Electrochemical Bromofunctionalization of Alkenes and Alkynes—To Sustainability and Beyond
Round 1
Reviewer 1 Report
This contribution is a review about Electrochemical Bromo-functionalization of Alkenes and Alkynes. The paper contains an excellent revision of the subject and the discussions are complemented with clear schemes of reaction that give an excellent overview and present in a clear way the selected information. I found the manuscript easy to read, concise and with information related with the sustainability of the electrobromination process showed. I support its publication with the following minor corrections.
a1) Indicate in the introduction the redox potential of the bromide/bromine and bromide/tribromide redox couple both can trigger reactions of functional groups. As indicated in scheme 4 the equilibrium between both species can determine the success of the reaction. A short paragraph about this can be helpful for the readers.
2) A classic example of the use of bromine in electroorganic synthesis is the Tori selective electrooxidation of alcohols using double mediator system Br2/TEMPO JOC 1991, 56, 2416 and the the Clauson-Kaas electroxidation of furanes Acta Chem. Scand. 1953, 7, 234-235 and J. Org. Chem. 2005, 70, 4538-4541 for example. It could be convenient to comment these reactions to complete the last phrase of page 1 lines 43-44. In the Clauson-Kaas electroxidation of furanes Br2 electrogenerated acts as selective oxidant of the furane ring, thus besides the halogenating, mediator properties, also the oxidant characteristic should be mentioned.
c 3) Table 1 should be completed with the conductivity of the bromide salts used as electrolytes, if possible, in different solvents besides aqueous solutions.
d4) For the reaction depicted in Scheme 2 that was reported as CPE, the use of Constant terminal voltage of the cell is not an adequate parameter to report electrolysis conditions. Formally a CPE should be carried out using a reference electrode, thus please add a note for the readers discouraging the use of the cell voltage as the control parameter to carry out the reactions.
e5) The phrase page 6 line 165, refers specifically to HFIP solvent stabilizing effects. I recommend specifying this to the readers changing the phrase as: “Solvent stabilizing effects have been reported in electrochemical synthesis, for example using HFIP.” The reference J. Electrochem. Soc. 167 155509 DOI 10.1149/1945-7111/abb83c would complete the cited references.
6) Some schemes don’t indicate current, current density or voltage used, please complete. E.g. Scheme 9, Scheme 10
7) I suggest homogenizing the schemes to the current density value used, thus reading the experimental part and using the reported electrode area the schemes showing current values eg. Scheme 4. If area is not reported, indicate this in the figure foot.
h8) Some schemes indicate Carbon graphite electrodes Cgr, others just C is indicated (is it gC, I suppose glassy carbon or Cgr or other carbon?) it could be convenient to clarify this.
9 9) Scheme 12. Indicate the CH3CN/HFIP proportion used.
10) In conclusion emphasize the sustainability aspects of the electrochemical bromine production, electro bromination and bromofunctionalization processes to fullfill the sustainability aspects of the journal.
Author Response
First of all, the authors like to thank Reviewer 1 for the comprehensible and valuable suggestions. After the revision, the following changes were included in the manuscript and changes were highlighted in yellow.
Reviewer 1: Point-by-point response
- Indicate in the introduction the redox potential of the bromide/bromine and bromide/tribromide redox couple both can trigger reactions of functional groups. As indicated in scheme 4 the equilibrium between both species can determine the success of the reaction. A short paragraph about this can be helpful for the readers.
Answer: Thank you for your suggestion. A short paragraph describing the electrochemical bromine generation under Section 2 (Bromine and brominating agents) was added for better clarity [75-88]. The authors of the chemistry described in Scheme 4 (now Scheme 5) indicate the formation of stable tribromide species in aprotic media as a result of a sufficient concentration of bromide and solvent effect, simultaneously providing both brominating species (Br2, Br3-). For better clarity, this was also mentioned in lines 221-222.
