Photocyclization of Alkenes and Arenes: Penetrating Through Aromatic Armor with the Help of Excited State Antiaromaticity

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review manuscript offers a timely and comprehensive overview of photocyclization reactions involving alkenes and arenes, emphasizing the role of excited state antiaromaticity in facilitating otherwise inaccessible transformations. The focus on the interplay between photochemistry and aromatic stabilization—particularly the application of Baird’s rule—is both conceptually engaging and synthetically valuable. By grounding the discussion in classical transformations (such as stilbene photocyclizations) and drawing connections to modern synthetic strategies, the authors make a compelling case for the expanding potential of photochemical methods in constructing complex molecular architectures.

The manuscript is well-organized and provides a breadth of examples that will be informative to readers aiming to deepen their understanding of photochemical cyclizations, especially within the polycyclic aromatic hydrocarbon (PAH) and nanographene synthesis communities. However, there are numerous typographical inconsistencies, formatting issues, and areas in which the scientific clarity could be improved. The manuscript gives the impression that it may have originated as a dissertation or thesis chapter and then was adapted into review format. While this is a reasonable approach, there remain many signs of that origin—compound numbering conventions, phrasing, and formatting—that should be corrected to make the manuscript suitable for publication as a professional review article.

Overall, the scientific content has strong potential and will likely be a widely cited reference for researchers in PAH synthesis and photochemistry. Nonetheless, the manuscript is not yet ready for publication in its current form. I recommend a thorough revision with a particular emphasis on consistency, formatting, and textual clarity. The attention to detail in the manuscript’s preparation is somewhat below expectations given the reputation of the research group. I offer the following specific comments to aid in the revision process. Please note that this list is not exhaustive; I strongly encourage the authors to carefully proofread the entire manuscript before resubmission.

Some suggested edits (not exhaustive):

