The Pinnick oxidation method produced by Lindgren is an innovative approach to preparing carboxylic acid from aldehydes, utilizing sodium chlorite (NaClO2) and hypochlorous acid (HClO) in the presence of scavengers, marking a significant departure from traditional methods.
Over the years, the Pinnick oxidation has emerged as a versatile and economical solution, offering enhanced selectivity and broad functional group tolerance.
History
The conversion of aldehydes into carboxylic acids is an important process in organic synthesis. Prior to the 1970s, this conversion was challenging due to factors like expensive reagents, severe reaction conditions, limited compatibility with functional groups, and poor selectivity.
In 1973, Lindgren introduced an economical and gentle method involving NaClO2 and HClO, along with scavengers like sulfamic acid. This method was first employed to convert vanillin to vanillic acid.
Later, Kraus utilized 2-methyl-2-butene as a scavenger in buffered conditions, and Pinnick showcased the broad applicability of NaClO2/2-methyl-2-butene for α,β-unsaturated aldehydes without disrupting double bonds.
Read about; Types of Organic Reactions with Examples
Mechanism of Pinnick Oxidation
The suggested reaction mechanism centers on chlorous acid as the operative oxidizing agent, generated under acidic conditions from chlorite.
Initially, chlorous acid participates in an addition process with the aldehyde substrate. Following this, the resultant structure undergoes a pericyclic fragmentation, causing the migration of the aldehyde hydrogen to an oxygen atom bonded to chlorine.
This results in the liberation of a chlorine component as hypochlorous acid (HOCl), while concurrently yielding the desired carboxylic acid product.
Side Reactions and Scavengers
The byproduct HOCl, known for its reactivity as an oxidizing agent, presents certain challenges. It has the potential to degrade the NaClO2 reagent, causing complications.
HOCl + 2ClO2− → 2ClO2 + Cl− + OH−
HOCl can hinder the intended reaction by rendering NaClO2 ineffective and inciting undesired reactions with organic components. For instance, it can engage in a halohydrin formation reaction, affecting double bonds in the reactants or products.
To deal with these issues, a scavenger is commonly introduced to the reaction mixture. By exploiting HOCl’s tendency for addition reactions, a sacrificial alkene-containing compound can be incorporated. This compound reacts with HOCl, impeding its interference with the Pinnick reaction itself. A frequent choice for this purpose is 2-methyl-2-butene.
Resorcinol and sulfamic acid are other prevalent scavengers utilized for this purpose.
Alternatively, hydrogen peroxide (H2O2) can serve as an HOCl scavenger, generating byproducts that do not disrupt the Pinnick oxidation reaction.
HOCl + H2O2 → HCl + O2 + H2O
Under mildly acidic conditions, a reasonably concentrated solution (35%) of H2O2 experiences swift oxidation without any concurrent reduction of HClO2, resulting in the formation of HOCl.
HClO2 + H2O2 → HOCl + O2 + H2O
Chlorine dioxide readily and quickly reacts with H2O2 to produce chlorous acid.
2ClO2 + H2O2 → 2HClO2 + O2
Observing the oxygen formation provides a reliable indicator of the reaction’s progress. For instances where H2O2 alone yields unsatisfactory results, DMSO has been employed as an alternative oxidizing agent. This is particularly useful for electron-rich aldehydes.
Moreover, solid-supported reagents like phosphate-buffered silica gel attached to potassium permanganate and polymer-supported chlorite have been developed. These reagents eliminate the need for conventional work-up procedures when converting aldehydes to carboxylic acids. The process entails trapping the product as potassium salts on silica gel. Consequently, this method simplifies the removal of neutral impurities through organic solvent washing.
Synthetic Applications
The complete synthesis of the intricate bioactive indole alkaloid ditryptophenaline, characterized by two adjacent quaternary stereocenters linked through C2 symmetry, was achieved within L.E. Overman’s laboratory. In the final stages of the synthetic endeavor, a multifaceted diol substrate underwent a two-step oxidation process.
Initially, a Dess-Martin oxidation converted it into a dialdehyde, which was subsequently subjected to Pinnick oxidation for transformation into the dicarboxylic acid. These steps were performed under mild conditions, ensuring the retention of the α-position stereocenters’ integrity.
In the process of total synthesizing (+)-zaragozic acid C, A. Armstrong et al. introduced an innovative triple oxidation method. For incorporating the tricarboxylic acid unit, the bicyclic triol substrate was initially subjected to Swern oxidation conditions, producing the corresponding trialdehyde.
In an attempt to convert the crude trialdehyde to the desired triacid, various oxidation methods (such as Jones oxidation and modified Ley oxidation) were explored. However, these endeavors led to intricate mixtures of products.
