Understanding and Controlling Fluorinated Diacyl Peroxides and Fluoroalkyl Radicals in Alkene Fluoroalkylations

The demand for practical methods for the synthesis of novel fluoroalkyl molecules is increasing owing to their diverse applications. Our group has achieved efficient difunctionalizing fluoroalkylations of alkenes using fluorinated carboxylic anhydrides as user‐friendly fluoroalkyl sources. Fluorinated diacyl peroxide, prepared in situ from carboxylic anhydrides, enables the development of novel reactions when used as a radical fluoroalkylating reagent. In this account, we aim to provide an in‐depth understanding of the structure, bonding, and reactivity of fluorinated diacyl peroxides and radicals as well as their control in fluoroalkylation reactions. In the first part of this account, the physical properties and reactivity of diacyl peroxides and fluoroalkyl radicals are described. In the subsequent part, we categorize the reactions into copper‐catalyzed and metal‐free methods utilizing the oxidizing properties of fluorinated diacyl peroxides. We also outline examples and mechanisms.


Introduction
A convenient method for synthesizing a diverse range of fluoroalkyl molecules from readily available feedstocks is needed to meet their high demand in various research areas, particularly medicine [1] and agrochemistry, [2] owing to their excellent properties, such as hydrophobicity, lipophilicity, membrane permeability, and metabolic stability, conferred by the fluorine atom. To efficiently expand the chemical space of fluoroalkyl molecules, the knowledge on alkene fluoroalkylation reactions have rapidly advanced since the 2010s. [3,4] However, early studies, including ours, [5] relied on the excellent reactivity and utility of sophisticated trifluoromethylating reagents, such as the Togni, Umemoto, and Langlois reagents, which limited the products to trifluoromethyl compounds. In addition, the high cost of these reagents is an obstacle for practical synthetic applications. To address these issues, we developed alkene fluoroalkylations using fluorinated carboxylic anhydrides as user-friendly fluoroalkyl sources (Scheme 1). [6,7] Several fluorinated carboxylic anhydrides, including trifluoro-, chlorodifluoro-, and difluoroacetic anhydrides, are commercially available and relatively inexpensive. However, it is difficult to use fluorinated carboxylic anhydrides as fluoroalkylating reagents for alkene fluoroalkylations. [8][9][10][11] We found that fluorinated diacyl peroxides prepared in situ from carboxylic anhydrides and H 2 O 2 can be employed in alkene fluoroalkylation reactions.
The key to a successful reaction is controlling the reactivity of not only the diacyl peroxide, but also the radical intermediate with the aid of a copper catalyst or substrate structure. This method is simple and allows access to a wide variety of fluoroalkyl molecules. In this Personal Account, we aim to provide an in-depth understanding of the reactivity of fluorinated diacyl peroxides and fluoroalkyl radical species and explain how they can be controlled in fluoroalkylation of alkenes.

Fluorinated Diacyl Peroxide
To effectively control fluorinated diacyl peroxides in catalytic fluoroalkylation of alkenes, a deeper understanding of their structures and physical properties is essential. Notably, fluorinated diacyl peroxides exhibit unusual thermal stability and decomposition modes compared to non-fluorinated diacyl peroxides. [12] We recently discovered that even a single fluorine substitution in the fluoroalkyl group can have a drastic effect on thermal stability (vide infra). [6g] This section discusses the structures and thermal stability of fluorinated diacyl peroxides.

Structure and Bonding of Fluorinated Diacyl Peroxides
The most stable conformer of diacyl peroxides, hydrogen peroxide, is not planar but rather bent along the OÀ O bond, which can be explained by the minimization of the repulsion between the lone pair of electrons in the non-bonding orbital (n O ) of the two oxygen atoms (Figure 1). [13,14] To examine the most stable conformer in greater detail, we conducted conformational analysis using DFT calculations. [15,16] Initially, we performed relaxed potential energy surface (PES) scanning along the CÀ OÀ OÀ C bond (UM06 CPCM(DCM) /6-31G(d), 20 steps of 10°size, Figure 2) to approximately determine the global minimum structures of bis(trifluoroacetyl)peroxide (BTFAP), bis(difluoroacetyl) peroxide (BDFAP), acetyl peroxide (APO), hydrogen peroxide (H 2 O 2 ), and dimethyl peroxide (Me 2 O 2 ). [17,18] The dihedral angles of the stable conformers of the three diacyl peroxides were found to be similar (~85°) and smaller than those of hydrogen and dimethyl peroxides (~106°). [19] The structures of the diacyl peroxides at the minimum PES were further optimized using UM06 CPCM(DCM) /6-311G + (d,p). The bond lengths, angles, and natural charges (Natural Bond Orbital (NBO) analysis) of the carbonyl and peroxide oxygen atoms are summarized in