• Page 1, line 35: Change “p-systems” to “π-systems”.
• Be consistent in italicizing cis/trans, i-PrOH, o-/m-/p- (ortho/meta/para), and other stereochemical or positional descriptors throughout the text.
• Italicize the “a” in benzo[a]coronene and similar nomenclature cases.
• Numerous extra or missing spaces throughout the text (e.g., page 3, line 93: missing space in “inefficient(e.g.”). I am not sure there is a typographical editor to fix these for this journal so I recommend finding these anomalies and fixing them yourself.
• Page 4, line 115: italicize cis and trans here and throughout manuscript for consistency.
• Page 4, line 127: Change “The broad goal of this chapter…” to reflect review article formatting, not thesis language as this is not a "chapter".
• Line 244: Spelling error – “usuall” should be corrected.
• Line 247: Reword “did not had” for grammatical correctness.
• Line 250: Adjust to “formation of B-F and D-F in a ratio of 1:0.8, respectively.” to correctly depict what is written in the scheme.
• Line 330: Change “2:1 ratio of products 1.1.42a:b…” to “1:2 ratio” to match earlier data.
• Line 338–340: Avoid unnecessary capitalization in “Cyano” and “Iodine” in various places.
• Line 374: Add space at beginning of sentence. Rephrase “which forcing distortion.”
• Line 620: Standardize use of “p-OMe-substituted” versus “p-methoxy-substituted”.
• Page 4, line 132: “Retro-6-π electrocyclization” is misleading as the intermediate is not a 6π electron system; consider replacing with “electrocyclic ring-opening” or “retro-electrocyclic reaction”.
• Page 4, line 140: Change “substituents in the benzene” to “substituents on the benzene.”
• Line 456–457: Ensure consistent hyphenation in “6-π-electrocyclization.”
• Clar sextet preference: In Scheme 7b and Scheme 21, consider placing Clar sextets in the outer rings for phenanthrene and triphenylene, respectively, for better resonance representation.
• Scheme 7c: The second intermediate’s transformation to 1.1.15 appears mechanistically questionable. Consider redrawing or revisiting this part as I believe 1.1.15 is still a phenanthrene.
• Scheme 10: Show the starting tin reagent over the arrow (likely tributyl tin hydride, if appropriate, with AIBN). The current depiction as a tin radical, which cannot be bought as a reagent, is misleading.
• Compound numbering beginning with “1” throughout (e.g., 1.1.1, 1.1.2…) mimics a thesis/dissertation structure. Simplify this if not necessary for the organization of the review.
• Scheme 3 caption: Capitalize “The” in “cyclization. the” and reword for clarity.
• Scheme 5A and 5B are not labeled as such; ensure all subfigures are clearly labeled and consistently referenced (capitalize consistently—e.g., Scheme 5A, Scheme 6B—or uncapitalize consistently—Scheme 5a, Scheme 6b).
• Scheme 6: Discussion lacks explanation for reversal of reactivity with I₂ vs O₂. For compound 1.1.9, if the original authors offered no mechanistic rationale, comment on this and propose one if feasible (e.g., lower oxidation potential due to electron-donating groups).
• Scheme 7b/7c: Discussion appears to switch the order; clarify.
• Scheme 9: Consider noting that similar electrocyclization has been done with chloro derivatives (e.g., Morin’s CDHC method). Cite the original reference if possible.
• Scheme 26a: Center the hν (consider using Greek “nu” instead of “v” if possible).
• Scheme 27: There appears to be a missing Scheme 27d—label it accordingly in the text (line 485) and scheme rather than cramming two transformations into scheme 27c.
• Scheme 28a: Described reaction on lines 491-493 does not match what is shown. Compound 1.4.17 was in Scheme 27a, not Scheme 28a, and seems to reflect older work from 1982 and not Alabugin's work. Revise accordingly.
• Compound 1.4.12: Methyl dashed bond is incorrectly drawn—redraw for appropriate sp2 hybridization of the carbon that the methyl group is bonded to.
• Compound 1.4.16: Benzene ring is distorted—fix for correct geometry.
• Reference numbers are mismatched with in-text citations (e.g., reference 51 is incorrectly cited in relation to Scheme 10). Ensure in-text citations match bibliography.
• Header formatting is inconsistent—some in all caps, some not. Standardize.
• Consider adding a tribute in Scheme 33 to the late Professor Reginald Mitchell, given his historical contributions in this area.
• Use of Latin phrases like de novo should be formatted consistently (italic or not—choose one).
• Finally, although this review contains valuable and potentially high-impact content, the manuscript requires a careful and thorough revision. I strongly recommend a meticulous round of editing, both for typographical and scientific issues, to ensure clarity and professionalism throughout.

 

Author Response

Reviewer 1:
This review manuscript offers a timely and comprehensive overview of photocyclization reactions involving alkenes and arenes, emphasizing the role of excited state antiaromaticity in facilitating otherwise inaccessible transformations. The focus on the interplay between photochemistry and aromatic stabilization—particularly the application of Baird’s rule—is both conceptually engaging and synthetically valuable. By grounding the discussion in classical transformations (such as stilbene photocyclizations) and drawing connections to modern synthetic strategies, the authors make a compelling case for the expanding potential of photochemical methods in constructing complex molecular architectures.

The manuscript is well-organized and provides a breadth of examples that will be informative to readers aiming to deepen their understanding of photochemical cyclizations, especially within the polycyclic aromatic hydrocarbon (PAH) and nanographene synthesis communities. However, there are numerous typographical inconsistencies, formatting issues, and areas in which the scientific clarity could be improved. The manuscript gives the impression that it may have originated as a dissertation or thesis chapter and then was adapted into review format. While this is a reasonable approach, there remain many signs of that origin—compound numbering conventions, phrasing, and formatting—that should be corrected to make the manuscript suitable for publication as a professional review article.

Overall, the scientific content has strong potential and will likely be a widely cited reference for researchers in PAH synthesis and photochemistry. Nonetheless, the manuscript is not yet ready for publication in its current form. I recommend a thorough revision with a particular emphasis on consistency, formatting, and textual clarity. The attention to detail in the manuscript’s preparation is somewhat below expectations given the reputation of the research group. I offer the following specific comments to aid in the revision process. Please note that this list is not exhaustive; I strongly encourage the authors to carefully proofread the entire manuscript before resubmission.

Answer: Thank you for the kind words and very helpful comments.

