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Phthalimide-N-oxyl (PINO) Radical, a Powerful Catalytic Agent: Its Generation and Versatility Towards Various Organic Substrates Sergiu Coseri a a “Petru Poni” Institute of Macromolecular Chemistry, Iasi, Romania Online Publication Date: 01 April 2009

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Towards Various Organic Substrates',Catalysis Reviews,51:2,218 — 292 To link to this Article: DOI: 10.1080/01614940902743841 URL: http://dx.doi.org/10.1080/01614940902743841

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Phthalimide-N-oxyl (PINO) Radical, a Powerful Catalytic Agent: Its Generation and Versatility Towards Various Organic Substrates Sergiu Coseri ‘‘Petru Poni’’ Institute of Macromolecular Chemistry, Iasi, Romania The last two decades represents a ‘‘start line’’ for the worldwide chemists, to develop new oxidizing methods, to replace the ‘‘old-fashioned’’ ones, which are expensive, pollute the environment, and proceed in harsh conditions. One of the best candidates to satisfy the present global needs is N-hydroxyphthalimide (NHPI), which can be used as a catalytic reagent successfully in a wide range of organic transformations. In this article, a review of the most frequently used methods to transform the NHPI into its nitroxyl radical correspondent, and the use of this powerful catalytic agent into various organic transformations, are presented.

Keywords N-hydroxyphthalimide (NHPI), Phthalimide-N-oxyl (PINO), Selective oxidation, Oxidizing catalysts, Dioxygen

1.

INTRODUCTION

Catalytic aerobic oxidation of organic substrates is of fundamental importance in the industrial synthesis of a large variety of oxy-functionalized compounds from both economic and environmental points of view. The (catalytic) autooxidation of hydrocarbons such as cyclohexane, p-xylene and cumene are very important industrial processes, converting cheap feedstocks into highly valueadded products such as cyclohexanone/cyclohexanol (KA-oil, 6 6 106 tones per year), terephtalic acid (30 6 106 tones per year) and cumene hydroperoxide (5 Received 22 November 2007; Accepted 23 September 2008. Address correspondence to Sergiu Coseri ‘‘Petru Poni’’ Institute of Macromolecular Chemistry, 41A, Gr. Ghica Voda Alley, Iasi, 700487, Romania. E-mail: [email protected]

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Phthalimide-N-oxyl (PINO) Radical, a Powerful Catalytic Agent

6 106 tones per year), respectively (1). In the last decade, there has been an upsurge in research directed toward improving the rates of oxidation of organic compounds and improving product selectivities. One promising approach uses radicals bearing the .NONmoiety. Persistent .NON radicals have often been employed as neat, stoichiometric oxidants. Both persistent and transient .NON have been even more frequently employed in catalytic quantities in radical chain reactions in the presence of oxygen and, frequently, also in the presence of a cocatalyst. Among all .NON radicals, N-hydroxyphthalimide (NHPI), has emerged as a powerful and popular catalyst for organic oxidation reactions. NHPI is thought to catalyze oxidation through initial generation of the phthalimide-N-oxyl (PINO) radical by abstraction of the O-H hydrogen in NHPI. The PINO radical then abstracts a hydrogen atom from a target substrate, thus reverting NHPI and a carbon-centered radical. This carbon radical reacts with O2 to yield a peroxy radical, and the peroxy radical abstracts the O-H hydrogen from NHPI, forming a stable hydroperoxide, while also regenerating the PINO radical. A reaction mechanism for this process is provided in Scheme 1. NHPI was first used by Grochowski in 1977 (2), to catalyze the reaction of ethers with azodicarboxylate (DEAD). A detailed description of this reaction was not presented, and production of PINO was not experimentally proven. However, since the reaction did not progress under the presence of a radical scavenger, the reaction process was believed to proceed as shown in Scheme 2 (2). The hydroxyimide group of NHPI is added to DEAD, achieving equilibrium between PINO and added radical. The PINO produced at this step abstracts the hydrogen atom of the a-carbon to the ether oxygen, and provides a radical species A, which adds to DEAD resulting in the generation of an added radical species B. Radical species B abstracts the hydrogen atom from ether to yield adduct C and regenerates radical species A. However, the PINO radical was for the first time reported as early as 1964, by Lemaire and Rassat (3), using EPR spectroscopy for the NHPI and lead tetraacetate reaction in benzene. Since there, a large variety of methods

Scheme 1: Mechanism for the Hydrocarbon (RH) Oxidation Catalyzed by N-Hydroxy Phthalimide (NHPI). RH is the target hydrocarbon site, usually a benzylic or allylic carbon site. I is an initiator radical. ROON is peroxy radical at target hydrocarbon. ROOH is hydroxyperoxide on the target hydrocarbon.

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220

S. Coseri

Scheme 2: The use of NHPI in the reaction of ethers with azodicarboxylate (DEAD) (2).

to generate PINO radical have been developed and reported. These methods to generate PINO radical, can be divided into three categories of catalytic systems: i) Biocatalytic systems for the generation of PINO radical; ii) Electrocatalytic systems for the generation of PINO radical; and iii) Chemocatalytic systems for the generation of PINO radical.

2. THERMOCHEMICAL INVESTIGATIONS OF THE BDEs VALUES OF THE O-H BOND IN NHPI To understand the catalytic system in which PINO radical is involved it is necessary to know the precise O-H bond dissociation energy (BDE) of its precursor, NHPI. The target hydrocarbon sites in NHPI-catalyzed oxidation reactions are typically resonantly stabilized benzylic or allylic sites, with C-H bond energies of around 85–90 kcal mol21. For NHPI to act as an efficient oxidation catalyst, it requires an O-H bond of similar strength so that the abstraction of H from the hydrocarbons is either exothermic or close to thermoneutral. However, it is also important that the O-H bond in NHPI not be too strong so that PINO regeneration by the capping of nontarget alkyl radicals and peroxy radicals (ROON) is also, ideally, exothermic. Generally, O-H BDEs in ROOH compounds are ca. 85 kcal mol21 in the gas phase, while typical C-H bonds on nonresonantly stabilized carbon atoms are around 95–105 kcal mol21 for single-bonded carbons and higher for double- and triple-bonded

Phthalimide-N-oxyl (PINO) Radical, a Powerful Catalytic Agent Table 1:

Liquid-Phase Bond Dissociation Energies (BDEs) for the NHPI O-H bond.

Solvent

O-H BDE (kcal mol21)

Reference

88 90 ¡ 2 89.6 ¡ 10 82.7 88.1

(4) (5) (6) (7) (8)

tert-Butyl alcohol Acetic acid Benzene Acetonitrile


Table 2: Absolute rate constants at 25uC for the hydrogen atom abstraction by PINO and tert-butylperoxyl radical (4). RH PhCH3 PhCH2CH3 PhCHMe2 PhCH2OH cyclohexane

kH

(PINO)

M21 s21

0.38 2.24 3.25 28.3 0.047

kH

(tBuOON)

M21 s21

0.036 0.20 0.22 0.13 0.0034

kH

(PINO)

/ kH

(tBuOON)

10.5 11.2 14.8 218 13.8

carbons. Thus, the ideal O-H bond energy for oxidation catalysts such as NHPI should be in the range of 85–95 kcal mol21. There have been reported, several measurements of the O-H bond energy of NHPI, Table 1, carried out by using the EPR radical equilibrium technique, or by a semi empirical equation, using a thermodynamic cycle. However, the reported results are still subject of controversy. Despite the fact that the values of the BDE of the O-H bonds in NHPI and tBuOO-H are almost identical (88 kcal mol21), the PINO radical is considerably more reactive in the abstraction of the hydrogen atom from a C-H bond, Table 2 (4), than is the peroxyl radical. This different reactivity cannot, therefore, be ascribed to the enthalpic effect, but instead to the polar effect in relation to a more-pronounced electrophilic character of the PINO radical relative to the peroxyl radical, considerably enhanced by the presence of the two carbonyl groups in PINO, Equation (1).

Da Silva and Bozzelli (9), recently carried out an ample theoretical study of the oxidation catalyst NHPI using ab initio and density functional theory

221

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S. Coseri Table 3: O-H Bond Dissociation Energies (BDEs) for N-Hydroxyphthalimide, Calculated Using the G3B3 Theoretical Method with Nonisodesmic and Isodesmic Work Reactionsa (9). BDE b

83.0

Bond dissociation reaction Isodesmic work reactions: NHPI + CH25CHON 5. PINON + CH25CHOH NHPI + PhenoxyN 5. PINON + Phenol NHPI + HOON 5. PINON + H2O2 NHPI + NO2N 5. PINON + trans-HONO Average a


All values in kcal mol21.

b

83.1 83.1 83.5 83.3 83.3

Calculated from the reaction enthalpy of RH 5. RN + H.

methods. Geometrical and thermochemical properties were calculated for NHPI and an analogous molecule, N-hydroxymaleimide (NHMI). The abovementioned authors concluded that catalysis by NHPI proceeds by O-H hydrogen abstraction, forming the phthalimide N-oxyl radical (PINO). The PINO radical subsequently abstracts hydrogen from hydrocarbons, providing a site for O2 addition. In the gas phase, G3B3 calculations using bond-isodesmic work reactions provide O-H BDEs of 83.3 kcal mol21 for NHPI, Table 3 (9). Koshino et al. (5) investigate the reactivity of PINO with various hydrocarbons that have different C-H, BDEs being measured. Table 4 (5), lists the obtained rate constants per reactive hydrogen atom. One can see that the kPR values (per H) decrease as the C-H BDEs increase. Table 4: Rate Constants, kPR per Active Hydrogen Atom, for the Reaction of the PINO Radical with Hydrocarbons in HOAc at 25uC, and Their C-H Bond Dissociation Energy (BDEs) (5).

