Ketone halogenation: Difference between revisions
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{{short description|Organic reaction: addition of a halogen to the alpha carbon of a ketone}} |
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{{Use dmy dates|date=November 2022}} |
{{Use dmy dates|date=November 2022}} |
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In [[organic chemistry]], '''α-keto halogenation''' is a special type of [[halogenation]]. |
In [[organic chemistry]], '''α-keto halogenation''' is a special type of [[halogenation]]. |
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The reaction may be carried out under either acidic or basic conditions in an aqueous medium with the corresponding elemental halogen. In this way, chloride, bromide, and iodide (but notably not fluoride) functionality can be inserted selectively in the [[Alpha and beta carbon|alpha position]] of a ketone. |
The reaction may be carried out under either acidic or basic conditions in an [[aqueous]] medium with the corresponding elemental [[halogen]]. In this way, [[chloride]], [[bromide]], and [[iodide]] (but notably not [[fluoride]]) functionality can be inserted selectively in the [[Alpha and beta carbon|alpha position]] of a [[ketone]]. |
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The position alpha to the [[carbonyl]] group in a |
The position alpha to the [[carbonyl]] group ({{chem2|C\dO}}) in a ketone is easily halogenated. This is due to its ability to form an [[enolate]] ({{chem2|C\dC\sO-}}) in [[basic (chemistry)|basic]] solution, or an [[enol]] ({{chem2|C\dC\sOH}}) in [[acidic]] solution. An example of alpha halogenation is the [[bromination|mono-bromination]] of [[acetone]] ({{chem2|(CH3)2C\dO}}), carried out under either acidic or basic conditions, to give [[bromoacetone]]: |
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Acidic (in acetic acid): |
Acidic (in acetic acid): |
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[[File:Acid mechanism.png|center|Reaction mechanism for the bromination of acetone while in the presence of acetic acid|650px]] |
[[File:Acid mechanism.png|center|Reaction mechanism for the bromination of acetone while in the presence of acetic acid|650px]] |
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Basic (in aqueous NaOH): |
Basic (in aqueous [[NaOH]]): |
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[[File:Base mechanism.png|center|Reaction mechanism for the bromination of acetone while in the presence of aqueous NaOH|650px]] |
[[File:Base mechanism.png|center|Reaction mechanism for the bromination of acetone while in the presence of aqueous NaOH|650px]] |
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In acidic solution, usually only one alpha hydrogen is replaced by a halogen, as each successive halogenation is slower than the first. The halogen decreases the basicity of the carbonyl oxygen, thus making protonation less favorable. However, in basic solutions, successive halogenation is more rapid due to inductive electron withdrawal by the halogen. This makes the remaining hydrogens more acidic. In the case of methyl [[ketone]]s, this reaction often occurs a third time to form a ketone trihalide, which can undergo rapid substitution with water to form a carboxylate in what is known as the [[haloform reaction]].<ref>"Organic Chemistry" Fifth Edition, by Paula Yurkanis Bruice. Pearson Prentice Hall, Upper Saddle River, NJ, 2007</ref> |
In acidic solution, usually only one alpha hydrogen is replaced by a halogen, as each successive halogenation is slower than the first. The halogen decreases the basicity of the carbonyl oxygen, thus making [[protonation]] less favorable. However, in basic solutions, successive halogenation is more rapid due to inductive electron withdrawal by the halogen. This makes the remaining hydrogens more acidic. In the case of methyl [[ketone]]s, this reaction often occurs a third time to form a ketone trihalide, which can undergo rapid substitution with water to form a [[carboxylate]] ({{chem2|\sC(\dO)O-}}) in what is known as the [[haloform reaction]].<ref>"Organic Chemistry" Fifth Edition, by Paula Yurkanis Bruice. Pearson Prentice Hall, Upper Saddle River, NJ, 2007</ref> |
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The regioselectivity also differs: The halogenation of an unsymmetrical ketone in acid results in the more substituted alkyl group being halogenated. A second equivalent of halogen results in the halogenation of the other alkyl substituent (without the halogen). In contrast, in basic solutions, an unsymmetrical ketone halogenates at the less substituted alkyl group. Subsequent halogenation (which usually cannot be stopped by control of stoichiometry) occurs at the position which already has a halogen substituent, until all hydrogens have been replaced by halogen atoms. For methyl alkyl ketones (2-alkanones), the haloform reaction proceeds to give the carboxylic acid selectively.<ref>{{Cite book|title=Organic chemistry|last=Clayden, Jonathan.|date=2012|publisher=Oxford University Press|others=Greeves, Nick., Warren, Stuart G.|isbn=9780199270293|edition= 2nd|location=Oxford|oclc=761379371}}</ref> |
