these oxidation systems is far beyond the scope of this work, so my suggestion for the manuscript is to move Fig. S7 into the main text. This analysis nicely shows the extent to which fragmentation could impact the results, and should be featured prominently since the true relationship is likely somewhere between Fig. 3 and Fig. S7.

3) The difference in predictive capability within a VOC system (Fig. 3a: TMB-only) and across the three VOCs studied (Fig S10b: all precursors, no label) gives the best chemical insight into the chemistry underlying EESI-TOF response factors. The authors have some discussion about this, but I think that this result supports further discussion. Molecular formula becomes a more useful parameterization when the carbon backbone and positions of functionalization of the analytes are consistent (a constraint brought on by using a single VOC precursor). To me, this indicates that a structure-activity relationship could be a very promising approach as e.g. EESI-MS-MS techniques are able to give information about the identity and position of functional groups.

4) The EESI-TOF ion transmission as a function of m/z is left unconstrained in this work. This is a gap that I would like to see addressed more in the text, especially since it gets a full treatment on the Vocus half of the analysis.

Line 89: “Milliliters” is missing a number

Line 104: L-ToF is not informative for readers who do not use Tofwerk instruments, please replace with a description of the mass resolution for the Vocus during this study.

Line 108: Please confirm for the reader that the H₃O⁺ depletion was negligible in this study.

Line 232: Equation 7 is not for NI_CO

Line 275: I do not follow the reasoning behind why the H₁₂ products should favor the particle phase to a greater extent than the H₁₄ products. I’m assuming that you’re comparing SIMPOL coefficients of (hydroperoxide) against (aromatic ring + alcohol + ketone), but this is certainly not going to be clear to many readers. More broadly, I think this is overstating the precision of SIMPOL, and that it would be sufficient to rely on the signal ratios and the identical numbers of oxygen and carbon atoms to rule out differences in partitioning.

Line 445: Do the authors have any levoglucosan calibrations from the same time period as these experiments to help connect these bulk sensitivities to those already published? If so, I strongly encourage the authors to include that value