Round 1

Reviewer 1 Report

This interesting theoretical study about the feasibility of forming complexes of paracetamol-B12N12 nanocage. Authors employed molecular DFT -D3calculations with GAMESS-US software, and provided also further analysis of studied compounds (QTAIM, NCI, RDG, EDD, Egap...). Authors also calculated thermodynamical values (H,G,S) and (T-dependent) recovery times.

Their results are presented clearly via 8 Figures and 3 Tables. Conclusions are fully supported by their obtained results.

Just minor issues:

In the introduction, please mention the work of https://www.sciencedirect.com/science/article/abs/pii/S1468699604001184 about how nanocage clusters of B12N12 were synthesized; if you find more experimental works about B12N12, cite also them, so that the reader knows about existance of these nanocages

lines 115-116 ..was carried out by using VMD software..- please provide appropriate references

line 111 - shift eq.1 to the right

line 358, 359 - please ensure proper formatting of numbers 10 at x, not 108, but 10 at 8

line 117 "Reduced density gradient (RDG) analysis using Multiwfn code.." ... please provide reference for the methodology+code

line 121 "..B3LYP/631-121 G(d,p) simulations were employed to obtain the wavefunction".. please correct, as the B3LYP is not for obtaining the wave function, but for the density, as the common DFT functional, plus add the reference

line 164, Figure 2: for the -...+ color scale add also numerical scale.. how much of the charge is red, how much is the blue

line 322 - please specify in methods description and provide the reference what kind of solvent effect inclusion did you include into your computations

line 365, Figure 8: provide units of temperature into graph description

line 370: use constistent notation for complexes, not CMP1 rather CMP-1

Do not forget to provide supplementary material with optimized structures of all studied compounds.

Author Response

Reviewer # 1:

The following minor issues suggested by the reviewer#1 are removed from the manuscript.   

 

1. In the introduction, please mention the of https:///www.sciencedirect.com/science/article/abs/pii/S1468699604001184 about how nanocage clusters of B₁₂N₁₂ were synthesized. If you find more experimental word about B₁₂N₁₂, cite also them, so that the reader knows about existence of theses nanocages

• Thank you for carefully reading the manuscript and for the suggestion. The work is mentioned accordingly.

2. Lines 115-116.. was carried out by using VMD software…-please provide appropriate references

• Appropriate references are provided for the analyses used in computational details and results and discussion. 

3. Line 111- shift eq.1 to the right

• Thanks to the referee comment. The eq.1 is shifted to the right

4. Line 358, 359- Please ensure proper formatting of numbers 10 at ×, not 108, but 10 at 8.

• All the numbers are formatted properly and highlighted.

5. Line 117 “Reduced density gradient (RDG) analysis using Multiwfn code…”… Please provide reference for the methodlogy+code

• The references are provided and highlighted.   

6. Line 121 “..B3LYP/631-121 G(d,p) simulations were employed to obtain the wavefunction”.. please correct, as the B3LYP is not for obtaining the wavefunction, but for the density, as the common DFT functional, plus ass the reference.

• Thanks for highlighting mistake. The sentence is corrected and reference is added accordingly.
•  
• Line 164, Figure 2: for the -….+ also add numerical scale.. how much of the charge is red. How much is the blue.
• Thanks for suggestion to improve the quality of the paper. The numerical values are also added in the Figure.
• Line 322- please specify in methods description and provide the reference what kind effect inclusion did you include into your computations,
• The effect included in our computations are specified with reference and highlighted accordingly.
• Line 365- Figure 8: provide units of temperature into graph description
• Units of temperature are provided into graph description.
• Line 370: use consistent notation for complexes, not CMP1 rather CMP-1
• Thanks for highlighting the mistake of wrong notation for CMP-1. The notation is changed upon the comment of the editor as the same notation we used in our previous article. We used consistent notation i.e., BNP-1 for CMP-1, BNP-2 for CMP-2 and BNP-3 for CMP-3 and highlighted all the notations (98 notations).
• Do not forget to provide supplementary materials with optimized structures of all studies compounds.

The supplementary materials of the optimized complexes are provided.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments on B₁₂N₁₂ nanocage extraction of paracetamol

 

The authors address the question of the favored structure of a complex between a B₁₂N₁₂ cage and a common pharmaceutical agent, paracetamol. Their density functional calculations establish structures and binding energies, and a family of bonding descriptions provide alternative insights. This report makes a contribution to knowledge, but is in need of substantial improvement before publication. The following detailed comments provide some guidance.