The [[regioselectivity]] also differs: The halogenation of an unsymmetrical ketone in acid results in the more substituted [[alkyl group]] being halogenated. A second equivalent of halogen results in the halogenation of the other alkyl substituent (without the halogen). In contrast, in basic solutions, an unsymmetrical ketone halogenates at the less substituted alkyl group. Subsequent halogenation (which usually cannot be stopped by control of stoichiometry) occurs at the position which already has a halogen substituent, until all hydrogens have been replaced by halogen atoms. For methyl alkyl ketones (2-alkanones), the haloform reaction proceeds to give the carboxylic acid selectively.<ref>{{Cite book|title=Organic chemistry|last=Clayden, Jonathan.|date=2012|publisher=Oxford University Press|others=Greeves, Nick., Warren, Stuart G.|isbn=9780199270293|edition= 2nd|location=Oxford|oclc=761379371}}</ref> |
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== Halogenation of α,β- |
== Halogenation of α,β-unsaturated ketones == |
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[[File:Ketone Halogenation.png|thumb|350x350px|<big>Halogenation of α,β- |
[[File:Ketone Halogenation.png|thumb|350x350px|<big>Halogenation of α,β-unsaturated ketone<ref name=":1">{{Cite journal |last=Wang |first=Zihua |last2=Yin |first2=Guodong |last3=Qin |first3=Jing |last4=Gao |first4=Meng |last5=Cao |first5=Liping |last6=Wu |first6=Anxin |date=November 2008 |title=An Efficient Method for the Selective Iodination of α,β-Unsaturated Ketones |url=http://www.thieme-connect.de/DOI/DOI?10.1055/s-0028-1083200 |journal=Synthesis |language=en |volume=2008 |issue=22 |pages=3675–3681 |doi=10.1055/s-0028-1083200 |issn=0039-7881}}</ref></big>]] |
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On α,β-Unsaturated ketones or enones, it's possible to halogenate with [[iodine]] selectively on the more saturated alpha on the ketone selectively over the unsaturated side. Iodine is preferred due to it being more reactive than alkyl bromides which makes this reaction quite useful.<ref>{{Cite journal |last=Wang |first=Zihua |last2=Yin |first2=Guodong |last3=Qin |first3=Jing |last4=Gao |first4=Meng |last5=Cao |first5=Liping |last6=Wu |first6=Anxin |date=November 2008 |title=An Efficient Method for the Selective Iodination of α,β-Unsaturated Ketones |url=http://www.thieme-connect.de/DOI/DOI?10.1055/s-0028-1083200 |journal=Synthesis |language=en |volume=2008 |issue=22 |pages=3675–3681 |doi=10.1055/s-0028-1083200 |issn=0039-7881}}</ref> By using CuO in conjunction with I<sub>2</sub>, it is possible to achieve this reaction under relatively mild conditions. This reaction undergoes a very reactive [[enol]] mechanism, facilitated by the CuO, which allows for the selective addition of I<sub>2</sub> on the |
On α,β-Unsaturated ketones or enones, it's possible to halogenate with [[iodine]] selectively on the more saturated alpha on the ketone selectively over the unsaturated side. Iodine is preferred due to it being more reactive than alkyl bromides which makes this reaction quite useful.<ref name=":1">{{Cite journal |last=Wang |first=Zihua |last2=Yin |first2=Guodong |last3=Qin |first3=Jing |last4=Gao |first4=Meng |last5=Cao |first5=Liping |last6=Wu |first6=Anxin |date=November 2008 |title=An Efficient Method for the Selective Iodination of α,β-Unsaturated Ketones |url=http://www.thieme-connect.de/DOI/DOI?10.1055/s-0028-1083200 |journal=Synthesis |language=en |volume=2008 |issue=22 |pages=3675–3681 |doi=10.1055/s-0028-1083200 |issn=0039-7881}}</ref> By using [[Copper(II) oxide|CuO]] in conjunction with I<sub>2</sub>, it is possible to achieve this reaction under relatively mild conditions. This reaction undergoes a very reactive [[enol]] mechanism, facilitated by the CuO, which allows for the selective addition of I<sub>2</sub> on the saturated alpha carbon of the ketone.<ref>{{Cite web |title=Halogenation of Ketones via Enols |url=https://www.masterorganicchemistry.com/reaction-guide/bromination-of-ketones-via-enols/ |access-date=2022-11-13 |website=Master Organic Chemistry |language=en-US}}</ref> However, the effectiveness of this reaction depends on the presence of [[aryl]] functional groups. |
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== Applications in |
== Applications in green chemistry == |
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Alpha halogenated products are very useful compounds as they have high reactivity which makes them very prone to reacting. Alpha halogenated [[ketone]]s react with [[nucleophile]]s to create many valuable compounds. However, many of the current method for ketone halogenation use hazardous chemicals, have complex procedures, and/or require a long time to go to completion. Additionally, the polar solvents that are primarily used (DMF, DMSO, and CH<sub>3</sub>CN) are major environmental pollutants. |