A straightforward and high-yielding solution was found through the use of Pinnick oxidation, which generated the sought-after triacid product. Subsequently, the tri-tert-butyl ester was established by esterification, employing N,N-diisopropyl-O-tert-butylisourea in dichloromethane.
The formal total synthesis of the discerning muscarinic receptor antagonist (+)-himbacine was realized by M.S. Sherburn and colleagues through a series of pivotal reactions including an intramolecular Diels-Alder reaction, a Stille cross-coupling, and a 6-exo-trig acyl radical cyclization.
To establish the precursor selenoate ester necessary for the acyl radical cyclization step, the aldehyde-enyne substrate underwent conversion to the carboxylic acid via Pinnick oxidation, all the while preserving the delicate enyne functional group.
Scope and Limitations
The reaction demonstrates remarkable compatibility with substrates possessing diverse functional groups. β-aryl-substituted α,β-unsaturated aldehydes respond well to the reaction conditions. Triple bonds directly connected to aldehyde groups or those in conjugation with other double bonds are also amenable to the process.
The stability of hydroxides, epoxides, benzyl ethers, and halides including iodides, as well as stannanes, is evident within the reaction framework. Illustrative reactions provided below underscore that α carbon stereocenters remain unaffected, and double bonds—especially those that are trisubstituted—maintain their configuration without undergoing E/Z-isomerization during the reaction.
Lower yields are often obtained when dealing with aliphatic α,β-unsaturated aldehydes, and more hydrophilic aldehydes. Electron-rich aldehyde substrates and double bonds can sometimes lead to chlorination as an alternate reaction pathway. In cases where these challenges arise, the inclusion of DMSO typically results in improved yields.
Certain substrates, such as unprotected aromatic amines and pyrroles, are not well-suited for these reactions. Chiral α-aminoaldehydes are particularly problematic due to epimerization and the potential conversion of amino groups into their corresponding N-oxides. To address these issues, standard protective group strategies, like employing t-BOC, prove effective solutions.
Thioethers are also particularly vulnerable to oxidation. For instance, when subjected to Pinnick oxidation, thioanisaldehyde yields a high carboxylic acid product yield, yet concurrently undergoes conversion of the thioether into the sulfoxide or sulfone form.
Key Points
1. Procedure: Dissolve aldehyde in tert-butanol with excess scavenger, add NaH2PO4 buffer and NaClO2 dropwise at room temperature.
2. Scavenger: Often 2-methyl-2-butene; must be added in large excess.
3. pH Control: Several equivalents of NaH2PO4 maintain constant pH.
4. NaClO2: Slightly more than one equivalent; dissolve in water just before use due to light and impurity sensitivity.
5. Reagent Purity: Crucial for some substrates; avoid steel needles, and use high-grade 2-methyl-2-butene.
6. Double Bonds: 2-methyl-2-butene scavenger preserves double bonds, unlike other scavengers (e.g., H2O2).
7. Stereocenters: α-position stereocenters in aldehydes remain unaffected.
8. Functional Group Tolerance: Excellent, hydroxyl groups need no protection.
As a Result;
Also Read;
- Omega Oxidation of Fatty Acids
- Beta Oxidation of Fatty Acids
- Oxidation vs Reduction: How to Remember the Difference?
Concept Berg
Who introduced this oxidation method, and when?
The Pinnick oxidation was first introduced by Lindgren in 1973.
What were the challenges with prior methods of converting aldehydes to carboxylic acids?
Prior methods faced issues like expensive reagents, harsh conditions, limited compatibility with functional groups, and poor selectivity.
What is the role of a scavenger in the Pinnick oxidation?
The scavenger, often 2-methyl-2-butene, helps maintain double bonds in the substrate while preventing unwanted side reactions.
How is the pH controlled in the Pinnick oxidation?
pH is controlled by using several equivalents of NaH2PO4 buffer.
What is crucial for the success of the Pinnick oxidation with certain substrates?
Reagent purity and the use of high-grade 2-methyl-2-butene are crucial for some substrates.
Does the Pinnick oxidation affect α-position stereocenters in aldehydes?
No, it does not affect α-position stereocenters.
How does the Pinnick oxidation tolerate other functional groups like hydroxyl groups?
It exhibits excellent tolerance for other functional groups, including hydroxyl groups, which do not require protection.
References Books
- A Textbook of Strategic Applications of Named Reactions in Organic Synthesis book by Laszlo Kurti and Barbara Czako
- A Textbook of Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications book by Jie Jack Li
References link
- An Article (Qi Group@NIBS | National Institute of Biological Sciences, Beijing)
