| Dakin reaction | |
|---|---|
| Named after | Henry Drysdale Dakin |
| Reaction type | Organic redox reaction |
| Identifiers | |
| Organic Chemistry Portal | dakin-reaction |
| RSC ontology ID | RXNO:0000169 |
TheDakin oxidation (or Dakin reaction) is anorganicredox reaction in which anortho- orpara-hydroxylatedphenylaldehyde (2-hydroxybenzaldehyde or4-hydroxybenzaldehyde) orketone reacts withhydrogen peroxide (H2O2) inbase to form abenzenediol and acarboxylate. Overall, thecarbonyl group is oxidised, whereas the H2O2 is reduced.
The Dakin oxidation, which is closely related to theBaeyer–Villiger oxidation, is not to be confused with theDakin–West reaction, though both are named afterHenry Drysdale Dakin.
The Dakin oxidation starts with (1)nucleophilicaddition of a hydroperoxideion to thecarbonylcarbon, forming a (2)tetrahedral intermediate. The intermediate collapses, causing [1,2]-aryl migration,hydroxideelimination, and formation of a (3) phenylester. The phenyl ester is subsequentlyhydrolyzed: nucleophilic addition of hydroxide ion from solution to the ester carbonyl carbon forms a (4) second tetrahedral intermediate, which collapses, eliminating a (5)phenoxide ion and forming acarboxylic acid. Finally, the phenoxide extracts theacidichydrogen from the carboxylic acid, yielding the (6) collected products.[1][2][3]
The Dakin oxidation has tworate-limiting steps: nucleophilic addition of hydroperoxide to the carbonyl carbon and [1,2]-aryl migration.[2] Therefore, the overall rate of oxidation is dependent on the nucleophilicity of hydroperoxide, theelectrophilicity of the carbonyl carbon, and the speed of [1,2]-aryl migration. Thealkyl substituents on the carbonyl carbon, the relative positions of the hydroxyl and carbonyl groups on the aryl ring, the presence of other functional groups on the ring, and the reaction mixturepH are four factors that affect these rate-limiting steps.
In general, phenyl aldehydes are more reactive than phenyl ketones because the ketone carbonyl carbon is less electrophilic than the aldehyde carbonyl carbon.[1] The difference can be mitigated by increasing the temperature of the reaction mixture.[4]
O-hydroxy phenyl aldehydes and ketones oxidize faster thanp-hydroxy phenyl aldehydes and ketones in weakly basic conditions. Ino-hydroxy compounds, when the hydroxyl group isprotonated, an intramolecularhydrogen bond can form between the hydroxyl hydrogen and the carbonyloxygen, stabilizing aresonance structure with positivecharge on the carbonyl carbon, thus increasing the carbonyl carbon's electrophilicity (7). Lacking this stabilization, the carbonyl carbon ofp-hydroxy compounds is less electrophilic. Therefore,o-hydroxy compounds are oxidized faster thanp-hydroxy compounds when the hydroxyl group is protonated.[2]
M-hydroxy compounds do not oxidize tom-benzenediols and carboxylates. Rather, they form phenyl carboxylic acids.[1][2] Variations in the aryl rings' migratory aptitudes can explain this. Hydroxyl groupsortho orpara to the carbonyl group concentrateelectron density at the aryl carbonbonded to the carbonyl carbon (10c,11d). Phenyl groups have low migratory aptitude, but higher electron density at the migrating carbon increases migratory aptitude, facilitating [1,2]-aryl migration and allowing the reaction to continue.M-hydroxy compounds do not concentrate electron density at the migrating carbon (12a,12b,12c,12d); their aryl groups' migratory aptitude remains low. Thebenzylic hydrogen, which has the highest migratory aptitude, migrates instead (8), forming a phenyl carboxylic acid (9).