Alpha halogenated products are very useful compounds as they have high reactivity which makes them very prone to reacting. Alpha halogenated [[ketone]]s react with [[nucleophile]]s to create many valuable compounds. However, many of the current method for ketone halogenation use hazardous chemicals, have complex procedures, and/or require a long time to go to completion. Additionally, the polar solvents that are primarily used (DMF, DMSO, and CH<sub>3</sub>CN) are major environmental pollutants. |
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An experiment conducted by Meshram et al. in 2005 investigated making ketone halogenation a greener reaction, according to the principles of [[green chemistry]].<ref>{{Cite web |title=12 Principles of Green Chemistry |url=https://www.acs.org/content/acs/en/greenchemistry/principles/12-principles-of-green-chemistry.html |access-date=2022-11-13 |website=American Chemical Society |language=en}}</ref><ref name=":0">{{Cite journal |last=Meshram |first=H. M. |last2=Reddy |first2=P. N. |last3=Vishnu |first3=P. |last4=Sadashiv |first4=K. |last5=Yadav |first5=J. S. |date=2006-02-06 |title=A green approach for efficient α-halogenation of β-dicarbonyl compounds and cyclic ketones using N-halosuccinimides in ionic liquids |url=https://www.sciencedirect.com/science/article/pii/S0040403905026304 |journal=Tetrahedron Letters |language=en |volume=47 |issue=6 |pages=991–995 |doi=10.1016/j.tetlet.2005.11.141 |issn=0040-4039}}</ref> Meshram et al. investigated alternatives to the hazardous chemicals that are primarily used in ketone halogenation, finding that room temperature ionic liquids were a promising option.<ref name=":0" /> Room temperature ionic liquids are interesting prospects as they have unique chemical and physical properties, and their properties can be modified by changing the cations that are attached. Additionally, these ionic liquids have high polarity and their ability to solubilize organic and inorganic molecules leads to enhanced reaction rates, which makes them more desirable. |
An experiment conducted by Meshram et al. in 2005 investigated making ketone halogenation a greener reaction, according to the principles of [[green chemistry]].<ref>{{Cite web |title=12 Principles of Green Chemistry |url=https://www.acs.org/content/acs/en/greenchemistry/principles/12-principles-of-green-chemistry.html |access-date=2022-11-13 |website=American Chemical Society |language=en}}</ref><ref name=":0">{{Cite journal |last=Meshram |first=H. M. |last2=Reddy |first2=P. N. |last3=Vishnu |first3=P. |last4=Sadashiv |first4=K. |last5=Yadav |first5=J. S. |date=2006-02-06 |title=A green approach for efficient α-halogenation of β-dicarbonyl compounds and cyclic ketones using N-halosuccinimides in ionic liquids |url=https://www.sciencedirect.com/science/article/pii/S0040403905026304 |journal=Tetrahedron Letters |language=en |volume=47 |issue=6 |pages=991–995 |doi=10.1016/j.tetlet.2005.11.141 |issn=0040-4039}}</ref> Meshram et al. investigated alternatives to the hazardous chemicals that are primarily used in ketone halogenation, finding that room temperature ionic liquids were a promising option.<ref name=":0" /> Room temperature ionic liquids are interesting prospects as they have unique chemical and physical properties, and their properties can be modified by changing the cations that are attached. Additionally, these ionic liquids have high polarity and their ability to solubilize organic and inorganic molecules leads to enhanced reaction rates, which makes them more desirable. |
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Many experiments found that ionic liquids with N-halosuccinimides as the solvent were an effective, greener alternative to conventional solvents.<ref name=":0" /> This process also resulted in enhanced yields, reduced reaction time, simplified the procedure, used less harmful chemicals (no strong acids), and did not require catalysts, all of which made the process greener. |
Many experiments found that ionic liquids with N-halosuccinimides as the solvent were an effective, greener alternative to conventional solvents.<ref name=":0" /> This process also resulted in enhanced yields, reduced reaction time, simplified the procedure, used less harmful chemicals (no strong acids), and did not require [[Catalysis|catalysts]], all of which made the process greener. |
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==References== |
==References== |
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Latest revision as of 15:08, 25 October 2023
In organic chemistry, α-keto halogenation is a special type of halogenation. The reaction may be carried out under either acidic or basic conditions in an aqueous medium with the corresponding elemental halogen. In this way, chloride, bromide, and iodide (but notably not fluoride) functionality can be inserted selectively in the alpha position of a ketone.