Some suggested edits (not exhaustive):

• Page 1, line 35: Change “p-systems” to “π-systems”.
  Answer: Thank you, we have changed “p-systems” and “pi-systems” throughout the document to “π-systems”.
• Be consistent in italicizing cis/trans, i-PrOH, o-/m-/p- (ortho/meta/para), and other stereochemical or positional descriptors throughout the text.
  Answer: Thank you, we have italicized the suggested as well as non-suggested stereochemical/positional descriptors throughout the document.
• Italicize the “a” in benzo[a]coronene and similar nomenclature cases.
  Answer: Thank you, we have Italicized the “a” in benzo[a]coronene and similar nomenclature cases.
• Numerous extra or missing spaces throughout the text (e.g., page 3, line 93: missing space in “inefficient(e.g.”). I am not sure there is a typographical editor to fix these for this journal so I recommend finding these anomalies and fixing them yourself.
  Answer: thank you for noticing these errors. We have carefully scanned through the paper to delete extra spaces and add spaces where missing including in “inefficient(e.g.”).
• Page 4, line 115: italicize cis and trans here and throughout manuscript for consistency.
  Answer: Thank you for the suggestion, we italicized cis/trans and other stereochemical descriptors in the text.
• Page 4, line 127: Change “The broad goal of this chapter…” to reflect review article formatting, not thesis language as this is not a "chapter".
  Answer: Thank you for the suggestion, we have changed the word “chapter” to “ review”.
• Line 244: Spelling error – “usuall” should be corrected.
  Answer: Thank you for the suggestion, we have corrected the spelling in “usuall” to “usual”
• Line 247: Reword “did not had” for grammatical correctness.
  Answer: Thank you for the suggestion, we have reworded “did not had” to “did not have”.
• Line 250: Adjust to “formation of B-F and D-F in a ratio of 1:0.8, respectively.” to correctly depict what is written in the scheme.
  Answer: Thank you for the suggestion, we have checked the paragraph and changed from “D-F and B-F…” to  the suggested “ B-F and D-F…”.
• Line 330: Change “2:1 ratio of products 1.1.42a:b…” to “1:2 ratio” to match earlier data.
  Answer: Thank you for the suggestion, we have updated the manuscript and changed the order of the ratio to “1:2 ratio” to correct this mistake.
• Line 338–340: Avoid unnecessary capitalization in “Cyano” and “Iodine” in various places.
  Answer: Thank you for the suggestion, we have scanned through the paper and changed the unnecessary capitalization of these words.
• Line 374: Add space at beginning of sentence. Rephrase “which forcing distortion.”
  Answer: Thank you for the suggestion, we have updated the manuscript by adding a space at the beginning of this sentence and changed “ which forcing distortion” to “ which forces distortion”.
• Line 620: Standardize use of “p-OMe-substituted” versus “p-methoxy-substituted”.
  Answer: Thank you for the suggestion, we have standardized the use of “OMe” instead of “methoxy” in all similarly written descriptions and compounds.
• Page 4, line 132: “Retro-6-π electrocyclization” is misleading as the intermediate is not a 6π electron system; consider replacing with “electrocyclic ring-opening” or “retro-electrocyclic reaction”.
  Answer: thank you for this comment, we have changed the wording in this line to “electrocyclic ring-opening” as suggested.
• Page 4, line 140: Change “substituents in the benzene” to “substituents on the benzene.”
  Answer: Thank you for the suggestion, we have changed this grammatical error as suggested in this comment.
• Line 456–457: Ensure consistent hyphenation in “6-π-electrocyclization.”
  Answer: Thank you for the suggestion, we have changed the hyphenation in this collection of words throughout the document to “6-π electrocyclization”.
• Clar sextet preference: In Scheme 7b and Scheme 21, consider placing Clar sextets in the outer rings for phenanthrene and triphenylene, respectively, for better resonance representation.
  Answer: thank you very much for this comment, we have changed the position of the Clar’s sextets for better resonance representation in the schemes mentioned above.
• Scheme 7c: The second intermediate’s transformation to 1.1.15 appears mechanistically questionable. Consider redrawing or revisiting this part as I believe 1.1.15 is still a phenanthrene.
  Answer: Thank you for the suggestion, we have edited the scheme. The suggestion was correct and the product should have been a phenanthrene.
• Scheme 10: Show the starting tin reagent over the arrow (likely tributyl tin hydride, if appropriate, with AIBN). The current depiction as a tin radical, which cannot be bought as a reagent, is misleading.
