Krapcho decarboxylation

Krapcho decarboxylation is a chemical reaction used to manipulate certain organic esters.^[1] This reaction applies to esters with a beta electron-withdrawing group (EWG).

Krapcho decarboxylation
Named after	A. Paul Krapcho
Reaction type	Substitution reaction
Identifiers
RSC ontology ID	RXNO:0000507

The reaction proceeds by nucleophilic dealkylation of the ester by the halide followed by decarboxylation, followed by hydrolysis of the resulting stabilized carbanion.^[2]

ZCH₂CO₂CH₃ + I⁻ + H₂O → ZCH₃ + CH₃I + CO₂ + OH⁻

Reaction conditions

The reaction is carried in dipolar aprotic solvents such as dimethyl sulfoxide (DMSO) at high temperatures, often around 150 °C.^{[3] [4][5]}

A variety of salts assist in the reaction including NaCl, LiCl, KCN, and NaCN.^[6] It is suggested that the salts were not necessary for reaction, but greatly accelerates the reaction when compared to the reaction with water alone. Some examples of salts used in the reaction are: .

The ester must contain an EWG in the beta position . The reaction works best with a methyl esters.^[2] which are more susceptible to S_N2 reactions.

Mechanisms

The mechanisms are still not fully uncovered. However, the following are suggested mechanisms for two different substituents:

α,α-Disubstituted Ester

For an α,α-disubstituted ester, it is suggested that the anion in the salt attacks the R₃ in an S_N2 fashion, kicking off R₃ and leaving a negative charge on the oxygen. Then, decarboxylation occurs to produce a carbanion intermediate. The intermediate picks up a hydrogen from water to form the products.^[2]

 

The suggested reaction mechanism of α,α-disubstituted esters in the Krapcho decarboxylation reaction. R₁, R₂, and R₃ are any carbon containing substituents.

The byproducts of the reaction (X-R₃ and CO₂) are often lost as gases, which helps drive the reaction; entropy increases and Le Chatelier's principle takes place.

α-Monosubstituted Ester

For an α-monosubstituted ester, it is speculated that the anion in the salt attacks the carbonyl group to form a negative charge on the oxygen, which then cleaves off the cyanoester. With the addition of water, the cyanoester is then hydrolyzed to form CO₂ and alcohol, and the carbanion intermediate is protonated.^[7]

 

The suggested reaction mechanism of α-monosubstituted esters in the Krapcho decarboxylation reaction. R₂ is a hydrogen.

The byproduct of this reaction (CO₂) is also lost as gas, which helps drive the reaction; entropy increases and Le Chatelier's principle takes place.

Advantages

The Krapcho decarboxylation is a comparatively simpler method to manipulate malonic esters because it cleaves only one ester group, without affecting the other ester group.^[1] The conventional method involves saponification to form carboxylic acids, followed by decarboxylation to cleave the carboxylic acids, and an esterification step to regenerate the esters. ^[8] Additionally, Krapcho decarboxylation avoids harsh alkaline or acidic conditions.^[9]

References

1. Krapcho, A. Paul; Glynn, Gary A.; Grenon, Brian J. (1967-01-01). "The decarbethoxylation of geminal dicarbethoxy compounds". Tetrahedron Letters. 8 (3): 215–217. doi:10.1016/S0040-4039(00)90519-7. ISSN 0040-4039. PMID 6037875.
2. Poon, Po. S.; Banerjee, Ajoy K.; Laya, Manuel S. (2011). "Advances in the Krapcho Decarboxylation". Journal of Chemical Research. 35 (2): 67–73. doi:10.3184/174751911X12964930076403. ISSN 1747-5198.
3. Hansen, Thomas; Roozee, Jasper C.; Bickelhaupt, F. Matthias; Hamlin, Trevor A. (2022-02-04). "How Solvation Influences the S N 2 versus E2 Competition". The Journal of Organic Chemistry. 87 (3): 1805–1813. doi:10.1021/acs.joc.1c02354. ISSN 0022-3263. PMC 8822482. PMID 34932346.
4. Olejar, Kenneth J.; Kinney, Chad A. (2021). "Evaluation of thermo-chemical conversion temperatures of cannabinoid acids in hemp (Cannabis sativa L.) biomass by pressurized liquid extraction". Journal of Cannabis Research. 3 (1). doi:10.1186/s42238-021-00098-6. ISSN 2522-5782. PMC 8408919. PMID 34465400.
5. Dunn, Gerald E.; Thimm, Harald F. (1977-04-15). "Kinetics and mechanism of decarboxylation of some pyridinecarboxylic acids in aqueous solution. II". Canadian Journal of Chemistry. 55 (8): 1342–1347. doi:10.1139/v77-185. ISSN 0008-4042.
6. Krapcho, A. Paul; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E.; Lovey, A. J.; Stephens, W. P. (1978-01-01). "Synthetic applications and mechanism studies of the decarbalkoxylations of geminal diesters and related systems effected in dimethyl sulfoxide by water and/or by water with added salts". The Journal of Organic Chemistry. 43 (1): 138–147. doi:10.1021/jo00395a032. ISSN 0022-3263.
7. Krapcho, A. Paul; Jahngen, E. G. E.; Lovey, A. J.; Short, Franklin W. (1974-01-01). "Decarbalkoxylations of geminal diesters and β-keto esters in wet dimethyl sulfoxide. Effect of added sodium chloride on the decarbalkoxylation rates of mono- and di-substituted Malonate esters". Tetrahedron Letters. 15 (13): 1091–1094. doi:10.1016/S0040-4039(01)82414-X. ISSN 0040-4039.
8. Flynn, Daniel L.; Becker, Daniel P.; Nosal, Roger; Zabrowski, Daniel L. (1992-11-24). "Use of atom-transfer radical cyclizations as an efficient entry into a new "serotonergic" azanoradamantane". Tetrahedron Letters. 33 (48): 7283–7286. doi:10.1016/S0040-4039(00)60166-1. ISSN 0040-4039.
9. Krapcho, A. Paul (2007-04-12). "Recent synthetic applications of the dealkoxycarbonylation reaction. Part 1. Dealkoxycarbonylations of malonate esters". Arkivoc. 2007 (2): 1–53. doi:10.3998/ark.5550190.0008.201. hdl:2027/spo.5550190.0008.201.