Letter to the Editor pubs.acs.org/OPRD
Response to the Letter to the Editor concerning “Carbon− Heteroatom Coupling Using Pd-PEPPSI Complexes”
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that now has enough examples demonstrating significant advances in reactivity and selectivity to present and describe work in more realistic and frankly accurate terms. I have to say upfront that my group is no different and that we use terms including “highly reactive” and “highly selective” to describe our work because the lack of such terms would be conspicuous by their absence. I, for one, would be very happy to eliminate the use of such descriptors and simply present the results and let readers make their own assessments. With reference to our own published work, I feel confident that, when we have used such terms, it is only in cases where substrates now can be coupled that could not be done routinely previously, that resulted in a dramatic improvement in reaction conditions (noticeably lower temperatures, much milder base, etc.), that can now accommodate more sensitive functional groups, or that have led to unprecedented levels of selectivity. Now we address why we felt compelled to try to address this issue of relative reactivity of catalysts in the field of Pd−NHCmediated cross-couplings in our review. In the publication entitled: “[Pd(IPr*OMe)(acac)Cl]: Tuning the N-Heterocyclic Carbene in Catalytic C−N Bond Formation” (Sebastien Meiries, Klaus Speck, David B. Cordes, Alexandra M. Z. Slawin, and Steven P. Nolan, Organometallics 2013, 32, 330− 339), the following passage on page 333 appears and refers to the amination results in Table 3: “More interestingly, highly deactivated heteroadducts illustrated in entries 4, 6, 7, and 8 were successfully isolated in 62, 86, 91, and 76% with 0.05− 0.40 mol % of 2. For comparison’s sake, the highly active PdPEPPSI-IPent afforded the same compounds in 90, 75, 65 and 66%, respectively, with the much milder Cs2CO3 as the base, but at a much higher catalyst loading of 4.0 mol %!19” This passage served as the catalyst for our original claims in the OPRD review. We feel that this comparison is misleading and brings to the forefront the inaccuracies in comparing catalysts under different reaction conditions. Professor Nolan writes in his Letter to the Editor in section (ii) that: “...we choose slightly more forcing conditions (alkoxide bases, although we would refute that these are as ‘aggressive’ as Organ implies)...”; we strongly disagree with this statement, which is key in this whole discussion. In the article by Ka Hou Hoi and myself entitled: “Potassium 2,2,5,7,8Pentamethylchroman-6-oxide: A Rationally Designed Base for Pd-Catalysed Amination” (Chem.Eur. J. 2012, 18, 804−807) we go to great lengths to show the effects of alkoxide bases (in particular tert-butoxide) on functionality. We demonstrated that even relatively simple, easy to couple substrates containing, for example, nitriles, ketones, and esters, with both Pd-PEPPSIIPent and Buchwald’s RuPhos catalyst (which is an excellent catalyst for amination) led to either low yield of product, or no product at all with tert-butoxide. Conversely, good-to-excellent yields were obtained in all cases with our potassium
o the Editor: Herein we respond, at your request, to the Letter to the Editor written by Professor Steven Nolan and David J. Nelson about our recently published review entitled: “Carbon−Heteroatom Coupling Using Pd-PEPPSI Complexes” (DOI 10.1021/op400278d) in Organic Process Research & Development (OPRD). I can appreciate if Professor Nolan feels that this review was critical of his related publications, but I commit that there was no ill intent to cast a negative light on his group’s work. Rather, the need that we felt to include the section in question, wherein we set out a ranking for Pd−NHC catalyst reactivity in sulfination and amination applications, was borne out of two main concerns that we hold. The first is general to the field of cross-coupling and how results are reported in the literature and the other was a result of a claim that was made in one of Nolan’s recent publications. Having read and reviewed extensively in the cross-coupling field over the past decade I have found the following phrase to appear over and over again: “the new catalyst was highly reactive”. I understand that we all prefer to juxtapose our work in a favorable light, and I have yet to see a manuscript that discloses a new catalyst that was supported by claims that it demonstrated mediocre reactivity. However, when one considers the results in any one of a number of these manuscripts, the question arises: “On what basis did the authors classify the catalyst as being highly reactive?” I have read many papers promoting such catalysts, yet the manuscript reports the coupling of what experts in the field would consider, for example, simple aryl bromides with simple aryl boronic acids, often