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peroxide (BPFPP), and lauroyl peroxide (LPO) to discuss the general tendencies. The OÀ O, C=O, and OÀ C bonds were shortened by the fluorine(s), whereas the CÀ C bond was elongated. The fluoroalkyl groups slightly widened the (dihedral) angles of CÀ OÀ OÀ C and O=CÀ O, whereas no such tendency was observed in the angle of OÀ CÀ R. As the number of fluorine substitutions increased, the natural charges of the oxygen atoms decreased as expected due to the strong electron-withdrawing effect of fluorine. Orbital interactions were investigated to gain a deeper understanding of the influence of fluorine. NBO analysis of BDFAP indicated that the OÀ O bond is formed by sp 6.7 orbitals. The lone pair of electrons residing in pure p-and sp 0.8 orbitals can delocalize to π* and σ* orbitals of the C=O bond, respectively. As briefly discussed above, the two pure p-orbitals of the oxygen atoms in the OÀ O bond are nearly orthogonal, thereby minimizing the repulsion ( Figure 1).
In addition, through the electron localization function (ELF) [20] and quantum theory of atoms in molecules (QTAIM) [21] topological analyses of electron density, we confirmed that the OÀ O bond of fluorinated diacyl peroxides is a charge-shift bond rather than a covalent bond (Figures 3  and 4). [17,[22][23][24] Charge-shift bonds occur due to large resonance stabilization resulting from covalent-ionic mixing. These bonds are observed when they are surrounded by lone pairs that cause three-electron repulsion with the bond-pair electron. [25] As demonstrated by ELF analysis of BDFAP (Figure 3), the electron density localization between the oxygen atoms of the OÀ O bond is depleted, which is characteristic of charge-shift bonding and contrasts with the density accumulation observed in covalent bonds. QTAIM analysis allows distinguishing bond types by the sign of the Laplacian of the electron density (r 2 ρ(OÀ O)) at the bond critical point: covalent bonds fulfill r 2 ρ(OÀ O) < 0, whereas charge-shift bonds fulfill r 2 ρ(OÀ O) > 0 due to electron repulsions. The Laplacians of the electron densities of the OÀ O bonds in diacyl peroxides, including benzoyl peroxides (BPOs), were all positive and correlated with the OÀ O bond lengths ( Figure 4). Importantly, substitution of the hydrogen in APO with fluorine tends to decrease r 2 ρ(OÀ O), which suggests that the OÀ O bond is shortened due to the reduced electron repulsion caused by the electron withdrawing effect of the fluoroalkyl groups. [26]

