2-Iodoxybenzoic acid

2-Iodoxybenzoic acid, commonly known as IBX, is an organic hypervalent iodine compound with the molecular formula C₇H₅IO₄ and a molar mass of 280.02 g/mol, widely recognized as a mild and selective oxidizing agent in organic synthesis.^[1] It exists as a white, crystalline solid that is insoluble in most organic solvents but soluble in dimethyl sulfoxide (DMSO), and it decomposes explosively above 200 °C, necessitating careful handling and often stabilization with additives like benzoic acid.^[2] First synthesized in 1893 by Christoph Hartmann and Viktor Meyer, IBX features a polymeric structure in the solid state, characterized by intermolecular iodine-oxygen bonds, and its iodine atom is in the +5 oxidation state, making it a versatile periodinane-like reagent.^[2]^[3] IBX is typically prepared by the oxidation of 2-iodobenzoic acid and is prized in organic synthesis for its ability to perform selective oxidations under mild conditions, serving as an environmentally benign alternative to heavy metal oxidants.^[2]^[3] Its applications have been documented in over 1,400 peer-reviewed publications as of 2025.^[4] Derivatives like Dess–Martin periodinane (DMP) have further expanded its utility by improving solubility in non-polar solvents.^[2]

Chemical identity

Structure and nomenclature

2-Iodoxybenzoic acid, commonly known by the abbreviation IBX, is an organoiodine compound characterized by its hypervalent iodine center in the +5 oxidation state. The molecule features a benzene ring with an ortho-substituted iodoxy group (-IO₂) and a carboxylic acid functionality that participates in forming a five-membered heterocyclic benziodoxole ring. This structure can be represented as a periodinane moiety where the iodine atom is bonded to three oxygen atoms: one from the hydroxy group, and two from the adjacent carboxylate, creating a cyclic anhydride-like arrangement with hypervalent bonding. In the solid state, IBX adopts a polymeric structure characterized by intermolecular iodine-oxygen bonds.^[5] The molecular formula is C₇H₅IO₄, and the molar mass is 280.02 g/mol.^[1]^[6] The preferred IUPAC name for this compound is 1-hydroxy-1λ⁵,2-benziodoxole-1,3-dione, reflecting the fused benziodoxole core with the hypervalent iodine denoted by the λ⁵ superscript to indicate its expanded valence shell. The hypervalent iodine center in IBX adopts a pseudo-trigonal bipyramidal geometry, typical of 10-I-4 hypervalent species, where the three oxygen ligands occupy equatorial and axial positions, and the carbon of the benzene ring serves as an additional equatorial ligand, stabilized by 3-center-4-electron (3c-4e) bonding interactions.^[7] This geometric arrangement contributes to the compound's reactivity as an oxidant. While 2-iodoxybenzoic acid is the ortho isomer, related structural analogs include the meta- and para-substituted iodoxobenzoic acids, though these are less commonly utilized due to reduced stability and reactivity compared to the ortho form. IBX also serves as a key precursor in the synthesis of the Dess-Martin periodinane, a related hypervalent iodine reagent.

Physical and chemical properties

2-Iodoxybenzoic acid (IBX) appears as a white crystalline solid. It has a melting point of 232–233 °C, at which point it decomposes. IBX exhibits low solubility in most organic solvents but is soluble in dimethyl sulfoxide (DMSO), often requiring mild heating for dissolution.^[8] As a hypervalent iodine(V) compound, IBX functions as a mild yet effective oxidant, capable of selective transformations under ambient conditions due to its electrophilic iodine center. The molecule possesses acidic character, with reported pKa values of 2.4 in water and 6.65 in DMSO, reflecting the influence of the iodyl and carboxylic acid groups.^[9] IBX demonstrates thermal instability, becoming impact-sensitive above 200 °C and prone to explosive decomposition if heated under confinement. To enhance safety, commercial preparations incorporate stabilizing additives such as benzoic acid and isophthalic acid, which reduce sensitivity while preserving reactivity. For handling, storage under an inert atmosphere at 2–8 °C is advised to prevent degradation.^[6]