 

The authors consider three isomers of the complex of paracetamol (P) with the B₁₂N₁₂ cage compound (C): Complex 1 establishes a connection a carbonyl oxygen of P with a boron atom of C; complex 2 has an interaction between the hydroxyl H atom of P with a nitrogen atom of C; and complex 3 has an interaction between an OH oxygen of P with a boron atom of C. (Fig 3) These assignments are consistent with intuitive ideas of electronegativity and partial charges on atoms, which notions are reinforced by the computed molecular electrostatic potentials on the molecular surfaces (Fig 2), which suggest attractive interactions between P’s carbonyl oxygen and C’s boron, P’s -OH hydrogen and C’s N, and (less obvious) a hydroxyl oxygen of P and a B atom of C.

 

The optimized geometries of P and C and strengths of interaction in the three clusters are estimated by density functional energy calculations in the B3LYP/6-31G(d,p) model, with dispersion correction D3. 

 

The computed binding energies are distinct: for complex #1, -28 kcal/mol; #2, -7 kcal/mol; and #3, -15 kcal/mol. The interatomic distances are consistent with these values, that is, 1.55, 1.97, and 1.66 Angs for =O…B, -OH…N, and >O…B respectively. Incorporating effects of water solvent by a polarizable continuum model alters these values slightly, to -31, -5, and -16 kcal/mol respectively. Enthalpy and Gibbs energy values are reported as well; DG is -19 kcal/mol for #1, dominating #2 (-1 kcal/mol) and also #3 (-8 kcal/mol).

 

Complementary descriptions of the bonding are provided by [a] charge density analysis in the quantum theory of atoms in molecules (Bader’s QTAIM), [b] the ideas in the theory of non-covalent interactions (Contreras-Garcia’s NCI), and [c] molecular orbital properties as expressed in the spatial distributions of frontier MOs and the natural charges of Weinhold’s NBO analysis. In short, all representations of bond strength are consistent in their prediction that complex #1 is most strongly bound. QTAIM parameters confirm the covalent nature of the bonding in #1, the H-bonding of #2, and the intermediate character of the bonding in #3.

 

We read that these computed parameters provide “…evidence of [the] efficiency of B₁₂N₁₂ nanocage in the removal of paracetamol from waste water” (Lines 273-4). And elsewhere (Line 368-9) the claim is made that “sensing capabilities for removing paracetamol drug from waste water” is being investigated. But isn’t the conclusion of this work only that the unambiguously favored complex is #1? Does that have any clear implications on the efficiency of extractions or sensing ability of B₁₂N₁₂? That must depend on concentrations – that is, what amount of B₁₂N₁₂ is required to purify a specific volume of contaminated water to some established standard of purity? And of course there are issues of cost for bulk purification. Maybe for an exotic reagent such as the best use of B₁₂N₁₂ is as a (possibly) accurate test for paracetamol in small amounts of waste water.

 

Please clarify the passage beginning “These promising results…” (Lines 360-363). What in specific are these “exceptional and stable characteristics”?

 

Minor points, usage.

 

Line 44: “studies” can be “studied”

Lines 49-50: …detected [in] surface water.

Line 55: “adsorbed” and similar throughout; if this is standard usage in waste water treatment, I do not object. But adsorption to me implies attachment to a surface. In this context I would prefer “binding.”

Lines 81-2: please clarify the passage “…such as low hydrophobicity… sustainability.”

Line 115: Does VMD conduct the NCI analysis, or does it only provide a graphic illustration? There is code for NCI analysis: NCIPLOT: A Program for Plotting Noncovalent Interaction Regions, J. Contreras-Garcia et al.,  J. Chem. Theory Comput. 2011, 7, 3, 625–632

Lines 122-125: Gaussian software does not incorporate QTAIM computations; AIMALL is the standard code.

Line 153: Please cite the reference source for BN bond distances.

Line 158: “detection of adsorption energies” could be “estimation of binding energies.”

Table 1 (and in discussion): I do not think a report to four decimal places is justified – these calculations are not so accurate or precise.

Line 188: “smallest bond length values” does not seem correct.

Lines 229ff: The discussion refers to natural charges rather than natural bond orbitals; the NBOs have other potentially interesting aspects, such as the extent of admixture with local antibonding NBOs.

Lines 244ff: “Close” should be “closed” and perhaps “shared” could be “covalent.”

Line 254: These results are computed, not “experimental.“

Lines 346-352: What is meant by the “adsorption mechanism”? Is it something other than “binding”? Surely the significant outcome is that complex #1 is by far the most likely to form. (Consider the Keq for #1 and #3.)