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 a g

Substrate

Number of H atoms

BDE (kcal mol21)

kPR (per H) (L mol21 s21)

9,10-Dihydroanthracene Benzhydrol Ph3CH Fluorene Benzyl alcohol PH2CH2 Cumene 1-Methylnaftalene Ethylbenzene Benzaldehyde Toluene 2-Methyl-1,4-naphthoquinone Cyclohexane

4 1 1 2 2 2 1 3 2 1 3 3 12

75.25a 77.88b 81.00c 81.00d 81.22e 83.85c 84.33a 85.05a 85.29a 86.96a 89.83a 89.83f 95.56a

2510 57.5 58.5 20.3 5.65g 6.63 26.6 1.43 2.68 10.6g 0.207g 0.0133 0.00193

From ref (10). b From ref (11). From ref (16).

c

From ref (12).

d

From ref (13).

e

From ref (14). f From ref (15).


To conclude, the differences founded by various authors for the O-H BDE in NHPI, can be fairly explained by the tendency of hydroxyl groups to form hydrogen bonds with polar solvents. Such hydrogen bonds could lead to a higher O-H BDE than that in nonpolar solvents (17). Although the founded values for the O-H BDE in NHPI are sometimes different, the differences are in quite good agreement (even those that have been obtained by different methods in different solvents).


3.

CHARACTERIZATION OF PINO RADICAL

Most of the kinetic data reported so far in literature concerning the PINO reactions with organic compounds use UV/vis, EPR spectroscopy and in a lesser extent the laser flash photolysis (LFP) method. Espenson et al. (18), reported for the PINO radical, (generated in acetic acid) a maximum peak at 382 nm in UV, and a molar absorptivity of 1.36 6 103 L mol21 cm21, Figure 1. Other 4-substituted radicals have been also characterized by means of UV and molar absorptivities, Table 5 (18). Thus, PINO and 4-PINO radicals, persist long enough for recording accurate UV/vis spectra. Masui (19), earlier reported for the PINO radical a maximum in UV at 380 nm in acetonitrile and a molar absorptivity of 1.46 6 103 L mol21 cm21. The measured rate constants for the self-decomposition of PINO and 4-PINO radicals, does not differ very much, being around of 0.5 L mol21 s21, except the 4-CH3-PINO, which decomposes three times faster than PINO, presumably due to electron-donating effect of CH3 group.

Figure 1: UV/Vis spectrum of PINO radical in acetic acid.

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S. Coseri Table 5: Maximum absorption wavelengths and molar absorptivities for PINO and 4-PINO radicals, in acetic acetic at 25uC. Radical


PINO 4-Cl-PINO 4-F-PINO 4-CH3-PINO

lmax/nm

emax/103 L mol21 cm21

382 394 382 397

1.36 1.38 1.21 1.39

The EPR technique has been applied for the characterization of PINO radical as early as 1964 by Rassat et al. (3). PINO presents a triplet signal, Figure 2, with a hyperfine coupling constant of aN 5 4.36 G in t-BuOH (4), and 4.3 G in benzene (20). Lanzalunga et al. (8) reported for PINO a hyperfine coupling constant of aN 5 4.76 in acetonitrile. Other substituted PINO radicals studied by EPR shows an increasing value of aN by decreasing the electron-withdrawing character of the ring substituent (8). The presence of the two acyl groups in PINO radical, lead to an increased value of g-factor: 2.0073 (20). Baciocchi et al. (21) employs the LFP technique for the kinetic study of PINO with more reactive N,N-dimethylanilines. PINO was produced by hydrogen atom abstraction from NHPI by the tert-butoxyl radical generated by 266 nm laser photolysis of di-tert-butyl peroxide in CH3CN at 25uC, according with the Scheme 3. The time-resolved spectrum obtained in a laser photolysis is presented in Figure 3. The absorption that appears 200 ns after the laser pulse, due to the tert-butoxyl radicals formation (22), is replaced after cca 20 ms by the absorption due to PINO, lMAX 5 380 nm (19). Recently, Lanzalunga et al. (23) performed a kinetic study of the oneelectron oxidation of a number of ferrocenes by PINO generated in acetonitrile by reaction of NHPI with the cumyloxyl radical, produced by LFP of dicumyl peroxide at 355 nm. According to this study, the intrinsic reactivity of PINO in electron-transfer reactions has been calculated as 7.6 6 102 M21 s21.

Figure 2: EPR spectrum of PINO radical.



Scheme 3: PINO generation by using di-tert-butyl peroxide and LFP.

4. BIOCATALYTIC SYSTEMS FOR THE GENERATION OF PINO RADICAL The world of biochemistry offers many examples of the role of a messenger. For example, the RNA-messenger delivers the genetic information to the proteins factory embodied by the ribosome, whereas cyclic-AMP promotes the metabolism of lipids and sugars. A messenger solves communication needs, but it may also act as a catalyst (24). Peculiarities of the role may require turning the name messenger into that of mediator: this becomes more appropriate in the field of enzymatic oxidations and, in particular, in the degradation of wood. The most important application of these biocatalyst

Figure 3: Transient absorption spectra measured 200 ns (squares) and 20 ms (circles) after laser excitation of a solution of di-tert-butyl peroxide (0.5 M) and NHPI in acetonitrile.

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226

S. Coseri

systems seems to be the lignin’s oxidation. Lignin, the largest alkylaromatic polymer in nature, is so structurally complex, that a direct interaction with the active site of an enzyme is sterically unfeasible. Appropriate messengers can however, solve the problem (25, 26). These low-molecular-weight metabolites, once oxidized by the enzymes, sneak away into the wood fibers and delivers oxidative equivalents to appropriate functional groups of the lignin polymer. For example, lignin peroxidase (27), a heme enzyme, endowed with a redox potential of 1.3–1.4 V/normal hydrogen electrode (NHE), and with a small site, oxidizes the metabolite veratryl alcohol (i.e., 3,4-dimethoxybenzyl alcohol) to its radical cation by electron abstraction. Another enzyme involved in the biodelignification of rotten wood is lacasse, a family of multicopper oxidases endowed with a redox potential in the 0.5–0.8 V/(NHE) range (28, 29). The laccases (p-diphenol: dioxygen oxidoreductase, EC 1.10.3.2) can be divided into two categories, plant and fungal, although diphenoloxidizing enzymes which are thought to be laccases have also been identified in insects (30–32) and eubacteria (33). By far the most studied plant laccases is from Rhus vernicifera, but it has also been purified and characterized from Rhus succedanea and two other sources. All of the plant laccases are extracellular monomeric proteins with 22–45% glycosolation. The only plant laccases to have been sequenced is from Acer pseudoplatanus (34). Laccases generally contain four copper ions per protein molecule. They are classified into three types according with their spectroscopic properties: one type 1 (T1), in which copper is coordinated to two histidines and a cysteine, one type 2 (T2) which coordinates to two histidines and a water molecule, and two types 3 (T3) coppers, coordinated to three histidines and a bridging hydroxyl group. Prior to 1992, it was thought by some, that laccases was present in few plant species outside of Rhus and its immediate relatives (35); it has since been purified from other sources and has been detected in a variety of plants (36–39). Although plant laccases was initially thought to catalyze lignin formation, peroxidase has long been considered the sole enzyme responsible for this function (40). Laccases activity has been detected in the xylem cell walls of a wide variety of plant species (41), even when catalase was added, thus eliminating the possible involvement of peroxidase. Most plant laccases are capable of oxidatively coupling monolignols to dimers and trimers, while peroxidase has a much greater activity toward higher oligomers (42, 43). Due to the lower redox potential (44), lacasses can oxidize monoelectronically only the phenolic groups of lignin (phenoloxidase activity), but these represent less than 20% of all the functional groups of the polymer. The benzyl alcohol and ether groups, summing up to about 70% of the residues but being more resistant to monoelectronic oxidation (redox potential . 1.5 V/NHE), cannot be oxidized by lacasses directly. Use of appropriate redox metabolites, or of purposely added compounds, enables lacasses to oxidize indirectly even



Scheme 4: The oxidation cycle of a lacasses/mediator system towards non-phenolic substrates (24).

