DOI: 10.1002/chem.201500146

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& Singlet Oxygen

New Singlet Oxygen Donors Based on Naphthalenes: Synthesis, Physical Chemical Data, and Improved Stability Matthias Klaper and Torsten Linker*[a] Abstract: Singlet oxygen donors are of current interest for medical applications, but suffer from a short half-life leading to low singlet oxygen yields and problems with storage. We have synthesized more than 25 new singlet oxygen donors based on differently substituted naphthalenes in only a few steps. The influence of functional groups on the reaction rate of the photooxygenations, thermolysis, half-life, and singlet oxygen yield has been thoroughly studied. We determined various thermodynamic data and compared them

Introduction Singlet oxygen (1O2)[1] is the lowest excited state of oxygen[2] and can undergo different reactions, such as Schenck Ene reactions with alkenes[3] or [2+ +2] cycloadditions.[4] Besides, it can react with dienes or aromatic systems in a [4+ +2] manner.[5] Furthermore, it has a 1 V higher oxidation potential relative to triplet oxygen (3O2) and can thus mediate oxidations.[6] The generation of 1O2 can be performed by sensitization and controlled sensitization,[7] chemical methods[8] or “in the dark” with singlet oxygen carriers.[9] A fairly recent application is the 1O2 mediated release of molecules and drugs that are bound either on surfaces or through a cleavable linker.[10] Another very interesting aspect is the activity of 1O2 against bacteria[11] and mammalian cells, especially cancer cells.[12] Hence, it is used as the medical active agent in photodynamic therapy (PDT).[1a, 13] Therefore, the patient is treated with a sensitizer that can generate 1O2 under irradiation.[14] If the sensitizer is localized at the tumor or taken up by cancer cells, malignant tissue will be destroyed more preferentially. Although the PDT features good results, it is limited by a number of problems, such as the non-transparency of human tissue.[15] Thus, optical fibers[16] can be used or sensitizers with two photon absorption in the IR region.[7a, 17] An attractive alternative is the thermal re[a] Dr. M. Klaper, Prof. Dr. T. Linker Department of Chemistry, University of Potsdam Karl-Liebknecht-Strasse 24–25 14476 Potsdam (Germany) E-mail: [email protected] Supporting information for this article (including detailed synthetic procedures, analytical data, determination of k1 and k¢1, DFT-calculated HOMO and LUMO energies, optimized structures of naphthalenes and endoperoxides, and their transition states) is available on the WWW under http:// dx.doi.org/10.1002/chem.201500146. Chem. Eur. J. 2015, 21, 8569 – 8577

with density functional calculations. Interestingly, remarkable stabilities of functional groups during the photooxygenations and stabilizing effects for some endoperoxides during the thermolysis have been found. Furthermore, we give evidence for a partly concerted and partly stepwise thermolysis mechanism leading to singlet and triplet oxygen, respectively. Our results might be interesting for “dark oxygenations” and future applications in medicine.

lease of 1O2 from endoperoxides 2 derived from the sensitized photooxygenation of acenes 1 (Scheme 1).[18] Naphthalene endoperoxides 2 (n = 0) with water-soluble groups (e.g., R = (CH2)2COOH) can be used as carriers for singlet oxygen in bio-

Scheme 1. Reversible photooxygenation of acenes 1 with 1O2 to the corresponding endoperoxides 2.

logical media,[19] in which first in vitro tests have already been realized (R = CH3 or remote alcohols).[20] Naphthalene endoperoxides (n = 0) are superior to anthracenes (n = 1) because they exhibit higher singlet oxygen yields.[18–21] The kinetics of photooxygenation and thermolysis of the class of singlet oxygen donors with n = 0 have been investigated previously.[22, 23] It was shown that the substitution pattern has a strong influence on the half-life (t = ) and singlet oxygen yield (h). In particular, the short half-life of these endoperoxides is a major disadvantage for their use as singlet oxygen carriers in PDT.[24] Herein, we present a detailed study on the influence of more than 25 substituents at the naphthalene 2-position on the kinetics of photooxygenation and thermolysis. We have determined the half-lives of endoperoxides and 1O2 yields to design new donors, which efficiently release oxygen in its excited state. In combination with theoretical calculations, we propose different reaction pathways of the thermolysis. Finally, our 2-substituted 1,4-dimethylnaphthalenes can be easily synthesized and oxygenated and might be used for large scale “dark oxygenations”

