The Reaction Mechanism of the Cu(I) Catalyzed Alkylation of Heterosubstituted Alkynes
Round 1
Reviewer 1 Report
In this manuscript, the authors described the alkynes be regioselectively alkylated to alkenes by organocopper reagents in a 10 reaction known as “carbocupration”, where an alkylCu(I) binds to the alkyne and transfers its 11 organic moieties to one of the alkyne carbon atoms.
In this work, authors also investigated the mechanism using density-functional theory and 18 describe a model that correctly explains both the reaction rates at sub-zero temperatures and the 19 regiochemistry profiles obtained with each of the heteroalkynes. The rate-determining step is 20 shown to vary depending on the hetero substituents, and the alkyl transfer is consistently demonstrated to 21 occur, somewhat counter-intuitively, to the alkyne carbon that is complexed by Cu rather than to 22 the “free” alkyne carbon atom, which instead interacts with the counter-cation which stabilizes the 23 developing electronic charge distribution. Overall the manuscript is written well and deserves to be published in the journal. But the introduction part is written poorly and it must be completely rewritten in light of the latest references to focus on the title of the manuscript.
Author Response
Response to Reviewer #1:
"In this manuscript, the authors described the alkynes be regioselectively alkylated to alkenes by organocopper reagents in a 10 reaction known as “carbocupration”, where an alkylCu(I) binds to the alkyne and transfers its 11 organic moieties to one of the alkyne carbon atoms.
In this work, authors also investigated the mechanism using density-functional theory and describe a model that correctly explains both the reaction rates at sub-zero temperatures and the regiochemistry profiles obtained with each of the heteroalkynes. The rate-determining step is shown to vary depending on the hetero substituents, and the alkyl transfer is consistently demonstrated to occur, somewhat counter-intuitively, to the alkyne carbon that is complexed by Cu rather than to the “free” alkyne carbon atom, which instead interacts with the counter-cation which stabilizes the developing electronic charge distribution. Overall the manuscript is written well and deserves to be published in the journal. But the introduction part is written poorly and it must be completely rewritten in light of the latest references to focus on the title of the manuscript."
I thank the reviewer for the thoughtful comments. I have now endeavored to include more information regarding exceptions to the regiochemical trends described, as well as several more recent references to the application of these reactions to the syntheses of complex products. More recent references regarding the reaction mechanism are, unfortunately, not readily available because recent interest in these reactions has focussed on their use as components of complex reaction chains, rather on the intricacies of their mechanistic details. I am afraid that not much can be added without turning the introduction into an uninspired recitation of data that are not germane to the paper and that have, moreover, been expertly reviewed in the reviews cited. I will be glad to improve the introduction further if more specific guidance is provided.
Reviewer 2 Report
In this contribution the author investigated detailed mechanism of Cu-catalyzed alkylation of heterosubstituted alkynes using DFT. It was shown that the rate determining step is substituent dependent and the alkyl transfer occurs to the alkyne carbon that is complexed by Cu. Overall, this study was well carried out and scientifically sound, thus the reviewer recommends it to be published in Catalysts, with a few minor revision points:
1. Motivation/discussion: What could be the potential applications of these systems? What are the implications of using different substituents?
2. In all Tables and main text it would be good to use “free energy” instead of just “energy”.
3. The supporting information was missing.
4. The method for computing TS was missing.
Author Response
Response to Reviewer #2:
"In this contribution the author investigated detailed mechanism of Cu-catalyzed alkylation of heterosubstituted alkynes using DFT. It was shown that the rate determining step is substituent dependent and the alkyl transfer occurs to the alkyne carbon that is complexed by Cu. Overall, this study was well carried out and scientifically sound, thus the reviewer recommends it to be published in Catalysts, with a few minor revision points:
1.Motivation/discussion: What could be the potential applications of these systems? What are the implications of using different substituents?
These systems are used to construct regioslective heterosubstituted alkenes. Naturally, different substituents will entail that different heterosubstituted alkenes are produced. This is now highlighted in the introduction.
2.In all Tables and main text it would be good to use “free energy” instead of just “energy”.
Corrected to “Gibbs free energy” throughout, as requested.
3.The supporting information was missing.
I am afraid this may have been a software glitch on the server side. I hope the current version has no troubles in this regard.
4.The method for computing TS was missing.
This has now been included, as requested.
Reviewer 3 Report
1. "In this work we investigate" why "we"? there is only one author!