non-phenolic groups in a catalytic cycle (24, 45, 46). Following monoelectronic interaction with the enzyme, the oxidized messenger (Medox) oxidizes unnatural non-phenolic substrates according to mechanisms not available to lacasses, as sketched in Scheme 4 (24) in very general terms. In this way, the messenger expands the oxidation ability of the enzyme, and more specifically fulfils the role of a ‘‘mediator’’ (24, 47). There have been found several good mediators for the lacasses, which share the structural feature of being N-OH derivatives: 1-hydroxybenzotriazole (HBT), violuric acid, N-hydroxyacetanilide, and N-hydroxyphthalimide (NHPI) (47–49). Previous studies have indicated that these compounds are oxidised by the type 1 (T1) Cu center of laccase to the corresponding N-oxyl radicals (Medox), which are the active species in the oxidation of the substrate (Scheme 4) (50–52). Among the N-OH mediators NHPI is of particular interest in consideration of the fact that this compound, in combination with molecular oxygen and metal salt co-catalysts like Co(OAc)2 or Co(acac)2, is able to efficiently catalyze the oxidation of a large variety of organic compounds under mild conditions at moderate oxygen pressure and temperature (53). In addition, in this case the PINO radical is considered the active oxidant. The laccase/NHPI/O2 system represents a convenient way of carrying out oxidation processes, like those involved in the degradation of lignin or environmental pollutants, in water (47). The laccase/NHPI system has been applied with some success in the delignification of kraft pulp samples; however, the mediation efficiency was significantly lower than that observed with another classical mediator, 1-hydroxybenzotriazole (54). The mechanism proposed in the literature for the NHPI mediated oxidation of benzylic alcohols by laccases is reported in Scheme 5 (47, 52). The oxidation of NHPI by laccases leads to the PINO radical (path a) that can abstract a benzylic hydrogen atom from the substrate (path b) regenerating the NHPI and leading to an a-hydroxyl benzyl radical. Reaction of the latter species with O2 leads to the formation of the a-hydroxyperoxyl radical (path c) from which the carbonyl product is formed by release of hydroperoxyl radical HOON (path d) (55).

227


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S. Coseri

Scheme 5: Mechanism of oxidation of benzyl alcohols promoted by the lacasses/NHPI/O2 systems (47, 52).

The NHPI (10 mmol), laccase (5 mmol) and the benzyl alcohol (30 mmol) were added to a buffered solution (0.1M sodium citrate, pH 5.0) with 25% dioxane as cosolvent, purged with O2 for 30 min before the addition of the reagents. The mixture was magnetically stirred at room temperature for 15 h under oxygen (filled balloon). Reaction products were extracted with CH2Cl2, dried over Na2SO4 and characterized by GC–MS and 1H NMR.

5. ELECTROCHEMICAL SYSTEMS FOR THE PINO RADICAL GENERATION In 1983, Masui et al. carried out a pioneering work on the synthetic application of NHPI as mediator in electrochemical oxidation of secondary alcohols to the corresponding carbonyl compounds, and showed that PINO formed by an electrochemical oxidation of NHPI abstracts selectively hydrogen atoms from the alcohols leading to ketones, Scheme 6 (57). After this first use of NHPI as a mediator in the electrochemical oxidation of alcohols, Masui and coworkers, applied the methods to a large variety of oxidation reactions, including another alcohols having a benzylic carbon or acarbon to a heteroatom (58), olefins (59), amides and lactams (60), ketals (61), and aldehyde acetals (62). It has been shown that the oxidation of NHPI was not a two-electron oxidation unlike those observed for other hydroxamic acids (63), and most of the starting NHPI was recovered from the solution after the passage of two Faradays (F) of electricity per mole of compound. During the electrolysis, the solution became yellow, but the colors disappeared on addition of an alcohol. NHPI has a low oxidation potential in the presence of added base



Scheme 6: Electrolytic oxidation of alcohols mediated by NHPI (57).

and a high number of turnovers and a high current efficiency without the assistance of photoexcitation (64). NHPI has an oxidation peak at 1.44 V vs. saturated calomel electrode (SCE) at a glassy-carbon electrode in acetonitrile containing 0.1 M NaClO4, and in the presence of pyridine, an extra peak (63, 65, 66) develops at 0.85 V. Table 6 shows the yields of the electrochemical oxidation of the primary alcohols, mediated by NHPI (57). The oxidation of the secondary alcohols was performed as follows: 5 mM of NHPI, 20 mM of alcohol, and 5 mM of pyridine were dissolved in 40 mL of acetonitrile containing 0.1 M NaClO4 in an undivided cell. The electrodes used are a glassy-carbon plate anode (50 6 15 6 2 mm), a glassy-carbon cylinder cathode (45 6 3 mm diameter), and a SCE reference electrode. 2F of electricity per mole of alcohol were passed at an anode potential of 0.85 V. The products were confirmed as carbonyl compounds by forming their 2,4-dinitrophenylhydrazone derivatives and their quantities estimated by g.c. of the solution after electrolysis, see Table 7 (57).

Table 6:

Yields of aldehydes from primary alcohols (57).

Alcohol

Solvent

Eappa

Yieldb of aldehyde

NHPI recovered (%)

PhCH2OH EtOH nPrOH nBuOH

MeCN EtOH nPrOHc nBuOHc

0.85 1.00 1.40 1.40

49 93 17 9

43 46 13 14

a Applied potential, V vs. SCE. bCurrent yield, 16 F/mol based on NHPI (5 mM). perchlorate was used as a supporting electrolyte.

c

Lutidinium

229

230

S. Coseri Table 7:

Yield of ketones from secondary alcohols (57).

Alcohol


Ph2CHOH PhCH(Me)OH Cyclohexanol 2-Isopropyl-5-methyl-cyclohexanol 1,7,7-Trimethyl-bicyclo[2.2.1]heptan2-ol MeCH(OH)Et MeCH(OH)-CH(OH)Me

Cyclohexane-1,2-diol

Yield (%) of ketone

NHPI recovered (%)

96 87 94 58 91

90 74 60 25 66

88 59a (diketone) 9a (hydroxyketone) 30b

84 11

12

a

3.9 F/mol based on the alcohol. b1.7 F/mol based on the alcohol.

6. CHEMOCATALYTIC SYSTEMS FOR THE PINO RADICAL GENERATION 6.1. 6.1.1.

Metallic Systems NHPI/Transition Metals System for the PINO Radical Generation

The search for an efficient system for the catalytic oxidation of organic compounds with molecular oxygen under mild conditions remains an important challenge. The use of NHPI in combination with molecular oxygen and metal salt cocatalysts, like Co(OAc)2, Mn(OAc)2, Co(acac)2, Mn(acac)2 was developed by Ishii and his group (53, 67), become known today as ‘‘Ishii system.’’ The NHPI/O2/transition metal system is able to efficiently catalyze the oxidation of a large variety of organic compounds, under mild conditions at moderate oxygen pressure and temperature (68–69). Below, the most important processes implying the use of ‘‘Ishii system’’ in selective oxidation of a wide range of organic substrates are reviewed.

6.1.1.1.

Alkanes and Alkylbenzenes Oxidations with Molecular Oxygen

During the past decades, a number of catalytic systems have been developed for the oxidation of alkanes with dioxygen in the presence of reducing agents, e.g., H2, metals, aldehydes, etc., under mild conditions (70– 77). However, effective and selective methods for the catalytic oxygenation of alkanes with dioxygen still remain a hot topic in organic chemistry. On the other hand, effective large-scale processes for the transformation of alkanes with molecular oxygen have been limited because of the exceedingly low



reactivity of alkanes. Typical examples of such processes are the autooxidation of cyclohexene and p-xylene. The reactions involve a free radical chain, and hence are carried out under relatively harsh conditions, i.e., higher oxygen pressure, and more severe temperature (usually . 150uC) (78). Therefore, the reactions are often difficult to control and exhibit poor product selectivity. The selective catalytic oxidation of alkylbenzenes with molecular oxygen is a very important reaction for the production of bulk and fine chemicals such as benzoic acid and terephtalic acid (79–80). Practically the oxidation of toluene is carried out in the presence of a catalytic amount of cobalt (II) 2ethylhexanoate under a pressure of 10 atm of air at 140–190uC (78). If the direct aerobic oxidation of alkylbenzenes can be done under normal pressure and temperature, it will vastly contribute to industrial chemistry from technical, economical, and environmental aspects, since undesired reactions due to the higher pressure and temperature will be minimized. Ishii and coworkers (68), have the firsts who reported the oxidation of toluene under normal pressure of dioxygen at room temperature by the use of a combined catalyst of NHPI and Co(II) species, Equation 2.

Representative results for the NHPI-catalyzed aerobic oxidation of various alkylbenzenes in the presence of Co(OAc)2 in acetic acid under ambient conditions are listed in Table 8 (67). Both p- and o-xylenes were selectively oxidized to p- and o-toluic acids without the formation of dicarboxylic acids. oEthyltoluene underwent selective oxidation to form a mixture of corresponding alcohol and ketone in which the ethyl moiety was selectively functionalized. It is of interest to examine the effect of substituents on the aromatic ring in the oxidation of substituted toluenes. p-Methoxytoluene was more rapidly oxidized than the toluene itself, while p-chlorotoluene was oxidized at a relatively slow rate. An electron-donating substituent anchoring to toluene stabilizes the partial positive charge on the benzylic carbon in the transition state for the abstraction of a benzylic hydrogen atom by PINO possessing an electrophilic character, Scheme 7 (67).