Stability and Reactivity of Fluorinated Diacyl Peroxides
We evaluated the thermal stability of fluorinated diacyl peroxides (BTFAP, BDFAP, and BDCAP) prepared in situ from the corresponding carboxylic anhydrides and urea · H 2 O 2 in CD 2 Cl 2 . To this end, we conducted 19 F NMR analysis at room temperature ( Figure 5). Interestingly, the replacement of only one fluorine in the CF 3 group of BTFAP had a significant impact on stability.
[6g] Although BTFAP is stable under the given conditions, BCDFAP gradually decomposed. Surprisingly, BDFAP decomposed rapidly, despite the fact that perfluoro diacyl peroxide is less stable than non-fluorinated peroxide. [12] To explain the observed difference in stability, we conducted DFT studies. Previous studies suggested that fluorinated diacyl peroxides have a different decomposition mechanism than non-fluorinated peroxides (Scheme 2). In general, non-fluorinated diacyl peroxides decompose stepwise via OÀ O and subsequent CÀ C bond cleavage. In contrast, it was suggested that perfluoro (aliphatic) diacyl peroxides undergo concerted multi-bond cleavage of the OÀ O and CÀ C bonds. Zhao's [27] and Sawada's [12] groups independently proposed a concerted two-and three-bond cleavage mechanism to explain the experimentally observed, but unexpected, instability of perfluoro diacyl peroxides compared to their non-fluorinated counterparts, despite the stabilizing effect of electron-withdrawing groups. [28] Balbuena et al. examined the decomposition mechanism of BTFAP using DFT calculations and found a pathway involving concerted two-bond cleavage of the OÀ O and CÀ C bonds, given that they could not obtain the transition structure for concerted three-bond cleavage. [29] We believe that there are essentially no significant differences between the two possible concerted pathways because of the negligible energy barrier required for CÀ C bond cleavage. Our DFT calculations indicated that the activation free energy of CÀ C bond cleavage of trifluoroacetoxy radical was only ΔG � = + 0.3 kcal/mol (for acetyl radical, the activation energy was ΔG � = + 2.4 kcal/mol). [17] To analyze the intrinsic bond strength of fluorinated diacyl peroxides, we calculated and compared the enthalpy changes in the homolytic fragmentation of these compounds with those of BPO (Table 2), which is a typical bench-stable diacyl peroxide. In addition to the enthalpy changes of OÀ O bond cleavage (ΔH OÀ O ) and subsequent CÀ C bond cleavage (ΔH CÀ C ) of carboxyl radicals, we estimated the enthalpy changes of three-and two-bond cleavages, denoted as ΔH 3BC and ΔH 2BC , respectively. Fluorine substitution of APO increased ΔH OÀ O , suggesting reinforcement of the OÀ O bond. Notably, the OÀ O bond of fluorinated diacyl peroxides was expected to be stronger than that of BPO. By contrast, ΔH CÀ C decreased with fluorine, which explains the weaker CÀ C bond. Increasing the number of fluorine atoms enhanced these tendencies. The enthalpy changes of multibond cleavages, i. e., ΔH 3BC and ΔH 2BC , were largely influenced by the ΔH CÀ C values. These results suggest that fluorinated diacyl peroxides are unstable for concerted multibond cleavage decomposition, but not for stepwise decom-

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position initiated by OÀ O bond cleavage. To further rationalize the unusual bond strength of fluorinated diacyl proxides, we examined the second-order perturbation energies (E(2)) using NBO analysis ( Figure 6). Significant stabilization was found in the delocalization of the lone pairs of carbonyl oxygen (n O ) to the σ* orbital of the CÀ C bond (σ* CÀ C ). Fluorine can enhance this stabilization effect, suggesting elongation of the CÀ C bond. In addition, the OÀ O bond was strengthened by suppressing the electronic repulsion between the two carbonyl oxygens of the diacyl peroxides.
The specific decomposition mode of fluorinated diacyl peroxides can be rationalized. However, the enthalpy changes (ΔH 3BC and ΔH 2BC ) suggest that the stability of fluorinated diacyl peroxides should rank as BTFAP > BDFAP > BCDFAP, which contradicts the experimental results shown in Figure 5. We carefully checked the 19 F NMR chart of the decomposition test of BDFAP; difluoromethyl difluoroacetate was identified (δ F~À 92 ppm) among several byproducts (Scheme 3). This ester byproduct was formed by the radical substitution of BDFAP with the CF 2 H radical, which competes with homo-coupling to form tetrafluoroethane.
According to the literature, "induced decomposition" of BPO and LPO is known to accelerate the decomposition rate [30] in which radical species generated by hydrogen abstraction of solvent by carboxylate radical participate in the substitution reaction of the diacyl peroxide. Indeed, the activation free energy of the substitution of BDFAP with the CF 2 H radical was lower than that of the others. We conclude that the extraordinarily fast decomposition of BDFAP is due to radical-chain decomposition involving substitution, which depends on the reactivity difference of the radicals (radical philicity).

Structure and Reactivity of Fluroalkyl Radicals
The enormous impact of a single fluorine atom on the reactivity of radical species encouraged us to investigate them in greater detail. The geometry of fluorinated radicals is pyramidal, in contrast to the planar geometry of the methyl radical ( Figure 7a). This structural difference can be explained by the delocalization of the lone pair of fluorines (n F ) to the vacant non-bonding orbital of the radical carbon (n* C ) and the anti-bonding orbitals of geminal bonds such as CÀ F, CÀ Cl, and CÀ H (σ* sum ) (Figure 7b). [31] The E(2) values of these delocalizations increased with the number of fluorines and chlorines ( Table 3). As a result, halogens increased the scharacter of the radical carbon, resulting in pyramidal structures. Substitution of the methyl radical with fluorine (and also with chlorine) significantly enhanced the positive charge and reduced the spin of the carbon atom due to the electron-withdrawing effect of fluorine and delocalization.
The energy levels of the frontier orbitals of the fluorinated methyl radicals and several radical species were examined to determine radical philicity (degree of nucleophilicity or