Preparation

Historical synthesis

2-Iodoxybenzoic acid (IBX) was first synthesized in 1893 by Christoph Hartmann and Victor Meyer through the oxidation of 2-iodobenzoic acid using potassium permanganate (KMnO₄) in alkaline solution.^[10] This pioneering work, detailed in their publication "Über Jodobenzoësäure," marked the initial preparation of IBX as a hypervalent iodine(V) compound, representing the earliest known example of a periodinane in this class. The original procedure involved dissolving 2-iodobenzoic acid in an alkaline medium and adding KMnO₄ as the oxidant, followed by acidification to isolate the product; however, this method suffered from low yields, typically below 50%, owing to over-oxidation and decomposition under the basic conditions.^[10] Despite these limitations, the synthesis demonstrated the feasibility of accessing hypervalent iodine species from simple aryl iodides, establishing a foundational route for subsequent investigations. In the early 20th century, synthetic approaches evolved to address the inefficiencies of the initial method. A notable advancement came in 1936 when F. R. Greenbaum reported an improved protocol using potassium bromate (KBrO₃) in dilute sulfuric acid to oxidize 2-iodobenzoic acid, yielding the calcium or ammonium salts of IBX with enhanced purity and yields approaching 70%. This acidic bromate oxidation became a standard historical variant, though it still required careful control to avoid explosive byproducts. These pre-1990s methods highlighted IBX's potential as the inaugural hypervalent iodine periodinane, influencing the broader field of organoiodine oxidants despite their modest efficiencies.

Modern laboratory methods

The primary modern method for synthesizing 2-iodoxybenzoic acid (IBX) in laboratory settings involves the oxidation of 2-iodobenzoic acid with Oxone (potassium peroxymonosulfate, 2KHSO₅·KHSO₄·K₂SO₄) in water, offering a safe, efficient, and environmentally friendly alternative to earlier oxidative protocols.^[3] In a typical procedure, 2-iodobenzoic acid (1 equiv) is suspended in water with Oxone (1.3 equiv), and the mixture is heated to 70 °C for 3 hours, during which IBX precipitates as a white solid upon cooling; filtration and washing with cold water afford the product in 80% yield with ≥95% purity.^[3] For higher purity (≥99%), an excess of Oxone (3 equiv) can be employed, reducing the reaction time to 1 hour at the same temperature while yielding 77% of IBX.^[3] The overall transformation is represented by the equation:

\text{2-iodobenzoic acid} + \text{Oxone} \rightarrow \text{IBX} + \text{byproducts (e.g., } \ce{K2SO4, H2SO4})

This approach contrasts with historical methods using potassium permanganate by providing higher yields, milder conditions, and benign byproducts without heavy metal waste.^[3] Alternative modern routes include electrochemical oxidation, which enables direct anodic conversion of 2-iodobenzoic acid to IBX in 0.2 M aqueous sulfuric acid at a boron-doped diamond anode, achieving up to 90% yield under controlled potential (1.5 V vs. Ag/AgCl) for 4-6 hours, suitable for small-scale preparations avoiding chemical oxidants.^[11] While sodium perborate has been explored for related hypervalent iodine compounds, it is not a standard route for IBX due to lower selectivity and yields compared to Oxone or electrochemical methods. Purification of crude IBX typically involves recrystallization from aqueous solutions containing stabilizing additives like benzoic acid (5-10 mol%) to prevent decomposition, as pure IBX is thermally unstable above 200 °C; the stabilized product is isolated by filtration in ≥99% purity for laboratory use. Scale-up to multigram quantities (e.g., 10-50 g) is feasible with the Oxone method in standard glassware, maintaining yields above 75% while ensuring safe handling through slow addition of Oxone and inert atmosphere to minimize explosion risks during drying.

