Alternating Ring-Opening Metathesis Polymerization Promoted by Ruthenium Catalysts Bearing Unsymmetrical NHC Ligands
Round 1
Reviewer 1 Report
This manuscript describes the catalysis of ring-opening metathesis reactions using four very similar catalysts, two of which had already been analyzed in previous papers. The results with the two novel catalysis are basically indistinguishable from those of the other two, and therefore this manuscript does not seem to be much of an advance over previous reports. There is some novelty in the moleculr modelling portion, but unfortunately the results are presented in a vey obscure way: the orientation of the topographic steric maps is not easy to perceive, and the scales are not propely labelled so that readers unacquainted with this method may understand them. The orientation of the molecules in Figures 7 and 8 is not the same, which additionally hampers proper reading.
In view of these defects, I think that authors should provide the structures of each catalyst (3, 4, and Buchmeiser) bound to the substrate, to ascertain how the affinities towards NBe and or CPe change and use those results to explain the selectivity in alternative copolymerization
Author Response
Thank you very much for reviewing our manuscript. With reference to the comments:
POINT 1: This manuscript describes the catalysis of ring-opening metathesis reactions using four very similar catalysts, two of which had already been analyzed in previous papers. The results with the two novel catalysis are basically indistinguishable from those of the other two, and therefore this manuscript does not seem to be much of an advance over previous reports. There is some novelty in the moleculr modelling portion, but unfortunately the results are presented in a vey obscure way: the orientation of the topographic steric maps is not easy to perceive, and the scales are not propely labelled so that readers unacquainted with this method may understand them. The orientation of the molecules in Figures 7 and 8 is not the same, which additionally hampers proper reading.
RESPONSE 1: As for topographic steric maps we adopted the orientation that is usually adopted for Grubbs catalysts, that should easier depict how the NHC ligand occupies the space around the metal, while the orientation of optimized structure is the one usually reported for Grubbs catalysts.
See for example refs Organometallics 2016, 35, 2286–2293, RSC Adv., 2016, 6, 95793–95804; Organometallics 2017, 36, 19, 3692–370; Dalton Trans., 2018, 47, 6615–6627; Nature Chemistry volume 11, pages 872–879 (2019).
POINT 2: In view of these defects, I think that authors should provide the structures of each catalyst (3, 4, and Buchmeiser) bound to the substrate, to ascertain how the affinities towards NBe and or CPe change and use those results to explain the selectivity in alternative copolymerization
RESPONSE 2: We agree with the referee that the coordination energy of NBE and CPE would give useful information. Indeed, in this revised manuscript we reported the geometries and energies of the minimum energy structures bearing CPE or NBE coordinated to the metal and compared the coordination energy for the three complexes.
The following text was added in the manuscript.
“To investigate the influence of the catalytic pocket shape on alternating copolymerization, CPE and NBE minimum energy coordination structures were located. Geometries and free coordination energies in CH2Cl2 (see SI for computational details) are depicted in Figure 9. According to computational results, all catalysts exhibit lower coordination energies for NBE with respect to CPE. This finding is in agreement with the higher reactivity of norbornene in copolymerizations. Nevertheless the DDG of the CPE coordination is significantly lower for 3 and 4, with respect to Buchmeiser catalyst (see also Table 3). Indeed, 3 and 4 show a coordination energy for CPE only 0.7 kcal/mol higher then NBE, whereas the energy gap is of 2.0 kcal/mol for Buchmeiser catalyst. As shown in Figure 9, comparing NBE minimum energy coordination structures, slightly shorter NBE-Cl as well as NBE-alkylidene distances were observed for 3 and 4, as possible effect of phenyls on NHC backbone. This suggest the presence of sterical interactions that could slightly penalize NBE coordination to 3 and 4 with respect to Buch-meiser catalyst.”
Figure 9 showing the optimized geometries was also added, as well as Table 3 summarizing the calculation results.
