Phenol Chlorination: A Structural Study

The initial focus was on determining the conformations of polychlorocyclohex-3-enones and polychlorocyclohex-2-enones both in solution and in the solid state. The study highlighted that two polychlorocyclohex-3-enones with gem-dichloro substituents at C5 showed conformational mobility in solution. Interestingly, two 4,4,5-trichlorocyclohex-2-enones were observed to adopt twist-boat conformations, but with a notable difference: the C5-Cl bond was found in the equatorial orientation. A strong correlation between ¹H NMR and infrared spectroscopic data and known solid-state structures suggested that these polychlorocyclohexenones maintain similar conformations in solution. This initial observation set the stage for a more in-depth investigation into the factors governing their stereochemistry.

A significant portion of the research centered around utilizing infrared spectroscopy to understand conformation. The study noted an unexpected trend reversal in infrared carbonyl stretching frequencies for certain compound pairs. This disparity between the observed frequencies of compounds (14) (ν 1752) and (15) (ν 1770), and compounds (17) (ν 1758) and (18) (ν 1768), was initially perplexing. The researchers attempted to resolve this discrepancy by comparing the data with that of compounds (11) and (12), but the data recorded was for a mixture of isomers, hindering a definitive comparison. This highlighted the complexity of relating infrared data to conformation and the need for further analysis using other techniques.

To definitively establish the stereochemistry and conformations, the researchers employed X-ray crystallography. The absence of 1,3-diaxial non-bonded interactions between pseudoaxial C5-substituents and substituents at C3 and C1 (both sp2 carbons) in the studied structures provided valuable structural information. The X-ray crystal structures of various cyclohex-3-enones (including compounds 22, 28, 38, 46, 48, 49, 57, 58, and 59) were crucial in establishing the prevalence of similar ring conformations. Furthermore, the use of ¹H NMR spectroscopy, particularly analysis of methyl proton chemical shifts, proved instrumental in assigning structures and clarifying the previously observed disparities in infrared data. This combined approach of X-ray crystallography and NMR provided a robust method for resolving conformational ambiguities.

The study explored the influence of various substituents on the conformation and spectroscopic properties of the polychlorocyclohexenones. The assumption that the ring conformations of certain compounds were similar was supported by their X-ray crystal structures. The impact of substituting the C5-H atom with a methyl group (or chlorine atom) resulted in a significant shift (approximately 20 cm⁻¹) in the infrared olefinic stretching frequency to lower frequency, regardless of whether the C3 substituent was chlorine or methyl (as observed in ketones 46 and 51). This finding highlighted the relationship between substituent effects, conformation, and infrared spectroscopy. The analysis of compound 54’s infrared olefinic stretching frequency (ν 1597 cm⁻¹) and its ¹H NMR methyl resonance (δ 2.27) further supported the proposed conformation and substituent positions, validating the established correlations between structure and spectroscopic data.

The investigation extended to the analysis of conformation in the solid state. The infrared carbonyl stretching frequency of compound 59 (∼1761 cm⁻¹) in a Nujol mull suggested the presence of a single conformer in the solid state. However, the researchers acknowledged the possibility of a conformational equilibrium (59a and 59b), emphasizing the limitations of solely relying on solid-state data to understand solution-state conformations. This highlighted the need to complement solid-state analysis with solution-phase studies, using techniques like NMR spectroscopy, to fully understand the range of conformations possible for these complex molecules.

The document begins by establishing the context of ipso-substitution reactions within aromatic chemistry. It states that substituted aromatics bearing OAc, OR, or NH2 substituents have been shown to undergo ipso-substitution reactions, resulting in the formation of cyclohexadienones. This introduction sets the stage for the detailed exploration of ipso-substitution reactions, specifically focusing on the chlorination of polysubstituted phenols and the resulting dienone formation. The mechanism of this reaction is crucial for understanding the overall process and its outcome. The ease with which ipso-substitution occurs depends on various factors, including the nature of substituents and reaction conditions. This initial discussion provides a foundation for further analysis of this key reaction in the subsequent sections.

A key focus is the chlorination of polysubstituted phenols. The chlorination of pentachlorophenol is given as a specific example, resulting in the formation of 2,4-dienones and 2,5-dienones as products of ipso-chlorine attack. The formation of the 2,4-dienone is favored in non-polar solvents, and high yields are obtained with the addition of pyridine or similar compounds. The study notes that many dienones resulting from ipso-halogen attack have been synthesized, with a few stable examples isolated. This substitution reaction is classified as an SE21 mechanism, indicating a bimolecular kinetic process that is electrophilic in nature. The prime designation suggests a rearrangement of the double bonds. The researchers’ investigation further explores the specific conditions that favor particular types of dienones and the mechanisms that underlie their formation.