Substitution of phenyl hydrogens withelectron-donating groupsortho orpara to the carbonyl group increases electron density at the migrating carbon, promotes [1,2]-aryl migration, and accelerates oxidation. Substitution with electron-donating groupsmeta to the carbonyl group does not change electron density at the migrating carbon; because unsubstituted phenyl group migratory aptitude is low, hydrogen migration dominates. Substitution with electron-withdrawing groupsortho orpara to the carbonyl decreases electron density at the migrating carbon (13c), inhibits [1,2]-aryl migration, and favors hydrogen migration.[1]
The hydroperoxide anion is a more reactive nucleophile than neutral hydrogen peroxide. Consequently, oxidation accelerates as pH increases toward thepKa of hydrogen peroxide and hydroperoxide concentration climbs. At pH higher than 13.5, however, oxidation does not occur, possibly due todeprotonation of the second peroxidic oxygen. Deprotonation of the second peroxidic oxygen would prevent [1,2]-aryl migration because the loneoxide anion is too basic to be eliminated (2).[2]
Deprotonation of the hydroxyl group increases electron donation from the hydroxyl oxygen. When the hydroxyl group isortho orpara to the carbonyl group, deprotonation increases the electron density at the migrating carbon, promoting faster [1,2]-aryl migration. Therefore, [1,2]-aryl migration is facilitated by the pH range that favors deprotonated over protonated hydroxyl group.[2]
The Dakin oxidation can occur in mild acidic conditions as well, with a mechanism analogous to the base-catalyzed mechanism. Inmethanol, hydrogen peroxide, andcatalyticsulfuric acid, the carbonyl oxygen isprotonated (14), after which hydrogen peroxide adds as a nucleophile to the carbonyl carbon, forming a tetrahedral intermediate (15). Following an intramolecular proton transfer (16,17), the tetrahedral intermediate collapses, [1,2]-aryl migration occurs, andwater is eliminated (18). Nucleophilic addition of methanol to the carbonyl carbon forms another tetrahedral intermediate (19). Following a second intramolecular proton transfer (20,21), the tetrahedral intermediate collapses, eliminating a phenol and forming an ester protonated at the carbonyl oxygen (22). Finally, deprotonation of the carbonyl oxygen yields the collected products and regenerates the acid catalyst (23).[5]
Addingboric acid to the acid-catalyzed reaction mixture increases the yield of phenol product over phenyl carboxylic acid product, even when using phenyl aldehyde or ketone reactants with electron-donating groupsmeta to the carbonyl group or electron-withdrawing groupsortho orpara to the carbonyl group. Boric acid and hydrogen peroxide form a complex in solution that, once added to the carbonyl carbon, favors aryl migration over hydrogen migration, maximizing the yield of phenol and reducing the yield of phenyl carboxylic acid.[6]
Using anionic liquid solvent with catalyticmethyltrioxorhenium (MTO) dramatically accelerates Dakin oxidation. MTO forms a complex with hydrogen peroxide that increases the rate of addition of hydrogen peroxide to the carbonyl carbon. MTO does not, however, change the relative yields of phenol and phenyl carboxylic acid products.[7]
Mixingurea and hydrogen peroxide yields urea-hydrogen peroxide complex (UHC). Addingdry UHC to solventless phenyl aldehyde or ketone also accelerates Dakin oxidation. Like MTO, UHP increases the rate of nucleophilic addition of hydrogen peroxide. But unlike the MTO-catalyzed variant, the urea-catalyzed variant does not produce potentially toxicheavy metal waste; it has also been applied to the synthesis ofamine oxides such aspyridine-N-oxide.[4]
The Dakin oxidation is most commonly used to synthesize benzenediols[8] and alkoxyphenols.[1][9]Catechol, for example, is synthesized fromo-hydroxy ando-alkoxy phenyl aldehydes and ketones,[8] and is used as the starting material for synthesis of several compounds, including thecatecholamines,[10] catecholamine derivatives, and4-tert-butylcatechol, a common antioxidant and polymerization inhibitor. Other synthetically useful products of the Dakin oxidation includeguaiacol, a precursor of several flavorants;hydroquinone, a common photograph-developing agent; and 2-tert-butyl-4-hydroxyanisole and 3-tert-butyl-4-hydroxyanisole, two antioxidants commonly used to preserve packaged food.[7] In addition, the Dakin oxidation is useful in the synthesis ofindolequinones, naturally occurring compounds that exhibit high anti-biotic, anti-fungal, and anti-tumor activities.[11]