at elevated temperatures. Such high reactivity claims are made despite existing literature reports detailing protocols that work with profoundly hindered, electronically deactivated, densely functionalized starting materials that would be of high interest, for example, in medicinal chemistry or materials science applications. Further, not only have these existing reports raised the bar for what products can be prepared using cross-coupling methodology, in some cases the new catalysts and protocols have vastly improved the ease (e.g., lower temperatures and very mild bases, etc.) and practicality with which these transformations can be performed. In my opinion, a manuscript promoting a catalyst that does not, at a minimum, match performance that is current state-ofthe-art should not be allowed to survive the review process as a “highly reactive catalyst”. While someone active in catalysis will be able to quickly place such results in context with the state-ofthe-art methodologies, others who are not experts, but who rely on using such catalysts for their own applications such as those in the pharma sector, are now faced with sifting through an unnecessarily large number of reports that claim new catalysts with high and inferred general reactivity. This is not helpful. Admittedly, the use of adjectives is subjective. That said, some journals have addressed related issues by, for example, forbidding the use of the word ‘novel’ in titles. Perhaps it is time to do something similar in the cross-coupling literature © 2014 American Chemical Society
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Organic Process Research & Development
Letter to the Editor
chromanoxide base, which is much less aggressive than tertbutoxide, that we created for the purpose of amination reactions. All important in this is the ability of these catalysts to work well under what are generally accepted as being very mild reaction conditions. There are no examples in the abovecited Nolan manuscript that contain sensitive functionality, and the only functional group that appears is a methyl ether, which is also the case in a related publication from the Nolan group (Organometallics 2012, 31, 6947−6951). Thus, the comparison of our catalyst using carbonate with Nolan’s using the alkoxide base simply carries no value and, in our opinion, should not have been attempted. It infers that the reactivity of both catalysts is necessarily similar, especially to the lay reader there is no available data to support making such a claim. When one has substrates that are robust enough to tolerate tertbutoxide, the rate acceleration using tert-butoxide over carbonate is stunning. For example, when we (Chem.Eur. J. 2011, 17, 3086−3090, Figure 1b) reacted the same substrates as in Table 3, entry 5, of the Nolan manuscript (Organometallics 2013, 32, 330−339) under the conditions of Cs2CO3 in dioxane at 80 °C using Pd-PEPPSI-IPent, the reaction completed after approximately 10 h. In the same publication we also have shown that this same reaction completes with tertbutoxide in less than one minute at room temperature. In any case, if the Nolan group were to do head-to-head comparisons with the sorts of substrates that our catalyst family has been proven to couple using carbonate base, and show similar reactivity, I would be happy to reflect this in an upcoming review that I have been asked to write on Pd−NHC crosscoupling. The sulfination work published by the Nolan group (J. Org. Chem. 2013, 78, 9303−9308) reports in the abstract: “The newly prepared complex [Pd(IPr*OMe)-(cin)(Cl)] provides high catalytic activity for carbon−sulfur cross-coupling reactions.” The work is very nicely done and provides interesting products. Historically, I would say that the stateof-the-art catalyst in this area is Pd−JosiPhos and the conditions used in the Nolan report are similar to those commonly used with that catalyst (tert-butoxide, dioxane, or toluene, 110 °C). In the absence of other results, these would be state-of-the-art conditions; hence, the catalyst would be considered ‘highly reactive’ and on par with Pd−JosiPhos. However, prior to the publication of the Nolan work, we reported the coupling of many similar substrates (Chem.Eur. J. 2011, 17, 11719−11722; and later Chem.Eur. J. 2013, 19, 2749−2756; Chem.Eur. J. 2013, 19, 16196−16199) at 40 °C and room temperature. As our protocols have been out in the literature for some time, they were available to be drawn into comparisons. I think that it is reasonable and fair to assume that any researcher is compelled to publish their best results under the most optimal conditions that they have developed. That all of the results in the Nolan JOC paper are at 110 °C would suggest that those forcing conditions (at least at this time) are necessary, and this was taken into account when we set the relative reactivity scale in our review. From Professor Nolan’s letter, it is clear that there is some debate surrounding the proper use of TON and TOF or, rather, what value carries more comparative weight. It is not that we put all our faith into one value over the other; rather, we aimed to highlight the lack of examples in some of the abovementioned manuscripts to prove that turnover of the catalysts employed is possible at all when milder conditions are employed, especially in cases where challenging substrates or