The research delves into the mechanistic details of the ipso-substitution reaction, focusing on the specific case of chlorination. It discusses the possibility of either direct ipso-chlorine attack on the phenol molecule or attack on a pre-equilibrium concentration of the phenoxide ion. This ambiguity is particularly relevant under specific reaction conditions. The study mentions that the resulting 2,4-dienones are formed via ipso-chlorine attack at a methyl-substituted ortho site on the parent phenol, with the SE21 mechanism strongly implicated. However, some uncertainties regarding the precise mechanism remain, underscoring the complexity of the process. The discussion also notes the preferential formation of a specific 2,4-dienone over another. This regioselectivity suggests that steric effects alone may not entirely determine the outcome of the ipso-substitution reaction, highlighting the need to consider other factors such as electronic effects.

The document explores subsequent reactions of the 2,4-dienones, particularly focusing on the addition of chlorine. It discusses the possibility of 2,3-chlorine addition, 2,5-chlorine addition, and 4,5-chlorine addition to the dienone system, noting that steric factors play a role in determining the outcome of these reactions. For instance, 2,4-dienones substituted at C5 by chlorine show decreased reactivity in further chlorine addition, suggesting steric hindrance. The regioselectivity of chlorine addition is discussed in detail, noting the influence of pre-existing substituents and the potential for both cis and trans addition depending on the substrate's structure. The study examines the stability of certain dienones and how different substituents and reaction conditions can lead to various adducts, emphasizing the dynamic nature of the reaction pathway.

The chlorination of 2,4-dichloro-6-methylphenol (27) yielded a mixture (approximately 3:1 ratio) of pentachlorocyclohex-3-enones (28) and (29). These isomers were separated using a Chromatotron silica gel plate. Compound (29), eluted first, contained approximately 20% impurity, possibly formed during the chromatographic separation. The infrared carbonyl stretching frequency of (29) was very similar to its isomer (28), suggesting they are C2 epimers. ¹H NMR analysis revealed a significant deshielding effect on the C2-methyl group in (28) due to the syn-axial C6-chlorine atom, allowing definitive structural assignment using spectroscopic methods. This example showcases the use of chromatographic separation and spectroscopic analysis (infrared and ¹H NMR) for the identification and characterization of chlorination products.

The chlorination of 2,6-dimethylaniline (39) produced a mixture (approximately 2:3 ratio) of tetrachlorocyclohex-3-enones (40) and (41). These isomers were separated using a Chromatotron silica gel plate. Structural assignments for (40) and (41) were made by analogy with trimethyl ketones (37) and (38), based on similar spectroscopic data. The ¹H NMR C2-methyl resonances for ketones (40) (δ 2.02) and (41) (δ 1.82) were particularly informative, indicating a 1,3-syn-axial relationship in compound (40). Infrared carbonyl stretching frequencies further supported the structural assignments. The successful separation and characterization using Chromatotron and spectroscopic techniques, highlight the analytical methods utilized to analyze complex product mixtures from chlorination reactions.

Single-crystal X-ray analysis played a critical role in confirming the structures of several key compounds. For example, the structure of compound (38), C₉H₁₀Cl₄O, was determined this way. The X-ray crystal structure revealed a twist-boat conformation almost identical to that observed for cyclohex-3-enone (22). Similarly, the structure of compound (46), C₈H₆Cl₆O, was also determined via X-ray crystallography, confirming a twist-boat conformation. The X-ray data provided crucial information about torsion angles and the spatial arrangement of substituents, including the confirmation of a flagpole orientation for certain C5-Cl bonds. This methodology emphasizes the importance of X-ray crystallography in providing unambiguous structural information that complements data from other analytical techniques like NMR and infrared spectroscopy.

The study emphasizes the use of spectroscopic data for structural elucidation of the chlorination products. ¹H NMR spectroscopy was crucial in determining the position and stereochemistry of substituents, especially methyl groups. The deshielding effect of syn-axial chlorine atoms on methyl proton resonances in ¹H NMR was particularly helpful in distinguishing isomers. Infrared spectroscopy was used extensively to determine carbonyl and olefinic stretching frequencies, providing additional insights into structural features and the presence of functional groups. The interpretation of both ¹H NMR and infrared data, often in conjunction, allowed the researchers to assign structures even in cases where mixtures of isomers were obtained. The comparative analysis of spectroscopic parameters of analogous compounds was also a valuable tool for structural assignment.

