Editor's synthesis & decision
Minor RevisionRevision requests
- Quantify the syn/anti atropisomer ratios for all mixtures used in screening and, where possible, compare their performance against isolated pure isomers to validate the screening data.
- Provide a proposed transition state model or computational insight to rationalize the observed substrate scope, specifically explaining why minor structural modifications lead to significant drops in enantioselectivity.
- Clarify the synthetic procedures in the Supporting Information, specifically regarding the one-pot process in Scheme 1 and the stability of non-iodinated control species under reaction conditions.
- Soften the interpretation of the amide's role in enantioinduction, acknowledging its potential contribution to conformational preorganization rather than dismissing it as merely 'assisting'.
Where this could be published
At its current quality
Solid specialist journals in organic synthesis and catalysis
- Journal of Organic Chemistry
- Organic Letters
- Advanced Synthesis & Catalysis
Then you could realistically aim for
Highly selective broad-interest chemistry journals
- Angewandte Chemie International Edition
- Journal of the American Chemical Society
- Chemical Science
The current manuscript is well-positioned for high-quality specialist journals, but reaching a broader-audience flagship venue requires deeper mechanistic insight to elevate the work from an empirical study to a generalizable catalytic principle. The most critical improvement is the development of a structural transition state model that explains the catalyst's substrate sensitivity. This guidance is not a guarantee of acceptance, and you should perform a current literature search to ensure your findings remain novel relative to the most recent publications.
edited by model: gemini-flash-lite-latest
Reviewer comments — reproduced in full, unabridged
Reviewer 1
gemini-flash-lite-latestThis manuscript describes the development of a second-generation, bidentate iodine(I)-based halogen bond donor catalyst for the enantioselective Mukaiyama aldol reaction. The authors demonstrate that a modifiable catalyst scaffold, derived from a chiral amino-indanol precursor, can achieve high stereocontrol (up to 98% ee) for specific substrates. The study includes a systematic evaluation of catalyst derivatives and substrate scope, alongside control experiments to confirm the role of halogen bonding. Overall, the work represents a significant, well-executed advancement in the field of halogen-bond-mediated organocatalysis. The findings are technically sound and provide a clear, albeit narrow, contribution to the development of non-covalent interaction-based catalytic systems.
Strengths
- Successful development of a highly enantioselective halogen-bonding catalyst system achieving up to 98% ee.
- Clear demonstration of the 'engine' role of halogen bonding through the use of non-iodinated control experiments.
- Effective use of a late-stage modification strategy to explore the catalyst structure-activity relationship.
Weaknesses
- The use of atropisomer mixtures in the majority of screening experiments complicates the interpretation of catalyst performance, despite the authors' attempt to justify it.
- The substrate scope for aryl glyoxals shows a high degree of specificity, with significant drops in enantioselectivity for seemingly minor structural modifications, which is not fully rationalized.
- The reliance on tentative atropisomer assignments without full crystallographic evidence for all derivatives limits the mechanistic clarity.
Detailed comments
The authors state that 'separation of atropisomers initially proved difficult and a mixture was typically obtained. All screening experiments reported in the following were consequently conducted with these mixtures'. While the authors attempt to validate this approach by comparing the performance of the mixture to the pure 'syn'-isomer for 7bBArF, this does not entirely resolve the issue for other derivatives (7c-e), where the ratio of atropisomers in the mixture might differ significantly. The authors should clarify if the syn/anti ratio was determined for all mixtures used in the screening to ensure that the observed enantioselectivities are indeed comparable and not skewed by varying amounts of the inactive or less selective anti-isomer.
Regarding the substrate scope, the authors note that 'surprisingly, even slight modifications, such as the addition of methyl groups towards products 10b-10d, led to noticeable drops in enantioselectivity'. This high sensitivity to substrate structure is a key observation, yet the discussion remains largely descriptive. To strengthen the manuscript, the authors should provide a more detailed analysis or a proposed transition state model that explains why, for instance, the 4-Me substituted product 10d shows a significantly lower ee (70%) compared to the parent 10a (94%). Without such a model, the 'tight entanglement between catalyst and substrate' remains a speculative assertion rather than a supported mechanistic insight.
