Design of Iridium N-Heterocyclic Carbene Amino Acid Catalysts for Asymmetric Transfer Hydrogenation of Aryl Ketones

Round 1

Reviewer 1 Report

This paper contains a detailed account of the development and applications of a new type of iridium-based catalyst for the asymmetric transfer hydrogenation of ketones.  Key to the structures are the incorporation of two NHC ligands (non chiral) and one amino acid, which provides the source of chirality in the subsequent applications. A number of derivatives were prepared and carefully characterised, including by X-ray crystallography and NMR spectroscopy of the hydrides. The structures of the compounds can form several diastereoisomers and this aspect was considered and discussed in detail. The application to ATH was optimised through variation of several variables and the applications were extended to a small range of substrates. The conversions were very good and the ees were excellent in several cases but not consistently high. The results are interesting and this represents a valuable contribution to the area which is worthy of publication. A mechanism is assumed for the hydride transfer, although this is not directly supported, but is reasonable based on related catalysts.

The experimental is detailed and contains the required information to communicate the results in sufficient detail.

I have some comments and suggestions below however:

Minor typo: Line 23: enantioseletive -> enantioselective

DPEN up to $200 per gram from commercial vendors? It is much cheaper from other sources and in bulk.

Minor typo: ther common ATH ligands

There is a useful summary of Ir catalysts in Figure 2.

The method is said to provide a lower-cost alternative, but iridium is quite expensive. See: platinum.matthey.com/prices/price-charts . About 15 x the cost of Ru. Not as bad as Rh though.

There was a good analysis of possible isomers in Figure 6. Is it known that the hydride is always trans to the acid of the amino acid? The authors could comment.

NMR analysis showed clear separation of hydride signals and was helpful.

Scheme 3, Table 3, 80 oC over 24 h for incomplete reduction is not very active…

Are there really 500 eq. of HCO2Na, for 120 mg (1 mmol) of acetophenone this would be 0.5 moles of HCO2Na, roughly 34g! Perhaps this is 500 eq. relative to catalyst, or 5.00 eq?

Table 4 – featuring other amino acids. Which solvent is used?

Temperature optimisation – what is the concentration, is the levelling off a thermodynamic equilibrium being reached – this is a common feature for ATH in isopropanol? The 25 oC reaction gives a much better ee. Loss of ee at 80oC could be due to racemisation by a non-chiral species formed by decomposition and the authors could comment on this.

Author Response

Please see the attached file.  Reviewer #1  comments are followed immediately by our answer in green.

Author Response File: Author Response.pdf

Reviewer 2 Report

This article describes the synthesis of Iridium N-Heterocyclic Carbene Amino Acid Catalysts and their study in asymmetric transfer hydrogenation of phenyl ketones. The interest of the work is justified by the introduction of inexpensive chiral aminoacids and accessible N-heterocyclic carbenes in the Ir complexes allowing obtaining “low cost” and modular catalytic systems that show good results in the enantioselective reduction of the studied ketones.

The work is well contextualized and justified, taking into account the most recent bibliography related to the subject. The article is also easy to read thanks to its clarity. The catalysts have been characterized using spectroscopical techniques. Also, X-ray crystallographic data have been provided for one representative complex. The work includes a good discussion regarding the stereochemistry of both the complexes and the asymmetric reaction. The reaction conditions have been optimized, including catalysis and substrate scope in the work, together with a proposal for the catalytic mechanism. For all these reasons, in my opinion, this work can be published with little minor revisions. Please find a list of remarks:

• Only phenyl ketones have been studied. However, the title of the article is too general. Therefore, I would change "hydrogenation of ketones" to "hydrogenation of phenyl ketones" in the title.
• Correct “acetpheone” in line 149
• It would be better to change the order of the spectra in figure 8 for clarity, presenting first (at the top) the spectrum of the complex alone and at the bottom the spectrum of the complex with NaOH.
• Following the international system standards, please change the units “hr” to “h” and “deg C” to “ºC” (line 180, figures 9 and 10)
• Please, change in scheme 3: “base” to “NaOH”. Attempts have only been carried out with NaOH when isopropanol is used.
• Change Figure 14 to scheme 4
• The only solvent used in trials with NaOH is isopropanol. It makes no sense, in the drawing of the catalytic mechanism, to generalize the solvent as S and specify NaOH, when only one solvent has been used employing this base. Please, change this “S” to the isopropanol structure.
• In the article, "sodium hydroxide base" is insistently indicated. Although, in the drawing of the proposed mechanism, the only function of NaOH is to capture the iodide from the initial complex. The role of NaOH should be clarified both in the mechanism and in the text.
• In the spectroscopical data of the Ir complexes, the two NH protons of the aminoacid fragment should show a geminal coupling of approximately 12 Hz, common for the two protons. This coupling correlation is not observed in most of the cases, showing an important disparity in the data corresponding to some of the catalysts (for example Gly 9.4 and 22.2 Hz, line 330; L-Val: 10.6, 12.5 Hz, line 363). A revision of these spectroscopical data should be done.