  Answer: Thank you for the suggestion, we have changed the reagent over the first arrow in this scheme to tributyl tin hydride.
• Compound numbering beginning with “1” throughout (e.g., 1.1.1, 1.1.2…) mimics a thesis/dissertation structure. Simplify this if not necessary for the organization of the review.
  Answer: The current numbering scheme is helpful for the organization of the review. Since the sections are divided as 1.1, 1.2, etc… The numbering of 1.1.1 indicated it is compound 1 in section 1.1. It helps the reader to find the information faster and also saves labor needed for renumbering atoms in the revision.
• Scheme 3 caption: Capitalize “The” in “cyclization. the” and reword for clarity.
  Answer: Thank you for the suggestion, we have shortened the title of this scheme and ensured correct grammar to be used in this sentence.
• Scheme 5A and 5B are not labeled as such; ensure all subfigures are clearly labeled and consistently referenced (capitalize consistently—e.g., Scheme 5A, Scheme 6B—or uncapitalize consistently—Scheme 5a, Scheme 6b).
  Answer: Thank you for the suggestion, we have standardized the lowercase use for schemes 5 to match with the rest of the manuscript descriptions.
• Scheme 6: Discussion lacks explanation for reversal of reactivity with I₂ vs O₂. For compound 1.1.9, if the original authors offered no mechanistic rationale, comment on this and propose one if feasible (e.g., lower oxidation potential due to electron-donating groups).
  Answer: the authors did not offer a mechanistic rationale for this difference and it is hard to know if there is a difference in triplet state energy for these molecules or not that could explain this reversal of reactivity. We have added this comment to the discussion in the text as well.
• Scheme 7b/7c: Discussion appears to switch the order; clarify.
  Answer: Thank you for the suggestion, we have switched the order of discussion for the two parts of this schemes for proper flow of the manuscript.
• Scheme 9: Consider noting that similar electrocyclization has been done with chloro derivatives (e.g., Morin’s CDHC method). Cite the original reference if possible.
  Answer: Thank you for the comment! That is indeed true and we have added a original reference from the work of morin to this part of the discussion!
• Scheme 26a: Center the hν (consider using Greek “nu” instead of “v” if possible).
  Answer: Thank you for the suggestion. The use of nu in our chemdraw simply adds the same character as the lowercase v, which is why we have been using this. also, we believe latin nu does not look the best in chemdraw and decreases clarity of the schemes.
• Scheme 27: There appears to be a missing Scheme 27d—label it accordingly in the text (line 485) and scheme rather than cramming two transformations into scheme 27c.
  Answer: Thank you for the suggestion, section c of scheme 7 includes two reactions described in the same article. Thus they were included as one section of the scheme. However we do understand how it can cause confusion and made the requested change.
• Scheme 28a: Described reaction on lines 491-493 does not match what is shown. Compound 1.4.17 was in Scheme 27a, not Scheme 28a, and seems to reflect older work from 1982 and not Alabugin's work. Revise accordingly.
  Answer: Thank you for the suggestion, compound numbers were updated accordingly. The formatting of the previous numbers was not updating with the rest of this manuscript, we have fixed this and the following numbers were updated accordingly.
• Compound 1.4.12: Methyl dashed bond is incorrectly drawn—redraw for appropriate sp2 hybridization of the carbon that the methyl group is bonded to.
  Answer: Thank you for the suggestion, we have fixed the orientation of this methyl to properly show sp2 hybridization.
• Compound 1.4.16: Benzene ring is distorted—fix for correct geometry.
  Answer: Thank you for the suggestion, we have fixed the distortion in this benzene ring and slightly adjusted the orientation of the amide group as to not overlap with the methyl.
• Reference numbers are mismatched with in-text citations (e.g., reference 51 is incorrectly cited in relation to Scheme 10). Ensure in-text citations match bibliography.
  Answer: Thank you for this comment, this section was missing another reference which we have added to fix this inconsistency.
• Header formatting is inconsistent—some in all caps, some not. Standardize.
  Answer: Header information has been modified by editors and is now standardized as per the “Chemistry” requirements.
• Consider adding a tribute in Scheme 33 to the late Professor Reginald Mitchell, given his historical contributions in this area.
  Answer: Thank you for this suggestion! We have added a reference and a tribute to professor Reginald Mitchell above this scheme.
  
