Continuing from the previous article, this section will further introduce the types of radicals.The research team from Ohio State UniversityNagibsummarized the polarities of oxygen-centered radicals and sulfur-centered radicals.Oxygen-centered radicals are shown in Table 8. Unlike carbon-centered radicals substituted with oxygen (e.g., α– or β– alcohols), where the influence is determined by polarizability rather than electronegativity, these heteroatom-centered radicals are more affected by the latter. Therefore, due to the higher electronegativity of oxygen compared to carbon or nitrogen (χ: 3.4 vs 2.6, 3.0), oxygen-centered radicals are more electrophilic than most other radicals (ω > 2). Notably, hydroxyl radicals (in red) are more electrophilic than their amine counterparts. Typical examples include:MeO• (2.2 eV) compared toMe(H)N• (1.4 eV);PhO• (2.2 eV) compared toPh(H)N• (1.7 eV); evenHO• (2.8 eV) compared toH2N• (1.9 eV). 
Generally, these oxygen-centered radicals are strongly electrophilic, making them very suitable for HAT, typically exhibiting high chemical selectivity, or showing opposite site selectivity compared toMe•, such as in the C−H functionalization of ibuprofen. This electrophilicity is further enhanced with the addition of receptor groups, such as carboxyl or sulfonyl groups. Further observations include:
1.α–Heteroatoms: As mentioned, the presence of adjacent electron-donating lone pairs increases nucleophilicity, as seen in peroxy (blue) and hydroxylamine (red) radicals. Notable substituent effects include:EtOO• (1.6 eV)< HOO• (1.8 eV)< AcOO• (2.2 eV);Me2NO• (0.9 eV)< AcN(H)O• (1.7 eV)< PhthNO• (2.4 eV).
2.Acetoxy: As a class, carboxyl radicals (green) are among the most electrophilic radicals, such asAcO• (2.9 eV) orBzO• (3.0 eV), which can be modulated by donor groups (PivO• (2.8 eV),pMeOBzO• (2.7 eV)) or receptor groups (TFA• (3.9 eV) orpNO2BzO• (3.3 eV)). Therefore, theAcO• derived fromPhI(OAc)2 and its analogs are used as usefulHAT reagents—especially when using non-polar solvents to suppress β–cleavage (i.e., this cleavage is less likely to occur whenAcO• formsMe• with the loss of CO2).
3.Phenoxy Regulation: Phenoxy radicals (purple) are more susceptible to electronic regulation by substituents, with their ω window (1.7−5.0 eV) being wider than that of carboxyl radicals (2.7−3.9 eV). For example, ω increases with the addition of the following para-substituents:−OMe,−H,−CF3,−NO2 (ω:1.8,2.2,2.8,3.4 eV). Useful variants also includeBHT, para-substituted, and diCF3 or tri-nitro analogs, which further expand the range. Notably, the unusually high electrophilicity of phenoxy radicals has recently been utilized to achieve nucleophilic aromatic substitution of halophenols.
4.Diphenyl Ketone: The Nagib research team found that the triplet biradical of diphenyl ketone is more electrophilic than almost all other oxygen-centered radicals (4.1 eV; top), including those with strong electron-withdrawing groups (carboxyl, sulfonyl) radicals, demonstrating the significant influence of adjacent open-shell layers. Synthetically, this amplified electrophilicity of the biradical (easily obtained through photoexcitation of aryl ketones) has been used to achieve directHAT, without the need for additionalHAT media.
5.Oxygen: Triplet oxygen (black), such as peroxy radicals, is less electrophilic thanH• (1.7 eV). This amphoteric property allowsO2 to react with nucleophilic or electrophilic species. Therefore, synthetic chemists often strive to exclude atmospheric oxygen from radical reactions.
6.TEMPO: The hydroxylamine radicalTEMPO is more nucleophilic than most heteroatom-centered radicals. Its ω (0.8 eV) is close to that of alkyl radicals (0.7 eV), which does not match the polarity for capturing such radicals. Therefore, users should note that the absence ofTEMPO adducts does not always exclude the presence of nucleophilic radicals in the reaction mechanism—other indirect detection methods may be more appropriate.
7.Protective Oxygen: Given the high electrophilicity of siloxy (blue), sulfinyl, and especially sulfonyl (orange) radicals, it is expected that these species can also mediateHAT reactions well—if synthetically accessible. However, oxidizing trifluoromethanesulfonate to its oxygen-centered radical may be challenging. In contrast, phosphonyl (black) radicals can be obtained through photo-induced oxidation of phosphates, thereby facilitatingC−H functionalization under very mild conditions.
Sulfur-centered radicals are shown in Table 9, as they are common intermediates in radical chemistry. One of the most important roles of thiol radicals is to enable the polarity inversion catalysis inHAT reactions. AlthoughS−H bonds are much weaker thanO−H bonds (bond dissociation energy:88 vs 96 kcal/mol), the larger atomic size of sulfur (and poorer orbital overlap) makes the resulting thiyl radicals slightly more electrophilic (ω: 2.2 vs 2.1 eV). Therefore, a nucleophilicC radical abstractsH• from thiols to generate an electrophilicRS• in aHAT transition state that is also favored kinetically due to this polarity matching (in addition to the thermodynamic advantage provided by the weakS−H bond). The electrophilic nature of thiyl radicals also makes them useful for rapid addition to alkenes as a “click reaction,” such as thiol-alkene reactions. Recently, elemental sulfur has been added to nucleophilic acyl radicals to exploit this polarity inversion for electrophilic reactions.
Given the widespread application of thiyl radicals in these mechanisms,Nagib’s research team has determined the polarities of various alkyl (red) and aryl (blue) thiyl radicals. Most thiyl radicals were found to be more electrophilic thanH• (2 eV), ranging between2−3 eV. Surprisingly, more oxidized sulfur variants, such as sulfonyl (purple) and thiosulfate (red) radicals, also fall within this narrow range, which may explain the similar behavior and utility of these electrophilic intermediates in facilitating group transfer reactions, whether as radical leaving groups or through nucleophilic catalysis. The only consistently lower thanH• (<2 eV) sulfur-centered radicals are sulfoxide (green) radicals, which are similar to acyl radicals and are also nucleophilic. Interestingly, disulfide (orange; 1.9−2.1 eV) radicals have polarities similar toH• and, due to their weakerRSS−H bond (70 kcal/mol) and reactivity over 104 times higher than thiyl radicals, are described as idealHAT reagents.
The article is quite lengthy, and we will continue to discuss various types of radicals in detail over the next few days. Interested readers can like, follow, and bookmark.
References:
https://doi.org/10.1021/jacs.4c06774
J. Am. Chem. Soc. 2024, 146, 28034−28059
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