- A classic example of the use of bromine in electroorganic synthesis is the Tori selective electrooxidation of alcohols using double mediator system Br2/TEMPO JOC 1991, 56, 2416 and the the Clauson-Kaas electroxidation of furanes Acta Chem. Scand. 1953, 7, 234-235 and Org. Chem. 2005, 70, 4538-4541 for example. It could be convenient to comment these reactions to complete the last phrase of page 1 lines 43-44. In the Clauson-Kaas electroxidation of furanes Br2 electrogenerated acts as selective oxidant of the furane ring, thus besides the halogenating, mediator properties, also the oxidant characteristic should be mentioned.
Answer: Thank you for the suggestions. The aforementioned examples with references were implemented in the introduction [45-49]. Detailed description was not included as the review aims to provide an overview of the halogenation and not mediator properties of electrogenerated bromine.
- Table 1 should be completed with the conductivity of the bromide salts used as electrolytes, if possible, in different solvents besides aqueous solutions.
Answer: Thank you for the suggestions. Table 1 includes information of the bulk and molar prices and therefore availability of the chosen bromide salts and brominating agents for comparison. Including conductivity data with different solvent systems does not align with the purpose of the table and would cause confusion for the readers. Therefore, the authors do not think that this data is necessary in the table, since the suggested data are highly sensitive to temperature, concentration etc.
- For the reaction depicted in Scheme 2 that was reported as CPE, the use of Constant terminal voltage of the cell is not an adequate parameter to report electrolysis conditions. Formally a CPE should be carried out using a reference electrode, thus please add a note for the readers discouraging the use of the cell voltage as the control parameter to carry out the reactions.
Answer: Thank you for the suggestions, a short explanation was ready included in the caption of Scheme 2 and 3. A short clarification was included in the text [170-174].
- The phrase page 6 line 165, refers specifically to HFIP solvent stabilizing effects. I recommend specifying this to the readers changing the phrase as: “Solvent stabilizing effects have been reported in electrochemical synthesis, for example using HFIP.” The reference Electrochem. Soc. 167 155509 DOI 10.1149/1945-7111/abb83c would complete the cited references.
Answer: Thank you for your suggestions. Corrections and the reference were included in the text [191-192].
- Some schemes don’t indicate current, current density or voltage used, please complete. E.g. Scheme 9, Scheme 10.
Answer: Thank you for the suggestions. Corrections were made to Scheme 9, 10 and 11 (now Scheme 11, 12 and 13).
- I suggest homogenizing the schemes to the current density value used, thus reading the experimental part and using the reported electrode area the schemes showing current values eg. Scheme 4. If area is not reported, indicate this in the figure foot.
Answer: Thank you for the suggestion. Corrections were made to Scheme 4, 8, 10, 11 and 14 (now Scheme 5, 10, 12, 13 and 16).
- Some schemes indicate Carbon graphite electrodes Cgr, others just C is indicated (is it gC, I suppose glassy carbon or Cgr or other carbon?) it could be convenient to clarify this.
Answer: Thank you for the suggestion. Clarifications were included in Scheme 2, 3, 5, 9, 11 and 12 (now Scheme 2, 3, 6, 11, 13 and 14) where the carbon material was specified.
- Scheme 12. Indicate the CH3CN/HFIP proportion used.
Answer: Thank you. The additive ratio was specified in Scheme 12 (now Scheme 14).
- In conclusion emphasize the sustainability aspects of the electrochemical bromine production, electro bromination and bromofunctionalization processes to fullfill the sustainability aspects of the journal.
Answer: Thank you for the suggestion, changes emphasizing the sustainability aspects were included to the conclusion.
Reviewer 2 Report
The review is devoted electrochemical dibromination and bromofunctionalization of alkenes and alkynes. Via this process bromine can be generated under controlled parameters to form the desired brominated products and intermediates in a highly sustainable fashion. The utilization of alkali bromide salts in a dual role as reagent and supporting electrolyte augments electrochemical bromination protocols over the traditional ones, providing a greener and accessible alternative for the scientific community. The topic is interesting, well-covered and a timely submission. I have a few comments that need author's attention.