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electrophilicity of the radical species). [32] Multiple substitutions of methyl radicals with fluorines lowered the energy levels, suggesting an enhancement in the electrophilic character. Plots depicting energy levels versus free activation energy (ΔG � ) of the substitution of BDFAP with radicals indicated a stronger correlation with the HOMO (SOMO-α) energy level (Figure 8). [17] In addition, we evaluated the radical philicity in the addition reaction of radicals to alkenes (Figure 9). Unlike the other plots, a stronger correlation with the LUMO (SOMOβ) energy level can be observed in this case, and the slope of the approximate line was the opposite. These results demonstrate that a more general discussion of radical philicity can be achieved by examining the correlation between the energy level of frontier orbitals of radical species and the free activation energy of reactions. Specifically, for both reactions, the activation energies are strongly correlated with the energy levels of HOMO and LUMO, respectively. Notably, the magnitude of the slope of the approximate line allows evaluating the sensitivity of the reaction to radical philicity and distinguishing between "nucleophilic" and "electrophilic" reactions by their sign.

Alkene Fluoroalkylation
Despite their long history, [9] the fluoroalkylation of simple alkenes using fluorinated diacyl peroxides remains a challenging task. Indeed, our preliminary results indicated that the reaction of simple alkene 1 with BTFAP, prepared in situ from trifluoroacetic anhydride (TFAA) and urea·H 2 O 2 , resulted in a complex mixture consisting of trifluorometh-

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ylated molecules (Scheme 4a). We hypothesized that CF 3 radicals could be easily generated by the fragmentation of BTFAP; however, the alkyl radical subsequently formed by the reaction of alkenes with CF 3 radicals should be selectively converted to the desired product (Scheme 4b). A wide variety of fluoroalkyl molecules were synthesized by exploring efficient alkyl radical conversion methods. This section provides an overview of catalytic and metal-free reactions.

Catalytic Approach
In 2016, we reported the first successful transformation of alkyl radicals generated from simple alkenes and perfluoroalkyl radicals using a copper catalyst to obtain the desired products (Scheme 5). [6a,e] Allylic perfluoroalkylation of alkenes with perfluoro diacyl peroxide prepared in situ was achieved in the presence of a catalytic amount of [Cu-(CH 3 CN) 4 ]PF 6 . Various functional groups are tolerated under these conditions. Importantly, the reaction not only allowed for trifluoromethylation but also perfluoroalkylations with longer perfluoroalkyl chains, which can be accomplished by simply replacing the carboxylic anhydrides. These conditions were successfully applied to intramolecular amino-perfluoroalkylation of alkenes bearing a pendant amino group, providing easy and efficient access to a wide range of valuable molecules containing aziridine and pyrrolidine skeletons (Scheme 6). [6b] CF 3 -containing aziridines have proven to be excellent building blocks, with various ring-opening nucleophilic substitutions available. Scheme 7 shows the proposed catalytic cycle to discuss the role of the copper catalyst. At the beginning of the cycle, the diacyl peroxide is reduced by the copper(I) species via single-electron transfer (SET), generating a perfluoroalkyl radical ( * R f ) and a copper(II) intermediate. The perfluoroalkyl radical then reacts with alkene and forms the alkyl radical intermediate. Oxidation of the alkyl radical with the resulting copper(II) species forms a carbocation as a metastable intermediate and recovers the copper(I) species, as supported by our DFT calculations. [33] Deprotonation or intramolecular cyclization affords the desired products from the carbocation intermediate. In this catalytic cycle, the copper catalyst plays a role in accelerating the generation of the perfluoroalkyl radical from the diacyl peroxide and converts the alkyl radical into the product, thus improving the rate and selectivity of the desired reaction.
To expand the scope of this method, reactions using other fluorinated acetic anhydrides were investigated. Initially, we attempted to develop a chlorodifluoromethylation reaction