Author Response

Please see the attached file for our responses.  Reviewer #2 comments are followed by our responses in green.

Author Response File: Author Response.pdf

Reviewer 3 Report

Bernier and Merola describe the synthesis of Iridium NHC complexes bearing aminoacids and their application in assymetric transfer hydrogenation of ketones. My comments on the work, which I enjoyed reading very much,  are the following:

• X-Ray: Hydrides are indeed difficult to detect. The structure that is provided in the CDC contains calculated hydrogens for every position expect the hydride (from what I could see, my apologies if that is not the case), and I fail to understand why. Also, in figure 5  and since the structure is supported by 1H NMR, it would be far more elucidative if it contained the hydride.

• For the aminoacids containing secondary amines, 4 structures can be potentially formed, but the number of hydrides formed indicates a higher number of isomers. The authors attribute this to the formation of other structural isomers. This being the case, we would see also a higher number of hydrides for aminoacids containing primary amines.  In the experimental and in the SI specs and characterization is detailed for minor and major isomers, both of which containing 2 hydrides, but this is barely discussed, and should be discussed further, since the compounds are already characterized. Also, the generation of the active catalytic species was examined by 1H NMR for L-Proline.  Since there is a major compound, characterization should be more facile...
• Regarding the number of active catalytic species….the authors state that upon the addition of the base there was a “notable change in the hydride region”, and that this probably” indicates the presence of four potentially active catalytic species as indicated earlier”. One might expect the opposite to occur…. If a more than 4 hydrides species  are  observed before the addition of the base, why should the number of hydrides decrease upon base addition? And importantly, why such a variety of diastereomers would  lead to a higher enantioselectivity? Have the authors considered that the higher ee can result from major single catalytic species, i.e, the major hydride observed  (Fig 8, top)?
• I think that the tables with be more clear to follow in the discussion if they contained the abbreviations for the ligands, in parenthesis.

• In the characterization of the compounds, any other proof of the formation of the compounds beyond a mass spec? Can all the NMRs be provided in SI? can the specs be compared with others and with the corresponding proligands? While I understand the difficulty of purification, It would be desirable to see all the NMRs of the aminoacids containing secondary amines, I think a bit more of discussion on this aspect should be provided, since these are the most active catalysts, the ones that are used in the design of a potential catalytic cycle, and as such a more detailed characterization is needed. .

Author Response

Please see the attached file.  Reviewer #3 comments are listed followed by our responses in green.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

I appreciate the changes introduced by the authors and the clarifications regarding some of the points made. Again, I think that in the supporting information all the spectra should be given, and I also note the 13C provided for some of the compounds (fig S9, Fig 10) have plenty of room for improvement regarding concentration/acquisition time. While I agree with the relevance of the research work provided, and I have no doubt on the importance of the work for the research community in catalysis, unambiguous characterization of the compounds or of the mixtures, or at least their 1H and 13 NMR should be given. A mass spec is not, under my view, enough, and therefore I leave the final decision to the editor.  

Author Response

Please see our response below.

Reviewer #3 – Round 2

I appreciate the changes introduced by the authors and the clarifications regarding some of the points made. Again, I think that in the supporting information all the spectra should be given, and I also note the 13C provided for some of the compounds (fig S9, Fig 10) have plenty of room for improvement regarding concentration/acquisition time. While I agree with the relevance of the research work provided, and I have no doubt on the importance of the work for the research community in catalysis, unambiguous characterization of the compounds or of the mixtures, or at least their 1H and 13 NMR should be given. A mass spec is not, under my view, enough, and therefore I leave the final decision to the editor.

We once again appreciate the reviewer for taking the time to provide feedback on our manuscript. We are in agreement that the article is certainly strengthened by inclusion of the NMR spectra of the other secondary amino acid complexes. We have now provided the 1H and 13C NMR spectra of these complexes. Due to the reasons described previously regarding the complicated mixture of isomers and poor enantioselectivity of these particular catalysts, the spectra are unassigned. The first author of this manuscript has recently transitioned to a new position and cannot conduct any further experiments and/or characterization for these compounds, and we hope the editorial staff will be understanding of this situation. However, we still feel the spectra we have now included, along with the assigned spectra of the other catalysts (including the most enantioselective variant) will be of great interest to the catalytic community, especially with the notably high ee’s obtained by the Ir(IMe)2(L-Pro)(H)(I) catalyst. We thank the editorial staff and reviewers for the thorough feedback of this manuscript, and we are very excited to publish this work in Catalysts. Please let us know if you require any additional information on our end.