Ipso-Nitration of Phenols

The initial step in aromatic nitration involves the diffusion of the nitronium ion (NO₂⁺) and the aromatic substrate (ArX) to form an 'encounter pair' denoted as [ArX·NO₂⁺]. The structure of this encounter pair remains undefined. This encounter pair subsequently generates relatively unstable σ-complexes, also known as Wheland intermediates. The formation of nitro compounds then occurs through the loss of X⁺ from these Wheland intermediates. The rate-determining step in this reaction sequence is dependent on the specific reaction conditions, including the type of nitrating agent (e.g., fuming nitric acid) and the structure of the aromatic compound. Early research primarily focused on conventional electrophilic substitution where X = H. The text mentions examples where nitration with fuming nitric acid in acetic acid yielded cyclohexadiene derivatives, which could be further converted into acyclic derivatives through reactions with aqueous sodium carbonate or water.

The text highlights the renewed interest in ipso substitution in 1961. This refers to a type of electrophilic aromatic substitution where the electrophile attacks a position already substituted on the aromatic ring. Fischer et al. demonstrated this in the nitration of o-xylene using nitric acid and acetic anhydride, yielding 3,4-dimethylphenyl acetate as a major product. The ratio of conventional nitration products to the nitro-acetate formed remains consistent across various conditions and provides insights into the positional reactivities within the aromatic substrate. The relative stability of Wheland intermediates influences the extent of ipso substitution. Further examples are provided, including the nitration of 4-methylanisole in sulfuric acid, which produced both 4-methyl-2-nitrophenol and 4-methyl-2-nitroanisole, illustrating the formation of both conventional and ipso Wheland intermediates.

The document emphasizes the extramolecular migration and rearrangement of 4-nitrocyclohexa-2,5-dienones, a significant aspect of the research. In the absence of ortho-substitution, these compounds rearrange to produce o-nitrophenols. Specific examples include the rearrangement of 4-methyl-, 3,4-dimethyl-, and 3,4,5-trimethyl-4-nitrocyclohexa-2,5-dienones to their corresponding o-nitrophenols in various solvents (hexane, acetic acid, ethanol, water, and dimethyl sulfoxide). The text further discusses instances where a component 'leaks' from the encounter pair, such as in the reaction of 4-chloroanisole, resulting in the formation of either 4-chloro-2-nitrophenol and 4-chloro-2-nitroanisole or 4-chloro-2,6-dinitrophenol depending on concentration. Studies using H₂¹⁸O enriched mixtures supported these observations.

The document describes two main types of substituent modifications during nitration reactions. The first involves hydroxyl groups located ortho or para to the ipso-position. These hydroxyl groups lose a proton, leading to the formation of a carbonyl function. Methoxyl groups can also undergo similar transformations. The second major category encompasses a broader range of modifications including alkoxylation, arylation, hydroxylation, and the formation of aldehydes, carboxylic acids, and ketones. The interplay between these substituents and the nitration process is a key focus of the research. The position of the substituent relative to the ipso-attack site significantly influences the reaction pathway and product formation. Understanding these substituent effects is crucial for predicting and controlling the outcome of nitration reactions.

The formation of side-chain nitro compounds is another important aspect of the research. Systematic investigations have primarily focused on the formation of these compounds in polymethylbenzenes. Early studies used benzoyl nitrate to achieve side-chain nitration. Later research by Robinson and Thompson demonstrated high-yield side-chain nitro compound formation from the nitration of 1,4-dimethylnaphthalene with nitric acid in acetic acid. A proposed mechanism involves initial ipso attack at the most activated ring position. This is followed by proton loss from the methyl group para to the ipso-position, yielding a methylenecyclohexadiene compound. This intermediate is then susceptible to nucleophilic attack; attack by the nitronium ion would result in a side-chain nitro compound. Other side-chain substitution products, such as nitrates and acetates, may also be formed alongside the side-chain nitro compounds, depending on the substrate's structure and reaction conditions. A mechanistic pattern reflecting the substitution patterns observed in side-chain nitro formation is suggested.

The primary nitrating agent discussed is concentrated nitric acid. While molecular nitric acid is the dominant species, the text acknowledges the presence of other species in significant concentrations. Physical and spectroscopic studies indicate substantial self-hydration within the concentrated nitric acid. The reaction rate with concentrated nitric acid follows the rate law: rate = k[ArH], indicating that the reaction proceeds via molecular nitric acid or a species whose concentration maintains a constant ratio to the initial nitric acid concentration. This rate equation excludes terms involving nitric acid concentration because it serves as the solvent in these reactions.

Besides concentrated nitric acid, other nitrating agents and reaction mechanisms are explored. The text mentions the use of nitrogen dioxide (NO₂) in reactions with 2,4,6-tri-t-butylphenol and 2,6-di-t-butyl-4-methylphenol, demonstrating phenoxy radical formation via electron spin resonance (ESR) spectroscopy. Electron-transfer processes from aromatic compounds to the nitronium ion are proposed as key mechanistic features in certain cases. This involves direct bond formation to create a Wheland intermediate, followed by homolytic cleavage to yield a radical cation and nitrogen dioxide. The subsequent formation of ArNO₂ would then depend on proton loss and recapture of NO₂ by Ar. The text outlines how this electron-transfer mechanism might relate to reactions involving polysubstituted phenols and nitric acid, emphasizing that the formation of a Wheland intermediate followed by homolytic cleavage is a common element in both mechanisms, but proton loss differs.