Comments on figures
- In Table 1, the yield for entry 7 (5aBArF) is 6% and for entry 8 (5bBArF) is 12%. The text claims these results 'clearly indicate that halogen bonding is the key interaction', yet the low yields could also be attributed to poor solubility or catalyst decomposition. Have the authors performed control experiments to assess the stability of these non-iodinated species under the reaction conditions to rule out simple catalyst degradation as the cause for low activity?
- In Scheme 2, the enantioselectivity for product 10d (4-Me substituted) is reported as 70% ee, which is a significant drop compared to the 94% ee of 10a. Does the authors' proposed transition state model account for this electronic or steric effect, or is it possible that the 4-Me group disrupts the halogen-bonding interaction with the glyoxal carbonyl? A brief discussion on this would be helpful.
Referee report rubric — reproduced exactly as submitted
Reviewer 2
gemini-3.1-flash-liteThis manuscript describes the development of a second-generation, modifiable bidentate halogen bond donor catalyst for the Mukaiyama aldol reaction, achieving high enantioselectivity (up to 98% ee) for specific substrates. The authors demonstrate that the halogen bond is the primary driver of stereocontrol through comparative studies with non-iodinated analogues. The work represents a notable advancement in the field of halogen-bonding organocatalysis, moving from moderate selectivity to high enantiocontrol with a modular catalyst design. The study is technically sound, well-controlled, and provides a clear, logical narrative that fits the scope of a high-impact chemistry journal. Overall, this is a significant contribution that will be of interest to researchers working on non-covalent interactions in asymmetric catalysis.
Strengths
- The modular design of the catalyst, allowing for late-stage modification via an Ullmann-type coupling, is a significant methodological improvement over previous generations.
- The authors provide compelling evidence for the role of halogen bonding through the use of non-iodinated reference compounds 5a and 5b, which show drastically reduced activity and selectivity.
- The study achieves high enantioselectivity (up to 98% ee) for a range of substrates, representing a substantial improvement over the moderate selectivities previously reported for this class of catalysts.
Weaknesses
- The reliance on mixtures of atropisomers for most screening experiments, while acknowledged, complicates the interpretation of catalyst performance and optimization.
- The substrate scope for aryl glyoxals reveals a high degree of specificity, with significant drops in selectivity for seemingly minor structural changes (e.g., 10n and 10o), which is not fully explained by the proposed transition state model.
- The yield for the synthesis of the key intermediate 3 is relatively low (24% over 5 steps), which may limit the scalability of this catalyst design.
Detailed comments
The authors state: 'The comparably low difference in enantiomeric excess between bromine- and amide-substituted donors 7aBArF and 7bBArF indicates that the key enantioinduction is exerted by the catalyst backbone, while the hydrogen-bonding amide plays more of an assisting role.' This interpretation seems slightly reductive. While the backbone is clearly crucial, the 'marked jump' from 77% ee to 94% ee upon introducing the trifluoroacetamide moiety suggests that the amide is not merely 'assisting' but is likely involved in critical secondary interactions or conformational preorganization that significantly enhances the stereochemical outcome. I suggest the authors soften this claim or provide further evidence, such as computational modeling of the transition state, to support the assertion that the backbone is the sole 'key' to enantioinduction.
Regarding the substrate specificity observed in Scheme 3, the authors note: 'all attempts to uncover the peculiar characteristics of a further substituent which enables this level of stereocontrol proved difficult'. This is a frank admission, but it leaves the reader without a clear understanding of the catalyst's limitations. Given that the catalyst shows such high sensitivity to the electronic and steric nature of the aryl glyoxal substituents, it would be beneficial to include a brief discussion or a speculative model explaining why the trifluoromethyl group (in 8) and the bromide (in 10m) work so well, while the isopropyl (10n) and cyano (10o) groups do not. Does this suggest a specific spatial requirement in the transition state that only certain substituents can satisfy, perhaps related to the directionality of the halogen bond?