231

Run

Substrate

Time (h)

Conv. (%)

Product

Yield (%)

1

20

95

85

2

20

93

83

3b

20

82

21

37

4

20

95

91

5b

6

89

80

6

20

71

67

S. Coseri


232

Table 8: Aerobic oxidation of various alkylbenzenes at room temperaturea (67).


Run

Substrate

Time (h)

7

20

8

12

Conv. (%)

Product

Yield (%)

No reaction

.99

93

a Substrates (3mmol) were allowed to react in the presence of NHPI (10 mol %) and Co(OAc)2 (0.5 mmol %) in AcOH (5mL) under dioxygen (1 atm) at 25uC. bCH3CN was used as the solvent.


Table 8: Continued.

233

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S. Coseri

Scheme 7: Transition state for the reaction of PINO with substituted benzene (67).


Therefore, the oxidation of toluenes having electron-donating groups by the NHPI catalyst is facilitated. Indeed, p-nitrotoluene substituted by a strong electron-withdrawing nitro group was not oxidized at all under these conditions.

6.1.1.2. General Procedure for the Oxidation of Toluene under Ambient Conditions (67) An acetic acid (5 mL) solution of toluene (276 mg, 3 mmol), NHPI (10 mol %, 48.9 mg) and Co(OAc)2 (0.5 mol%, 3.7 mg) was placed in a two-necked flask equipped with a balloon filled with O2. The mixture was stirred at 25uC. After 20 h, evaporation of the solvent followed by flash chromatography (n-hexane/AcOEt 5 5/1) on silica gel afforded benzoic acid as a white solid; yield: 296 mg (81%). A plausible reaction pathway for the aerobic oxidation of toluene by the combined use of NHPI and Co(OAc)2 is illustrated as Scheme 8 (69). The complexation of Co(II) with dioxygen to generate a labile dioxygen complex such as superoxocobalt (III) or m-peroxocobalt (III) complex is present during the oxidation step. Such cobaltoxygen species are reported to be easily formed by the one-electron reduction of dioxygen using Co(II), Scheme 9 (69). The generation of PINO by the reaction of the NHPI with the cobalt (III)oxygen complex under ambient conditions would be the most important step in the present oxidation. The next step in the reaction involves the hydrogen abstraction from toluene by the PINO to form a benzyl radical, which is readily trapped by dioxygen to provide the benzylperoxy radical followed by benzyl hydroperoxide and eventually the formation of benzoic acid. The reaction of the benzylperoxy radical with Co(II) is known to lead to benzaldehyde as the primary product of benzoic acid. The combined catalyst of NHPI with Co species, led to a dramatic enhacement of the oxidation rate of alkanes. Ishii and coworkers (67) investigated the effect of the Co species on the NHPI-catalyzed aerobic oxidation of alkanes. The absorption rates of dioxygen during the oxidation of ethylbenzene by several catalytic systems were measured using a constant-pressure absorption apparatus (68). Ishii and coworkers extended their work on various benzylic compounds, which were allowed to react in the presence of a catalytic amount of NHPI (10 mol %) under an atmosphere of oxygen (1 atm) at 100uC for 20 h, Table 9 (68).



Scheme 8: A plausible reaction pathway for the aerobic oxidation of toluene by the combined use of NHPI and Co(II) (69).

It is interesting that oxygen-containing substrates such as benzyl methyl ether, isochroman, and xanthene were smoothly oxidized by the NHPI-O2 system to produce methyl benzoate, 1-isochromane, and xanthone in 60%, 83%, and 99% yields, respectively. Recupero and Punta very recently

Scheme 9: One electron reduction of dioxygen by using Co (II) (69).

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S. Coseri Table 9:


Run

NHPI-Catalyzed Aerobic Oxidation of Benzylic Derivativesa (68). Substrate

Product

Yieldb (%)

1

80

2c

15

3

73

4

34

5

64

8

6

20

30

7

37

13

Phthalimide-N-oxyl (PINO) Radical, a Powerful Catalytic Agent Table 9: Run

Continued. Substrate

Product

Yieldb (%)

8

42


7

9

60

10

83

11

99

a

Substrate (2 mmol) was reacted in the presence of NHPI (10 mol %) in PhCN (5 mL) under dioxygen atmosphere at 100uC for 20 h. bGLC yields. c80uC for 20 h.

published an ample review on the alkane, alkylbenzene, and other substrates radical functionalization by using NHPI (81).

6.1.1.3. General Procedure for the NHPI-Catalyzed Aerobic Oxidation of Benzylic Derivatives (68) A benzonitrile (5 mL) solution of alkane (2 mmol) and NHPI (33 mg, 0.2 mmol) was placed into a three-necked flask and equipped with a balloon filled with O2. The mixture was stirred at 100uC for 20h. After the reaction, the catalyst was filtered off and the resulting solution was extracted with diethyl ether (20 mL 6 3). The combined extracts were dried over MgSO4 and analysed by GLC. Removal of the solvent under reduced pressure afforded a clean liquid, which was purified by column chromatography on silica gel (nhexane/AcOEt) to give the corresponding ketones and alcohols.

6.1.2.1.

NHPI/Co(OAc)2 System for the Oxidation of Methylpiridines

Pyridinecarboxylic acids are useful and important intermediates in pharmaceutical syntheses. Although the synthesis of these carboxylic acids

237


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S. Coseri

by the aerobic oxidation of alkylpyridines is straightforward, the oxidation is usually difficult to carry out selectively owing to their low reactivity (82–84). In general, pyridinecarboxylic acids are prepared by the oxidation of alkylpyridines with nitric acid or by the hydrolysis of pyridinecarboxamides derived from pyridinecarbonitrile (85). The oxidation of b-picoline in the presence of NHPI and Co(OAc)2 was reported by Shibamoto and coworkers (86), to produce nicotinic acid. Nicotinic acid is used as a precursor of vitamin B3 and is commercially manufactured on a large scale by nitric acid oxidation of 5-ethyl-2-methylpyridine (87). Representative results for the oxidation of bpicoline with molecular oxygen (1 atm) catalyzed by NHPI combined with small amounts of a transition metal ion in acetic acid at 100uC are given in Table 10 (86). The oxidation of b-picoline in the presence of NHPI (10 mol %) and Co(OAc)2 (0.5 mol %) produced 3-pyridinecarboxylic acid, along with small amount of 3-pyridinecarboaldehyde. However, the oxidation of b-picoline in the presence of Co(OAc)2 under these conditions did not lead to any oxidation product at all. Although Co(acac)2 was also effective for the oxidation of bpicoline (Table 10, run 2), transition metal salts other than Co salts did not accelerate the oxidation of b-picoline (Table 10, runs 3–7).

Table 10: (86).

Effect of transition metal salt on aerobic oxidation of b-picoline by NHPIa

Yield (%)

Run 1 2 3 4 5 6 7

Metal No reaction Co(acac)2 Mn(OAc)2 Cu(OAc)2 VO(acac)2 Fe(acac)3 Ni(OAc)2

Conversion (%) 60 3 5 2 8 3

53 Trace 2

1

1

a b-Picoline (2 mmol) was allowed to react with O2 (1 atm) in the presence of NHPI (10 mol %) and a transition metal (0.5 mol %) in acetic acid (7 mL) at 100uC for 15 h.

Phthalimide-N-oxyl (PINO) Radical, a Powerful Catalytic Agent Table 11: Oxidation of c-picoline with air by NHPI-Co(OAc)2-Mn(OAc)2 system under various conditionsa (81).


Run 1 2 3 4 5 6b 7 8 9c 10c,d

NHPI (mol Co(OAc)2 %) (mol %) 10 10 10 10 10 10 15 20 10 10

0.5 0.5 1 1 0.5 1 1 1 1

Mn(OAc)2 (mol %) 0.1 0.5 0.5 1 1 1 1 0.5 0.5

Conversion (%) 25 3 no reaction 46 52 15 62 67 18 43

Yield (%) 4-pyridinecarboxilic acid 22 2 44 46 10 56 60 15 39

a c-Picoline (2 mmol) was allowed to react with 20 atm of air in the presence of NHPI, Co(OAc)2, and Mn(OAc)2 in AcOH (7 mL) at 150uC, for 5 h. bThe reaction was carried out at 120uC. cThe reaction was carried in MeCN (7 mL). dAcOH (2 mmol) was added.

Interestingly c-picoline was oxidized with difficulties under 20 atm of air by the NHPI-Co(OAc)2-Mn(OAc)2 system to form 4-pyridinecarboxilic acid in moderate yield (22 %) (Table 11, run 1) (86). The absence of the Mn(OAc)2 from the initial composition of the catalytic system, led to only 2% yield of 4-pyridinecarboxilic acid. When the NHPI (10 mol %)-Co(OAc)2 (1.0 mol %)-Mn(OAc)2 (1 mol %) system was employed as the catalyst, 4-pyridinecarboxilic acid was obtained in 46% yield at 52% conversion (Table 11, run 5). Oxidation using 20 mol % of NHPI under these conditions afforded 4-pyridinecarboxilic acid in 60% yield (67% conversion). Oxidation of c-picoline using acetonitrile as solvent resulted in low conversion (18%) (Table 11, run 9). However, it is important to note that the addition of small amounts of acetic acid to the reaction system lead to considerable improvements in the conversion of c-picoline and the yield of 4-pyridinecarboxilic acid (Table 11, run 10).