Reviewer 2 Report
My principial problem with this manuscript is that I cannot follow the main conclusion, which is essentailly depicted in Firgure 8 "Topographic steric maps of...". First of all, in the Figure caption, it says "of zinc and magnesium monomeric species". An obvious oversight of the authors, which still poses the question how much attention to detail and effort was put into the manuscript by the authors? Furthermore I cannot understand and do not agree with the authors' main finding that the two Ph groups on the NHC-ligand, which are the furthest away on the opposite site of where the metathesis happens, should have such a steric influence on monomer selectivity. Furthermore, to model, calculate and discuss the "percent burried volume" and all its consequences for selectivity based on the pre-catalyst structures, where the Hoveyda-type styrene-ether is only a placeholder and exchanged in the first step of the catalysis by the real substrate, also seems to me to be of no avail. I think the authors finding which is shown in Figure 7 is the real key to understanding the monomer selectivity. There, the optimized structures do show a closer interaction of the cyclohexyl or cyclopentyl-substitutent with the catalytic pocket, which, in my oppinion, much better explains the observed monomer selectivity. Here, it would be interesting to calculate the minimum structures for both the NBE and CPE coordinated active catalyst. Only with these structures, a valid discussion of the steric influence on monomer selectivity seems useful to me.
A further aspect that is totally missing is a potential electronic influence. As I stated above, I disagree with the steric influence suggested by the athors of the two Ph-groups on the NHC ligand. But what about an electronic influence? Ph-groups usually excert a small -I effect, so this would make the Ru slightly electron-deficient. Maybe this altered electronic situation on the Ru center explains the higher selectivity towards the CPE-monomer? Here, a calculation of, for example, the NBO-charges on the Ru would be of interestest.
Author Response
Thank you very much for reviewing our manuscript. With reference to the comments:
POINT 1: My principial problem with this manuscript is that I cannot follow the main conclusion, which is essentailly depicted in Firgure 8 "Topographic steric maps of...". First of all, in the Figure caption, it says "of zinc and magnesium monomeric species". An obvious oversight of the authors, which still poses the question how much attention to detail and effort was put into the manuscript by the authors?
RESPONSE 1: We apologize for the mistake, and we have corrected in the revised version of the manuscript.
POINT 2: Furthermore I cannot understand and do not agree with the authors' main finding that the two Ph groups on the NHC-ligand, which are the furthest away on the opposite site of where the metathesis happens, should have such a steric influence on monomer selectivity.
RESPONSE 2: As reported below, other investigations have been conducted in this revised version. Nevertheless, we have to underline that the steric influence of substituents on the NHC backbone on reaction selectivity (e.g. enantioselectivity) as well as activity in Ru catalysts were shown in several experimental and computational studies. See for example refs Org. Lett. 2001, 3, 20, 3225–3228; J. AM. CHEM. SOC. 2004, 126, 9592-9600; Organometallics 2008, 27, 4649–4656; Organometallics 2009, 28, 4988–4995; Chem. Eur. J. 2011, 17, 8618 – 8629; Chem. Eur. J. 2013, 19, 10492 – 10496; RSC Adv., 2016, 6, 95793–95804; Organometallics 2017, 36, 19, 3692–3708; Adv. Synth. Catal. 2019, 361, 4133– 4139; Symmetry 2022, 14, 1615.
POINT 3: Furthermore, to model, calculate and discuss the "percent burried volume" and all its consequences for selectivity based on the pre-catalyst structures, where the Hoveyda-type styrene-ether is only a placeholder and exchanged in the first step of the catalysis by the real substrate, also seems to me to be of no avail. I think the authors finding which is shown in Figure 7 is the real key to understanding the monomer selectivity. There, the optimized structures do show a closer interaction of the cyclohexyl or cyclopentyl-substitutent with the catalytic pocket, which, in my oppinion, much better explains the observed monomer selectivity. Here, it would be interesting to calculate the minimum structures for both the NBE and CPE coordinated active catalyst. Only with these structures, a valid discussion of the steric influence on monomer selectivity seems useful to me.
RESPONSE 3: As we reported also for the comment of reviewer 1, we agree with the referee that the coordination energy of NBE and CPE would give useful information. Indeed, in this revised manuscript we reported the geometries and energies of the minimum energy structures bearing CPE or NBE coordinated to the metal and compared the coordination energy for the three complexes.
The following text was added in the manuscript.