Lines 357-360: The discussion is marred by careless use of exponentials. Figure 8 seems uninformative since the values plotted are so disparate. Perhaps a graph is redundant?

 

Language is clear and grammatical.

Author Response

Reviewer # 2:

The minor issues mentioned by Reviewer#2 were resolved accordingly.  

• Please clarify the passage beginning “These promising results”…. (Line-360-363). What in specific are these “exceptional and stable characteristics”?
• Thanks for highlighting the ambiguous statement given in the recovery time calculations. The statement is clarified and highlighted.

 

• Line 44: “studies can be “studied”
• Thank you so much for carefully reading the manuscript and recommending grammatical corrections. The mistake is corrected and highlighted.
• Line 49-50:… detected [in] surface water
• The grammatical mistake is removed and highlighted.
• Line 55: “adsorbed” and similar throughout; this is standard usage in waste water treatment, I do not object. But adsorption to me implies attachment to a surface. In this context I would prefer “binding”.
• Thanks, referee, for the suggestion. The word “adsorbed” is changed with “absorbed” as we are discussing the absorption of ciprofloxacin in body. The word absorbed is highlighted as ciprofloxacin is absorbed in body and its bioavailability is 70%.
• Line 81-2: please clarify the passage “..such as low hydrophobicity ….sustainability’.
• Thanks again for highlighting ambiguous statement. The sentence is clarified and highlighted accordingly.
• Line 115: Does VMD conduct the NCI analysis, or does it only provide a praphic illustration? There is code for NCI analysis: NCIPLOT: A program for plotting Noncovalent interaction regions, J.Contreras-Garcia et al., Chem. Theory Comput. 2011, 7, 3,, 625-632.
• We thanks to the reviewer for their critical investigations. The VMD was used to obtain the NCI map and the analysis was carried out using Multiwfn program using wfn file obtained in the gaussian program from the optimized geometries of the complexes using energy option and additional keywords ‘density output=wfn”. The sentence is clarified and highlighted.
• Line 122-125; Gaussian software does not incorporate QTAIM computations; AIMALL is the standard code.
• Thanks for highlighting the mistake. We performed the QTAIM analysis with Multiwfn program using wfn file. The wfn file is obtained from the optimized geometries using Gaussian 16 code with additional keyword: density output=wfn. The sentence is clarified and highlighted.
• Line 153:I Please cite the reference source for BN bond distances.
• The reference suggested is cited and highlighted accordingly.
• Line 158: “detection of adsorption energies” could be “estimation of binding energies”.

Thanks for suggestion. Then heading is corrected and highlighted accordingly.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors have responded conscientiously to referees’ comments, and this report should appear in Computation. I do consider the conclusion to be a bit optimistic.

“Overall, the study highlights B12N12 nanocage [as] a promising adsorbent for decontaminating paracetamol from wastewater and suggests its potential for eliminating other emerging pollutants from wastewater.”

There are many steps between establishing that B12N12 binds strongly to paracetamol and concluding that it is a practical agent for removing that specific pharmaceutical species from wastewater. A more modest statement might be something like “We have shown that B12N12 binds strongly to paracetamol, the first step in establishing its possible utility as an agent to remove pharmaceuticals from wastewater.” I do not insist that the authors adopt this particular wording, but they should express some recognition that practical issues matter – specificity to particular pharmaceuticals, effective binding at the concentrations encountered in actual wastewater, and cost.

 

Author Response

Reviewer-2

The authors have responded conscientiously to referees’ comments, and this report should appear in Computation. I do consider the conclusion to be a bit optimistic.

“Overall, the study highlights B₁₂N₁₂ nanocage [as] a promising adsorbent for decontaminating paracetamol from wastewater and suggests its potential for eliminating other emerging pollutants from wastewater.”

There are many steps between establishing that B₁₂N₁₂ binds strongly to paracetamol and concluding that it is a practical agent for removing that specific pharmaceutical species from wastewater. A more modest statement might be something like “We have shown that B12N12 binds strongly to paracetamol, the first step in establishing its possible utility as an agent to remove pharmaceuticals from wastewater.” I do not insist that the authors adopt this particular wording, but they should express some recognition that practical issues matter – specificity to particular pharmaceuticals, effective binding at the concentrations encountered in actual wastewater, and cost.

Reply: Dear esteemed reviewer, we greatly appreciate your suggestion. We have now modified the recommended section of the conclusion as per your guidance.

Author Response File: Author Response.docx