6.1.2.2. General Procedure for NHPI/Transition Metal Oxidation of aPicoline (86) To a solution of NHPI (10 mol %) and transition metals in acetic acid (7 mL) in a pear-shaped flask was added a-picoline (2 mmol). The flask was

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S. Coseri Table 12: (89).

Aerobic oxidation of 1a catalyzed by NHPI under selected conditionsa

Selectivity (%)b Run


1 2 3 4 5c 6c 7c 8c

Metal

Conversion (%)

2a

3a

4a

5a

— Co(acac)2 Cu(acac)2 Mn(acac)2 — Co(acac)2 Cu(acac)2 Mn(acac)2

34 70 69 No reaction 48 85 83 63

23 20 22

69 75 77

,1 ,1 ,1

,1 ,1 ,1

18 2 5 4

63 72 70 62

,1 2 2 3

,1 2 3 5

a Compound 1a was allowed to react under O2 atmosphere (1 atm) in the presence of NHPI (10 mol%) and a metal species (0.5 mol%) in MeCN (5 cm3) at room temperature (25uC) for 30 h. bSelectivity of the products was determined by GC. cThe reaction was carried out at 50uC for 6 h.

equipped with a balloon filled with O2 (1 atm). The mixture was stirred at 100uC for 15 h. After the reaction, the solvent was removed under reduced pressure to afford a brown solid. To remove NHPI, metal salts, and side products, the resulting solids obtained by oxidation of a-picoline were dissolved in small amount of methanol or DMSO, respectively, and the solution was refluxed. The solution was cooled in an ice bath, and excess acetonitrile was added to give a pure white solid, 3-pyridinecarboxylic acid.

6.1.3.

Oxygenation of Alkynes by using NHPI/Transition Metal System

Since the bond dissociation energy of the prop-2-ynylic C-H bonds of alkynes (87.3 ¡ 2 kcal mol21 for pent-2-yne) is approximately equal to that of the benzylic C-H bond of alkylbenzenes (88.0 ¡ 1 kcal mol21) (88), the researcher’s interest was directed toward the NHPI-catalyzed oxidation of alkynes. Oct-4-yne 1a was chosen as a model substrate and allowed to react with dioxygen in the presence of a catalytic amount of NHPI and a transition metal, Scheme 10, Table 12 (89).

Scheme 10: Alkyne’s oxidation performed with NHPI/transition metal salts and dioxygen (89).



Surprisingly, the oxidation of 1a (Scheme 10) with molecular oxygen (1 atm) under the influence of NHPI (10 mol %) at room temperature produced oct-4-yn-3-one, 3a (69%) along with oct-4-yn-3-ol 2a (23%) at 34% conversion, Table 12, run1. In analogy with the aerobic oxidation of alkylbenzenes by NHPI (69), the oxygenation of 1a was found to be significantly accelerated by adding a transition metal such as Co(acac)2. Thus, the oxidation of 1a (Scheme 10) catalyzed by NHPI (10 mmol%) in the presence of Co(acac)2 (0.5 mmol%) gave 3a (75%) and 2a (20%) with 70% conversion, Table 12, run 2. The same oxidation using Cu(acac)2 (0.5 mmol%) in place of Co(acac)2 (0.5 mmol%) afforded 3a with 77% selectivity together with 2a (22%) at 69% conversion, Table 12, run 3. However, no reaction took place when Mn(acac)2 was employed in place of Co(acac)2 under these conditions. When the reaction of 1a (Scheme 10) with NHPI/Co(acac)2 was carried out at elevated temperatures (50uC), the oxidation was almost complete after 6 h to give 3a with 72% selectivity along with small amount of a cleaved product, butanoic acid, 5a, Table 12, run 6. In the oxidation of 1a using the NHPI/Mn(acac)2 system at 50uC, 3a, was formed with 62% selectivity at 63% conversion.

6.1.3.1. General Procedure for the Aerobic Oxidation of Alkyne, Using NHPI/Transition Metal System (89) To a solution of NHPI (0.2 mmol, 10 mol%) and a transition metal complex (0.01 mmol, 0.5%) in MeCN (5 cm3) was added alkyne (2 mmol), the flask was flushed with oxygen and equipped with a balloon filed with O2. The reaction mixture was stirred at 25uC for 30 h. The solvent was evaporated under reduced pressure. The products were purified by column chromatography on silica gel (hexane – ethyl acetate 10:1 to 3:1) and characterized by 1H and 13C NMR, GC-MS, and IR spectroscopy.

6.1.4.

Oxygenation of Alcohols by Using NHPI/Transition Metal System

The selective oxidation of alcohols to the corresponding carbonyl compounds is a frequently used transformation in organic synthesis, and hence a wide variety of methods has been developed. Among the catalytic processes promoted by the NHPI/O2/Co(II) system, the oxidation of alcohols to carbonyl compounds is of particular synthetic importance since most of the reagents, which perform this transformation are required in amounts of 1 equiv or more; moreover some of them are hazardous or toxic. Oxidation of primary aliphatic alcohols with the NHPI/O2/Co(II) system leads to the corresponding carboxylic acids, while that of secondary alcohols leads to corresponding ketones (90, 91). Iwahama and coworkers (91) reported an efficient catalytic system consisting of N-hydroxyphthalimide and a Co ion for

241

242

S. Coseri


Scheme 11: Oxidation of alcohols with molecular oxygen as an oxidant and NHPI as cocatalyst (91).

the oxidation of alcohols and diols with molecular oxygen as an oxidant, Scheme 11 (91). The oxidation of 2-octanol to 2-octanone, was later examined by the same author (90). The representative results for this transformation with molecular oxygen (1 atm) under various conditions, with or without using additives are presented in Table 13 (91). The oxidation of 2-octanol with molecular oxygen catalyzed by NHPI (10 mol %) combined with Co(OAc)2 (0.5 mol %) in CH3CN at 70uC for 20 h gave 2-octanone in high yield (93%) (Table 13, run 2). The most suitable solvent was found to be AcOEt (Table 13, run 3). Interestingly, benzoic acids, such as mchlorobenzoic acid (MCBA) enhance the oxidation of alcohols to carbonyl compounds, as well as benzoic acid (BA), p-methoxybenzoic acid (PMBA), pnitrobenzoic acid (PNBA) (Table 13, runs 4, 5, 7–11). A plausible reaction path for the aerobic oxidation of 2-octanol by the present catalytic system is illustrated in Scheme 12 (90). The above proposed reaction mechanism is similar with the proposed reaction mechanism for the aerobic oxidation of alkanes catalyzed by NHPI

Table 13: Oxidation of 2-octanol to 2-octanone with molecular oxygen catalyzed by NHPI combined with Co(OAc)2 under various conditionsa (91).

Run

Solvent

Additiveb

Temp. (uC)

Time (h)

Conversion (%)

Yield (%)c

1d 2 3 4 5 6 7e 8f 9 10 11

CH3CN CH3CN AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt

— — — MCBA MCBA — MCBA MCBA BA MCBA MCBA

70 70 70 70 25 25 25 25 25 25 25

20 20 12 3 20 20 20 20 20 20 20

9 93 84 90 75 21 62 75 70 67 42

9 93 84 90 75 21 60 75 70 64 41

a

2-Octanol (3 mmol) was allowed to react with molecular oxygen (1 atm) in the presence of NHPI (10 mol %), Co(OAc)2 (0.5 mol %), and additive (5 mol %) in solvent (5 mL). bMCBA 5 mchlorobenzoic acid, BA 5 benzoic acid, PMBA 5 p-methoxybenzoic acid, PNBA 5 pnitrobenzoic acid. cGC yield. dWithout Co(OAc)2. eMCBA (1 mol %) used. fMCBA (10 mol %) was used.



Scheme 12: A possible path for the oxidation of 2-octanol (90).

combined with Co(OAc)2 (68), with the Co(III)-dioxygen complex formation, which assist the PINO radical formation from NHPI. Iwahama et al. (90), extended their work on NHPI/transition metals oxidation of diols. Table 14 (90), shows the aerobic oxidation of several diols by NHPI/Co(acac)3 system. This method seems to be very reliable to get oxidized products from diols in relatively high yields. Figiel et al. (92) recently proposed a new catalytic system composed of NHPI, VO(acac)2 and some additives for the cyclohexanol oxidation reaction in acetonitrile at 75uC and 1 atm of O2. VO(acac)2 is well known as a catalyst for oxidation reactions of unsaturated hydrocarbons (93), hydroquinones (94), and propargylic alcohols (95), using dioxygen as oxidant. Nevertheless, under the reaction conditions described above, VO(acac)2 does not catalyze the cyclohexanol oxidation reaction with dioxygen and shows hardly any influence

243

244

S. Coseri Table 14:


Run

Oxidation of various diols with molecular oxygena (90). Alcohol

Time (h)

Conv. (%)

Products

Yield (%)

1

6

80

80

2

12

88

72

16

3

12

76

75

4

12

75

61

5

20

80

66

a

Diols (3 mmol) were allowed to react with molecular oxygen (1 atm) in the presence of NHPI (10 mol %) and Co(acac)3 (1 mol %) in CH3CN (5 mL). bGC yield.

on the course of reactions with the participation of NHPI, although positive catalytic activity of VO(acac)2 towards the oxidation of adamantane with NHPI has been reported (96).


