Highlights on the General Preference for Multi-Over Mono-Coupling in the Suzuki–Miyaura Reaction

Round 1

Reviewer 1 Report

The paper "Highlights on the general preference for multi- over mono-coupling in the Suzuki-Miyaura reaction" deals with an important subject referring to the elucidation of mechanism in the Suzuki-Miyaura reaction. The data obtained by the authors are of high interest for the understanding of mechanism of the Suzuki-Miyaura reaction with di- and tri-halobenzenes. However, two points in the present form of this work are ambiguous. Therefore, the paper can be published after the major revisions will be made.

 

Major revisions:

 

1.        The higher reactivity of dibromoaryls compared to monobromoaryls in oxidative addition may be the reason for the observed increased selectivity for bis-coupled products. Note that the phenyl substituent in the monophenylated product is slightly EWG and hence activates the aryl halide in oxidative addition. The authors conducted competitive experiments (section S3, table S3) that could clarify this issue. However, structurally different substrates competed in these experiments (para- and meta-). The close reactivity of 1,4-dibromobenzene and 4-bromobiphenyl does not follow from these experiments as these substrates were used in two different competitive experiments. Differences in the structure can determine reactivity. Therefore, it is important to experimentally evaluate the relative reactivity of structurally related substrates, for example, para-dibromobenzene with para-bromobiphenyl and/or meta-dibromobenzene with meta-bromobiphenyl. It is important to use arylboronic acid with an aryl substituent other than phenyl to obtain unsymmetrical biaryls and triaryls. Then, the relative reactivity can be determined both by the residual amounts of competing substrates and by the amount of products formed.

2.       The authors should discuss possible alternative reasons for the effect of dilution on the selectivity of the reaction. Changes in selectivity may be due to a change in the nature of the active species (or a change in the contributions of several active species to the catalysis) resulting from a dilution, or due to a change in catalyst loading. This phenomenon is characteristic of cross-coupling reactions, including the Suzuki-Miyaura reaction. Note that the literature actively discusses the issue of the reaction proceeding via the heterogeneous mechanism on the catalyst formed in situ, the simultaneous occurrence of the reaction via the homogeneous and heterogeneous mechanisms, and dynamic catalysis. See, for example:

Schmidt, A. F.; Kurokhtina, A. A.; Larina, E. V. Simple Kinetic Method for Distinguishing between Homogeneous and Heterogeneous Mechanisms of Catalysis, Illustrated by the Example of “Ligand-Free” Suzuki and Heck Reactions of Aryl Iodides and Aryl Bromides. Kinet. Catal. 2012, 53 (1), 84–90. https://doi.org/10.1134/S0023158412010107.

Eremin, D. B.; Ananikov, V. P. Understanding Active Species in Catalytic Transformations: From Molecular Catalysis to Nanoparticles, Leaching, “Cocktails” of Catalysts and Dynamic Systems. Coord. Chem. Rev. 2017, 346, 2–19. https://doi.org/10.1016/j.ccr.2016.12.021.

 

Minor revisions:

1.       p. 1 “One of the most famous topics of discussion concerns the role of the base in the transmetalation step.[7-12]”. It is necessary to add a reference to one of the first papers on the base role in Suzuki-Miyaura reaction: Schmidt, A. F.; Kurokhtina, A. A.; Larina, E. V. Role of a Base in Suzuki-Miyaura Reaction. Russ. J. Gen. Chem. 2011, 81 (7), 1573–1574. https://doi.org/10.1134/S1070363211070334.

2.       Table 2, compound 1 lacks an iodine atom or is it hard to see.

Author Response

Reviewer comment R1.1: “The higher reactivity of dibromoaryls compared to monobromoaryls in oxidative addition may be the reason for the observed increased selectivity for bis-coupled products. Note that the phenyl substituent in the monophenylated product is slightly EWG and hence activates the arylhalide in oxidative addition. The authors conducted competitive experiments (section S3, table S3) that could clarify this issue. However, structurally different substrates competed in these experiments (para-and meta-). The close reactivity of 1,4-dibromobenzene and 4-bromobiphenyl does not follow from these experiments as these substrates were used in two different competitive experiments. Differences in the structure can determine reactivity. Therefore, it is important to experimentally evaluate the relative reactivity of structurally related substrates, for example, para-dibromobenzene with para-bromobiphenyl and/or meta-dibromobenzene with meta-bromobiphenyl.It is important to use arylboronic acid with an aryl substituent other than phenyl to obtain unsymmetrical biaryls and triaryls. Then, the relative reactivity can be determined both by the residual amounts of competing substrates and by the amount of products formed.”