Line 45: “bromination” should be “dibromination”
Scheme 2. The designations of the substituents R1, R2, R3 in the Scheme 2 (22 examples) and others are not clear, please clarify.
Lines 167-177, 215-223, 236-242, 401-409: It is not easy to understand without scheme. Please add scheme.
Line 206: What means "DMSO stabilized bromine"? It needs to be explained.
Future perspectives and author's point of view on the topic should be added.
Author Response
First, the authors like to thank Reviewer 2 for the comprehensible and valuable suggestions. After the revision, the following changes were included in the manuscript and changes were highlighted in yellow.
Reviewer 2: Point-by-point response
- Line 45: “bromination” should be “dibromination”
Answer: Thank you for the suggestion. Correction was implemented.
- Scheme 2. The designations of the substituents R1, R2, R3 in the Scheme 2 (22 examples) and others are not clear, please clarify.
Answer: Thank you for the suggestion. The substituents R1, R2, R3 and R4 were specified in Scheme 2.
- Lines 167-177, 215-223, 236-242, 401-409: It is not easy to understand without scheme. Please add scheme.
Answer: Thank you for your suggestion. For reference 85, 91 and 107 schemes were provided in the discussion (see Scheme 4, 7 and 18).
- Line 206: What means "DMSO stabilized bromine"? It needs to be explained.
Answer: Thank you for the suggestion. For clarification, plausible mechanism was included in Scheme 6.
- Future perspectives and author's point of view on the topic should be added.
Answer: Thank you for the suggestion. Both the authors point of view and future perspectives have been sufficiently described in the conclusions [488-509]. Therefore, the authors think it is not necessary to complement the conclusions further.
Reviewer 3 Report
Electrochemical synthesis is a hot topic in sustainable chemistry. Gombos and Waldvogel reviewed the electrochemical conversion of alkenes and alkynes with focus on bromofunctionalization, which is important for both academic research and industrial application. The topic of this review fits the scope of the journal, and is well-arranged for both text and Schemes, though several parts can be further improved. Therefore, I suggested the paper to be accepted after Minor Revision on the following aspects.
(1) It is better to change the title as "The Electrochemical Bromofunctionalization of Alkenes and Alkynes – To Sustainability and Beyond", which emphasizes the topic and makes the word "Bromofunctionalization" shown in one line.
(2) In the part "2. Bromine and bromination agents", in both text and Table 1, bromide salts were introduced and compared with traditional bromination agents, but the information is rare for organic bromine sources that appeared in later examples. Related information and discussion should be added to make this part more complete. The organic bromine sources are more expensive, and may lower the atom economy of the reaction. Therefore, the advantages of other aspects such as safety and mild reaction conditions should be discussed more.
(3) Non-universal abbreviations in the text and Schemes should be noted with full names to make it more friendly to the broad readership. These include but is not limited to: "CCE" and "CPE" in Schemes 2/3, "gC" and "Cgr" in Scheme 4/7/9, "FEP" in page 10, line 275.
(4) In Scheme 14, the structure 35a contains a R group, and represents two examples according to ref[98], but only one yield and one Z/E value were shown.
(5) The part "4. Electrochemical bromofunctionalization of alkynes" seems not as fruitful as the alkene part. Though the examples of alkynes were indeed less, more Schemes and discussions can be added. For example, ref[99] and ref[100] represent unique examples of cascade reactions for construction and functionalization of heterocycles, which should be illustrated with Schemes. The mechanisms of ref[98-100] are more complicated than simple functionalization reaction, which can be discussed more deeply and illustrated with Schemes. Different Z/E selectivity of the products in ref[98] and [100] can also be further discussed.
(6) In many Schemes, such sentences "xx examples with up to xx%" are separated in two lines as "xx examples with up" and "to xx%", which is a little strange. It may be better to revise as "xx examples with yields up to xx%" or "xx examples; up to xx%", or be shown as "xx examples" and "yields up to xx%" (or simply "up to xx%") in two lines.