Comments on figures
- Table 1: The table presents data for a mixture of atropisomers, which the authors admit are 'diluted to different degrees'. While the authors argue that the comparison is valid, the yield data (entries 1-6) are inherently ambiguous. It would be helpful if the authors could provide a more rigorous assessment of the syn/anti ratio for each catalyst derivative to clarify whether the observed differences in yield are truly due to catalyst activity or simply variations in the concentration of the active syn-atropisomer.
Referee report rubric — reproduced exactly as submitted
Reviewer 3
gemini-flash-lite-latestThis manuscript reports the development of a second-generation bidentate iodine(I)-based halogen bond donor for asymmetric Mukaiyama aldol reactions. The authors demonstrate that late-stage modification of a chiral backbone allows for the tuning of catalyst performance, achieving up to 98% ee for specific substrates. Control experiments using non-iodinated analogues provide compelling evidence that halogen bonding is the primary driver of both activity and enantioselectivity. The work represents a notable advancement in the field of halogen-bond-mediated organocatalysis, successfully addressing previous limitations regarding catalyst activity and substrate scope. The study is technically sound and provides a clear, logical progression from catalyst design to substrate screening.
Strengths
- Clear demonstration of the 'engine' role of halogen bonding through the use of non-iodinated control analogues.
- Successful development of a modular, late-stage functionalization strategy for halogen bond donor catalysts.
- Achievement of high enantioselectivity (up to 98% ee) in a challenging organocatalytic transformation.
- Rigorous investigation of atropisomerism and its effect on catalyst performance.
Weaknesses
- The manuscript relies on mixtures of atropisomers for most substrate screening, which complicates the interpretation of absolute catalyst efficiency.
- The discussion of substrate specificity in Scheme 3 lacks a clear mechanistic rationale for why certain substituents (e.g., isopropyl vs. trifluoromethyl) lead to such drastic drops in enantioselectivity.
- The yield for the synthesis of the key intermediate 3 is relatively low (24% over 5 steps), which may limit the scalability of this approach.
Detailed comments
The authors state that 'the crucial role of halogen bonding in this catalytic process was demonstrated by the low performance of the non-iodinated variants.' This is a central claim of the paper, and the data in Table 1 (entries 7 and 8) strongly support this conclusion. However, the authors should explicitly discuss whether the residual activity (6% and 12% yield) in these control experiments is due to trace hydrogen bonding or background reactivity. A more detailed analysis of the reaction kinetics or a comparison with a non-hydrogen-bonding control would further strengthen this assertion.
Regarding the substrate screening, the authors note that 'there appear to exist narrow requirements on the substrates to see truly exceptional enantio-control.' While the empirical data in Schemes 2 and 3 are valuable, the manuscript would benefit from a deeper discussion of the transition state. The authors mention that 'this hints at a tight entanglement between catalyst and substrate in the transition state,' but they do not provide a structural model or computational insight to explain why, for instance, the 4-Me substituted product 10d shows only 70% ee compared to the 98% ee observed for the 2-naphthyl derivative 10l. Providing a proposed transition state model would significantly elevate the impact of these findings.
Comments on figures
- In Scheme 1, the synthesis of 5a-eCl is described as a 'one-pot process over three steps.' It is unclear if intermediate purification is required between these steps or if the '53% yield' refers to the isolated final product after all three steps. The authors should clarify the experimental procedure in the Supporting Information to ensure reproducibility.
- In Table 1, the yield for entry 11 is 63% using the 'syn'-atropisomer, whereas entry 3 shows 45% yield for the mixture. The authors state this is because the active species is 'diluted' in the mixture. It would be helpful if the authors provided a more precise quantification of the syn/anti ratio in the mixture to confirm that the yield increase is strictly proportional to the concentration of the active atropisomer.
Referee report rubric — reproduced exactly as submitted
This document was generated by PsiPi, an AI-assisted manuscript review tool. It is not a product of real peer review, was not issued by any journal, and creates no publication record. The reviews and editorial synthesis above were written by large language models and may contain errors, omissions, or hallucinated claims — treat them as a starting point for revision, not as an authoritative expert assessment.