Author reply: This comment is very insightful. The reviewer is right in that our competitive experiments can be masked by the different reactivities of the meta- and para-substrates. We tried to circumvent this limitation by switching the order of the substrates in the two test-synthesis (para-dibromobenzene vs 3-bromobiphenyl and meta-dibromobenzene vs 4-bromobiphenyl). In this way, the relative reactivities of the meta- and para-substrates are taken into account and the nearly symmetric selectivity observed for the two possible products (meta- vs para-ArArAr in Table S3) supports that the preference for bis-coupling, over mono-coupling, is not due to different reactivities of the dibromo and monobromo species. However, we agree that this is not a conclusive proof and we performed two additional syntheses, as suggested by the reviewer: para-dibromobenzene + 4-bromobiphenyl + 4-methoxyphenylboronic acid (one synthesis with Pd(OAc)₂ and the other with Pd-PEPPSI). The results are presented in the revised version of the Supplementary Materials (Table S3) and confirm the similar reactivities of the dibromo and monobromoaryls towards oxidative addition. We acknowledge the reviewer for this useful comment and suggestion, which has improved the consistency of our arguments and the overall quality of the manuscript. Thank you.

 

Reviewer comment R1.2: “The authors should discuss possible alternative reasons for the effect of dilution on the selectivity of the reaction. Changes in selectivity may be due to a change in the nature of the active species (or a change in the contributions of several active species to the catalysis) resulting from a dilution, or due to a change in catalyst loading. This phenomenon is characteristic of cross-coupling reactions, including the Suzuki-Miyaura reaction. Note that the literature actively discusses the issue of the reaction proceeding via the heterogeneous mechanism on the catalyst formed in situ, the simultaneous occurrence of the reaction via the homogeneous and heterogeneous mechanisms, and dynamic catalysis.”

Author reply: We added a small discussion of this topic in section 2.4 of the revised manuscript, together with some relevant new references. We thank the reviewer for the very constructive feedback.

 

Reviewer comment R1.3: “p. 1 “One of the most famous topics of discussion concerns the role of the base in the transmetalation step.[7-12]”. It is necessary to add a reference to one of the first papers on the base role in Suzuki-Miyaura reaction: Schmidt, A. F.; Kurokhtina, A. A.; Larina, E. V. Role of a Base in Suzuki-Miyaura Reaction. Russ. J. Gen. Chem. 2011, 81 (7), 1573–1574. https://doi.org/10.1134/S1070363211070334.”

Author reply: This reference is indeed relevant to this topic, and we cited it, as suggested by the reviewer.

 

Reviewer comment R1.4: “Table 2, compound 1 lacks an iodine atom or is it hard to see.”

Author reply: The reviewer is right; the iodine atom is hard to see. The figure was modified accordingly. Thank you.

Reviewer 2 Report

The authors report an insightful systematic study on the known selectivity of multi- over monocoupling for the Suzuki-Miyaura (SM) reaction of phenylboronic acid with dihalo- and trihalobenzenes. The relative yields of mono- and polysubstituted products are then compared with the statistical ratios expected assuming either equal or different probabilities of attack for the starting polyhaloarene and for the monosubstituted intermediate. Most reactions show significant deviation for these statistical ratios in the sense that the formation of multicoupling products, confirming previous observations.

The statistical ratios are calculated by a step-iteration method with increasing number of steps and extrapolating for an infinite number of steps. Please note that a simpler derivation of the ratios could have been estimated by assuming a steady-state for the monosubstituted intermediate. Equal reaction rates for ArBr2 and ArPhBr would give a 33/33/33 ratio, while double reaction rate for ArBr2 would give a 25/50/25 ratio. 

The results provide strong experimental proof for the reaction proximity effect between intermediate and Pd(0) catalyst in the SM reaction, provide important experimental hints for favouring the formation of monosubstituted adducts, and can be in principle extrapolated to other Pd-catalysed couplings such as Heck and Sonogashira reactions.

I recommend publication after minor revision, since:

a) Minor editing of English language is required, see next section.

b) In the "Materials and Methods" section (as well as in the SI) the authors only state that a HP-5 column was used in the GC analyses; film thickness, length and internal diameter should be specified.

Minor editing of English language is required, Cf. line 26 "Its" for "It's", "became" for "has become"; line 45 "studied" for "have studied"; line 47 "explained" for "have explained"; line 57 "oxidative" for "oxidate", etc.

Author Response

Reviewer comment R2.1: “The statistical ratios are calculated by a step-iteration method with increasing number of steps and extrapolating for an infinite number of steps. Please note that a simpler derivation of the ratios could have been estimated by assuming a steady-state for the monosubstituted intermediate. Equal reaction rates for ArBr2 and ArPhBr would give a 33/33/33 ratio, while double reaction rate for ArBr2 would give a 25/50/25 ratio.”

Author reply: The referee is right, and we thank for the pertinent comment. The ratios 33/33/33 and 25/50/25 can be derived from a simple kinetic model assuming the steady-state approximation for the intermediate. However, the rigorous kinetic analysis of Suzuki reaction for two consecutive coupling cycles is considerably complex. Considering that oxidative addition is the rate-determining step, occurring via a S_N2 type mechanism, we can approximate the rate law of each coupling cycle to a pseudo-first-order reaction (assuming the concentration of the catalyst constant), which depends on the concentration of the bromoaryl. To better contextualize the reader, we added a small comment about the estimation suggested by the reviewer in the revised version of the Supplementary Materials. Given the mechanistic complexity of the Suzuki reaction, and consequently, of the rate law, we opt to keep this explanation simple.

 

Reviewer comment R2.2: “a) Minor editing of English language is required, see next section.