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because of the synthetic utility of chlorodifluoromethylated molecules as promising building blocks for difluoromethylene molecules.
[6c] However, replacing only one fluorine atom of TFAA with a chlorine atom made catalytic control more challenging. When chlorodifluoroacetic anhydride (CDFAA) was used instead of TFAA under the conditions for allylic trifluoromethylation, a poor yield of the desired chlorodifluoromethylation product was obtained (Scheme 8).
The gradual decomposition of BCDFAP (vide supra), prepared in situ from CDFAA, was considered to cause side reactions by producing excess radical species that could not be converted by the catalyst. To address this issue, we used a copper(II) catalyst instead of a copper(I) catalyst, which led to efficient chlorodifluoromethylation (Scheme 9). Using Cu(O 2 CCF 3 ) 2 as the catalyst and pyridine as an additive, allylic and amino-chlorodifluoromethylation of alkenes proceeded smoothly. The copper(II) catalyst was postulated to gradually participate in the reaction, which was triggered by the oxidation of alkyl radicals generated from the alkene and

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CF 2 Cl radicals derived from the spontaneous decomposition of BCDFAP. Next, we developed a difluoromethylation method using difluoroacetic anhydride (DFAA) because of the increasing importance of difluoromethyl compounds in drug and agrochemical applications. [6g] The CF 2 H group features a chemically stable CÀ H bond that acts as a hydrogen bonding donor and serves as a bioisostere of OH, NH 2 , and SH groups, [34] in addition to the general properties conferred by the fluoroalkyl groups. While photocatalytic difluoromethylation of alkenes has been extensively studied, [4] catalytic difluoromethylation reactions under thermal conditions have been barely reported, [35] possibly because of the highly nucleophilic nature of the CF 2 H radical, which can cause side reactions and decrease product selectivity with increasing reaction temperature. Fortunately, we could perform catalytic difluoromethylation using difluoroacetic anhydride at lower temperature (Scheme 10), where BDFAP was prepared in situ from DFAA (10 equiv) and urea·H 2 O 2 (2.4 equiv) at À 40°C and reacted with alkenes at 0°C. The reaction exhibited good generality in terms of difunctionalizing difluoromethylations including not only allylic and amino-difluoromethylations, but also intramolecular oxy-difluoromethylation of alkenylamides.
To understand the reactive species containing the CF 2 H group in the reaction, we conducted DFT calculations for amino-difluoromethylation and compared them with those of the corresponding trifluoromethylation (Scheme 11). Although the energy barrier for the addition of an alkene with CF 2 H radical (ΔG � = + 11.8 kcal/mol) is higher than that with CF 3 radical (ΔG � = + 9.3 kcal/mol), the addition reaction proceeds in preference to the undesired substitution with BDFAP (ΔG � = + 15.2 kcal/mol) (see, Scheme 3). The oxidation step differed between difluoromethylation and trifluoromethylation, with difluoromethylation exhibiting higher activation energy and free energy difference. The oxidation in difluoromethylation has a low energy barrier but is an uphill process (ΔG = + 3.7 kcal/mol), in contrast with

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the downhill process in trifluoromethylation (ΔG = À 0.6 kcal/mol). The energetic difference is due to the counter anion derived from the carboxylic anhydride, which further increases the free energy difference in the oxidation of the alkyl radical bearing the CF 3 group with Cu(O 2 CCF 2 H) 2 (ΔG = + 8.0 kcal/mol). The subsequent cyclization, which leads to the desired product, is irreversible and rapid. However, the transiently high concentration of alkyl radicals at equilibrium increases the possibility of side reactions, necessitating strict reactivity control in radical difluoromethylation of alkenes under thermal conditions. To finish this section, 1,2-bis-perfluoroalkylation of alkenes and alkynes using perfluorocarboxylic anhydride is introduced (Scheme 12). [6g] Although recent advances in fluoroalkylation have enabled the synthesis of a wide variety of 1,2-bis-trifluoromethylated molecules, [36] methods for synthesizing 1,2-bis-perfluoroalkyl molecules bearing longer perfluoroalkyl chains are limited. Our preliminary result indicated that BTFAP prepared in situ from TFAA reacted with alkene 1 in the presence of 2.0 equiv. of copper(I) salt yielded a mixture of almost equal yield to 1,2-bistrifluoromethylated product 2 (30 %) and allylic trifluoromethylation product 3 (28 %). We found that the addition of 2,2'-bpyridyl (bpy) improved the selectivity, affording product 2 in 75 % yield with excellent product selectivity. Under the conditions, various 1,2-bis-perfluoroalkylated alkanes and alkenes were synthesized from alkenes and alkynes, respectively.
Our mechanistic studies suggested that [Cu(bpy) 2 ] + is the reactive species, part of which reacts with BTFAP to generate perfluoroalkyl radicals. The perfluoroalkyl radical can react not only with alkenes but also with other [Cu(bpy) 2 ] + complex, forming perfluoroalkylcopper(II) species. The activation energy of formation of perfluoroalkylcopper(II) is low (ΔG � = + 5.2 kcal/mol). DFT calculations suggested that bpy can significantly stabilize the complex and increase its concentration by suppressing the reverse reaction. The perfluoroalkyl copper(II) complex was then coupled with the alkyl radical bearing perfluoroalkyl group, resulting in the desired 1,2-bis-perfluroalkylation product.

