Controllable multiple-step configuration transformations in a thermal/photoinduced reaction

Solid-state photochemical reactions of olefinic compounds have been demonstrated to represent powerful access to organic cyclic molecules with specific configurations. However, the precise control of the stereochemistry in these reactions remains challenging owing to complex and fleeting configuration transformations. Herein, we report a unique approach to control the regiospecific configurations of C = C groups and the intermediates by varying temperatures in multiple-step thermal/photoinduced reactions, thus successfully realizing reversible ring closing/opening changes using a single-crystal coordination polymer platform. All stereochemical transitions are observed by in situ single-crystal X-ray diffraction, powder X-ray diffraction and infrared spectroscopy. Density functional theory calculations allow us to rationalize the mechanism of the synergistic thermal/photoinduced transformations. This approach can be generalized to the analysis of the possible configuration transformations of functional groups and intermediates and unravel the detailed mechanism for any inorganic, organic and macromolecular reactions susceptible to incorporation into single-crystal coordination polymer platforms.

well, and the experimental part appears technically sound and solid. However, I find the topic too specialized and not of sufficiently broad appeal to be suitable for Nature.
In the computational part, which is a smaller part of the manuscript though, I also have a few critical remarks.
1) The authors assume the reaction to occur in the triplet state. Is this justified? 2+2 reactions are allowed photochemical reactions and should quickly proceed also in the singlet manifold.
2) Only ground state methods were employed to study excited states. For a comprehensive understanding TDDFT calculations are needed, singlet and triplet states calculated and the corresponding reaction pathways should be studied. For an efficient intersystem crossing, the spinorbit couplings should be large and also calculated.
From the perspective of a computational chemist like me, the theory part is rather weak and premature. I can serve, if at all, as a weak support of the experimental findings, but not as a full fledged analysis of the reaction mechanism.

NCOMMS-22-03066-T
To reviewer #1 (Remarks to the Author): Comment 1: Although thermal control of photo-induced solid-state cycloaddition products has been demonstrated before (References 35 and 41), this work goes far beyond what has been achieved to date. As such, this manuscript describes an important step forward and it is suitable for publication in Nature Communications after minor revision.
The main findings of the work are nicely summarised in Figure 2, which provides a powerful demonstration of thermal control over a wide range of possible products for photoreaction between two diolefin compounds. The results described in the manuscript are fully supported by a comprehensive set of supplementary material, including all of the necessary crystal structures and details of other complementary analytical techniques. The main conclusions are also nicely supported by computational work. I fully appreciate the difficulties in obtaining suitable single crystals after significant 'abuse' in the form of irradiation and thermal treatment, so the crystallography is impressive despite some minor disorder issues.
Regarding any possible mechanisms, it is not easy to rule out that photodimerisation at one site may cause changes in the relative arrangement of the molecules, which may lead to favorable arrangement of the remaining site for photoreaction -a type of cooperative effect. Nevertheless, the authors have provided a convincing argument with regard to the intermediate stages of some of the multistep reactions.
I have the following suggestions for minor revision of the text:

Response:
We thank the reviewer for the very positive comments and support of our work. Comment 2：Page 5: Replace "got changed" with "were altered" in the sentence "Interestingly, the original configuration of the monomer in the initial CP1 got changed at different temperature during the thermal/photoinduced reaction process."

Response:
We agree with the valuable suggestion of the reviewer. Per the reviewer's suggestion and formatting instructions, the sentence "Interestingly, ...in the initial CP1 got changed at different...." has been replaced by the sentence "Interestingly, ...in the initial CP1 is altered at different ..." in the revised MS. (see Page 5, lines 4-6) Comment 3：Page 6: Rewrite "According to Schmidt's rule, the distance between the two parallel C=C groups is 3.82 Å, which allows the photocycloaddition reaction." as "The distance between the two parallel C=C groups is 3.82 Å, which, according to Schmidt's rule, should allow the photocycloaddition reaction to occur."