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Full Paper corresponding acid chloride 4 b (entry 3). From the acid chloride 4 b, all esters, thio esters, and amides (4 c–l), are available in good to excellent yields (Table 1, entries 4–13). The naphthalenes 4 p–u were also synthesized through the bromide 4 o and lithiation followed by functionalization (Table 1, entries 17– Results and Discussion 22). The naphthalenes 4 w–z were synthesized by using palladium-catalyzed Sonogashira[26] and Suzuki–Miyaura[27] couplings To investigate the influence of various functional groups on in good to excellent yields (Table 1, entries 24–27). Detailed the photooxygenation and thermolysis, we used 1,4-dimethylprocedures and analytical data of the products are given in the naphthalene (3) (1,4-DMN) as a reference system and syntheSupporting Information. sized 26 differently 2-substituted 1,4-DMN derivatives 4 The corresponding endoperoxides 5 were subsequently ob(Scheme 2, Table 1). tained through sensitized photooxygenation (Scheme 3 and Table 1). We used methylene blue (MB) as sensitizer because it can be easily separated by filtration over a short silica bed. Since the endoperoxides 5 are thermo labile, a fast workup and purification is crucial. Hence, column chromatography and solvent reScheme 2. Synthesis of naphthalene derivatives 4 a–z. moval was carried out at ¢20 8C. All corresponding 1,4-endoperTable 1. Synthesis and reversible photooxygenation of 2-substituted 1,4-DMN derivatives 4 a–z. oxides were isolated in excellent yields (Table 1), except for 4 v. [b] [b,c] [b,c] [d] k¢1 t= h Entry No. R Yield 4 Yield 5 k1 Here, two different endoperox[103 m¢1 s¢1] [10¢7 s¢1] [h] [%] [%][a] [%][a] ides 5 v-1 and 5 v-2 (Table 1, [34] [22] [22, 23] 1 – H – 96 12.0 œ 0.11 362.5 œ 0.96 5.3 76 entry 23) were found (Scheme 4). 2 a CO2H 81 98 1.82 œ 0.05 8.8 œ 0.02 218.8 80 œ 1 The formation of such mono3 b COCl 91 99 1.21 œ 0.03 5.6 œ 0.01 343.8 78 œ 1 97 98 2.61 œ 0.07 12.7 œ 0.03 151.6 81 œ1 4 c CO2Me and bisendoperoxides has previ95 99 2.47 œ 0.06 10.3 œ 0.03 186.9 81 œ1 5 d CO2Et ously been observed for dihy93 97 2.22 œ 0.06 9.1 œ 0.02 211.6 82 œ 1 6 e CO2iPr dronaphthalenes[28] and styrene 7 f CO2tBu 93 95 2.12 œ 0.06 5.5 œ 0.01 350.1 82 œ 1 derivatives.[29] Interestingly, we 86 99 0.99 œ 0.03 14.1 œ 0.04 136.6 80 œ 1 8 g CO2Ph 9 h COSEt 83 94 1.44 œ 0.02 6.1 œ 0.01 315.6 83 œ 1 found some remarkable stabili10 i COSPh 86 97 0.70 œ 0.03 8.5 œ 0.02 226.5 79 œ 1 ties of functional groups during 96 94 2.11 œ 0.02 36.2 œ 0.08 53.2 78 œ 1 11 j CONEt2 the photooxygenations. 93 92 2.38 œ 0.05 36.7 œ 0.07 52.5 77 œ 1 12 k CONiPr2 Thus, the amides react quite 87 88 2.21 œ 0.05 36.5 œ 0.07 52.8 78 œ 1 13 l CONPh2 14 m CHO 91 93 0.83 œ 0.01 6.0 œ 0.02 320.9 79 œ 1 fast with 1O2, although it is 15 n C(O)Me 87 95 2.41 œ 0.02 5.7 œ 0.01 337.8 80 œ 1 known that the tertiary nitrogen 16 o Br 99 97 0.90 œ 0.02 22.1 œ 0.06 87.1 84 œ 1 can act as physical and chemical 17 p I 99 95 1.69 œ 0.02 21.8 œ 0.06 88.3 83 œ 1 quencher for 1O2 due to its lone 99 98 36.84 œ 0.12 12.0 œ 0.04 160.5 80 œ 1 18 q CH2OH 98 99 6.44 œ 0.04 15.6 œ 0.04 123.4 79 œ 1 19 r CH2Br electron pair (Table 1, entries 11– 20 s CH2PPh3Br 89 89 1.43 œ 0.04 9.4 œ 0.01 204.8 76 œ 1 13).[30] Thus, the Lewis basic [22] 81 œ1 21 t Me 78 98 84.83 œ 0.12 25.1 œ 0.07 76.7 character of amines must be re22 u Et 71 98 60.63 œ 0.12 23.1 œ 0.01 83.4 80 œ 1 sponsible for the strong quench23 v CH=CMe2 90 54 (5 v-1), 44 (5 v-2) 56.02 œ 0.09[e] –[f] –[f] –[f] 24 w CŽC-TMS 79 91 3.81 œ 0.03 18.0 œ 0.04 107.0 82 œ 1 ing, which is absent in amides.[31] 25 x Ph 95 97 23.54 œ 0.09 58.1 œ 0.03 33.1 80 œ 1 Furthermore, the sulfur in the 26 y p-MeO-Ph 74 98 30.33 œ 0.11 57.5 œ 0.02 33.5 80 œ 1 here-shown thio esters is not 94 9.31 œ 0.06 41.1 œ 0.05 46.8 79 œ 1 27 z p-CO2Me-Ph 83 oxidized by 1O2 (Table 1, en[a] Yield of isolated material. [b] Average value from at least four measurements. [c] At 296 K. [d] By using NMR tries 9 and 10), although thio spectroscopy.[1a, 23, 39] [e] Reaction to 5 v-1. [f] No back reaction observed. compounds (such as thio ethers) are sometimes sensitive towards The key step for the synthesis of nearly all electron-deficient oxidation.[32] Again, the lone pair of the sulfur in our thio esters naphthalenes (Table 1, entries 2–13) was the regioselective brois delocalized and deactivated by the adjacent carbonyl group. mination to 4 o followed by lithiation and carboxylation with Although the oxidation of phosphorous compounds proceeds evaporated dry ice. Thus, the free acid 4 a was isolated in 81 % through quaternary phosphonium salts,[33] this side reaction (Table 1, entry 2), which was subsequently transferred into the was not observed for compound 4 s by 1O2 (Table 1, entry 20). and future applications in PDT. Furthermore, they could benefit from synergetic effects during the application because the naphthalene moiety is also found in virus inhibitors.[25]

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Scheme 3. Reversible photooxygenation of substituted 1,4-DMN derivatives 4 a–z to the corresponding endoperoxides 5 a–z.

Figure 1. Highest occupied molecular orbitals (HOMO) of 4 c and 4 q.

Scheme 4. Products from photooxygenation of naphthalene 4 v.

The reaction rates of photooxygenation (k1) and thermolysis (k¢1) were determined after isolation and characterization of the endoperoxides 5 a–z (Table 1). Therefore, we determined the kinetics by measuring the decrease of absorption at a specific wavelength (290–300 nm) by using UV/Vis spectroscopy (for details see the Experimental Section). As expected from literature for electron-rich anthracenes,[34] naphthalenes that contain more electron-donating groups react quite fast with singlet oxygen (Table 1, entries 18–27). However, naphthalenes with an electron-withdrawing group are less reactive during the photooxygenation (Table 1, entries 2–17). The 2-alkyne-substituted 1,4-DMN 4 w (Table 1, entry 24) reacts slower than the unsubstituted 1,4-DMN 3 (Table 1, entry 1), although alkyne groups are known as electron-donating groups,[35] especially with the trimethylsilyl substituent. The behavior of alkyne-substituted arenes had been already investigated in our group; it was found that triple bonds protect acenes from oxidation.[36] The different reactivities of the naphthalenes 4 towards 1O2 can be explained by the highest occupied molecular orbital and lowest unoccupied molecular orbital (HOMO–LUMO) interactions. Therefore, the energy of the orbitals from 1O2 and naphthalenes were calculated on B3LYP/6-31G* level (for details see the Supporting Information). The highest occupied MOs for the methyl ester 4 c and the alcohol 4 q are shown as examples in Figure 1. Evidently, the latter molecular orbital (MO) is more electronrich and thus, reacts faster with the electrophilic singlet oxygen, which is already known from literature.[37] Thus, we found a good correlation between the HOMO energies and the reaction rate of photooxygenation (k1) (Figure 2). It can be clearly seen that the reactivity towards 1O2 increases with increasing HOMO energy (the Supporting Information), although other influences such as steric demand and 1O2 directing properties are not considered herein. Interestingly, also remote substituents, such as the phenyl naphthalenes 4 x–z (Table 1, entries 25–27), still show a strong influence on the reactivity in accordance to our previous studies.[36, 38] Chem. Eur. J. 2015, 21, 8569 – 8577

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Figure 2. Correlation of HOMO energies with k1 for naphthalenes 4 (~: electron-withdrawing, 4 a–p, 4 r, 4 s, 4 w, 4 z; &: neutral, 3; *: electron-donating, 4 q, 4 t, 4 u, 4 x, 4 y).