  
• Use of Latin phrases like de novo should be formatted consistently (italic or not—choose one).
  Answer: Thank you for the suggestion, we have italicized all uses of “de novo” throughout the document.
• Finally, although this review contains valuable and potentially high-impact content, the manuscript requires a careful and thorough revision. I strongly recommend a meticulous round of editing, both for typographical and scientific issues, to ensure clarity and professionalism throughout.

Reviewer 2 Report

Comments and Suggestions for Authors

The review by Dos Santos, Wu, and Alabugin represents a comprehensive overview of the excited-state reactivity of arenes, particularly in the presence of olefins. There is extensive focus on the role external olefin partners have in assisting in arene reactivity, particularly through alleviation of excited state antiaromaticity via geometric constraints. The review is detailed and well structured, and highlights several examples and guiding principles in understanding selectivity in arene-olefin photocyclizations. This also captures some of the more specific advances that nunerous groups are making towards using these reactions to synthesize valuable polyaromatic hydrocarbons. The discussion of specific examples within a class of reactions is generally well written and detailed.

 

In my view, this review is very helpful and serves as a useful overview of an interesting and important field of chemistry. However, there are several instances (specifically in introductory/background sections) that could benefit from more specific schemes and information to contextualize the reactivity shown. Before publication, this issues outlined below should be addressed to increase the clarity, pedagogical impacts, and overall comprehensiveness:

 

1. In the introduction, the discussion of excited states (line 48-52) “twisting” vs “pyramidalization” is unspecific and would benefit from either more explanation and an associated diagram.
   1. This is also true for content in lines 86 and line 88
2. The introductory paragraph of section 1.1 isa bit vague and could either be removed or further extended.
3. Baird’s rules are mentioned several times (line 14, 59, 123) and I think a little more could be done to introduce this concept to a non-expert audience. A figure would be appreciated.
4. The discussion of free valence numbers and localization energies deserves much more explanation and emphasis (line 175). There is no associated literature reference for this, and the meanings are not clear. The authors then expand on this to predict site-selectivity in cyclization, but without stronger background the rules of cyclization are note obvious. Generally, I think his section could be rewritten with more detail (particularly Scheme 5).
5. There are several mistakes with compound numbering – for example, compound 1.1.12 does not match the schemes shown. Generally, speaking this is present in a few figures, which should be checked and addressed throughout.
6. The sentence in line 268 is repeated almost word for word in line 276.
7. There are several numbering mistakes in Scheme 29 and the associated text (line 509). The word “oxidative” is misspelled.
8. The phrase “excited-state engineering” is not defined (line 668).
9. The conclusion would benefit from a brief discussion of what the future of this field looks like, as currently it is more of a summary.
10. Scheme 52 contains an error.

11.  

     

     More detailed discussion is needed on the escape from antiaromaticity of excited-state benzene and ensuing cyclization reactivity enabled by the twisting of attached alkenes (lines 83-94). How does the twisting of exocyclic alkenes, or the lack of twisting of alkynes, influence arene aromaticity considering it is not part of the cyclic π system? Also, alkene twisting in the excited state is known to be detrimental to reactivity in [2+2] photocycloadditions due to unproductive isomerization. Hence, cyclic alkenyl substrates with limited capability to twist undergo [2+2] photocycloadditions much more effectively than acyclic substrates (J. Am. Chem. Soc. 2023, 145 (46), 25061–25067; Chem. Rev. 2016, 116 (17), 9748–9815.). How would this phenomenon be reconciled with the proposal that alkene twisting enables the photocyclization reactivities described in this review? 