Response:
We agree with the valuable suggestion of the reviewer. Per the reviewer's suggestion, the sentence "According to Schmidt's rule, ....which allows the photocycloaddition reaction." has been replaced by the sentence "The distance between the two parallel C=C groups is 3.82 Å, which, according to Schmidt's rule, should allow the photocycloaddition reaction to occur." in the revised MS. (see Page 6, bottom to lines 1-3) Comment 4: Page 10: Rewrite "Since a temperature increase can restore the C=C pairs by breaking cyclobutane rings, the transformation of CP1-2β to CP1-2α was investigated by in situ SCXRD at 208 °C, as determined by DSC measurements ( Supplementary Fig. 24)." as "Since a temperature increase can restore the C=C pairs by breaking cyclobutane rings, as inferred from measurements ( Supplementary Fig.   24), the transformation of CP1-2β to CP1-2α was investigated at 208 °C by in situ SCXRD."

Response:
We agree with the valuable suggestion of the reviewer. As suggested, the sentence "Since a temperature increase can restore the C=C pairs by breaking cyclobutane rings, the transformation of CP1-2β to CP1-2α was investigated by in situ SCXRD at 208 °C, as determined by DSC measurements (Supplementary Fig. 24)." has been replaced by the sentence "Since a temperature increase can restore the C=C pairs by breaking cyclobutane rings, as inferred from measurements ( Supplementary   Fig. 24), the transformation of CP1-2β to CP1-2α was investigated at 208 °C by in situ SCXRD." (see Page 10, lines 9-12 in the revised MS) Comment 5: Page 11: Change "Upon heating the crystals of CP1-2β to 208 °C led to a decrease in the sharp pristine diffraction peaks of ..." to "Heating the crystals of CP1-2β to 208 °C led to a decrease in the sharp pristine diffraction peaks of ..."

Response:
We agree with the valuable suggestion of the reviewer. As suggested, the sentence "Upon heating the crystals of CP1-2β to 208 °C led to a decrease in the sharp pristine diffraction peaks of ..." has been replaced by the sentence "Heating the crystals of CP1-2β to 208 °C led to a decrease in the sharp pristine diffraction peaks of ..." (see Page 11, bottom to lines 7-8 in the revised MS)

To reviewer #2 (Remarks to the Author):
Comment: In this manuscript the authors describe the mechanism of the combined photochemical/thermal control of stereochemistry in a solid-state photochemical 2+2 reaction. The manuscript reads very well, and the experimental part appears technically sound and solid. However, I find the topic too specialized and not of sufficiently broad appeal to be suitable for Nature.

Response:
We thank the reviewer for the comments. In this work, we focused on the synergistic control of configuration transformations in a single-crystal coordination polymer platform, which represents a significant work in synthetic chemistry.
Photochemical [2+2] cycloaddition reaction is a green and powerful strategy that has been widely applied in diverse fields, ranging from drug discovery to materials engineering, because it generates specific molecules that would otherwise be difficult to access. As mentioned in this MS, various supramolecular templates, hostguest assemblies, quantum dots, chiral molecular catalysts, and Lewis acid Therefore, we have modified the original descriptions as follows: "As shown in Fig. 4a, the barrier for the thermal C-C bond formation of Int1(S0) via

TS1(S0)
having an open-shell character is 52.9 kcal/mol, which is too high. Therefore, Int1(S0) will first undergo photoexcitation, and the C-C bond formation may occur on the T 1 energy surface, to form Int3 (CP1-1). Given that 1 Int3 is thermodynamically favoured over 1 Int4, a likely pathway involves photoexcitation of 1 Int3, and the rotation and C-C bond formation events then occur in the triplet state, before forming 1 Int6 (CP1-2β) (Fig. 4b)." (see Page 13, bottom to lines 1-7 in the revised MS) "If this C-C bond cleavage event occurs in the triplet state, the process would involve spin inversions. Furthermore, 3 TS4 is less stable than 1 TS4. These factors make it unlikely that the triplet pathway is used under thermal conditions.". (see Page 15,

Comment:
Only ground state methods were employed to study excited states. For a comprehensive understanding TDDFT calculations are needed, singlet and triplet states calculated and the corresponding reaction pathways should be studied. For an efficient intersystem crossing, the spin-orbit couplings should be large and also calculated.