The position alpha to the carbonyl group (C=O) in a ketone is easily halogenated. This is due to its ability to form an enolate (C=C−O−) in basic solution, or an enol (C=C−OH) in acidic solution. An example of alpha halogenation is the mono-bromination of acetone ((CH3)2C=O), carried out under either acidic or basic conditions, to give bromoacetone:
Acidic (in acetic acid):
Basic (in aqueous NaOH):
In acidic solution, usually only one alpha hydrogen is replaced by a halogen, as each successive halogenation is slower than the first. The halogen decreases the basicity of the carbonyl oxygen, thus making protonation less favorable. However, in basic solutions, successive halogenation is more rapid due to inductive electron withdrawal by the halogen. This makes the remaining hydrogens more acidic. In the case of methyl ketones, this reaction often occurs a third time to form a ketone trihalide, which can undergo rapid substitution with water to form a carboxylate (−C(=O)O−) in what is known as the haloform reaction.[1]
The regioselectivity also differs: The halogenation of an unsymmetrical ketone in acid results in the more substituted alkyl group being halogenated. A second equivalent of halogen results in the halogenation of the other alkyl substituent (without the halogen). In contrast, in basic solutions, an unsymmetrical ketone halogenates at the less substituted alkyl group. Subsequent halogenation (which usually cannot be stopped by control of stoichiometry) occurs at the position which already has a halogen substituent, until all hydrogens have been replaced by halogen atoms. For methyl alkyl ketones (2-alkanones), the haloform reaction proceeds to give the carboxylic acid selectively.[2]
Halogenation of α,β-unsaturated ketones
[edit]
On α,β-Unsaturated ketones or enones, it's possible to halogenate with iodine selectively on the more saturated alpha on the ketone selectively over the unsaturated side. Iodine is preferred due to it being more reactive than alkyl bromides which makes this reaction quite useful.[3] By using CuO in conjunction with I2, it is possible to achieve this reaction under relatively mild conditions. This reaction undergoes a very reactive enol mechanism, facilitated by the CuO, which allows for the selective addition of I2 on the saturated alpha carbon of the ketone.[4] However, the effectiveness of this reaction depends on the presence of aryl functional groups.
Applications in green chemistry
[edit]Alpha halogenated products are very useful compounds as they have high reactivity which makes them very prone to reacting. Alpha halogenated ketones react with nucleophiles to create many valuable compounds. However, many of the current method for ketone halogenation use hazardous chemicals, have complex procedures, and/or require a long time to go to completion. Additionally, the polar solvents that are primarily used (DMF, DMSO, and CH3CN) are major environmental pollutants.
An experiment conducted by Meshram et al. in 2005 investigated making ketone halogenation a greener reaction, according to the principles of green chemistry.[5][6] Meshram et al. investigated alternatives to the hazardous chemicals that are primarily used in ketone halogenation, finding that room temperature ionic liquids were a promising option.[6] Room temperature ionic liquids are interesting prospects as they have unique chemical and physical properties, and their properties can be modified by changing the cations that are attached. Additionally, these ionic liquids have high polarity and their ability to solubilize organic and inorganic molecules leads to enhanced reaction rates, which makes them more desirable.
Many experiments found that ionic liquids with N-halosuccinimides as the solvent were an effective, greener alternative to conventional solvents.[6] This process also resulted in enhanced yields, reduced reaction time, simplified the procedure, used less harmful chemicals (no strong acids), and did not require catalysts, all of which made the process greener.
References
[edit]- ^ "Organic Chemistry" Fifth Edition, by Paula Yurkanis Bruice. Pearson Prentice Hall, Upper Saddle River, NJ, 2007
- ^ Clayden, Jonathan. (2012). Organic chemistry. Greeves, Nick., Warren, Stuart G. (2nd ed.). Oxford: Oxford University Press. ISBN 9780199270293. OCLC 761379371.
- ^ a b Wang, Zihua; Yin, Guodong; Qin, Jing; Gao, Meng; Cao, Liping; Wu, Anxin (November 2008). "An Efficient Method for the Selective Iodination of α,β-Unsaturated Ketones". Synthesis. 2008 (22): 3675–3681. doi:10.1055/s-0028-1083200. ISSN 0039-7881.
- ^ "Halogenation of Ketones via Enols". Master Organic Chemistry. Retrieved 13 November 2022.
- ^ "12 Principles of Green Chemistry". American Chemical Society. Retrieved 13 November 2022.
- ^ a b c Meshram, H. M.; Reddy, P. N.; Vishnu, P.; Sadashiv, K.; Yadav, J. S. (6 February 2006). "A green approach for efficient α-halogenation of β-dicarbonyl compounds and cyclic ketones using N-halosuccinimides in ionic liquids". Tetrahedron Letters. 47 (6): 991–995. doi:10.1016/j.tetlet.2005.11.141. ISSN 0040-4039.