Transition-Metal Free Approach
Fluorinated diacyl peroxides can be regarded as bifunctional reagents that act as sources of fluoroalkyl radicals and an oxidant. By utilizing their oxidation properties, we realized metal-free difunctionalizing fluoroalkylations. Metal-free methods are valuable and essential for the practical production of bioactive molecules because metal contamination can adversely affect their activity. Fortunately, we found a possibility for the development of a metal-free reaction from a byproduct of catalytic allylic trifluoromethylation (Scheme 13). [6a] Specifically, the reaction of aromatic alkene 4 with TFAA (BTFAP) provided allylic trifluoromethylation product 5 and carbocyclized product 6. After examining the optimal conditions for selective formation of 6, we surprisingly found that just heating the mixture at 40°C without copper catalyst gave product 6 with excellent yield. This result proves that the reaction using diacyl peroxide allows for diverse syntheses in which fluoroalkylated molecules containing different skeletons can be obtained from the same starting materials with or without a copper catalyst. Importantly, this method has a wide application scope (Scheme 14) and can use TFAA and other carboxylic anhydrides, such as CDFAA, DFAA, and perfluorocarboxylic anhydrides bearing longer perfluoroalkyl chains as the fluoroalkyl source. [6a-c] Furthermore, a wide variety of hetero-and carbo-cyclic skeletons frequently found in bioactive molecules can be easily constructed using this method.

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The mechanism of this carbo-fluoroalkylation is discussed next (Scheme 15). [6b] We postulated that the reactions proceed via a radical-chain mechanism driven by aromatization. The radical chain reaction is initiated by the thermal decomposition of diacyl peroxide. The resulting fluoroalkyl radical reacts with the alkene to generate an alkyl radical bearing a fluoroalkyl group. In the absence of a copper catalyst, radical cyclization involving CÀ C bond formation between the aromatic ring and radical carbon occurs, affording a cyclohexadienyl radical intermediate. Subsequently, aromatization of the cyclohexadienyl radical by oxidation with diacyl peroxide gives the desired product and regenerates the fluoroalkyl radical. DFT calculations indicated that cyclization required~11.5 kcal/mol of activation energy and almost no free energy change in the formation of the cyclohexadienyl radical. [17] The activation energy and free energy change were not influenced by the type of fluoroalkyl group; however, the fluorine substituent increased very slightly. The HOMO energy level was increased by the cyclization event.Interestingly, the fluorine in the fluoromethyl groups significantly decreased only the HOMO energy level of the uncyclized alkyl radical intermediate, which was likely due to the effective distance of the σ-induction effect. Then, the LUMO energy levels of the diacyl peroxides were compared to examine the oxidation potential of the aromatization step. The fluorine and chlorine in the diacyl peroxides significantly decreased the LUMO energy level, indicating a higher oxidation potential. These results suggest that fluorine plays a significant role in this reaction. Although fluorine decreases the reactivity of alkyl radicals towards oxidation, it has no influence on the reactivity of cyclohexadienyl radicals. In contrast, the fluorine in diacyl peroxides accelerates oxidation by decreasing the LUMO energy level. Thus, fluorines allow for the selective oxidation of the cyclohexadienyl radical with diacyl peroxide, which may be difficult in reactions using the corresponding non-fluorinated diacyl peroxide.
Furthermore, we developed a metal-free approach for intermolecular perfluoro carboxy-and intramolecular aminoperfluoroalkylations (Scheme 16). [6d] Various conditions for similar oxy-and amino-trifluoromethylations have been reported; however, in general, transition-metal catalysts are essential for carbocation generation. [37,38] We found that diacyl peroxides can effectively facilitate this process without the need