6.1.5. Aerobic Oxidation of N-Alkylamides Catalyzed by NHPI/Co(OAc)2 System


The amino group is a more effective electron-releasing substituent than the hydroxyl group (the values of the ap Hammet constants are 20.57 and 20.35 for –NH2 and –OH groups, respectively) and therefore we would expect a higher reactivity and a stronger polar effect in the oxidation of alkyamines by O2 and NHPI catalysis compared to the corresponding alcohols. However, Minisci et al. (97) observed that under conditions in which alcohols are easily oxidized, the corresponding amines are substantially inert. This inertness is due to the degradation of the catalyst (NHPI) by the amine, according with Equation 3 (97).

To avoid the deactivation of the catalyst, Minisci et al. (97), considered the possibility of protecting the amino group by acylation. The oxidation of alkylamides by O2, catalyzed by NHPI and Co salts, occurs under mild conditions, leading to carbonyl products (imides, carboxylic acids, ketones, aldehydes) (21). The exact product distribution depends on the structure of the alkyl group and the reaction conditions, Equation 4 (97).

Tertiary benzylamines cannot react with NHPI (according to Eq. 3), due to the lack of any hydrogen, bonded to nitrogen, thus being easily oxidized by O2 to the corresponding aldehydes, in the presence of NHPI and transition metal salts catalyst (98).

6.1.5.1. General Procedure for Aerobic Oxidation of N-alkylamides Catalyzed by NHPI/Co(OAc)2 System (97) A solution of the amide (5 mmol), NHPI (0.5 mmol) and Co(OAc)2 (0.025 mmol) in 10 mL of the solvent (CH3CN or AcOH) was placed in a

245

246

S. Coseri

three-necked flask under an atmosphere of O2. The solution was stirred at the temperatures ranging from 20–80uC depending on the initial substrate, for 1– 5 h. The catalyst was removed through silica gel and the solution was analyzed by gas chromatography by using the internal standard technique.


6.1.6.

The Hydroxyacylation of Alkenes Using NHPI/Co(OAc)2 System

Addition of aldehydes to terminal alkenes has received attention as a method for the synthesis of ketones from aldehydes (99). Although there have been reported the hydroxyacylation of alkenes, like acrylates with acyl radicals from aldehydes using dioxygen as a hydroxyl source assisted by a cobalt(II) Schiff-base complex (100), the attempt was not fully successful due to the decarbonylation from acyl radicals as well as the reaction of acyl radicals with O2 leading to carboxylic acids, which cause undesired side reactions. To overcome these drawbacks arising from acyl radicals, Hirano et al. (101) employed 1,3-dioxolanes, masked aldehydes, as an acyl source in place of aldehyde, Equation 5 (101).

A plausible reaction path for the apparent hydroxyacylation of methyl acrylate with 2-methyl-1,3-dioxolane under dioxygen is shown in Scheme 13 (101). The reaction may be initiated by the hydrogen atom abstraction from NHPI by the action of the Co(III)-dioxygen complex, giving PINO which then abstracts the dioxolane hydrogen of the 2-methyl-1,3-dioxolane to form an dioxolane radical I (Scheme 13). This radical having a highly nucleophilic character seems to readily add to methyl acrylate, yielding a radical species II (Scheme 13). Under the conditions, which O2 is present in the reaction system, the resulting radical II is rapidly trapped by O2 to give a hydroperoxide III (Scheme 13). It is well known that hydroperoxides like III are subjected to redox decomposition by Co ions to form an alkoxy radical IV (Scheme 13) which is eventually converted into 2-hydroxy-4-(1,3-dioxolan-2-yl)valerate through the hydrogen abstraction from either NHPI or 2-methyl-1,3-dioxolane.

6.1.6.1. General Procedure for the Reaction of 2-Methyl-1,3-dioxolane with Methyl Acrylate in the Presence of the NHPI/Co(OAc)2 System (101) To a solution of 2-methyl-1,3-dioxolane (15 mmol), NHPI (0.15 mmol) in a two-necked flask, equipped with a balloon filled with O2 (1 atm), was added



Scheme 13: Proposed reaction path for the radical addition of methyl acrylate with 2methyl-1,3-dioxolane under dioxygen in the presence of NHPI and Co(OAc)2 (101).

methyl acrylate (3 mmol). The mixture was vigorously stirred at room temperature for 3 h. The recovery of unreacted 2-methyl-1,3-dioxolane under a reduced pressure followed by flash chromatography on silica gel (n-hexaneethyl acetate 5 1:2) afforded 2-hydroxy-4-(1,3-dioxolan-2-yl)valerate (462 mg, 81% yield) as a colorless liquid.

6.1.7. NHPI/Lead Tetraacetate, (Pb(OAc)4) System for the PINO Radical Generation NHPI/Pb(OAc)4 system, was shown to produce PINO radical as early as 1964 by Lemaire and Rassat (3), using EPR spectroscopy. On the other hand, Koshino et al. (18) reported the molar absorptivity of PINO generated from NHPI/Pb(OAc)4 in acetic acid, as 1.366103 L mol21 cm21 at lmax 382 nm, and investigate the reactions of PINO with substituted toluenes, benzaldehydes, and benzyl alcohols, presenting the PINO’s reactivity with these species in terms of polar effects (Hammett analysis) and kinetic isotope effects. The

247

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S. Coseri


Scheme 14: PINO-hydrocarbons hydrogen bond intermediate complex (18).

differences between the rate constants for the p-xylene, benzaldehyde, and benzyl alcohol reactions with PINO, founded in acetonitrile and acetic acid were attributed to the formation of a hydrogen bond intermediate complex, Scheme 14, adjacent with the quantum mechanical tunneling phenomenon (18, 102). Baciocchi et al. (21) employed the NHPI/Pb(OAc)4 for the study of PINO’s reactivity toward the N-methyl C-H bond of a number of 4-X-substituted N,Ndimethylanilines by product and kinetic analysis. Interestingly, the authors (21) claimed that for this process the hydrogen transfers from the N-CH3 group to PINO ‘‘does not occur by a classical free radical hydrogen abstraction mechanism (as suggested for the PINO reactions with benzylic C-H bonds)’’. Baciocchi et al. (21) proposed for this process a two-step mechanism (Scheme 15) involving a reversible electron transfer from the substrate to PINO in the first step, that is supported by inter- and intramolecular deuterium kinetic isotope effects. The cross-coupling product of PINO and a-aminomethyl radical formed by the PINO-induced hydrogen abstraction from the N-Me group of the substrate (path c, Scheme 15) was detected by authors (21) only before the reaction work-up. Without the work-up reaction, this adduct can react with small quantities of water present in the solvent, forming a carbiolamine which decomposes into the N-methylaniline (path f, Scheme 15) and CH2O. In another study, Baciocchi et al. (103), investigate the reactivity of the PINO toward the OH bond of a series of substituted phenols, Equation 6, PINO radical generation being achieved by the reaction between NHPI and Pb(OAc)4 in CH3CN.

To simplify the analysis of the complex reaction mixture obtained, Bacciocchi et al. (103) used a substituted phenol, such as 2-tert-butyl-4methylphenol as substrate. It was found that the major product for this reaction is that coming from the cross-coupling of PINO with phenoxyl radical, Equation 7.



Scheme 15: PINO reaction with N-methyl C-H bond compounds (21).

249


250

S. Coseri

Based on the cross-coupled product formed in the above-mentioned reaction, Baciocchi et al. (21) acquiesce to the Mayer and his associate opinion (104), that ‘‘a reaction between an oxyl radical and phenol can be better seen as proton coupled electron transfer (PCET) rather than as classical hydrogen atom transfer (HAT)’’. In a PCET reaction, a hydrogen-bonded complex is first formed between the reactants, and the electon and the proton are transferred through different orbitals. The PINO’s tendency to form adducts is obvious in a series of studies performed by Coseri et al. (105–107) concerning the competition between abstraction-addition and addition-abstraction as the first step in the aminoxyl (nitroxide), iminoxyl, and imidoxyl radicals with alkenes. For the NHPI/ Pb(OAc)4/alkene system, it was found that the major product was a diadduct in which two PINO moieties had added across the double bond of the alkene, Equation 8.

The diadducts formation can rationally be explained only if we consider the coexistence of both radical and nonradical mechanisms. Our results (107), prove that free PINO radicals cannot be involved in the formation of the di-adducts in the alkene/NHPI/Pb(OAc)4 system. We therefore suggest a mechanism based on that proposed for the lead tetraacetate oxidation of cyclohexene to cis- and trans-1,2-diacetoxycyclohexanes and 3-acetoxycyclohexene via a symmetric intermediate, (108, 109), see Scheme 16 (107). We cannot rule out the possibility that the first step in Scheme 16 involve the substitution of one or two acetate groups in the Pb(OAc)4 by PINO moieties, Scheme 17 (107), followed by chemistry similar to that shown in Scheme 16.