The most important result of our investigations is the reaction rate of the thermolysis (k¢1) and release of 1O2. The kinetics were determined by following the increase of the absorption through the UV/Vis measurement (the Experimental Section). The k¢1 values for the endoperoxides 5 a–z are shown in Table 1. It is evident that all substituents, independent of their electronic character, stabilize the endoperoxide 5 a–z compared with the unsubstituted 1,4-DMN endoperoxide 5. The electronic effects play a minor role for the thermolysis compared with oxygenation, but there is still a trend present. All endoperoxides exhibiting electron-donating groups as methyl- or ethyl (Table 1, entries 21–22) as well as the phenyl naphthalenes (entries 25–27) reveal a faster back reaction compared with the electron-deficient naphthalenes (entries 2–17 and 20). Instead, steric demand is more important, which was already found for the methyl group.[22] Yet no detailed study on the steric influence of different substituents in the 2-position on the thermolysis of endoperoxides exists in the literature. Therefore, we calculated structures of the sterically demanding tert-butyl ester f (Table 1, entry 5) versus the less hindered phenyl group x (Table 1, entry 25 and Figure 3). The carbonyl group in the endoperoxide 5 f can occupy the favored 180 8 conformation with respect to the remaining double bond. This is not possible for the parental naphthalene 4 f due to steric hindrance. This behavior can be compared with the

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Full Paper in high yields.[23] The singlet oxygen has then a specific lifetime in the solvent ranging from 10¢6 up to 10¢4 s.[41] The thermolysis experiments were performed in chloroform, in which 1O2 has a very long lifetime (2.5 Õ 10¢4 s).[41b] Thus, it is possible that a six-membered transition state is formed through hydrogen bonds (Scheme 5).[40a] Hence, the singlet oxygen can react reversibly and the macroscopic half-life of the endoperoxide 5 q appears much longer than expected (Table 1, entry 18, t = … 161 h). Typical hydrogen bridge bond lengths, determined from crystal structures,[42] are in the range of 2–3 æ. As a consequence, we calculated the transition state of the thermolysis of 5 q (Figure 4) and measured the O¢H···O2 distance in the transition state. 1

2

Figure 3. Calculated structures of 4 f/5 f and 4 x/5 x by using B3LYP/6-31G*.

known 1,8-strain in 1,8-dimethyl naphthalene endoperoxide.[22] Hence, the endoperoxide 5 f (Table 1, entry 5, t = = 29.6 h) is energetically more preferred and better stabilized relative to the naphthalene/endoperoxide pair 4 x/5 x (entry 25, t = = 4.0 h). Here, a reduction of steric hindrance is neither achieved in 4 x nor in 5 x. Thus, the phenyl group is less stabilizing than the tert-butyl group. An increasing stabilizing effect was also found for the array of the alkyl esters 5 c–f. The half-life increases from methyl to the tert-butyl ester (Table 1, entries 4–7). The methyl ester is one of the least stable endoperoxides with an electron-withdrawing group (t = = 151.6 h, Table 1, entry 4), whereas the tert-butyl ester on the other hand is the most stable endoperoxide examined (t = = 350.1 h, Table 1, entry 7). The dependence of t = from the steric demand was underlined by similar observations for the aryl 5 g (Table 1, entry 8) and thio esters 5 h–i (entries 9 and 10). Considering the above-mentioned naphthalene endoperoxides 5 a–z, in general, large groups stabilize better than small or less sterically demanding substituents. Thus, the shown endoperoxides 5 a–z are much more stable and thus better 1O2 donors than the unsubstituted 1,4-DMN endoperoxide 5 (Table 1, entry 1). Another interesting result concerning the carbonyl-substituted naphthalenes can also be discussed with steric and electronic effects. Electron-poor arenes react slowly with 1O2,[34] whereas the corresponding endoperoxides exhibit prolonged half-lives (t = ). As shown above (Figure 3), the carbonyl group in the parental tert-butyl ester 4 f is not in full conjugation with the naphthalene system, thus, it withdraws less electron density compared with a system that has a 180 8 conformation. Thus, the naphthalene reacts still reasonably fast with 1O2. Apart from this, the carbonyl group in the endoperoxide 5 f is in full conjugation. This reduces the electron density in the endoperoxide and additionally prolongs the t = . Interestingly, another effect influences the half-life as shown for the alcohol 5 q (Table 1, entry 18). It is known that alcohols can direct 1O2 during photooxygenation through hydrogen bonding.[40] In addition, naphthalenes liberate singlet oxygen 1

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Scheme 5. Explanation for the long half-life of the endoperoxide 5 q.

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Figure 4. Calculated transition state for the thermolysis of the endoperoxide 5 q.

The shorter distance is 2.16 æ, whereas the longer one is 3.09 æ; both are in the region of hydrogen bridges. When we calculated the reaction pathway, the singlet oxygen reaction coordinates were controlled by the hydrogen bridge. With this strong binding also a stereo selective transfer of 1 O2 to a second acceptor should be possible, if chiral alcohols are employed.[43] Besides, bonding of this type is important for deactivation of 1 O2 by amines.[44] The amides 4 j–l, however, are not able to achieve hydrogen bonds and thus do not decelerate the photooxygenations. But their corresponding endoperoxides 5 j– l exhibit shorter half-lives compared with those of the corresponding esters (Table 1, entries 4–13). As mentioned before, this cannot be ascribed to the lone pair.[30] Furthermore, density functional calculations revealed a distance between 1.5 and 1.6 æ for an optimal overlap of the nitrogen lone pair in 1,4-diazabicyclo[2.2.2]octane (dabco) and the oxygen p* orbital, which leads to quenching.[45] Hence, we calculated the transition state for the thermolysis (Figure 5). We measured an O···N distance of 4.0 and 4.2 æ, which is too far for an interaction. Thus, the short lifetime of the endoperoxide cannot be attributed to a lone pair···p* inter-