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for a catalyst. This reaction is proposed to proceed according to the following steps (Scheme 17), which are characterized by the specific redox properties of both perfluoro diacyl peroxides and styrenes. First, electron-rich styrene can promote the fragmentation of diacyl peroxide by reduction, producing perfluoroalkyl radical and radical cation of styrene. The electrophilic perfluoroalkyl radical preferentially reacts with styrene rather than with the electron-deficient radical cation. The formation of benzyl radical species was confirmed by radical trapping tests using TEMPO and a radical clock substrate. Our DFT calculations showed that the activation energy of the addition of the CF 3 radical to 4-chlorostyrene is ΔG � = + 8.2 kcal/mol. Despite numerous attempts, we could not obtain the transition state for the addition of the CF 3 radical to the radical cation using an open-shell singlet spin state; however, the use of a triplet spin state led us to identify a transition state with a higher energy of ΔG � = + 17.5 kcal/ mol. [17] The benzyl radical was subsequently oxidized by the radical cation, which is a stronger oxidant than copper(II)(O 2 CCF 3 ) 2 , the proposed reactive species in the catalytic reaction. [39] The carbocation intermediate resulted in the desired products via the addition of perfluoroacetate or nucleophilic cyclization with a pendant amino group.

Summary and Outlook
Fluorinated diacyl peroxides and fluoroalkyl radicals exhibit completely distinct physical and chemical properties with respect to their non-fluorinated counterparts owing to the presence of fluorine. This account sheds light on their unique properties and explains how to tune them in difunctionalizing fluoroalkylations of alkenes.
In the first part of this account, the structure and bonding of fluorinated diacyl peroxides were examined using DFT calculations, and the influence of fluorine(s) was analyzed in detail. We also compared the thermal stability of fluorinated diacyl peroxides (BTFAP, BCDFAP, and BDFAP) using 19 F NMR analysis, and the results were theoretically rationalized. It was concluded that both the thermal stability of the diacyl peroxides and radical philicity of the fluoroalkyl radicals formed by decomposition influence the decomposition rate. Encouraged by this discussion, we evaluated their structure and properties, including the energy levels and reactivity of fluoroalkyl radicals, and were able to generalize the correlation

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between LUMO or HOMO energy levels as well as the activation energy for radical-involving reactions, such as the nucleophilic substitution of BDFAP and electrophilic addition to an alkene. We then introduced methods for controlling the fluorinated diacyl peroxides and radical species in the difunctionalizing fluoroalkylation reactions of alkenes. The selective transformation of alkyl radicals generated by fluoroalkyl radicals and alkenes is assumed to be the key step in developing an efficient reaction and diversifying product variation. The catalytic approach involves the formation of a carbocation from an alkyl radical bearing a fluoroalkyl group by oxidation with Cu(II) species, resulting in the efficient production of a wide variety of allylic and amino-fluoroalkylation molecules. We determined suitable conditions for each fluoroalkylation reaction using perfluorocarboxylic anhydrides, including TFAA, CDFAA, and DFAA. In addition, a copper-mediated 1,2-bis-perfluoroalkylation was developed in which the reaction pathway could be controlled by the ligand. We describe two metal-free strategies that utilize fluorinated diacyl peroxide as a bifunctional reagent that acts as both a fluoroalkyl source and a relatively strong oxidant. Carbo-fluoroalkylation of aromatic alkenes via a radical chain reaction enables a convenient access to diverse arrays of carbo-and hetero-cyclic compounds bearing fluoroalkyl groups. In this reaction, the aromatization of the cyclohexadienyl radical intermediate formed by the radical cyclization of the alkyl radical is the key step. The fluoroalkyl group plays a crucial role in creating a contrast in reactivity between the alkyl and cyclohexadienyl radicals, enabling selective oxidation of the latter. We also developed unprecedented metal-free intermolecular oxy-and intra-molecular amino-perfluoroalkylations of styrenes via carbocation. In these reactions, the radical cation species generated by oxidation of styrene with diacyl peroxide was the key intermediate, enabling the oxidation of a benzyl radical bearing a fluoroalkyl group to the carbocation.
We believe that the introduced fluoroalkylation reactions, along with the resulting products, are promising for the discovery of novel drugs, agrochemicals, and functionalized organic materials. In addition, our research group is currently working in the development of further challenging reactions, building on the insights gained from the ligand effect and other key findings presented in this account.