6.1.7.1. General Procedure for the PINO Radical Generation by Using NHPI/Pb(OAc)4 System (18) The NHPI (1.5 mmol L21) with Pb(OAc)4 (0.15 mmol L21) in glacial acetic acetic or CH3CN solutions is stirred and bubbled with argon for 15 min. The absorbance of the resulting solution was ca. 0.3 at 382 nm, indicating that about 0.2 mmol L21 of PINO had been generated in solution.



Scheme 16: The proposed mechanism for the cyclohexene/NHPI/Pb(OAc)4 reaction (107).

6.1.8.

NHPI – Cerium (IV) Ammonium Nitrate (CAN) System

Cerium (IV) ammonium nitrate (CAN) itself is a well-known oxidizing agent that oxidizes various organic substrates (110–112). Aerobic oxidation of alkyl malonates into ketomalonates (113) employs catalytic amount of CAN. In the continuing interest of alcohol oxidation studies, Kim and Rajagopal (114) reported the aerobic oxidation of benzylic alcohols using NHPI/CAN system. Sec-Phenylethyl alcohol was chosen for several control experiments to study the role of the each reagent utilized in the reaction, Table 15 (114). NHPI and CAN are the most important species for this oxidation process. Without these reagents, there is very little oxidation reaction (Table 15, entries 1 and 2) taking place. Without oxygen bubbling, the oxidation gives only 51 % of acetophenone (Table 15, entry 3). Elevated temperatures are also needed for efficient oxidation (Table 15, entry 4). The reaction mechanism for the oxidation of alcohols catalyzed by NHPI/ CAN system is presented in Scheme 18 (114). Dioxygen is reduced to H2O2 by the oxidation of Ce3+ to Ce4+. NHPI can be converted into PINO radical. PINO then oxidizes the alcohol to the corresponding ketone.

Scheme 17: Possible substitution of one or two acetate groups in the Pb(OAc)4 by PINO (107).

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S. Coseri Table 15: Oxidation of sec-phenylethyl alcohol under various condition by using NHPI/CAN system in CH3CN (114).a Entry 1 2 3 4 5 6

CAN (mol %)

NHPI (mol %)

O2b

Time (h)

Yield (%)

— 20 20 20 10 20

10 — 10 10 10 10

O2 O2 — O2 O2 O2

5 1.15 1.15 4 1.15 1.15

Trace Trace 51 48 68 91


a All the reactions except for entry 4 were carried out with reflux temperature of CH3CN (b.p. 82uC). Entry 4 was reacted at Room Temperature. bO2 was bubbled in all reactions except for entry 3. Entry 3 was reacted on the air without O2 bubbling.

6.1.8.1. General Procedure for the Oxidation of Alcohols Catalyzed by NHPI/CAN System (113) The alcohol (1 mmol), CAN (20 mol%), and NHPI (10 mol%) were dissolved in 3 mL of CH3CN in a three necked round-bottom flask equipped with a condenser and magnetic bar. This mixture was heated to reflux with an oil bath under continuous stream of oxygen. The progress of the reaction was monitored by using TLC. After completion of the reaction, excess solvent was evaporated under reduced pressure and the product was purified by flash column chromatography on silica gel by using ethyl acetate/hexane mixture as eluent. The products thus separated were identified by 1H NMR spectroscopy. Notably, the NHPI/CAN system was also efficient for the Ritter-type reactions. Thus, treatment of ethylbenzene with CAN in the presence of catalytic amounts of NHPI in CH3CN under argon produced the corresponding amide in good selectivity, Equation 9 (115).

Scheme 18: The reaction mechanism for the oxidation of alcohols catalyzed by NHPI/CAN system (114).



It is reasonable to assume that the present reaction is initiated by the reaction of NHPI with CAN to form PINO, which is thought to be a key species for the generation of alkyl radicals, Scheme 19 (115). In fact, PINO was generated upon treatment of NHPI with CAN in CH3CN at 70uC. The resulting PINO abstracts a hydrogen atom from these hydrocarbons to generate the corresponding alkyl radicals (A), which undergoes the one-electron oxidation by Ce4+ to form carbocations (B). The carbocations B thus generated are trapped by nitriles, followed by H2O, which would be contained in the solvent, to afford amide derivatives. According to this reaction pathway, Scheme 19, 2 equiv. of CAN with regard to the substrate is required to complete the reaction. 6.1.8.2. General Procedure for the Ritter-type Reaction Performed by Using NHPI/CAN System (114) To a solution of ethylbenzene (1 mmol) and CAN (1.5 mmol) in CH3CN (5 mL) in a three-necked flask was added NHPI (0.1 mmol). The flask was cooled to 278uC to freeze the solvent, and degassed in vacuo and filled with AR gas. Then the frozen solvent was melted at room temperature, and refrozen to reiterate the evacuation-Ar purge procedure. The series of operations was repeated three times. The reaction mixture was allowed to react under an atmospheric pressure of Ar at 80uC for 6 h. Selectivity (%) of the product was based on the substrate reacted.

6.2. METAL FREE CATALYTIC SYSTEMS FOR THE PINO RADICAL GENERATION After the discovery of the powerful catalyst activity of the NHPI/metals systems, the researches’ attention was directed toward developing new

Scheme 19: The PINO radical generation catalyzed by CAN (115).

253

254

S. Coseri

approaches for the oxidation using dioxygen under ‘‘environmentally friendly’’ conditions. One the other hand, the disadvantages of metallic toxicity and the high expense could not be avoided. Thus, metal-free and more efficient catalytic systems for oxidation of various substrates with molecular oxygen become particularly desirable. Below are presented the most suitable methods and reagents frequently used to generate PINO radical from NHPI without any metal as catalyst.


6.2.1.

NHPI/NO system, for the PINO radical generation

Nitric oxide (NO) is one of the simplest molecules, its structure and reaction chemistry has been the subject of study by chemists, physicist and biologists for many years. Despite the apparent exhaustive character of knowledge on NO, the recent two decades have revealed a new and unexpected role for NO as a key physiological regulator. This finding for NO has reinvigorated research into the fundamental chemistry of this ‘‘simple molecule’’, much to the delight of chemists, and led Science magazine to designate NO as ‘‘molecule of the year’’ in 1992 (116). However, its application to synthetic organic chemistry is limited because of the sparse information available on the chemical behavior of NO and the difficulty incurred in controlling its reactivity. Nitric oxide can be used as a nitrogen source for the synthesis of nitrogen-containing compounds such as 2-nitrosocarboxamines (117), and nitroalkenes (118). In addition, it has been shown that amines, (119, 120) phenothiazines (121), and dienes (122) react with nitric oxide in the presence or absence of dioxygen. The researchers’ attention was directed toward the use of NO, which has a radical character analogous to molecular oxygen, in many organic transformations with NHPI. Thus, the reaction of adamantane with NO (1 atm) in the presence of NHPI (10 mol %) in a mixed solvent of benzonitrile and acetic acid at 100uC for 20 h afforded 1-Nadamantylbenzamide in substantial yield along with small amount of nitroadamantane, Equation 10, (123).

On the other hand, benzyl ethers reacted with NO in the presence of the NHPI catalyst to afford the corresponding aromatic aldehydes, Equation 11, (124).



The reaction of 4-methoxymethyltoluene catalyzed by NHPI (10 mol %) under NO (1 atm) for 5 h lead to p-tolualaldehyde in 50% yield. tert-Butoxymethyltoluene was transformed into the aldehyde in 72% yield. tert-Butyl benzyl ethers were found to be converted into the corresponding aldehydes in reasonable good yields. The most important application of this procedure is the transformation of ethers to benzenedicarbaldehydes, which represents valuable starting materials in pharmaceutical synthesis, Equations 12, 13.

Mechanistically, the reactions of adamantane and ethers with NO are rationally explained by considering the formation of carbocations as transient intermediates, Scheme 20. The generation of PINO from NHPI in the presence of NO was confirmed by ESR measurements (123). Suzuki has suggested the formation of a cationic

Scheme 20: Reaction of adamantane or ethers with NO through the formation of carbocations as transient intermediates (123).

255

256

S. Coseri


species via a diazonium nitrate in the nitration of alkenes with NO (125). The nucleophilic attack of the benzonitrile and water to the adamantyl and benzylic cations would result in the amide and aldehyde, respectively. Indeed, an intermediate carbocation generated from phthalane by the NHPI/NO system has been trapped by a nucleophile such as alcohol, Equation 14, (126).

6.2.1.1. General Procedure for the Reaction of Ethers with NHPI/NO System To a solution of ether (1 mmol) in acetonitrile (5 mL) in a three-necked flask was added NHPI (10 mol %). The flask was cooled to -78uC to freeze the solvent, degassed under vacuum, and then filled with Ar gas. Next, the frozen solvent was melted at room temperature and refrozen to reiterate the evacuation-Ar purge procedure. This series of operations was repeated three times, and then NO was added to the reaction vessel. The reaction mixture was allowed to react under an atmospheric pressure of NO at 60uC for 5 h. After solvent was removed under vacuum, the aldehydes products were isolated by flash chromatography.