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Figure 5. Calculated transition state (B3LYP/6-31G*) for the thermolysis of the diethyl amide endoperoxide 5 j. Figure 7. Optimized geometry (B3LYP/6-31G*) for the ethyl amide 4 j.

action. Apart from this, the distance to the next hydrogen atom in the ethyl chain is very short (2.4–2.5 æ, Figure 5). It is known that 1O2 has a shorter lifetime in solvents with many C¢ H groups, because they absorb in the IR region at which singlet oxygen has its monomer phosphorescence.[46] In deuterated solvents that absorb elsewhere, the lifetime of 1O2 is much prolonged.[47] This energy transfer is strongly distance dependent.[48] Therefore, we calculated the transition state of the corresponding ethyl ester endoperoxide 5 d (Figure 6). Here, the distance to the next ethyl chain proton is much longer (6.2– 6.3 æ). Thus, the energy transfer is less effective or even does not occur and 1O2 has a longer lifetime in the transition state. Considering the alcohol endoperoxide 5 q again, we assumed a reversible reaction between the transition state and the endoperoxide as long as 1O2 is close enough and is not deactivated.

Consequently, suitable 1O2 donors must not only offer prolonged half-lives, but they must also have high 1O2 yields (h). Accordingly, we determined h by trapping experiments with tetramethylethylene (Scheme 6).[22, 23, 39] The singlet oxygen yields are very high for all substances 5 a–z (Table 1) and agree with the literature data of the simple 1,4-DMN endoperoxide 5.[22, 23]

Scheme 6. 1O2 trapping experiments.

Subsequently, the thermolysis of the most promising electron-deficient endoperoxides, and thus the longest t = , were performed at different temperatures (Table 2) to generate Arrhenius and Eyring plots (Figure 8). The change of activation energy (DEaexptl), entropy (DS#), and enthalpy (DH#), as well as Gibbs energy (DG#), were determined. The activation energy (DEath) was computed additionally, by using B3LYP/6-31G* (Table 2). The theoretical and experimental data are in accordance but with a general error, which will be discussed below. The experimental activation energies (DEaexptl) fit well with the thermolysis rate k¢1; higher DEaexptl result in slower reactions and thus, more stable endoperoxides with prolonged half-lives. The transition state for the thermolysis of 1,4-DMN endoperoxide 5 and other endoperoxides had been already calculated,[22, 49] but not the reaction pathway. Thus, we computed the transition state[50] for all substances by QST3 method[51] from the optimized endoperoxide over a transition state guess to the naphthalene by using B3LYP/6-31G*. Each vibrational spectra of the transition states 5# contained one imaginary frequency. Along this, the intrinsic reaction coordinate was followed again for all endoperoxides 5# by using the intrinsic reaction coordinate (IRC) method showing the reaction pathway, which is exemplified for acetylene 5 w (Figure 9).[51] The shown pathway is concerted; singlet oxygen is liberated at first. This data agrees with the singlet oxygen yields (h) from literature for 1,4-DMN endoperoxide 5.[23] However, the calcu1

Figure 6. Calculated transition state (B3LYP/6-31G*) for the thermolysis of the ethyl ester endoperoxide 5 d.

The gain of energy back to the endoperoxide is much higher than to the parental naphthalene and oxygen in its excited state but vice versa for 3O2, which will be shown later. If an effective energy transfer is possible, the system will preferentially complete the thermolysis to the naphthalene and triplet oxygen and exhibit shorter lifetime as in the case of the amides (Table 1, entries 11–13). If the energy transfer is less effective, the system will return to the energetically more favored endoperoxide as for the free acid, acid chloride, and esters (Table 1, entries 2–10). Additionally, the carbonyl group is not in conjugation with the residual double bond in the amide 5 j. Thus, the endoperoxide is more electron-rich and the thermolysis is slightly faster. Even in the parental amide 4 j, we saw that the carbonyl group is not in conjugation making the naphthalene system less electron-deficient (Figure 7). Furthermore the two ethyl chains are located more at one side of the naphthalene; the other side is free for an attack by 1O2. This could explain the reasonably fast reactivity with 1O2. Chem. Eur. J. 2015, 21, 8569 – 8577

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Full Paper set would lead in general to even smaller energies,[52] as [a] [a] exptl th[b] # # # k¢1 k¢1 DEa DEa DH DS DG 296K shown for the comparison of the 321 K 330 K [kJ mol¢1] [kJ mol¢1] [kJ mol¢1] [J K¢1 mol¢1] [kJ mol¢1] bromide 5 o (6-31G*) and the iodide 5 p (3-21G*), in which 3235.2 711.5 96.8 œ 2.5 96.2 94.2 œ 2.5 ¢40.7 œ 1.2 106.2 œ 0.5 231.0 661.1 100.5 œ 2.5 98.3 97.9 œ 2.5 ¢29.66 œ 1.1 106.7 œ 0.4 21G* was used. Because the 224.3 728.6 107.3 œ 2.5 100.5 104.7 œ 2.6 ¢9.60 œ 0.5 107.5 œ 0.3 base set 6-31G* is incremented 212.0 668.3 115.8 œ 2.6 105.9 16.9 œ 1.0 ¢113.2 œ 2.6 108.2 œ 0.2 to krypton only,[53] 3-21G* reach269.5 752.2 96.9 œ 2.5 101.2 94.3 œ 2.6 ¢40.3 œ 1.2 106.2 œ 0.4 es to xenon instead.[54] 191.5 563.7 109.9 œ 2.6 103.1 107.3 œ 2.7 ¢2.40 œ 0.2 83 œ 0.4 198.7 833.2 109.1 œ 2.6 103.0 106.5 œ 2.6 ¢3.22 œ 0.3 75 œ 0.3 To explain the discrepancy be103.9 œ 0.6 785.5 2902.4 104.9 œ 2.6 92.7 102.3 œ 2.6 ¢5.3 œ 0.2 tween the calculated and experi680.0 2288.6 98.6 œ 2.4 97.1 95.4 œ 2.5 ¢27.04 œ 1.1 103.4 œ 0.4 mentally determined data, we 1022.4 3421.7 100.5 œ 2.5 96.8 97.9 œ 2,5 ¢17.33 œ 0.9 103.0 œ 0.2 suggest that the thermolysis 454.3 917.6 125.3 œ 2.6 92.0 122.7 œ 2.6 + 50.5 œ 1.4 107.8 œ 0.6 137.5 384.9 112.6 œ 2.6 95.3 110.0 œ 2.6 + 3.0 œ 0.1 109.1 œ 0.7 does not proceed through a con579.3 1652.3 103.7 œ 2.8 96.1 101.1 œ 2.7 ¢11.8 œ 0.9 104.6 œ 0.1 certed mechanism exclusively[21] [c] 84.9 œ 2.5 ¢68.5 œ 1.3 105.2 œ 0.6 268.5 842.3 87.5 œ 2.5 151.6 (transition state Figure 10). The 736.6 2524.5 118.2 œ 2.7 103.7 115.6 œ 2.6 + 35.6 œ 1.0 105.1 œ 0.2 activation energy of the concert1279.2 4009.5 110.1 œ 2.5 101.0 107.5 œ 2.5 + 14.8 œ 0.5 103.1 œ 0.2 ed mechanism for methyl least four measurements [10¢7 s¢1]. [b] Calculated values with B3LYP/6-31G*. ester 5 c is 96.2 kJ mol¢1; this value was calculated under singlet state enforcement. In contrast, the calculation of the stepwise mechanism of 5 c was carried out with a triplet state guess (UB3LYP/6-31G*, charge 0, total spin: 3, Figure 11). Here, the calculated activation energy is much higher with 288.2 kJ mol¢1. This mechanism is much less favored compared with that of the concerted one. In fact, the reaction does not proceed exclusively in a concerted way. Instead, a minor fraction runs through a stepwise path, resulting in total in higher and actually measured activation energies. At this point, the stepwise mechanism can either undergo a diradical or ionic mode for C¢O bond cleavage, which we have already discussed in earlier work on anthracene endoperoxides.[38] A homolytic O¢O cleavage, such as in the case of alkyl- or unsubstituted anthracene endoperoxides,[55] was not observed