1. b) In the "Materials and Methods" section (as well as in the SI) the authors only state that a HP-5 column was used in the GC analyses; film thickness, length and internal diameter should be specified.”

Author reply: The corrections were made and the info about GC was added to the revised version of the manuscript. Thank you.

Reviewer 3 Report

The authors describe the preferential di-coupling of Suzuki reactions over mono-coupling and factors that might influence this effect. The manuscript can be accepted with the following comments:

1. The following paper should be cited that precisely documented the concentration and reactivity effect on the di-coupling selectivity: DOI: 10.1021/jacs.7b13701 J. Am. Chem. Soc. 2018, 140, 4335−4343

There are a lot more paper from this group that should be considered by the authors. These papers are more up-to-date as well.

2. The authors should also consider ligand effect, which is hugely important in affecting selectivities. It has been shown that Buchwald ligands can be very influential. The authors might find it useful to demonstrate a few entries with these ligands together with Pd catalysts studied. 

3. The following paper describes the temperature effect with Suzuki  selectivity (PEPPSI was also used): https://doi.org/10.1002/marc.201500030

4. What is the reason for the authors to use DMF as solvent. Please specify.

 

Quality of English is fine 

Author Response

Reviewer comment R3.1: “The following paper should be cited that precisely documented the concentration and reactivity effect on the di-coupling selectivity: DOI:10.1021/jacs.7b13701 J. Am. Chem. Soc. 2018, 140, 4335−4343. There are a lot more paper from this group that should be considered by the authors. These papers are more up-to-date as well.”

Author reply: The paper indicated by the reviewer, and a few others that we searched for, are relevant to our research and were cited in the introduction and section 2.3 of the revised manuscript. We thank the reviewer for indicating these interesting works.

 

Reviewer comment R3.2: “The authors should also consider ligand effect, which is hugely important in affecting selectivities. It has been shown that Buchwald ligands can be very influential. The authors might find it useful to demonstrate a few entries with these ligands together with Pd catalysts studied.”

Author reply: This suggestion is very interesting. However, we do not have Buchwald ligands in stock. As reported in the paper suggested by the reviewer in comment R3.1, the use of Buchwald ligands with Pd₂dba₃ in Suzuki syntheses with 2,5-dibromothiophene increases the ratio of the disubstituted product relative to the mono-intermediate. According to the results in our manuscript and knowing that bromothiophenes are less reactive towards oxidative addition, Pd₂dba₃ seems not that effective in increasing the reactivity, and thus the selectivity towards the mono-intermediate is higher. The use of Buchwald ligands shall increase the reactivity towards oxidative addition; consequently, the ratio of the bis-coupling product increases. Considering the time and money required for adding these additional experiments and the fact that our paper already explores a good quantity of experimental factors, we think that including this new study is not justified. However, the results reported for the bromothiophene in the paper suggested by the reviewer go in line with our observations and we added a small commentary to it and to Buchwald ligands in section 2.3 of the revised manuscript. Thank you very much for the very interesting suggestion.

 

Reviewer comment R3.3: “The following paper describes the temperature effect with Suzuki selectivity (PEPPSI was also used): https://doi.org/10.1002/marc.201500030”

Author reply: The paper mentioned by the reviewer reports the synthesis of polymers by Stille coupling, using the catalyst Pd-PEEPSI-iPr. However, the effect of temperature is only indirectly addressed in this paper. This paper does show that the molecular weight of the synthesized polymer can be modulated by varying the monomer/catalyst ratio. However, the paper focuses on the synthesis of polythiophenes and is only slightly related to our manuscript. It is, however, an interesting example of the use of Pd-PEEPSI-iPr in cross-coupling reactions involving polymers, and we cited this paper in the introduction and in section 2.1 of the revised manuscript (top of page 4 where we speak about the Pd-PEPPSI-iPr catalyst).

 

Reviewer comment R3.4: “What is the reason for the authors to use DMF as solvent. Please specify.”

Author reply: There was no particularly important reason for choosing DMF in this study. Besides being a typical solvent for Suzuki reactions, DMF has the following advantages: (i) it has comparatively low volatility, ensuring that the solvent composition is maintained during the reactions at high temperatures (acetone is an example of a bad choice here); (ii) it is completely miscible with water, affording a homogeneous medium for the reaction (toluene is an example of a bad choice here); in this study, we wanted to avoid the additional complexity associated with heterogeneous synthesis; and (iii) in all syntheses the 1:1 mixed solvent with water was able to completely dissolve all the reactants in the initial reaction mixture, ensuring an homogeneous starting point for the synthetic study. Actually, a fully comprehensive synthetic study of preferential oxidative addition in Suzuki-Miyaura cross-coupling should include testing more solvents. However, we think that the effect of solvent is quite a complex topic and deserves a paper of its own (a probable future project in our research group). Including that in this paper would probably make it too long and confusing. We recognize, however, that the choice of DMF should be better explained in the manuscript and we included a small explanation for that at the end of section 2.4 of the revised manuscript. We thank the reviewer for the comment.

Round 2

Reviewer 1 Report

I am satisfied with the changes and additions made by the authors and recommend the article for publication