Author Response

Reviewer 2:

The review by Dos Santos, Wu, and Alabugin represents a comprehensive overview of the excited-state reactivity of arenes, particularly in the presence of olefins. There is extensive focus on the role external olefin partners have in assisting in arene reactivity, particularly through alleviation of excited state antiaromaticity via geometric constraints. The review is detailed and well structured, and highlights several examples and guiding principles in understanding selectivity in arene-olefin photocyclizations. This also captures some of the more specific advances that nunerous groups are making towards using these reactions to synthesize valuable polyaromatic hydrocarbons. The discussion of specific examples within a class of reactions is generally well written and detailed.

 

In my view, this review is very helpful and serves as a useful overview of an interesting and important field of chemistry. However, there are several instances (specifically in introductory/background sections) that could benefit from more specific schemes and information to contextualize the reactivity shown. Before publication, this issues outlined below should be addressed to increase the clarity, pedagogical impacts, and overall comprehensiveness:

 

1. In the introduction, the discussion of excited states (line 48-52) “twisting” vs “pyramidalization” is unspecific and would benefit from either more explanation and an associated diagram. This is also true for content in lines 86 and line 88

Answer: Thank you for this comment. We believe this comment is similar to the last comment this reviewer has made “More detailed discussion is needed on the escape from antiaromaticity of excited-state benzene and ensuing cyclization reactivity enabled by the twisting of attached alkenes (lines 83-94). How does the twisting of exocyclic alkenes, or the lack of twisting of alkynes, influence arene aromaticity considering it is not part of the cyclic π system? Also, alkene twisting in the excited state is known to be detrimental to reactivity in [2+2] photocycloadditions due to unproductive isomerization. Hence, cyclic alkenyl substrates with limited capability to twist undergo [2+2] photocycloadditions much more effectively than acyclic substrates (J. Am. Chem. Soc. 2023, 145 (46), 25061–25067; Chem. Rev. 2016, 116 (17), 9748–9815.). How would this phenomenon be reconciled with the proposal that alkene twisting enables the photocyclization reactivities described in this review? “. We have added suggested and new references to this section and expanded upon this discussion.

       2. The introductory paragraph of section 1.1 is a bit vague and could either be removed or further extended.
Answer: thank you for this comment. The introductory paragraph of section 1.1 is used only to introduce the concept. In the second paragraph we expand on the specific pros of photochemistry which apply to the contents of this review.

    3. Baird’s rules are mentioned several times (line 14, 59, 123) and I think a little more could be done to introduce this concept to a non-expert audience. A figure would be appreciated.
Answer: Thank you for this comment. We have added extra discussion and references about Baird’s rules before Scheme 1 and have added a visual summary of these rules in Scheme 2.

    4. The discussion of free valence numbers and localization energies deserves much more explanation and emphasis (line 175). There is no associated literature reference for this, and the meanings are not clear. The authors then expand on this to predict site-selectivity in cyclization, but without stronger background the rules of cyclization are note obvious. Generally, I think his section could be rewritten with more detail (particularly Scheme 5).

Answer: thank you for this suggestion. We have added expanded this discussion and added new literature references to this section.
“Mallory cyclizations were shown to depend strongly on the nature of the chromophore, especially the position of conjugating substituents and the presence of fused aromatic rings. To address that, two reactivity parameters, free valence numbers (F*r) and localization energies (Lrs), have been considered. These parameters are conceptually different since F*r is based on the electronic structure of the excited state yes (i.e., the reactant in the photocyclization) while Lrs is based solely on the structure of the ground state cyclization product. They can be derived from Hückel Molecular Orbital (HMO) theory46 or higher level singlet-state wavefunctions.47,48

More specifically, F_r is defined as F_max - F_r, where F_max is the maximum possible p-bonding capacity of the atom and F_r is the sum of the p-bond orders of all bonds at the atom. This estimates how much bonding potential is still "available" at a given atom. The F*_r​ indexes provide information on which atoms in the molecule become more reactive upon excitation. More specifically, it quantifies the availability of an atomic center to form new bonds in a given electronic state (typically, the first excited state).