Table 2. Physical parameters of the naphthalene endoperoxides 5. Entry

No.

k¢1[a] 296 K

k¢1[a] 312 K

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

c d e f g h i j k l m n o p w z

12.7 10.3 9.1 5.5 14.1 6.1 8.5 36.2 36.7 36.5 6.0 5.7 22.1 12.7 10.3 9.1

83.8 83.7 43.1 64.6 74.6 56.7 63.8 232.8 350.8 272.1 109.5 41.8 243.0 95.1 319.7 485.6

[a] Average value from at [c] B3LYP/3-21G*.

Figure 8. Thermolysis experiments for the methyl ester endoperoxide 5 c at different temperatures (T = 296, 312, 321, 330 K). Insets: Arrhenius and Eyring plots.

Figure 10. Transition state for concerted (singlet) thermolysis of methyl ester 5 c#.

Figure 9. Thermolysis pathway for acetylene naphthalene endoperoxide 5 w enforcing singlet states.

lated DEath values for a concerted mechanism do not fit very well with the experimental activation energies DEaexptl ; the calculated energies are too small on average. Using a higher basis Chem. Eur. J. 2015, 21, 8569 – 8577

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Figure 11. Transition state for a stepwise (triplet) thermolysis of methyl ester 5 c#.

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Full Paper at all. Further experiments revealed a radical intermediate for the stepwise naphthalenes 5 a–z. Therefore, we thermolyzed the endoperoxides 5 a–z in p-xylene (8), in which a well-stabilized radical can be formed by hydrogen atom abstraction, which, on the other hand, gives a stable and nonvolatile product 9 (Scheme 7).

Scheme 7. Thermolysis of endoperoxide 5 in p-xylene (8).

We were able to isolate the parental naphthalene 4 a–z in quantitative yield. From the literature and our own studies we know that the naphthalene endoperoxides 5 a–z yield 1O2 in about 80 %.[23] Furthermore, we isolated the hydroperoxide 9 in … 25 % yield, which is also formed by air autoxidation very slowly.[56] Additionally, the oxidation can be accelerated by catalysts[57] or through a radical pathway with cerium(IV) ammonium nitrate.[58] Thus, it is clear that the formation of 9 can only occur under radical conditions. From the quantity of p-xylene for our experiments (100 mmol, 10.62 g) we isolated 1.4 mg (13.2 mmol) of 9 before thermolysis (0.02 %). The hydroperoxide 9 is neither formed under identical conditions without the presence of an endoperoxide, nor with 1O2 under irradiation, as revealed in an additional competition experiment. In summary, the naphthalene endoperoxides should thermolyze mainly through a retro [4+ +2] cycloaddition as well as less effectively through a stepwise radical mechanism. Furthermore, the formation of the hydroperoxide 9 in this way seems to be important as they are found in some applications,[59] but the catalytic synthesis is difficult and results in a broad mixture of products.[57] Finally, we determined the value of DG# (at 296 K). With increasing positive DG#, the k¢1 value drops. More important is the value of DS#; from the literature it is known that thermolysis reactions will release high amounts of 1O2 if the DS# value is small or negative.[60] This requires a concerted pathway.[21] A stepwise mechanism would lead to lower 1O2 yields along with a more positive DS# value,[23] earlier shown for anthracenes in our group.[36] A very interesting work about this topic deals with 1,4- and 9,10-anthracene endoperoxides. The first one features a low DS# value together with high h and decays over a concerted pathway, whereas the latter one reacts in the opposite manner.[21] Here, we found the first evidences for a partly concerted and partly stepwise mechanism. The endoperoxides 5 a–z liberate oxygen in … 80 % in its singlet state and … 20 % in the triplet state proven by 1O2- and 3O2 scavengers, respectively. A comparison of the experimental and calculated DS# shows an interesting result. The experimental data, which were ensured by at least four independent measurements, show different beChem. Eur. J. 2015, 21, 8569 – 8577

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havior for the diverse substitution patterns from ¢113 up to + 50 J K¢1 mol¢1 (Table 2) but still give high 1O2 yields (Table 1). This seems to be contradictory at the first glance; however, the thermodynamic properties were determined in pure chloroform (spectroscopic grade), whereas the singlet oxygen yields were determined according to literature by using NMR experiments in [D]-chloroform with excess of tetramethylethylene (TME) in a concentration of solvent regime to reduce loss by physical deactivation.[23, 39] This could influence the 1O2 yield by substitution of solvent molecules in the solvent cage.[61] TME could already develop an O¢O···p interaction[42] and thus drive the mechanism towards a concerted pathway. Hence, the values determined in this way must be understood as maximum 1O2 yields or transfer rates. By using B3LYP/6-31G*, the calculated DS# values (T: 296 K, scaling factor 1.0015,[62] normal pressure) range from + 4.4 up to + 17.5 J K¢1 mol¢1, only, and were calculated for a strictly singlet (concerted) pathway. A stepwise mechanism was calculated for benzene endoperoxides under irradiation very recently.[63] The discrepancy between our calculated and the experimental data underline again that also the thermolysis does not proceed exclusively in a concerted manner.