The document examines the diverse reaction pathways arising from the interaction of nitrogen dioxide with various substrates, particularly focusing on polysubstituted phenols and the formation of nitro dienones. The interaction of nitrogen dioxide with the initially formed 4-nitro dienone can lead to addition products or rearrangements to 4-hydroxy dienones followed by further addition reactions. The formation of 6-nitro dienones and 6-hydroxy dienones is also discussed, with differences in reactivity noted; for instance, the reaction of 2,3,5,6-tetramethyl-4-nitrophenol with nitrogen dioxide produces dihydroxycyclohex-3-enone through an ONO attack and subsequent hydrolysis. The possible conformations of 6-nitro dienones are discussed in relation to intramolecular hydrogen bonding and its effects on reaction pathways and product stereochemistry, with specific examples provided to illustrate these complex reaction mechanisms.

The reaction of polysubstituted phenols with nitric acid to yield nitro dienones is a central theme. The mechanism is generally considered to proceed via initial ipso attack, followed by the loss of the hydroxyl proton. In 1977, Perrin suggested that for nitronium ion-mediated nitration of all aromatic substrates, the initial step is ipso attack. A key feature highlighted is the formation of nitro dienones, which are intermediates in the formation of nitro ketones. The text notes that the reaction of polysubstituted phenols with nitric acid generally proceeds by initial ipso attack followed by loss of the hydroxyl proton. Specific examples and reaction schemes are used to illustrate these processes. The stereochemistry of the resulting products, especially nitro ketones, is highlighted as a significant aspect, often determined using X-ray crystal structure analysis.

The formation of cis-nitro ketone products is discussed extensively. A notable feature of these ketones is their all-cis stereochemistry of the two nitro groups and the hydroxyl group, confirmed by X-ray crystal structure analysis. Similar nitrations of 3,4,5,6-tetrabromo-2-methylphenol and chlorinated 2-methyl phenols also produce analogous cis-nitro ketone products. The research delves into the stereochemical aspects of the reaction, showing how intramolecular carbonyl-hydroxyl hydrogen bonding can influence the orientation of the nitro groups and the hydroxyl group in the final product. The relative stereochemistry of the nitro groups and the hydroxyl group are determined using X-ray crystallography. The text highlights the importance of understanding the stereochemical outcomes in relation to the reaction conditions and the structure of the starting phenol.

The research involved the isolation and structural characterization of a range of reaction products using various techniques. The text mentions the isolation and structural determination of hydroxy trinitro ketones and dihydroxy dinitro ketones using X-ray crystal structure analysis. Specific compounds, such as t-6-hydroxy-2,6-dimethyl-r-2,4,t-5-trinitrocyclohex-3-enone, are described with their melting points and structural details provided. The identification and characterization of these compounds involved the use of ¹H NMR and other spectroscopic techniques. The text further mentions the isolation of C2-epimeric bromo hydroxy dinitro ketones, which were purified by HPLC before their structure was also determined by X-ray crystallography. This exemplifies the detailed structural analysis undertaken to understand the reaction products and the mechanisms leading to their formation.

The nitration of 1,2,3-trimethylbenzene is described using a mixture of fuming nitric acid and concentrated sulfuric acid at temperatures below 10°C. The reaction yielded a precipitate, which was filtered, washed, and air-dried. The resulting product was subjected to further analysis. The experimental procedure involved adding 1,2,3-trimethylbenzene dropwise to a stirred mixture of fuming nitric acid and concentrated sulfuric acid maintained below 10°C. After a 2-hour stirring period, the mixture was poured into excess ice to precipitate the product. The precipitate was then filtered, washed with water, and air-dried, yielding approximately 10g of crude product. This indicates the nitration reaction was successful, and further separation and identification techniques would be required to fully characterize the products formed.

A similar nitration procedure was followed for 1-bromo-2,3,4-trimethylbenzene. Fuming nitric acid was added dropwise to a solution of 1-bromo-2,3,4-trimethylbenzene. The reaction mixture was then poured onto ice, and the resulting precipitate was filtered and washed. Column chromatography was used for separation of the crude product mixture (approximately 27g), using 5% deactivated alumina and ether/petroleum ether mixtures as eluents. This suggests a complex mixture of products was obtained, necessitating chromatographic separation to isolate and identify individual components. The use of column chromatography with a specific adsorbent and eluent system indicates the researchers were prepared for a complex product mixture, possibly involving isomeric or other closely related compounds.

The nitration of 1,2,4,5-tetramethylbenzene is detailed, using a solution of the compound in chloroform added to concentrated sulfuric acid. The mixture was then nitrated with fuming nitric acid, keeping the temperature below 50°C. After removing the acid layer and washing the chloroform layer, the chloroform was evaporated. The nitration of 1,2,4,5-tetramethylbenzene involved adding a chloroform solution of the compound to concentrated sulfuric acid. The mixture was cooled before slow nitration with fuming nitric acid, keeping the temperature below 50°C. The acid layer was separated, and the chloroform layer washed with sodium carbonate and water, then dried. The solvent was removed, leaving a residue for further analysis, indicating the intention to analyze the resultant nitration product and characterize it by other means.

The nitration of other trimethylbenzene derivatives is discussed, although specific details of the experimental procedures are limited in this excerpt of the provided text. The text briefly mentions the nitration of 4-cyclopropyl-2-methyl-6-nitrophenol, yielding a hydroxy trinitrocyclohex-2-enone, whose structure was determined by X-ray crystal structure analysis. The formation of this product is linked to a proposed mechanism involving a 4-nitro dienone intermediate. The nitration of 2,4-dimethyl-6-nitrophenol with fuming nitric acid or nitrogen dioxide is also mentioned, with a proposed reaction pathway involving the formation and rearrangement of 6-nitro dienones and 6-hydroxy dienones. These examples illustrate the variety of reaction pathways and products possible even with relatively similar starting materials.