Localization energy L_r is the energy cost (loss of delocalization stabilization) defined as the decrease in π delocalization energy when the π orbital at atom r is removed from the conjugated system (e.g., to form a s-bond in the photocyclization product)​. Lower L_r means that removing that atom’s electron from delocalization costs little energy. Localization energies can be calculated either for the ground state (L) and for an excited state (L*). Since photocyclizations form a new s-bond and, hence, remove two atoms from conjugation, localization energies for evaluating cyclizations have two indexes r and s corresponding to the atoms C_r and C_s connected with the new C-C bond (L_rs)

The empirical rule for using the localization energy (L*) as a reactivity parameter is that photocyclizations only occur when L* < 3.45b. Even though this approach includes energy difference between two actual molecular species (aromatic precursor and dearomatized cyclic product), the L* values have been used less often.

Laarhoven^46,49,50 has suggested a set of rules for predicting the regioselectivity of such photochemical cyclizations in non-symmetric systems using the F*_r​ indexes. In Mallory photocyclization for instance, the site with the highest value for the (F*_r + F*_s) sum at the two reacting atoms r and s indicates highest reactivity. When multiple reactive positions exist, the value of F*_r + F*_s helps to predict which site will control selectivity.”

The rules can be formulated as follows: 1) photocyclizations do not occur when F*_r + F*_s < 1.0; 2) one product is formed when the difference in ∑F* between the reacting sites is more than 0.1; and 3) when there is a choice between planar or non-planar products, selectivity favors the planar product. Scheme 5a shows an example of how these calculations can predict reactivity of naphthyl-substituted substrate where reaction can take place at either the α- or the β-positions of the naphthalene ring. The sum of the F*_r and F*_s indexes is larger for the attack at the α-position. Indeed, experiment showed that cyclisation takes place only there.

      5. There are several mistakes with compound numbering – for example, compound 1.1.12 does not match the schemes shown. Generally, speaking this is present in a few figures, which should be checked and addressed throughout.
Answer: Thank you for the suggestion, we have checked the formatting of numbers and fixed the codes, then double checked to make sure all compound numbers match their respective schemes and text mentions.

    6. The sentence in line 268 is repeated almost word for word in line 276.
Answer: Thank you for the suggestion, we have updated the second phrase to remove the redundancy of this of this repetition.

    7. There are several numbering mistakes in Scheme 29 and the associated text (line 509). The word “oxidative” is misspelled.

Answer: Thank you for these comments, the numbering in this section has been fixed as well as the misspelled word.

    8. The phrase “excited-state engineering” is not defined (line 668).
Answer: Thank you for noting this, we have expanded this paragraph to clarify its meaning and better explain the difference in reactivity for N-substituted substrates.

    9. The conclusion would benefit from a brief discussion of what the future of this field looks like, as currently it is more of a summary.

Answer:

   10. Scheme 52 contains an error.
Answer: thank you for pointing this out. We have fixed the error in the scheme. (i.e the incorrect intermediate after cyclization.)

 

 

 More detailed discussion is needed on the escape from antiaromaticity of excited-state benzene and ensuing cyclization reactivity enabled by the twisting of attached alkenes (lines 83-94). How does the twisting of exocyclic alkenes, or the lack of twisting of alkynes, influence arene aromaticity considering it is not part of the cyclic π system? Also, alkene twisting in the excited state is known to be detrimental to reactivity in [2+2] photocycloadditions due to unproductive isomerization. Hence, cyclic alkenyl substrates with limited capability to twist undergo [2+2] photocycloadditions much more effectively than acyclic substrates (J. Am. Chem. Soc. 2023, 145 (46), 25061–25067; Chem. Rev. 2016, 116 (17), 9748–9815.). How would this phenomenon be reconciled with the proposal that alkene twisting enables the photocyclization reactivities described in this review? 

Answer: The higher reactivity of alkenes incapable of twisting (https://pubs.acs.org/doi/full/10.1021/jacs.3c08105) is consistent with twisting as a way to escape antiaromaticity. Thank you for bringing this example to our attention.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have address my comments pretty well. However, there are still some minor typos here and there that the authors might want to find and fix before the final version is published. It's a big document and I understand it can be difficult to spot all of these errors (i.e., "an electrocyclic" vs "a electrocyclic"; extra spaces inserted before punctuation on line 63 and other places). This is a great review and I do not need to see another version of it before publication.