Reactivity

General mechanism

2-Iodoxybenzoic acid (IBX) functions as an oxidant through a hypervalent iodine-mediated oxygen transfer process, commonly described by the hypervalent twisting mechanism. This pathway initiates with a reversible ligand exchange at the hypervalent iodine(V) center, where the substrate alcohol displaces a carboxylate ligand to form an alkoxyiodinane intermediate.^[12] The subsequent oxygen transfer proceeds via a coordinated rearrangement involving a twist-boat transition state, in which the iodine center undergoes pseudorotation to facilitate bond formation between the transferred oxygen and the substrate while weakening the I-O bond.^[13] This twisting motion enables selective oxidation without over-oxidation to carboxylic acids under mild conditions. Early computational studies using density functional theory proposed the twisting of the iodine center as the rate-determining step,^[13] but subsequent kinetic isotope effect (KIE) experiments and refined DFT calculations have identified the reductive elimination step, involving C-H bond cleavage, as the actual rate-determining step following a fast pre-equilibrium to form the key intermediate.^[14] A representative example is the oxidation of primary alcohols, depicted by the general equation:

\ce{RCH2OH + IBX -> RCHO + 2-iodobenzoic acid + H2O}

In this transformation, cleavage of the I-O bond in the intermediate releases the oxidized product and regenerates 2-iodobenzoic acid as the primary byproduct, which can be reoxidized to IBX for catalytic use.^[12]

Influencing factors

The reactivity of 2-iodoxybenzoic acid (IBX) is significantly influenced by solvent choice, with dimethyl sulfoxide (DMSO) being the preferred medium due to its unique ability to dissolve IBX, which is otherwise insoluble in most common organic solvents, thereby enhancing its solubility and enabling efficient oxidation reactions.^[15] Water is generally avoided as a solvent because IBX undergoes hydrolysis under aqueous conditions, leading to decomposition and reduced stability, although specialized protocols using additives like β-cyclodextrin can mitigate this in water-acetone mixtures for specific applications.^[16] Temperature and pH conditions also play key roles in modulating IBX reactivity, with room temperature (typically 20–25 °C) serving as the optimal range for most oxidations to balance efficiency and prevent thermal decomposition, while elevated temperatures (e.g., 70–80 °C) may be employed for solubility in alternative solvents like ethyl acetate.^[17] The pKa of IBX is 2.4 in water and 6.65 in DMSO, reflecting its acidic nature that influences protonation states; in neutral to mildly basic media, the deprotonated form predominates in DMSO, minimizing acid-catalyzed side reactions such as substrate isomerization and promoting selective oxidation.^[9] Steric and electronic factors at the iodine center critically affect IBX's oxidation potential, with the ortho-carboxylic acid group providing electronic stabilization to the hypervalent iodine(V) through resonance, enhancing its electrophilicity, while steric congestion from the benziodoxolone framework facilitates the hypervalent twist conformation essential for oxygen transfer. Modifications such as tetramethyl substitution on the aromatic ring (as in TetMe-IBX) reduce the activation barrier for this twist by altering steric interactions, leading to rate enhancements in alcohol oxidations. Isotopic labeling and computational studies provide deeper insights into rate enhancements, with kinetic isotope effect (KIE) experiments using deuterated alcohols revealing that C-H bond cleavage in the reductive elimination, rather than the hypervalent twist, is rate-determining, as evidenced by substrate KIE values of 3.3–6.3 that align with computed transition states for this step.^[14] Density functional theory calculations further demonstrate that Lewis acid coordination can tune the trans influence at iodine, accelerating the twist step and overall reactivity by 10–20-fold in model systems.^[14]

Synthetic applications

Alcohol oxidations

2-Iodoxybenzoic acid (IBX) serves as a mild oxidant for the selective conversion of primary alcohols to aldehydes and secondary alcohols to ketones under neutral conditions, typically in dimethyl sulfoxide (DMSO) at room temperature. This process avoids over-oxidation of primary alcohols to carboxylic acids, providing high chemoselectivity even in the presence of sensitive functional groups such as olefins or sulfides. The reaction proceeds efficiently with 1.1–1.5 equivalents of IBX, often completing within hours, and the byproduct, 2-iodobenzoic acid, is readily separable by filtration due to its differing solubility properties. The general reaction scheme is depicted as follows:

\ce{R^1R^2CHOH + IBX -> R^1R^2C=O + 2-iodobenzoic acid}

where \ce{R^1} and \ce{R^2} represent hydrogen or organic substituents. This transformation highlights IBX's utility in synthesizing carbonyl compounds without the need for acidic or basic catalysis. IBX has proven particularly effective for oxidizing benzylic and allylic alcohols. For instance, in the asymmetric total synthesis of an eicosanoid, a benzylic primary alcohol was oxidized to the corresponding aldehyde in 94% yield using IBX (1.5 equiv) in DMSO/THF at room temperature over 4 hours.^[18] Allylic alcohols are similarly converted to \alpha,\beta-unsaturated aldehydes or ketones with yields typically exceeding 90%, preserving the double bond integrity and enabling applications in natural product synthesis. These examples underscore IBX's compatibility with unsaturated systems. Compared to traditional oxidants like the Swern oxidation or pyridinium chlorochromate (PCC), IBX offers distinct advantages, including operation under neutral, aprotic conditions without cryogenic temperatures or toxic activators such as oxalyl chloride. Unlike PCC, which generates heavy metal waste and requires aqueous workup, IBX produces no chromatographic byproducts beyond the easily removable 2-iodobenzoic acid, facilitating scalable and environmentally friendlier processes. These features have made IBX a preferred reagent in complex syntheses where functional group tolerance is paramount.

Oxidative cleavage of diols

2-Iodoxybenzoic acid (IBX) mediates the oxidative cleavage of vicinal (1,2-)diols to the corresponding carbonyl compounds under mild conditions, serving as a less harsh alternative to periodate-based methods that can be incompatible with sensitive functional groups. This transformation involves the scission of the carbon-carbon bond between the two hydroxyl-bearing carbons, yielding aldehydes from primary-secondary diols or ketones from secondary-secondary and tertiary-involved diols. The reaction is particularly effective for a range of diol types, including those derived from carbohydrates, where selectivity and compatibility with protecting groups are advantageous.^[19] The mechanism proceeds via initial coordination of the diol to the hypervalent iodine center of IBX, forming a cyclic five-membered alkoxyperiodinane intermediate. This adduct undergoes dual oxygen transfer, facilitating C-C bond cleavage and regeneration of 2-iodobenzoic acid as the byproduct. Unlike standard alcohol oxidations, the protonated environment or specific solvents promote fragmentation over simple dehydrogenation.^[19]^[20] The general reaction scheme is represented as:

\ce{R-CH(OH)-CH(OH)-R' + 2 IBX -> RCHO + O=CR' + 2 (2-iodobenzoic acid)}

where R and R' can be hydrogen, alkyl, or aryl groups, leading to aldehydes or ketones accordingly.^[19] Representative examples include the cleavage of benzpinacol to benzophenone in trifluoroacetic acid (TFA) at room temperature, proceeding in high yield. Similarly, sterically hindered diols such as camphane-2,3-diol undergo fragmentation in dimethyl sulfoxide (DMSO) at 30 °C, affording camphorquinone alongside aldehydic fragments. These conditions (1.2–2.5 equiv IBX, DMSO or TFA, room temperature to 80 °C) typically deliver yields of 70–90%, making the method suitable for applications in natural product synthesis where precise control over bond scission is required.^[19]^[21]

α-Hydroxylations of carbonyls

2-Iodoxybenzoic acid (IBX) enables the selective introduction of a hydroxyl group at the α-position of carbonyl compounds, particularly ketones and esters, through the oxidation of preformed enolates. This transformation is valuable for synthesizing α-hydroxy carbonyl derivatives, which are common motifs in natural products and pharmaceuticals. The method leverages IBX's mild oxidizing properties to avoid over-oxidation or side reactions, offering a hypervalent iodine-based alternative to traditional reagents like oxaziridines or peracids.^[22] The standard procedure involves generating the lithium enolate of the carbonyl substrate using lithium diisopropylamide (LDA) in tetrahydrofuran (THF) at -78 °C to ensure kinetic control and regioselectivity. IBX, typically 1.1-1.5 equivalents, is then added in dimethyl sulfoxide (DMSO) as the solvent, with the reaction warmed to room temperature over 1-2 hours. This protocol has been applied to β-keto esters and simple ketones, yielding α-hydroxy products in 70-95% isolated yields depending on substrate sterics.^[22]^[23] The reaction follows the stoichiometry:

\text{R-C(O)-CH}_2^- \text{(enolate)} + \text{IBX} \rightarrow \text{R-C(O)-CH}_2\text{OH} + \text{2-iodobenzoic acid}

where the enolate attacks the hypervalent iodine center, transferring an oxygen atom and regenerating 2-iodobenzoic acid as a benign byproduct. For β-dicarbonyl compounds like ethyl acetoacetate, the process achieves up to 91% yield under these conditions, highlighting IBX's efficiency for activated substrates.^[23] This approach excels in regioselectivity, favoring the less substituted α-site via kinetic enolate formation with LDA, which is crucial for unsymmetrical ketones. In pharmaceutical synthesis, α-hydroxy ketones derived from such oxidations serve as intermediates for drugs like atorvastatin analogs, where the hydroxyl group facilitates further functionalization or stereocontrol. For instance, the α-hydroxylation of cyclohexanone derivatives has been employed to construct chiral building blocks with >90% ee when combined with chiral auxiliaries.^[22]^[23] IBX also supports α-hydroxylation of silyl enol ethers under modified conditions, though yields are substrate-dependent and often lower (50-80%) compared to enolates; this variant is useful for acid-sensitive carbonyls. Overall, the method's operational simplicity and compatibility with diverse functional groups make it a preferred choice in modern organic synthesis.^[22]

Oxidation of β-hydroxyketones

The oxidation of β-hydroxyketones to 1,3-diketones using 2-iodoxybenzoic acid (IBX) provides a selective method for constructing β-diketone motifs, which are valuable intermediates in organic synthesis. This transformation involves the chemoselective oxidation of the β-hydroxyl group in the presence of the existing ketone, proceeding under mild conditions without over-oxidation of the product. IBX excels in this application due to its operational simplicity, involving straightforward mixing in ethyl acetate at 77 °C for 3–12 hours, followed by filtration to remove the iodine-containing byproduct.^[24] The reaction scope encompasses a wide range of substrates, including benzylic, aliphatic, cyclic, and α-halo β-hydroxyketones, with both syn and anti diastereomers tolerated. Yields are typically near-quantitative (96–99%), surpassing those achieved with alternatives like the Swern oxidation (e.g., 35% yield for a model substrate) or Dess-Martin periodinane (DMP; e.g., 40% yield), which suffer from side reactions such as over-oxidation of the β-diketone product or complex byproducts requiring chromatography. IBX's selectivity stems from its inability to further oxidize the β-diketone, enabling clean conversions even on gram scales (up to 2.1 g).^[24] Mechanistically, the process follows the general oxygen-transfer pathway of IBX for secondary alcohols, where the hypervalent iodine facilitates ligand exchange with the hydroxyl group, followed by reductive elimination to form the carbonyl. For β-hydroxyketones, this initial oxidation is accompanied by elimination of water, yielding the 1,3-diketone without C–C bond cleavage or other complications. The overall stoichiometry is represented as:

\text{R-CO-CH}_2\text{-CH(OH)-R'} + \text{IBX} \rightarrow \text{R-CO-CH}_2\text{-CO-R'} + \text{H}_2\text{O} + 2\text{-iodobenzoic acid}

This equation highlights the efficient transfer of oxygen from IBX, with 3 equivalents typically employed to drive completion. Representative examples include the oxidation of various β-hydroxyketones to the corresponding 1,3-diketones in 96–99% yields, demonstrating compatibility with aryl and alkyl substituents. These β-diketones serve as precursors in subsequent transformations, such as Knoevenagel condensations for alkene synthesis, Tsuji-Trost allylations for C–C bond formation, and DeMayo reactions for photocycloadditions in complex molecule assembly. The method's mildness and high efficiency make it particularly suited for late-stage functionalizations in total synthesis.^[24]