Computational Insight into the Rope-Skipping Isomerization of Diarylether Cyclophanes

Round 1

Reviewer 1 Report

In general, the study performed by T. J. Summers et al. fits well the scope of Symmetry journal. The authors focused on deeper understanding of an interesting aspect of restricted rotation, which may lead to formation of conformationally chiral molecules, and the stability of these conformers. The results of the study are well presented and organized. Overall, the article is well-written and concise, therefore, I recommend its acceptance.

The authors may wish to consider minor change in the synthetic Scheme 1. Compounds 3a and 3b are drawn with a double bond in its (Z)-configuration. Since the utilized ylides are non-stabilized, the relative configuration shall be (E).

Author Response

We thank the reviewer for their kind words. We agree with and have completed their recommended corrections to Scheme 1. Additionally, we identified a typo in Scheme 1 (two sets of parentheses on compound 3a/3b) that has similarly been corrected in this most recent revision.

Reviewer 2 Report

pg. 1: "Racemization activation energies are observed to decay from 48 kcal/mol for a 7-carbon tether to 9.2 kcal/mol for a 14-carbon tether, with 
this reduction effectively converged by the 11-carbon tether."
- I do not understand the part: "with this reduction effectively converged". Can you please rephrase this to make it more comprehensible?

Pg. 5: The "QM" abbreviation should be explained with its first mention.

pg. 5: "For each of the molecules investigated, the 7 lowest-energy, unique QM-optimized conformations were selected as starting geometries for the isomerization TS search; the most stable conformation identified by the RIPS algorithm was also included as a starting geometry if it was not one of the 7 initial selected structures."
- What was the process of selection of the conformers for QM calculations? From what I've read I thought that the most probable conformations from RIPS search were used (based on the description of Methods). However, if this was the case, the most stable RIPS conformation should always be among those. Maybe I am just not "connecting the dots" properly, but explain this more, please.

Fig. 3: I suggest to put the information about the solvent into the respective charts (as it is the sole differentiating factor).

Fig. 3: I assume median is used to characterize the data since it softens the impact of outliers. Nevertheless it could be mentioned in the manuscript.

pg. 7: "net shifts of ΔG‡ ≤1.1 kcal/mol" are described based on the solvent used. However from the charts in Fig. 3, such subtle differences cannot be observed. Either the median ΔG‡ values should be stated in Fig. 3 or a table should be added into the paper.

Table S1: I do not fully follow what do the two mole fractions in the table represent. For the "MM Conformers Selected" column I assume that it informs of the fraction of all calculated MM minima (from the RIPS) which were subjected to the QM calculations. In the cases where the number is less than 1, the fraction of lowest-energy conformations (according to the force-field calculations) was selected for the QM. Correct? However, I am a bit lost in conceptualization of the meaning of the second column ("Selected QM-Optimizes Sample models"). Could you explain it more?

Also, as I am not an organic chemist I can't provide expertise regarding dicussed synthesis of cyclophanes.

Author Response

We thank the reviewer for their feedback and address their comments below:

Page 1: Can you please rephrase [“[…] this reduction effectively converged by the 11-carbon tether.”] to make it more comprehensible.

                We have removed the confusing verbiage altogether to better improve the flow of the abstract.

Page 5: The “QM” abbreviation should be explained with its first mention.

                We thank the reviewer for catching this and have added its full name and abbreviation note to its first mention in the methods section.

Page 5:  What was the process of selection of the conformers for QM calculations? From what I've read I thought that the most probable conformations from RIPS search were used (based on the description of Methods). However, if this was the case, the most stable RIPS conformation should always be among those. Maybe I am just not "connecting the dots" properly, but explain this more, please.

                We appreciate Reviewer 2 noting that this section could be explained better. To improve this, we have moved two of the sentences from the beginning of the Results section into the Methods section, and incorporated information from the SI into the methods section (in conjunction with Reviewer 3’s recommendation). This places the model construction/selection process into a single, linear narrative that we believe better explains the operations we have done for this work.

Figure 3. I suggest to put the information about the solvent into the respective charts (as it is the sole differentiating factor.

                We agree with Reviewer 2’s recommendations and have added this information to the figure.

Figure 3/Page 7: I assume median is used to characterize the data since it softens the impact of outliers. Nevertheless it could be mentioned in the manuscript.  "net shifts of ΔG^‡ ≤1.1 kcal/mol" are described based on the solvent used. However from the charts in Fig. 3, such subtle differences cannot be observed. Either the median ΔG^‡ values should be stated in Fig. 3 or a table should be added into the paper.

                We appreciate Reviewer 2’s suggestion and have labeled the median ΔG^‡ values in Figure 3. An additional comment on the minimal differences in median ΔG^‡ for the DAEC molecules in different solvents has been added to Page 9.

Table S1: I do not fully follow what do the two mole fractions in the table represent. For the "MM Conformers Selected" column I assume that it informs of the fraction of all calculated MM minima (from the RIPS) which were subjected to the QM calculations. In the cases where the number is less than 1, the fraction of lowest-energy conformations (according to the force-field calculations) was selected for the QM. Correct? However, I am a bit lost in conceptualization of the meaning of the second column ("Selected QM-Optimizes Sample models"). Could you explain it more?              

Reviewer 2 is correct in their interpretation of the meaning of the first column. To improve clarity of the second column, the name of the second column has been changed to “Mole Fraction of 7 Sampled QM-optimized Models”. This change better matches how the column of data is described in the main text.  The table and the description of its data has also been moved from Table S1 to Table 1 in the manuscript (at the recommendation of Reviewer 3). We believe this more linear explanation of the methods section will greatly improve the clarity of the operations and interpretability of the results.

Reviewer 3 Report

This is an excellent paper on using computational chemistry approaches at the density functional theory (DFT) level to design cyclophanes that cam isomerize. They use DFT with the B3LYP functional and a modest basis set and include the effects of solvent. They use an appropriate technique to sample conformation space using a molecular mechanics approach to generate initial coordinates. The computational work is well done, and the results make sense.

They show initial experimental attempts to generate these species and, although not fully successful, they show the types of approaches that could work.

The pages in the supporting information up to the coordinates should be in the actual manuscript.

Overall, a very nice contribution. Accept after moving the few pages from the Supporting Information to the text.

Author Response

We thank the reviewer for their praise.  We have largely followed their recommendation to move the data from the SI into the main manuscript with the exception of Figure S2 (now Figure S1). We decided to keep this one figure in the SI as most of its illustrated data is the same as Figure 3, and its additional elements are not vital for comprehending the narrative but remain interesting additional information.