Response:
We thank the reviewer for the comment and valuable suggestion. If our main conclusion is that the reaction proceeds exclusively in the triplet state but not in the singlet state to yield a specific product, careful excited-state calculations are certainly needed. This is because the reaction is impossible in that case without sufficiently large spin-orbit coupling. However, we do not intend to argue it. We just assume that the triplet state is used for the above-mentioned reasons, and even if the singlet state is used, the reaction product is not altered.
We would also like to point out that there are several technical concerns in TDDFT calculations, especially for the application to our coordination polymer system.
1. First of all, the computational demands of the TDDFT reaction-pathway calculations with geometry optimization calculations are prohibitively high. As we have >100 atoms, geometry optimization of intermediates in excited states is already too demanding, and Gaussian 09 cannot calculate analytic 2 nd -order derivatives for transition-state geometry optimization.
2. An alternative strategy may be employed to calculate excited-state energies by single-point calculations using the ground-state geometries. However, the singlet ground state has a significant open-shell character around TS1 (see new Fig. 4a).
Therefore, TDDFT-calculated triplet excited states suffer from severe spin contamination compared to triplet TS1 in the ground-state calculation. Thus, we cannot expect significant improvement in the description of the T 1 excited state by performing demanding TDDFT calculations for our system.

Comment:
From the perspective of a computational chemist like me, the theory part is rather weak and premature. I can serve, if at all, as a weak support of the experimental findings, but not as a full fledged analysis of the reaction mechanism.
Response: We thank the reviewer for the comment. We would like to humbly make the following comments. After doing computational studies, we realized that the hypothetical mechanism that we had long ago was completely different from the mechanism presented in the manuscript (and was not very reasonable in hindsight).
The computational study indeed has played a crucial role in this work, especially in delineating the mechanistic picture. We have also amended detailed descriptions of our computational study to the Supplementary Information, which we hope will minimize potential misunderstandings.

Response to referees and editors
To reviewer #2 (Remarks to the Author) Comment 1: The authors have addressed my scientific comments sufficiently and comprehensively, however, I still find the paper too specialized for Nature. The latter decision however lies with the editors.

Response:
We thank the reviewer for the comments. We highly appreciate that the editor made the very positive decision to accept this article. Our paper highlights the successful configuration control of C=C pairs and of the intermediates by varying temperatures, thus allowing to understand the detailed mechanism of a multi-step thermal/photo-induced reaction by using a single-crystal coordination polymer platform. Such a platform facilitates tracking, trapping and identification of reaction intermediates by e.g. in-situ SCXRD, PXRD, and IR techniques acompanied by DFT calculations deciphering the reaction mechanism for the entire process. This protocol opens a door for the more predictable photosynthesis of cyclobutane compounds with specific configurations that cannot be isolated in solution and unravels the detailed reaction mechanisms for any inorganic, organic and macromolecular reactions incorporated into single-crystal coordination polymer platforms. It will particularly attract a broad readership for the researchers focusing their research on the mechanisms of inorganic, organic, macromolecular reactions, supramolecular assembly, etc.

To the editor:
Your manuscript entitled "Controllable multiple-step configuration transformations in a thermal/photoinduced reaction" has now been seen again by our referees, whose comments appear below. In light of their advice I am delighted to say that we are happy, in principle, to publish a suitably revised version in Nature Communications under the open access CC BY license (Creative Commons Attribution 4.0 International License).

Comment 1:
We therefore invite you to revise your paper one last time to address the remaining concerns of our reviewers and our editorial requests in the attached document(s). At the same time we ask that you edit your manuscript to comply with our policies and formatting requirements and to maximise the accessibility and therefore the impact of your work.
Please see the attached document(s), listing a number of points that must be addressed. Failure to comply with our editorial requests will cause delays in accepting your manuscript. Please also see the Nature Communications formatting instructions for further information.