DOI 10.1515/pac-2013-0812 Pure Appl. Chem. 2014; 86(6): 945–952 Conference paper Erbay Kalay, Hamdullah Kılıç*, Mustafa Catir, Murat Cakici and Cavit Kazaz 1 Generation of singlet oxygen ( O2) from hydrogen peroxide decomposition by in situ generated hypervalent iodoarene reagents Abstract: A novel method for the production of singlet oxygen from H2O2 was developed. A combina- tion of iodoarene (ArI), methyltrioxorhenium (MTO), and H2O2 in the presence of pyridine as the co- 1 catalyst efficiently produced singlet molecular oxygen ( O2) under biphasic conditions. The existence of 1 O2 was demonstrated by trapping experiments with aromatic dienes, 1,3-cyclodienes, and alkenes. The 1 mechanism of O2 production from the iodoarene/MTO/35 % H2O2 system and the reaction scope was also discussed. Keywords: catalysis; homogeneous catalysis; hypervalent compounds; IUPAC Congress-44; Chemical Syn- thesis; oxidation; oxygen; oxygenation; peroxides; radicals; singlet oxygen. *Corresponding author: Hamdullah Kılıç, Faculty of Science, Department of Chemistry, Ataturk University, 25240 Erzurum, Turkey, e-mail: [email protected] Erbay Kalay, Murat Cakici and Cavit Kazaz: Faculty of Science, Department of Chemistry, Ataturk University, 25240 Erzurum, Turkey Mustafa Catir: Faculty of Arts and Sciences, Department of Chemistry, Erzincan University, 24100 Erzincan, Turkey Article note: A collection of invited papers based on presentations on the Chemical Synthesis theme at the 44th IUPAC Congress, Istanbul, Turkey, 11–16 August 2013. Introduction 1 Oxyfunctionalization of organic substances with singlet molecular oxygen ( O2) has received significant atten- tion, both from the academic and industrial points of view, as it is an important method for the construction 1 of the carbon–oxygen bond [1]. More importantly, O2 is a well-established oxidant in photodynamic therapy, 1 which is widely used to treat some malignant cancers [2]. The common method of generating O2, dye-sensi- tized excitation of triplet molecular oxygen, can be challenging when applied to industrial-scale production, because of the need for specially designed photochemical reactors and materials for safe processing [3]. This 1 problem is partially solved by the availability of various chemical sources of O2 that also allow for precise 1 control of the O2 concentration over the substrate amount [4–6]. Recently, we introduced a novel protocol for 1 3 the generation of O2 via H2O2 decomposition by hypervalent aryl-λ -iodane phenyliodine bis(trifluoroacetate) (PIFA) 1a (Scheme 1) [7]. A key feature of this protocol is the oxidation of H2O2 with 1a to give a reactive interme- diate hydrogen tetraoxide (H2O4), which subsequently undergoes homolytic dissociation to singlet oxygen and 1 H2O2. Inspired by the mechanism underlying O2 generation from the PIFA/H2O2 system, we hypothesized that if a hypervalent aryl-λ3-iodane reagent such as an iodosylarene (ArIO) is generated in situ by the oxidation of 1 an iodoarene, subsequent oxidation of H2O2 with this reactive species would produce O2. Thus, we needed to develop a protocol in which H2O2 would first oxidize the iodoarene to an iodosylarene and finally reduce iodo- 1 sylarene to iodoarene, thereby producing O2. Unfortunately, direct oxidation of the iodine atom of the arene using H2O2 is not possible, and therefore, H2O2 must be activated by a catalyst for efficient oxygen transfer. © 2014 IUPAC & De Gruyter 946 E. Kalay et al.: Chemical generation of singlet oxygen from H2O2 3 1 (λ =1270nm) hν + O2 O2 + H2O2 2H2O2 H2O4 PhI(OCOCF3)2 PhI + 2TFA 1a Scheme 1 Singlet oxygen generation from the PIFA (1a)/H2O2 system. Herein, we report the first example of the methyltrioxorhenium (MTO) [8]-catalyzed in situ generation of an iodosylarene (ArIO) from an iodoarene and H2O2, followed by subsequent reaction with H2O2 to produce 1 O2 (eq. 1). MeReO3, H2O2 H2O2 1 + ArI ArIO O2 ArI (1) Oxidation Reduction Results and discussion At the outset of our study, we chose the oxidation of iodobenzene (4a, 1 equiv, Fig. 1) with the MTO/35 % H2O2 (0.05 equiv/10 equiv) system [9] at ambient temperature in dichloromethane (DCM) as a model reaction 1 in order to monitor O2 generation in the presence of 9,10-dimethylanthracene (DMA, 2a) as the chemical 1 trap. The results are summarized in Table 1. The 4a/MTO/35 % H2O2 combination afforded O2, as evidenced by the formation of 3a [10] in 20 % yield (entry 1). It is important to note that in the absence of the 4a, a 1 complex mixture was obtained, indicating that the 4a is essential for the O2 generation. To improve the level of conversion through MTO stabilization [11], a series of tertiary amines – imidazole, 2,6-dimethylpyridine, phenanthroline, N-methylimidazole, and pyridine – were tested for use as the co-catalyst (entries 2–6). The results showed that pyridine had a significant influence on the reaction rate and the yield of 3a (entry 6). Next, attempts were made to further optimize the reaction conditions by screening a series of iodoarenes 4b–n [12] (Fig. 1). Depending on the structure of the iodoarene, the conversion and yield varied from 56 to 98 % and from 26 to 86 %, respectively (Table 1, entries 7–18). The highest efficiency in terms of yield and conversion was achieved with 2-iodomesitylene (MesI, 4d) (entry 9). Thus, we concluded that the best choice of iodoarene and co-catalyst would be the 4d and pyridine, respectively, for obtaining endoperoxide 3a in high yield with a high conversion. It is well known that MTO [8] is a very efficient catalyst for olefin epoxidation with H2O2 as the oxidant. Hence, we must take into account the chemoselectivity of the present oxidation system in terms of epoxide 4a,R1 =R2 =R3 =H 1 R 4b,R1 =R2 =H,R3 =Me I 4c,R1 =H,R2 =Me, R3 =H 4d,R1 =R2 =R3 =Me R3 R2 4e,R1 =R2 =H,R3 =OMe 4a–m 4f,R1 =H,R2 =OMe,R3 =H 1 2 3 R1 4g,R=H,R =R =OMe 4h,R1 =R2 =H,R3 =Cl 4i,R1 =H,R2 =Cl, R3 =H R4 R2 4k,R1 =R2 =H,R3 =Br 4l,R1 =R2 =H,R3 =F 3 R 1 2 3 4m,R=R =H,R =CF3 4n 1 2 3 4 4n,R=R =R =R = p-IC6H4 Fig. 1 Structure of iodoarenes (ArI, 4a–n) employed in this study. E. Kalay et al.: Chemical generation of singlet oxygen from H2O2 947 1 a Table 1 Reaction conditions for O2 generation from the ArI/MTO/35 % H2O2 system. Me ArI/MTO/ Me 35 %H2O2, co-catalyst O O CH2Cl2,rt, 6h Me Me 2a 3a Entry ArI Co-catalyst Conversionb (%) Yieldb (%) 1 4a None 44 20 2 4a Imidazole 66 46 3 4a 2,6-Dimethylpyridine 70 40 4 4a Phenanthroline 72 50 5 4a N-Methylimidazole 82 62 6 4a Pyridine 96 70 7 4b Pyridine 70 50 8 4c Pyridine 98 66 9 4d Pyridine 90 86 10 4e Pyridine 66 42 11 4f Pyridine 80 58 12 4g Pyridine 96 78 13 4h Pyridine 72 44 14 4i Pyridine 56 26 15 4k Pyridine 92 56 16 4l Pyridine 92 72 17 4m Pyridine 86 56 18 4n Pyridine 80 54 a Reaction conditions: iodoarene (4, 1 mmol); MTO (0.05 mmol); co-catalyst (0.25 mmol); 35 % H2O2 (10 mmol); DMA (2a,1 mmol); 6 h; rt. bConversions and yields were assessed by 1H NMR analysis with diphenylmethane as internal standard. formation vs. peroxide formation in the presence of olefin substrates. To assess the synthetic feasibility and chemoselectivity of the present oxidation system, oxidation of a set of substrates, including aromatic dienes 2a–d, 1,3-cyclodienes 2e–g, and alkenes 2h,i, was examined. The results are listed in Table 2. In order to minimize epoxide formation and shift the balance in favor of iodine oxidation, an essential 1 step for O2 generation, the reaction conditions were reoptimized to include the 4d/MTO/35 % H2O2/pyridine in 4:0.1:15:0.5 ratio relative to substrate 2. When 2a was exposed to the chemical peroxidation conditions, complete conversion of the starting material was observed, and the corresponding endoperoxide 3a [10] was obtained in 94 % yield (entry 1). With 2b, fast oxygenation occurred, as indicated by the disappearance of the intense color of the starting material and the formation of 3b [13] (entry 2). The relatively less reactive sub- strate 2c was oxygenated to 3c [14] but with a slightly lower yield of 48 % at 60 % conversion (entry 3). The phenolic substrate 2d (entry 4) gave a low yield of hydroperoxide 3d [15], with 45 % conversion. Oxygenation of α-terpinene (2e) at complete consumption gave ascaridole (3e) [16] in 75 % yield, along with p-cymene (5a) in 80:20 ratio (entry 5). Likewise, 1,3-cyclohexadiene (2f) was transformed into the corresponding endoper- oxide 3f [17] in high yield (72 %), along with benzene (5b) as the byproduct (entry 6). Aromatic products 5a,b were formed by oxidation of the starting material with the in situ generated iodosylmesytilene (MesIO, 10) [18] species, as confirmed by a control experiment involving 1,3-cyclodienes 2e,f and 10. Notably, no trace of epoxide resulting from the starting materials 2e,f or products 3e,f was detected by NMR analysis. Oxidation of 2g gave endoperoxide 3g [19] in high yield (87 %), with an appreciable amount of epoxide 6a [20] in 93:7 ratio (entry 7). An electron-rich alkene, 2,3-dimethyl-2-butene (2h), when subjected to the established reac- tion conditions afforded a mixture of oxidized products consisting of allylic hydroperoxide 3h [21], allylic alcohol 7a [21], and epoxide 6b [22] (entry 8). The formation of 7a can be rationalized in terms of the reduction of 3h under the reaction conditions.