those containing sensitive functional groups are used. TON and TOF are metrics that are both substrate and reaction-condition specific. Certainly there is no doubting the TON generated from the above-discussed amination work by Nolan and they are impressive, but again, this is with quite stripped down substrates (e.g., 4-chloroanisole and morpholine) and using, in our opinion, strongly basic conditions. Nothing from such data can be automatically inferred concerning the general reactivity of the catalyst for use with more elaborate, and therefore interesting substrates. Again, it is up to the authors to demonstrate generality, and to me that is where the most meaningful aspect of ‘high reactivity’ is derived, and to be clear, none of our catalysts including Pd-PEPPSI-IPent could do any better than the ones used by Professor Nolan or anyone else when sensitive, functionalized substrates are subjected to aggressive reaction conditions (vide supra). That is why we moved to new catalyst designs that would hopefully increase catalyst performance sufficiently under more mild reactions conditions, thus broadening the scope of substrates that can be coupled. We are grateful for the correction suggestion from Professor Nolan for some typos that managed to survive countless edits. We have prepared the corresponding errata document (DOI: 10.1021/op500093w) although there is no change in thrust of the catalyst comparison section as a result of these changes. In summary, the ongoing publication of cross-coupling catalysts that have been called “highly reactive” has led us to assemble a relative reactivity scale of Pd−NHC catalysts for sulfination and amination in this OPRD review article. This is based on some head-to-head comparisons, minimum temperatures that are necessary to see catalyst reactivity, the nature of the bases involved, the substrate scope demonstrated, and the nature of functional group tolerance. We appreciate that this is subjective and that others may look at reactivity from other points of view; we respect those points of view. However, this is the thought process that we use to classify catalyst reactivity and what we use to move results to publication. It was not our intent to focus on, nor paint negatively Professor Nolan’s results in our review, which was limited to sulfination and amination. These manuscripts simply happened to fall, we feel, into a grouping of manuscripts that claim high reactivity where we would feel more investigation to be necessary in order to make such claims, in particular where direct comparisons were attempted to be made with catalysts developed in our group. We greatly admire Professor Nolan’s contributions to catalysis in general and we routinely use many of his creative innovations, including buried bulk assessments and modified Tolman Electronic Parameter measurements, to help us design and predict the properties of new Pd−NHC complexes. As to where we go with the continued use of reactivity descriptors, that is an interesting question. A similar issue was faced when I was on the editorial board of the Journal of Combinatorial Chemistry. Very diverse results were coming into the journal for how well a library synthesis worked, with each author calling his/her result a high success. In that case, experts in the field sat down at that time and determined that in order to be able to even submit an article to the journal, 80% of the reactions run had to have worked and to have followed conventional parallel synthesis purification strategies (e.g., SCX filtration); the products thus obtained had to be 80% pure. I do not know if it is possible to do something similar in the field of catalysis, but it would make for interesting discussion. As things stand at the moment, we have what amounts to a grade 459
dx.doi.org/10.1021/op500092z | Org. Process Res. Dev. 2014, 18, 458−460
Organic Process Research & Development
Letter to the Editor
inflation problem that is rampant in the fieldwhen everyone gets an ‘A’ grade, what does an ‘A’ mean anymore?
Michael G. Organ
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Chemistry, York University, Room 460 CCB, 4700 Keele Street, Toronto, Ontario M3J 1P3, Canada
AUTHOR INFORMATION
Corresponding Author
E-mail:
[email protected] Notes
The authors declare the following competing financial interest(s): Some of the catalysts reported in this manuscript are distributed by Sigma-Aldrich, from which the PI receives a royalty payment.
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