(7) In some examples, the original papers demonstrate other types of functionalization such as chlorination, iodination and trifluoromethylation. Though the focus is bromofunctionalization, selected examples of these related reactions can be also added in the Schemes, which may demonstrate the generality and power of electrosynthesis and attract more readers.
Author Response
First, the authors like to thank Reviewer 3 for the comprehensible and valuable suggestions. After the revision, the following changes were included in the manuscript and changes were highlighted in yellow.
Reviewer 3: Point-by-point response
- It is better to change the title as "The Electrochemical Bromofunctionalization of Alkenes and Alkynes – To Sustainability and Beyond", which emphasizes the topic and makes the word "Bromofunctionalization" shown in one line.
Answer: Thank you for the suggestion. The title has been changed accordingly.
- In the part "2. Bromine and bromination agents", in both text and Table 1, bromide salts were introduced and compared with traditional bromination agents, but the information is rare for organic bromine sources that appeared in later examples. Related information and discussion should be added to make this part more complete. The organic bromine sources are more expensive, and may lower the atom economy of the reaction. Therefore, the advantages of other aspects such as safety and mild reaction conditions should be discussed more.
Answer: Thank you for the suggestions. The table was complemented with two classical organobromine reagents for comparison. The disadvantages of these traditional brominating agents were discussed in Section 2 (Bromine and bromination agents) [64-72]. A short discussion of the advantages and disadvantages of organic bromide salts were also implemented in Section 2 [96-99].
- Non-universal abbreviations in the text and Schemes should be noted with full names to make it more friendly to the broad readership. These include but is not limited to: "CCE" and "CPE" in Schemes 2/3, "gC" and "Cgr" in Scheme 4/7/9, "FEP" in page 10, line 275.
Answer: Thank you for the suggestions. Abbreviation has been clarified in the text and in figure captions.
- In Scheme 14, the structure 35a contains a R group, and represents two examples according to ref[98], but only one yield and one Z/E value were shown.
Answer: Thank you for the comment. The R group has been specified in the reaction scheme (Scheme 16).
- The part "4. Electrochemical bromofunctionalization of alkynes" seems not as fruitful as the alkene part. Though the examples of alkynes were indeed less, more Schemes and discussions can be added. For example, ref[99] and ref[100] represent unique examples of cascade reactions for construction and functionalization of heterocycles, which should be illustrated with Schemes. The mechanisms of ref[98-100] are more complicated than simple functionalization reaction, which can be discussed more deeply and illustrated with Schemes. Different Z/E selectivity of the products in ref[98] and [100] can also be further discussed.
Answer: Thank you for the suggestion. Ref 98 (now Ref 105) was extended with the plausible mechanism and discussion over the selectivity and reaction mechanism was included. Respectively, Ref 99 and 100 (now Ref 106, 107) was extended with schemes and further discussed deeply in the text, as suggested.
- In many Schemes, such sentences "xx examples with up to xx%" are separated in two lines as "xx examples with up" and "to xx%", which is a little strange. It may be better to revise as "xx examples with yields up to xx%" or "xx examples; up to xx%", or be shown as "xx examples" and "yields up to xx%" (or simply "up to xx%") in two lines.
Answer: Thank you for the suggestion. The aforementioned sentences were unified and implemented in all schemes.
- In some examples, the original papers demonstrate other types of functionalization such as chlorination, iodination and trifluoromethylation. Though the focus is bromofunctionalization, selected examples of these related reactions can be also added in the Schemes, which may demonstrate the generality and power of electrosynthesis and attract more readers.
Answer: Thank you for the suggestion. Modification to Schemes 7, 11, 17 and 18 were made. Moreover, regarding to references 62, 72, 87, 93, 103, 105 and 108 other functionalization methods were discussed in the text demonstrating the broad applicability of the methods.