2. I am really worried about the charge on the catalytic metal centers in the mechanism!
3. Is this model of study applicable to other copper-catalyzed organic reactions? It can be a good idea to propose to others by introducing copper-catalyzed organic reactions such as
https://pubs.rsc.org/en/content/articlehtml/2020/sc/d0sc04012f
https://onlinelibrary.wiley.com/doi/abs/10.1002/aoc.5600
4. Also for more metal-catalyzed organic reactions such as
https://www.mdpi.com/2073-4344/12/10/1163
https://www.mdpi.com/1420-3049/27/15/4942
5. The conclusion is very long.
6. Please reconsider the charge on metallic centers.
Author Response
Response to Reviewer #3:
1. "In this work we investigate" why "we"? there is only one author!
I felt that using “I” was stylistically awkward and relatively unusual in scietific communication. I have now complied with the reviewer’s request by rewriting those sentences into the passive voice, to avoid both the jarring use of “we” and the sylistically awkward “I” .
2. I am really worried about the charge on the catalytic metal centers in the mechanism!
Experimentally, all of there reactions are performed with Cu(I) reactants. In all computations, Cu therefore had a +1 charge, Mg had 2+, Li had charge +1, and the methyl groups bound to Cu had -1 charge each. These are the charges corresponding to the experimentally described species, and can be confirmed through inspection of the input files uploaded to Figshare.
3. Is this model of study applicable to other copper-catalyzed organic reactions? It can be a good idea to propose to others by introducing copper-catalyzed organic reactions such as
https://pubs.rsc.org/en/content/articlehtml/2020/sc/d0sc04012f
https://onlinelibrary.wiley.com/doi/abs/10.1002/aoc.5600
4. Also for more metal-catalyzed organic reactions such as
https://www.mdpi.com/2073-4344/12/10/1163
https://www.mdpi.com/1420-3049/27/15/4942
Although these computational methods may be applied to all of the systems mentioned by the reviewer, I am afraid that any direct analogy of these results to these systems suggested is premature, since they vary in metal used, oxidation state, etc. I do expect that some of the insights in my work may eventually be applicable to some of those reactions, but I cannot state, without performing those detailed an intricate computations, which details are transferable and which of them are idiosyncratic. Therefore, to avoid any impression of “over-reach”, I would prefer to remain silent on such speculation.
5. The conclusion is very long.
I am afraid that I find myself unable to trim the discussion any further. Although the information in these three paragraphs may seem redundant to an attentive reader (since it is admittedly a restatement of the highlights of the results section) , I think that the large number of pathways analyzed requires that such a summary be present so that a casual reader may easily understand the main points of the work, and to enable a better grasp of the nuances of the work from the part of an attentive reader.
6. Please reconsider the charge on metallic centers.
I am afraid that I do not quite understand the reviewer’s point, since I used the correct charges of the experimentally-used reactants and catalysts. These reactions are known to be Cu(I), rather than Cu(II) based, for example.
Round 2
Reviewer 3 Report
I think the charge on metal can change within the mechanism. It is not stable.
Could you please provide strong evidence or (at least an article as a reference)?
Author Response
Response to Reviewer #3:
I think the charge on metal can change within the mechanism. It is not stable.
I am afraid that there has been some miscommunication: as mentioned in the paper (lines 66-70, referring early computational results from other groups, and lines 129-132 and 177-178, and 258-260, as well as Figure 3 when discussing my results) “ the reaction proceeds through initial charge-transfer from Cu+ to the alkyne and formal oxidation of Cu+ to Cu3+, yielding an intermediate with two Cu-C bonds with almost unity bond order, and a reduction of the bond order of the alkyne to that of an alkene” and “ [the alkyne] accept electrons from Cu+ as it undergoes oxidative addition to the alkyne”. The Supporting information shows that the CM5 charge on Cu increases a bit and that the change in total bond order is indeed compatible with the interpretation of formal oxidation of Cu+ to Cu3+. As the reaction proceeds to completion, CM5 and total bond order return to the initial values, so that Cu returns to the +1 oxidation state. I have added this last sentence to the text, and hope this sufficiently emphasizes both the description of Cu+ oxidation and its transient nature.
Could you please provide strong evidence or (at least an article as a reference)?
The text calls attention to Figure 3 and to the extensive Supporting Information, which shows the variation in bond orders that shows that oxidative addition is occurring (Figure 3) , as well as the small increases in positive charge in the Cu (Supporting Information). All of this agrees with early computational results by Nakamura et al. (1997) (cited in the introduction text in the previous versions and now also cited in the results section)