Conclusion We have synthesized a broad number of new naphthalenes and their corresponding endoperoxides, which we then isolated and fully characterized. The kinetics of the photooxygenations and thermolysis have been investigated in detail and revealed interesting influences of functional groups. We demonstrated that our new endoperoxides are more suitable donors for 1O2 because they exhibit prolonged half-lives and improved storing properties. Additionally, longer half-lives reduce the total amount of physical deactivation and increase the singlet oxygen yield. Because 1O2 is constantly liberated over a longer time period, slow acceptors can also be reacted with these 1O2 donors. Moreover, we determined the thermodynamic properties through experiments and calculations. We showed that the O2 cleavage does not proceed by a concerted pathway exclusively, but predominantly. As well as the the transition state of the concerted pathway, we detected radical intermediates in the stepwise reaction through trapping experiments. The singlet oxygen donors shown herein should play an important role in “dark oxygenations” for light-sensitive acceptors, and also with some more modifications, for medical applications, which are currently under investigation in our laboratories.

Experimental Section Determination of the photooxygenation kinetics (k1) The exact mass of naphthalene 4 (7.811–25.572 mg, Metler Toledo MX5, D = 1 mg) was dissolved in chloroform (100 mL) to obtain an accurate concentration of 5 Õ 10¢4 m. This solution was diluted to 5·10¢5 m and stored in the dark. After dissolving in chloroform

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Full Paper (100 mL), a 10 mm solution of methylene blue (MB, sensitizer, 319.863 mg, 1 mmol) was obtained. For a typical photooxygenation experiment, 2 mL of the naphthalene solution was poured into a quartz cuvette. In a two beam UV/Vis spectrometer (Shimadzu UV-160A) a second cuvette with the pure solvent (2 mL) was put into the reference beam. The UV/Vis absorption spectrum was measured and the absorption maximum was determined (290– 300 nm). Exactly 25 mL of the sensitizer solution was added to both cuvettes through a micro liter syringe and the spectrum was recorded again. Next, both cuvettes were irradiated with 250 W sodium lamp (Osram VIALOX). The photooxygenation was monitored by the decrease of the absorption maximum of the naphthalene 4 (the Supporting Information, Figure S1). The kinetics were determined at least four times for each substance. In additional experiments (ten times), the k1 value for 1,4-dimethylnaphthalene (3) as a reference system was determined (k1 = 12.0 Õ 103 m¢1 s¢1).[34] All other reactions were referred to this value.

Determination of thermolysis kinetics (k¢1) A solution of the corresponding endoperoxide 5 was prepared from the isolated product as described before. The solution (2 mL) was poured into a quartz cuvette and brought to the correct temperature (296, 312, 321, or 330 K) in a heatable UV/Vis spectrometer (ATI Unicam UV/Vis UV3 Spectrometer) until constant temperature. The thermolysis was monitored by the increase of the absorption maximum of the corresponding naphthalene 4. The details for the synthesis of the naphthalenes 4 and the endoperoxides 5 as well as the calculations are described in the Supporting Information.

Acknowledgements We thank the University of Potsdam for generous financial support. We thank Dr. Heidenreich for assistance in NMR spectroscopic analysis, Dr. Starke for measurement of mass spectra, and Dr. Fudickar for helpful discussions. Keywords: density functional calculations · oxygenation · peroxides · photodynamic therapy · singlet oxygen [1] a) A. A. Frimer in Singlet Oxygen, Vol. I: Physical-Chemical Aspects, CRC, Boca Raton, 1985; b) A. Greer, M. Zamadar in Handbook of Synthetic Photochemistry, Singlet Oxygen as a Reagent in Organic Synthesis, WileyVCH, Weinheim, 2010; c) P. R. Ogilby, Chem. Soc. Rev. 2010, 39, 3181. [2] K. Hasegawa, K. Yamada, R. Sasase, R. Miyazaki, A. Kikuchi, M. Yagi, Chem. Phys. Lett. 2008, 457, 312 – 314. [3] a) A. Eske, B. Goldfuss, A. G. Griesbeck, A. de Kiff, M. Kleczka, M. Leven, J.-M. Neudçrfl, M. Vollmer, J. Org. Chem. 2014, 79, 1818 – 1829; b) A. G. Griesbeck, A. de Kiff, Org. Lett. 2013, 15, 2073 – 2075; c) W. Adam, S. G. Bosio, N. J. Turro, B. T. Wolff, J. Org. Chem. 2004, 69, 1704 – 1715. [4] W. Adam, S. G. Bosio, N. J. Turro, J. Am. Chem. Soc. 2002, 124, 8814 – 8815. [5] W. Adam, M. Prein, Acc. Chem. Res. 1996, 29, 275 – 283. [6] D. B. Ushakov, K. Gilmore, D. Kopetzki, D. T. McQuade, P. H. Seeberger, Angew. Chem. Int. Ed. 2014, 53, 557 – 561; Angew. Chem. 2014, 126, 568 – 572. [7] a) E. Clû, J. W. Snyder, N. V. Voigt, P. R. Ogilby, K. V. Gothelf, J. Am. Chem. Soc. 2006, 128, 4200 – 4201; b) P. K. Frederiksen, S. P. McIlroy, C. B. Nielsen, L. Nikolajsen, E. Skovsen, M. Jørgensen, K. V. Mikkelsen, P. R. Ogilby, J. Am. Chem. Soc. 2005, 127, 255 – 269; c) T. Tørring, R. Toftegaard, J. Arnbjerg, P. R. Ogilby, K. V. Gothelf, Angew. Chem. Int. Ed. 2010, 49, 7923 – 7925; Angew. Chem. 2010, 122, 8095 – 8097; d) D. T. McQuade, P. H. Seeberger, J. Org. Chem. 2013, 78, 6384 – 6389. Chem. Eur. J. 2015, 21, 8569 – 8577