“To investigate the influence of the catalytic pocket shape on alternating copolymerization, CPE and NBE minimum energy coordination structures were located. Geometries and free coordination energies in CH2Cl2 (see SI for computational details) are depicted in Figure 9. According to computational results, all catalysts exhibit lower coordination energies for NBE with respect to CPE. This finding is in agreement with the higher reactivity of norbornene in copolymerizations. Nevertheless the DDG of the CPE coordination is significantly lower for 3 and 4, with respect to Buchmeiser catalyst (see also Table 3). Indeed, 3 and 4 show a coordination energy for CPE only 0.7 kcal/mol higher then NBE, whereas the energy gap is of 2.0 kcal/mol for Buchmeiser catalyst. As shown in Figure 9, comparing NBE minimum energy coordination structures, slightly shorter NBE-Cl as well as NBE-alkylidene distances were observed for 3 and 4, as possible effect of phenyls on NHC backbone. This suggest the presence of sterical interactions that could slightly penalize NBE coordination to 3 and 4 with respect to Buch-meiser catalyst.”
Figure 9 showing the optimized geometries was also added.
POINT 4: A further aspect that is totally missing is a potential electronic influence. As I stated above, I disagree with the steric influence suggested by the athors of the two Ph-groups on the NHC ligand. But what about an electronic influence? Ph-groups usually excert a small -I effect, so this would make the Ru slightly electron-deficient. Maybe this altered electronic situation on the Ru center explains the higher selectivity towards the CPE-monomer? Here, a calculation of, for example, the NBO-charges on the Ru would be of interestest.
RESPONSE 4: The NBO-charges on the Ru were calculated and reported in Table 3 of the revised manuscript.
The following sentences were added in the “molecular modelling studies” section as well
“Finally, to gain informations on the electronic influence of the different NHC ligands on the catalyst behavior, we calculated the Ru charge for all catalysts by Natural Bond Orbital (NBO) analysis. As shown in Table 3, the absolute value of negative charges of Ru decreases in the order 4 > 3 > Buchmeiser. The lower coordination free energy observed for Buchmeiser catalyst for the more electron-donating NBE could be partially consequence of the less negative Ru charge.
In summary, according to DFT studies, 3 and 4 present higher %VBur for NHC moiety that entails also a dissymmetrical distribution of the catalytic pocket due to the syn phenyls on the backbone. The coordination of NBE with respect to CPE is more favored for Buchmeiser catalyst with respect to 3 and 4, in agreement with the lower percentange of alternating copolymer produced by this catalyst. This difference would be caused by both sterical and electronic effects.”
The following sentences were added in the “conclusions”
“According to DFT studies, 3 and 4 present a dissymmetrical shape of the catalytic pocket due to the syn phenyls on the backbone. The coordination of NBE is only slightly favored with respect to CPE, in agreement with the high percentage of alternating copolymer produced by these catalysts. Comparison with similar unsymmetrical NHC-Ru catalysts highlighted that both sterical and electronic effect of NHC ligand in 3 and 4 would be involved in determining the selectivity in copolymerization.”
Round 2
Reviewer 1 Report
I am afraid that the changes introduced were too sparse and that I still remain unpersuaded. For example, rather than claiming that the stereotopographic maps use standard orientations, authors SHOULD have made all efforts to properly explain to the reader how those maps should be interpreted. Authors also did not include any discussion aiming at dispelling my impression of lack of novelty of the experimental portion.
The new structures of the catalysts in the precence of norbornene or cyclopentene are welcome, but they are not at all shown in a convincing way: the energies of the complexes (presumably relative to infinitely-separate reactants) are extremely high (>28 kcal/mol) which implies reaction rates below 3*10-8 s-1 at 298 K, which is completely at odds with experiment. The difference in complex energy between the catayst+cyclopentene and catalyst+norbornene systems is also far too small (i.e. it is within the DFT margin of error) to account for the preference of incorporation of one over the other. The lack of hydrogens in the structures in figure 9 also prevents the reader from ascertaining whether indeed the coordination is occurring (as one would expect) between the metal and the substrate pi-bond or whether (as I suspect) the structures shown lack electronic bonds between substrate and catalyst. I am afraid that significant more work will be needed to bring the computational part of this study to a publisheable standard: I urge the authors to perform scans of the approach of the substrate pi-bond to the Ru, and use those results to obtain the transition states and correct geometries of the catalyst+substrate systems. I understand this will take longer that the 10 days usually allotted by MDPI for the revisions, but this is absolutely crucial to ensure the paper is indeed roust and a proper addition to the literature
Author Response
Please see the attachment.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
The authors have addressed all the points that I had raised initially. It seems to me that the manuscript is much improved, and that the results are much more conclusive now.
Author Response
Thank you for your very careful review of our paper and for the precious suggestions that have allowed us to improve the quality of our manuscript.
