Solvent-Mediated Rate Deceleration of Diels–Alder Reactions for Enhanced Selectivity: Quantum Mechanical Insights
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis manuscript reports the DFT calculation results of the influence of solvent on the selectivity of Diels-Alder reactions of between 9-methylanthracene with (5-oxo-2H-furan-2-yl) acetate and different anhydrides. This work highlights the importance of solvent in influencing reaction. The manuscript could be acceptable after considering the following issues.
1. The real Diels-Alder reactions are occurred in solvent, thus, the detailed discussion should base on the results in solvent, not in gas phase.
2. For a work to discuss to the influence of solvent, the solvents only contain acetones and toluene are insufficient. The authors should do the benchmark work on the various common used solvents in organic synthesis. Moreover, how the solvents influence on reactivity should be discussed.
3. The discussion about the MEP is not enough, because it does not provide more useful information except the positive and negative regions. The exact positions and values of most positive and negative MEP should be given in graphs and more deeply discussion is hoped.
Author Response
Please find a point-by-point response in the attached document.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for Authors
In the present mns Rehman et al studied computationally via DFT the Diels-Alder reactions of 9-methylanthracene with (5-oxo-2H-furan-2-yl) acetate and different anhydrides.
The used methodologies are appropriate for the study.
The present mns is a rather trivial computational study, but it provides some results that may be useful.
Thus, I recommend the publication of the mns after a major revision.
1. The introduction part must be revised and published theoretical studies on other DA should be added.
2. Comments regarding the TS of the present DA reactions with other published DA should be added. These comments will increase the scientific significance of this study.
3. Given that only one DFT methodology is used, the authors should explain their methodology selection by adding one or two theoretical papers that have proven that this DFT methodology is appropriate for DA reactions.
Author Response
Please find a point-by-point response in the attached document.
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsPEER REVIEW REPORT
The paper titled “Solvent-mediated rate deceleration of Diels-Alder reactions for
enhanced selectivity: quantum mechanical insights” focuses on the influence of the solvent environment on the reactivity and selectivity of Diels-Alder reactions. The authors employ the density functional theory (DFT) to evaluate the thermodynamical quantities and analyze the molecular orbitals associated with the two reaction paths that lead to distinct stereoisomer products in the Diels-Alder cycloaddition. The simulations are performed under different environmental conditions, namely, in the gas-phase, polar, and non-polar solvents. The results show that for the considered group of Diels-Alder reactions—with 9-methylanthracene as diene, and (i) maleic anhydride (ii) chloro-maleic anhydride, (iii) cyano-maleic anhydride and (iv) (5-oxo-2H-furan-2-yl) acetate as dienophiles—the reaction exhibit faster rates in the non-polar environment (toluene) while the selectivity is enhanced in the polar environment (acetone). The authors thus emphasize the role that the solvent can play in mediating the Diels-Alder reactions and hint at a potential approach to control the Diels-Alder selectivity.
The article makes quantitative predictions on the molecular reactivity under complex reaction conditions (i.e. under different solvation environments) and provides novel conceptual insights into the reaction mechanism from a microscopic, quantum-mechanical scale. The research topic is of broad interest and significance to the community of computational chemistry (or broadly, physical chemistry) and organic chemistry. Thus, the article matches the scope of the Section Theoretical and Computational Chemistry in the Journal Chemistry. Furthermore, the article is well-structured. Background knowledge of the Diels-Alder reactions and their wide chemistry applications, the computational protocols, results as well as their insights on the reaction mechanisms are clearly presented. Furthermore, the authors provide the molecular geometries and the calculation input/output files that enhance the data accessibility, and the computational details are reported in a manner easy for the potential reproduction of the data. Overall, I recommend the publication of the article on Chemistry, providing that the authors can clarify the specific concerns listed below. Those changes, I believe, will help potential readers interpret the science with less ambiguity.
General Comments
[1] The core result and conclusion of this paper is the influence of the polar/non-polar environment on the transition-state energy barrier of the Diels-Alder reactions. To make a general statement on the trend, two solvents as data points are not adequate, despite that toluene and acetone could be conventional solvents to host the DA reactions. Since the solvation model that is used in the article—the polarizable continuum model (PCM), which is an implicit solvent model—takes the solvent dielectric constant as the input, I would suggest a figure including two curves of the energy barrier (y-axis, given one particular choice of the reaction, e.g. 1+2d->3d/3d’) with respect to the solvent dielectric constant (x-axis), and including a few more solvent data points. This figure compares the reactivity and selectivity quantitatively and straightforwardly as a function of the solvent types and would significantly strengthen the conclusion.