www.chemeurj.org

[8] a) J.-M. Aubry, S. Bouttemy, J. Am. Chem. Soc. 1997, 119, 5286 – 5294; b) J. Wahlen, D. E. de Vos, M. H. Groothaert, V. Nardello, J.-M. Aubry, P. L. Alsters, P. A. Jacobs, J. Am. Chem. Soc. 2005, 127, 17166 – 17167; c) C. Pierlot, V. Nardello, J. Schrive, C. Mabille, J. Barbillat, B. Sombret, J.-M. Aubry, J. Org. Chem. 2002, 67, 2418 – 2423. [9] G. R. Martinez, J.-L. Ravanat, M. H. G. Medeiros, J. Cadet, P. Di Mascio, J. Am. Chem. Soc. 2000, 122, 10212 – 10213. [10] a) T. Tørring, S. Helmig, P. R. Ogilby, K. V. Gothelf, Acc. Chem. Res. 2014, 47, 1799 – 1806; b) S. Helmig, A. Rotaru, D. Arian, L. Kovbasyuk, J. Arnbjerg, P. R. Ogilby, J. Kjems, A. Mokhir, F. Besenbacher, K. V. Gothelf, ACS Nano 2010, 4, 7475 – 7480; c) D. Bartusik, D. Aebisher, G. Ghosh, M. Minnis, A. Greer, J. Org. Chem. 2012, 77, 4557 – 4565. [11] a) Z. Malik, J. Hanania, Y. Nitzan, J. Photochem. Photobiol. B 1990, 5, 281 – 293; b) E. C. Ziegelhoffer, T. J. Donohue, Nat. Rev. Microbiol. 2009, 7, 856 – 863; c) D. Arian, L. Kovbasyuk, A. Mokhir, J. Am. Chem. Soc. 2011, 133, 3972 – 3980; d) R. Choudhury, A. Greer, Langmuir 2014, 30, 3599 – 3605. [12] a) E. Clû, J. W. Snyder, P. R. Ogilby, K. V. Gothelf, ChemBioChem 2007, 8, 475 – 481; b) M. K. Kuimova, G. Yahioglu, P. R. Ogilby, J. Am. Chem. Soc. 2009, 131, 332 – 340; c) T. J. Dougherty, C. J. Gomer, B. W. Henderson, G. Jori, D. Kessel, M. Korbelik, J. Moan, Q. Peng, J. Natl. Cancer Inst. 1998, 90, 889 – 905. [13] a) A. M. Asadirad, Z. Erno, N. R. Branda, Chem. Commun. 2013, 49, 5639; b) R. Bonnett, Chem. Soc. Rev. 1995, 24, 19; c) D. Bartusik, D. Aebisher, A. Ghogare, G. Ghosh, I. Abramova, T. Hasan, A. Greer, Photochem. Photobiol. 2013, 89, 936 – 941. [14] B. W. Henderson, T. J. Dougherty, Photochem. Photobiol. 1992, 55, 145 – 157. [15] A. E. Profio, D. R. Doiron, Photochem. Photobiol. 1987, 46, 591 – 599. [16] L. Brancaleon, H. Moseley, Laser Med. Sci. 2002, 17, 173 – 186. [17] a) J. Schmitt, V. Heitz, A. Sour, F. Bolze, H. Ftouni, J.-F. Nicoud, L. Flamigni, B. Ventura, Angew. Chem. 2015, 127, 171 – 175; Angew. Chem. Int. Ed. 2015, 54, 169 – 173; b) F. M. Pimenta, R. L. Jensen, L. Holmegaard, T. V. Esipova, M. Westberg, T. Breitenbach, P. R. Ogilby, J. Phys. Chem. B 2012, 116, 10234 – 10246. [18] a) W. Fudickar, T. Linker in Patai’s Chemistry of Funtional Groups. Applications of Endoperoxides Derived from Acenes and Singlet Oxygen: The Chemistry of Peroxides, John Wiley & Sons, Chichester, 2014, pp. 21 – 86; b) D. McGarvey, P. Szekeres, F. Wilkinson, Chem. Phys. Lett. 1992, 199, 314 – 319. [19] a) D. Costa, E. Fernandes, J. L. M. Santos, D. C. G. A. Pinto, A. M. S. Silva, J. L. F. C. Lima, Anal. Bioanal. Chem. 2007, 387, 2071 – 2081; b) C. Pierlot, J.-M. Aubry, K. Briviba, H. Sies, P. Di Mascio in Methods in Enzymology, Academic Press, San Diego, 2000. [20] a) D. Posavec, M. Zabel, U. Bogner, G. Bernhardt, G. Knçr, Org. Biomol. Chem. 2012, 10, 7062 – 7069; b) C. M. Berra, C. F. M. Menck, G. R. Martinez, C. S. de Oliveira, M. da S. Baptista, P. Di Mascio, Qu†m. Nova 2010, 33, 279 – 283. [21] N. J. Turro, M.-F. Chow, J. Rigaudy, J. Am. Chem. Soc. 1979, 101, 1300 – 1302. [22] a) H. H. Wasserman, K. B. Wiberg, D. L. Larsen, J. Parr, J. Org. Chem. 2005, 70, 105 – 109; b) H. H. Wasserman, D. L. Larsen, J. Chem. Soc. Chem. Commun. 1972, 253. [23] N. J. Turro, M. F. Chow, J. Am. Chem. Soc. 1981, 103, 7218 – 7224. [24] K. Fujimori, T. Komiyama, H. Tabata, T. Nojima, K. Ishiguro, Y. Sawaki, H. Tatsuzawa, M. Nakano, Photochem. Photobiol. 1998, 68, 143 – 149. [25] a) S. Barman, L. You, R. Chen, V. Codrea, G. Kago, R. Edupuganti, J. Robertus, R. M. Krug, E. V. Anslyn, Eur. J. Med. Chem. 2014, 71, 81 – 90; b) B. Z˙ołnowska, J. Sławin´ski, A. Pogorzelska, J. Chojnacki, D. Vullo, C. T. Supuran, Eur. J. Med. Chem. 2014, 71, 135 – 147. [26] R. Chinchilla, C. N‚jera, Chem. Rev. 2007, 107, 874 – 922. [27] F.-S. Han, Chem. Soc. Rev. 2013, 42, 5270. [28] a) T. Linker, F. Rebien, G. Tûth, Chem. Commun. 1996, 2585; b) G. Tûth, T. Linker, F. Rebien, Magn. Reson. Chem. 1997, 35, 367 – 371. [29] M. Matsumoto, K. Kuroda, Angew. Chem. Int. Ed. Engl. 1982, 21, 382 – 383; Angew. Chem. 1982, 94, 376 – 377. [30] C. Ouannes, T. Wilson, J. Am. Chem. Soc. 1968, 90, 6527 – 6528. [31] P. Love, R. B. Cohen, R. W. Taft, J. Am. Chem. Soc. 1968, 90, 2455 – 2462. [32] a) E. L. Clennan, K. Yang, X. Chen, J. Org. Chem. 1991, 56, 5251 – 5252; b) E. L. Clennan, K. Yang, J. Org. Chem. 1992, 57, 4477 – 4487; c) E. L.