The formation of 6-chloro-6-methylcyclohexa-2,4-dienones is discussed, with the SE21 mechanism proposed as the most likely pathway. This mechanism involves ipso chlorine attack at a methyl-substituted ortho site on the parent phenol. However, the study acknowledges mechanistic uncertainties, particularly concerning whether the reaction proceeds via direct ipso-chlorine attack on the phenol molecule or on a pre-equilibrium concentration of the phenoxide ion. This ambiguity is important because it affects the understanding of the reaction kinetics and the role of the solvent. The study highlights the challenges of determining the exact mechanism, due to the complexity of the reaction and the potential involvement of intermediate species. Further investigation is needed to conclusively determine the exact mechanism of 2,4-dienone formation. The authors highlight the involvement of the halide ion, especially in hydrogen halide catalysis. The specific role of the halide ion emphasizes the importance of reaction conditions in influencing the reaction's pathway.

The section explores the reactions of various 2,4-dienones with chlorine under different conditions. The reaction of 2,4,6-trichloro-5,6-dimethylcyclohexa-2,4-dienone (70) with chlorine in acetic acid is examined, producing a mixture of products that implies that multiple addition pathways occur. The study also investigates the reactions of 2,4-dienones (70, 66, and 79) with chlorine in acetic acid with varying amounts of hydrogen chloride or sodium acetate. This exploration aims to understand the role of added reagents and their influence on the reaction's course and outcome. The addition of chlorine to the 2,4-dienone system is shown to be influenced by steric factors; 2,4-dienones substituted at C5 with chlorine exhibit a significant decrease in reactivity towards further chlorine addition reactions. This observation highlights the influence of steric hindrance and electronic effects in determining the course of reactions of the dienones.

The study pays close attention to the stereochemistry of chlorine addition to 2,4-dienones. It notes that the stereochemistry of 4,5-chlorine addition to a 2,4-dienone (66) cannot be definitively determined due to the indistinguishable nature of the C4-gem-dichloro substituents. Similar limitations were encountered when analyzing 2,5-chlorine addition due to the presence of indistinguishable gem-dichloro substituents. The discussion includes the observation that 2,5-chlorine addition likely proceeds via an electrophilic attack at the C5 position, trans to the C6-chlorine substituent. The study focuses on the different types of chlorine additions (2,3, 2,5, and 4,5) to understand the factors that determine the regio- and stereoselectivity of the addition reactions. The investigation also shows the impact of steric hindrance caused by C5 chlorine substitution on the reactivity of the 2,4-dienones toward further chlorine addition. The lack of reactivity of certain substrates is attributed to steric hindrance at the C5 position.

The experimental section details the source and purity of the starting materials. Phenols and anilines were obtained from various chemical suppliers and were used without further purification, or were prepared by chlorination of the appropriate alkyl precursors. The use of Analar glacial acetic acid, from which water had been azeotropically removed with benzene, then fractionated, is specifically mentioned, highlighting the importance of using high-purity solvents. The careful selection of reagents and solvents was crucial in ensuring the reproducibility and reliability of the experimental results and obtaining high-quality data for analysis. The purity of starting materials and solvents was carefully controlled and documented to ensure the integrity and reproducibility of the results of the experiments.

The chlorination reactions were typically conducted by adding chlorine (in the form of a solution in carbon tetrachloride or acetic acid) to a stirred solution of the substrate. Reactions were carried out in darkened flasks to minimize unwanted side reactions. After a specific reaction time (which varied depending on the experiment), the reaction mixtures were poured into ice-water to quench the reaction. The organic phase was then separated, dried using anhydrous magnesium sulfate, and the solvents removed under reduced pressure. This general procedure was followed for the majority of the chlorination experiments, emphasizing the standardized approach taken to maintain consistency in the experimental methodology. The use of standard techniques, such as drying with anhydrous magnesium sulfate and solvent removal under reduced pressure, are detailed to ensure reproducibility.

Many chlorination reactions produced mixtures of isomers which required separation. The document specifically mentions the use of a Chromatotron with a silica gel plate for separating isomeric mixtures of polychlorocyclohexenones. The elution order of compounds from the Chromatotron is noted in some cases, providing information about the relative polarities of the isomers. In some instances, crystallization from pentane or other solvents was also employed as a purification method. The application of both chromatographic and crystallographic methods showcases the combination of techniques employed to isolate and purify the products of the chlorination reactions. The use of a Chromatotron, a specialized type of chromatography, suggests the level of sophistication in the purification techniques used in this study.

The experimental procedures also outline the spectroscopic methods used for product characterization. ¹H NMR spectroscopy, utilizing deuteriochloroform with trimethylsilane as an internal standard, was a primary tool for structural elucidation. First-order analysis and double irradiation experiments were used when necessary to obtain complete spectral assignments. Infrared spectroscopy was employed to identify functional groups, including carbonyl and olefinic stretches. X-ray crystallography, using a Nicolet XRD-P3 four-circle diffractometer, was used for the determination of crystal structures. The detailed description of the spectroscopic techniques and instrumentation used illustrates the rigorous analytical methods applied throughout this study. The techniques used, including advanced methods such as double irradiation experiments, demonstrate the sophisticated approach to characterization.