It is also beneficial to clarify in the text that this conclusion is based on transition state theory. Certain kinetic effects, such as dynamical recrossing (one example can be “kinetic cage effects” of the solvents) are not included in the modeling, as authors said on Line 104 “[thermodynamical properties predict] whether a chemical reaction will occur spontaneously under a given set of conditions”.
[2] Another factor that influences the validity of the conclusion in this article is the approach to modeling the solvent environments. Since the energy difference in the transition-state barrier height is 3.7kJ/mol v.s. 5.5 kJ/mol (Figure 1d, reaction 1+2d), a relatively small difference (since k_BT = 2.5 kJ/mol for T=300 K), the modeling of the solvation environment has to be accurate enough to draw a confident conclusion on the reactivity.
I understand a comparison of the results obtained with the implicit solvent model v.s. those with the explicit solvent model might be beyond the scope of the current work. I would encourage the authors to consider explicit solvent modeling in the future, but for the current work, could authors (i) summarize the various ways of modeling solvation environment and their advantages or disadvantages in the Introduction, and (ii) find some support from the literature to validate/estimate the accuracy of implicit solvent modeling for reactivity?
[3] The article presents a strong logic in the Intro Section. It argues that “solvents are important to reactions”, then “still not understood very well”, and “computational studies are helpful” and motivates the current study. However, I found that a very crucial argument in the logic chain, “the atomic processes responsible for the solvent effects on the reaction mechanism are still not understood very well” (Line 46) is not sufficiently discussed and supported. Are Diels-Alder reactions special examples that are exposed to considerable solvent effect? Any specific development of the computational tools are needed to build the understanding of the solvent effects? I suggest the authors review the literature in more detail and provide the necessary background information for the subsequent discussion.
In addition, references that can provide more comprehensive background information (relevant reviews or books), instead of specific research articles are probably more appropriate to cite to support some of the arguments by the authors in the Introduction. For example, citations of less general literature appear in the place of citations [15-16], to describe the general understanding of the Diels-Alder reaction as “the addition of an electron-rich diene to an electron-poor dienophile”; near citation [19], solvents are usually “supposed to be a medium” for the reactions.
[4] Did the authors see multiple transition states for the D-A reactions considered in the article? I understand that the authors perform the check—“all the transition state structures have single imaginary frequencies”, but is it possible to comment more on the uniqueness of the transition state geometry, either with their results or discoveries in the literature?
In the Introduction, the authors also mentioned that “[The processes of Diels-Alder reactions] are thought to be concerted, but they are not always synchronous. In extreme examples, it may become a two-step chemical reaction with biradical or zwitterionic intermediates. (Line 32)” Is there enough evidence to comment on whether the reactions of consideration here are synchronous or not? Do the current calculation results directly hint that it is a one- or two-step process? Alternatively, do those reactions follow certain reaction mechanisms? The Frontier orbital analysis in Figure 4 seems to be good evidence, is it right?
[5] Fig. 2 can be a double-axis plot to emphasize the solvent-controlled reaction selectivity. The left axis (\Delta\Delta G) determines the product ratio (i.e. selectivity) and is a one-to-one function. I suggest having the ratio marked as axis ticks on the right axis of Fig. 2.
[6] Fig. S1 - I suggest reporting the energy data in the acetone/toluene environment as an energy difference with respect to the gas phase energy and in the unit of eV or kcal/mol for a more straightforward interpretation. Furthermore, is there a reason why only selected reactants or transition state geometries are reported in Fig. S1 despite the caption reading “of all the reactions as calculated in Gaussian”? My impression (from Fig. 1 in the main text) is that the authors indeed have carried out the simulation for b and c reactants. For example, I suggest reporting the energies for 2b, 2c, 3b/b’, 3c/c’, TSb/b’, TSc/c’ in the Table as well. Also similarly, it is helpful to include the data for b and c reactants in Fig. S2.
[7] Fig. S2 and S3 - It reads in Fig. 1(d) that the reaction 1+2d is exothermic, but the IRC energy path seems to suggest it is endothermic (since the product has higher energy than the reactant)? Maybe the reaction coordinate should be reversed? Please clarify.
Other specific comments—
[a] I suggest explicitly mentioning in Scheme 1 that 3a and 3a’ are the same products to avoid confusion.
[b] Line 110, I suggest changing the word “free-energy barrier” to “single-point free-energy barrier”. The word “free-energy barrier” could otherwise refer to the free energy difference as Boltzmann-weighted over the phase space, e.g. see Frenkel & Smit, Understanding Molecular Simulation: From Algorithms to Applications, Chapter 7.
[c] Fig. S4 - typo in the caption, should be “gas phase” and “optimized”.
Author Response
Please find a point-by-point response in the attached document.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThis paper can be accepted in this form.
Reviewer 2 Report
Comments and Suggestions for AuthorsAccepted