8576

Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper

[33] [34] [35] [36] [37] [38] [39] [40]

[41]

[42]

[43] [44] [45] [46]

[47] [48]

Clennan, S. E. Hightower, A. Greer, J. Am. Chem. Soc. 2005, 127, 11819 – 11826. T. Mukaiyama, O. Mitsunobu, T. Obata, J. Org. Chem. 1965, 30, 101 – 105. B. Stevens, S. R. Perez, J. A. Ors, J. Am. Chem. Soc. 1974, 96, 6846 – 6850. T. Yoshikawa, S. Mori, M. Shindo, J. Am. Chem. Soc. 2009, 131, 2092 – 2093. W. Fudickar, T. Linker, J. Am. Chem. Soc. 2012, 134, 15071 – 15082. A. G. Leach, K. N. Houk, Chem. Commun. 2002, 1243 – 1255. W. Fudickar, T. Linker, Chem. Commun. 2008, 1771. I. Saito, T. Matsuura, K. Inoue, J. Am. Chem. Soc. 1983, 105, 3200 – 3206. a) W. Adam, E. M. Peters, K. Peters, M. Prein, H. G. von Schnering, J. Am. Chem. Soc. 1995, 117, 6686 – 6690; b) W. Adam, M. Prein, J. Am. Chem. Soc. 1993, 115, 3766 – 3767. a) P. B. Merkel, D. R. Kearns, J. Am. Chem. Soc. 1972, 94, 1029 – 1030; b) J. R. Hurst, J. D. McDonald, G. B. Schuster, J. Am. Chem. Soc. 1982, 104, 2065 – 2067; c) J. Wang, J. Leng, H. Yang, G. Sha, C. Zhang, Langmuir 2013, 29, 9051 – 9056. a) G. R. Desiraju, Acc. Chem. Res. 2002, 35, 565 – 573; b) V. R. Vangala, B. R. Bhogala, A. Dey, G. R. Desiraju, C. K. Broder, P. S. Smith, R. Mondal, J. A. K. Howard, C. C. Wilson, J. Am. Chem. Soc. 2003, 125, 14495 – 14509; c) B. R. Bhogala, V. R. Vangala, P. S. Smith, J. A. K. Howard, G. R. Desiraju, Cryst. Growth Des. 2004, 4, 647 – 649. A. G. Griesbeck, T. T. El-Idreesy, J. Lex, Tetrahedron 2006, 62, 10615 – 10622. E. A. Lissi, M. V. Encinas, E. Lemp, M. A. Rubio, Chem. Rev. 1993, 93, 699 – 723. D. T. Browne, S. B. Kent, Biochem. Biophys. Res. Commun. 1975, 67, 133 – 138. a) R. Schmidt, H. D. Brauer, J. Am. Chem. Soc. 1987, 109, 6976 – 6981; b) P. B. Merkel, R. Nilsson, D. R. Kearns, J. Am. Chem. Soc. 1972, 94, 1030 – 1031; c) H. Seliger, Anal. Biochem. 1960, 1, 60 – 65. P. R. Ogilby, C. S. Foote, J. Am. Chem. Soc. 1982, 104, 2069 – 2070. L. Stryrer, R. P. Haugland, Proc. Natl. Acad. Sci. USA 1967, 58, 719 – 726.

Chem. Eur. J. 2015, 21, 8569 – 8577

www.chemeurj.org

[49] a) A. Castillo, A. Greer, Struct. Chem. 2009, 20, 399 – 407; b) M. J. Paterson, O. Christiansen, F. Jensen, P. R. Ogilby, Photochem. Photobiol. 2006, 82, 1136; c) P.-G. Jensen, J. Arnbjerg, L. P. Tolbod, R. Toftegaard, P. R. Ogilby, J. Phys. Chem. A 2009, 113, 9965 – 9973. [50] C. Peng, P. Y. Ayala, H. B. Schlegel, M. J. Frisch, J. Comput. Chem. 1996, 17, 49 – 56. [51] A. J. Adamczyk, M.-F. Reyniers, G. B. Marin, L. J. Broadbelt, J. Phys. Chem. A 2009, 113, 10933 – 10946. [52] C. A. Morgado, P. Jurecˇka, D. Svozil, P. Hobza, J. Sˇponer, J. Chem. Theory Comput. 2009, 5, 1524 – 1544. [53] C. Hartwigsen, S. Goedecker, J. Hutter, Phys. Rev. B 1998, 58, 3641 – 3662. [54] K. D. Dobbs, W. J. Hehre, J. Comput. Chem. 1986, 7, 359 – 378. [55] a) J. Rigaudy, M. C. Perlat, D. Simon, N. K. Chong, Bull. Soc. Chim. Fr. 1976, 493 – 500; b) H. Kotani, K. Ohkubo, S. Fukuzumi, J. Am. Chem. Soc. 2004, 126, 15999 – 16006. [56] G. Sereda, V. Rajpara, Green Sustainable Chem. 2011, 1, 26 – 30. [57] G. Sereda, V. Rajpara, Tetrahedron Lett. 2007, 48, 3417 – 3421. [58] E. Baciocchi, T. Del Giacco, C. Rol, G. Sebastiani, Tetrahedron Lett. 1985, 26, 3353 – 3356. [59] a) L. Zˇ†dek, M. Machala, L. Skursky´, Drug Metab. Drug Interact. 1991, 9, 209 – 224; b) L. Skursky´, A. N. Khan, M. N. Saleem, Y. Y. al-Tamer, Biochem. Int. 1992, 26, 899 – 904; c) N. N. Andreev, E. V. Starovoitova, N. A. Lebedeva, Prot. Met. 2008, 44, 688 – 691. [60] M. Matsumoto, M. Yamada, N. Watanabe, Chem. Commun. 2005, 483. [61] J.-M. Aubry, B. Mandard-Cazin, M. Rougee, R. V. Bensasson, J. Am. Chem. Soc. 1995, 117, 9159 – 9164. [62] A. P. Scott, L. Radom, J. Phys. Chem. 1996, 100, 16502 – 16513. [63] L. Mart†nez-Fern‚ndez, J. Gonz‚lez-V‚zquez, L. Gonz‚lez, I. Corral, J. Chem. Theory Comput. 2015, 11, 406 – 414. Received: January 13, 2015 Published online on April 27, 2015

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