6.2.2.

NHPI/NO2 system, for the PINO radical generation

A major problem in current industrial nitration is that the reaction must be run at high temperature, 250–400uC, because of the difficulty of the C-H bond homolysis by NO. Under such high temperatures, higher alkanes undergo not only homolysis of the C-H bonds, but also cleavage of the C-C skeleton. Hence, the nitration is limited to the lower alkanes (126). The catalytic nitration of alkanes under mild conditions would offer a promising and superior alternative. Since NO2 is a paramagnetic molecule, the generation of PINO from NHPI by the action of NO2 in analogy with O2 is expected. Indeed, when NO2 was added to NHPI in benzene at room temperature, an ESR signal attributable to PINO was instantly observed as a triplet. The nitration of cyclohexane with NO2 by NHPI without any solvent under air (1 atm) proceeded smoothly at 70uC to give nitrocyclohexane (70% based on NO2 used) and cyclohexyl nitrite (7%) along with only small amount of an oxygenated product, cyclohexanol (5%), Equation 15, (127).



It is important that the NHPI-catalyzed nitration be conducted under air, since the resulted NO, can be reoxidized to NO2 by O2. The absence of air reduced the yield of nitrocyclohexane to 43%. A plausible pathway for this process is shown in Scheme 21. The hydrogen atom abstraction from the hydroxyimide group of NHPI is induced by NO2 to form PINO. The PINO abstracts the hydrogen atom from an alkane to give an alkyl radical, which is readily trapped by NO2 to form a nitroalkane. It has been reported that the formed HNO2 is converted into HNO3, H2O, and NO, which is easily oxidized to NO2 under air (128). The most promising feature of the NHPI-catalyzed nitration of alkanes by NO2 is that the nitration can be conducted under air at moderate temperature. Owing to the higher concentration of NO2 than air, the alkyl radicals formed can react selectively with NO2 rather than with O2 to give nitroalkanes in preference to oxygenated products.

6.2.3.

NHPI/HNO3 system, for the PINO radical generation

Nitration of saturated hydrocarbons using nitric acid is usually carried out at fairly high temperature (250–400uC) because of difficulty in generating NO2 from HNO3. The reaction implies harsh condition being often difficult to control, and exhibit poor product selectivity. To carry out the nitration selectively, in situ generations of alkyl radicals from alkanes and NO2 from

Scheme 21: The mechanism of NHPI-catalyzed nitration of hydrocarbons.

257

258

S. Coseri


Scheme 22: The NHPI/HNO3 system for the PINO radical generation.

HNO3 must be achieved under mild conditions. It has been proposed by Sakaguchi and coworkers (127), a novel catalytic method for the nitration of aliphatic hydrocarbons using NO2 and NHPI as the catalyst under mild conditions, Scheme 22, (127). From EPR measurements it was found that the PINO radical was formed with the evolution of NO2 by the reaction of the NHPI with HNO3. Table 16 summarizes the representative results for the nitration of various saturated hydrocarbons and their derivatives with nitric acid under the influence of NHPI in trifluorotoluene at 60uC for 15 h, (129).

6.2.3.1. General procedure for the alkane’s nitration mediated by NHPI (129) Concentrated nitric acid (60% over) was used without any treatment. To a two necked flask was added the alkane (1 mmol), NHPI (0.1 mmol), and nitric acid (1.5 mmol) in trifluorotoluene (3 mL), and the mixture was reacted under argon at 60uC for 15 h. After evaporation of the solvent under reduced pressure, the reaction mixture was extracted with diisopropyl ether and the extracts were washed with NaHCO3.After separation of the organic phase, the mixture was subject to silicagel chromatography, giving the corresponding products.

6.2.4.

NHPI/aldehydes system, for the PINO radical generation

Aldehyde-mediated cooxidations have been used for the epoxidation of alkenes (130), Bayer-Villiger oxidation of ketones (131) and oxidation of alcohols and of some hydrocarbons (132, 133). Einhorn C. and coworkers (134), described the oxidation of organic substrates, in particular hydrocarbons, under aldehyde-promoted cooxidation conditions, in the presence of NHPI. The acetylperoxy radical (Scheme 23) is responsible for the PINO radical generation (134).



Entry

Nitration of various alkenes with HNO3 by NHPIa (129). Substrate

Conversion (%)

Product

Selectivity (%)

1

77

67

2

89

81

3

50

95d

4

89 (74)

57 (47)

5

75

56e

6f

–

32d,g

259

260

S. Coseri Table 16: Entry f


7

Continued. Substrate

Conversion (%)

Product

Selectivity (%) 60d,h

–

8

80

65

9

59

61

10

73

79

11

32

91

Parentheses show the conversion and selectivity in the nitration using NO2 instead of HNO3. b NHPI (0.2 mmol) was used. cSubstrate (3.00 mmol) was used. dBased on HNO3 used. e Dinitrocyclooctane (14%) and cyclooctanone (10%) were obtained. fSubstrate (5 mL) was used. gAdipic acid (5%) was obtained. hBenzyl alcohol (21%) and benzaldehyde (19%) were obtained.



Scheme 23: PINO radical generation involving the acetylperoxy radical (134).

The above mentioned authors (134), found that an efficient and reproducible way to perform such oxidations is to add the aldehyde to the vigorously stirred reaction medium slowly; when 1 equiv. of acetaldehyde was added over 5 h to a solution of ethylbenzene and NHPI under oxygen, and fast stirring maintained for an additional 5 h period, a 66% yield of acetophenone and a 4% yield 1-phenylethanol were obtained. Table 17, (134) shows further examples of oxidations performed under the same conditions: 4-nitro-1ethylbenzene is oxidized with lower efficiency than ethylbenzene itself (run 3) whereas 4-methoxy-1-ethylbenzene is oxidized almost quantitatively (runs 4, 5). 1-Phenylethanol is oxidized only slowly to acetophenone (runs 6, 7) indicating that a direct pathway leading from ethylbenzene to acetophenone is likely. In the case of cumene, demethylation giving acetophenone competes with hydroxylation (run 8). Indane and isochromane are oxidized almost quantitatively (runs 9, 10). Surprisingly, diphenylmethane is oxidized with lower conversion (49%) than ethylbenzene (70%), with a relatively high alcohol : ketone ratio (run 11). A higher conversion is obtained on the other hand with xanthene (run 12). Inactivate hydrocarbons are oxidized at a slow but nevertheless significant rate: 8% conversion of cyclohexane is observed after a 72 h reaction time, with a 1:7 alcohol : ketone ratio (run 13). Adamantane is oxidized almost exclusively to adamantane-1-ol with only trace amounts of adamantane-2-one (runs 14, 15).

6.2.5. NHPI/a,a9-Azobisisobutyronitrile (AIBN) system, for the PINO radical generation Phenols and naphthols are an important class of compounds needed for the syntheses of dyes, pharmaceuticals and polymers. Particularly, naphthalenediols represents essential components of intelligent polymers such as engineering plastics and liquid crystalline polymers. 2,6-Naphthalenediol has attracted much attention for its chemical and physical properties as a liquid crystalline monomer material. The production of 2, 6-naphthalenediol occurs

261

262

S. Coseri Table 17: Molecular oxygen oxidation of various substrates mediated by NHPI and acetaldehydea (134).


Run

Substrate

Conversionc (%) t (h) b

Products (yield, %)d

1 2

5 10

48 70

(4) (4)

(41) (66)

3

10

24

(2)

(22)

4

5

75

(7)

(68)

5

21

97

(7)

(90)

6

5

3

7

72

37

8

19

75

(46)

(29)

9

10

99

(5)

(94)

10

15

100

(3) –

–

(37)

(99)


tb (h)

Conversionc (%)

11

10

49

12

19

94

13

72

8

(1)

(7)

14

9

5

(5)

(trace)

15

24

10

(10)

(trace)

Run


Continued.

Substrate

Products (yield, %)d (10)

–

(36)

(70)

a

Performed on a 1 mmol scale, in the presence of 0.1 mmol NHPI, in 3 ml MeCN. A solution of 1 mmol acetaldehyde in 3 ml MeCN was added over 5 h via a syringe pump. bIncluding the aldehyde addition period. cDetermined by calibrated quantitative GLC. dAbsolute yield determined by GLC.

with low yields by sulfonation of naphthalene followed by alkali fusion of the resulting sulfonates, (135) process which give a complex mixture o several sulfonated products. Reaction of b-naphtol with hydrogen peroxide in the presence of a Lewis acid like SbF5 produces 2, 6-naphthalenediol, but this method also brings about a mixture of several regioisomeric naphthalenediols. (136, 137) Aoki et al. (137) developed an efficient synthesis of naphthalene-diols via aerobic oxidation of diisopropylnaphthalenes catalyzed by NHPI and AIBN, Equation 16, (137).

263

264

S. Coseri


2,6-Diisopropylnaphthalene was allowed to react under O2 (1 atm) in the presence of AIBN (3 mol %) and NHPI (10 mol %) in CH3CN (5 mL) at 75uC for 21 h followed by treatment of the reactants with 0.3 M sulfuric acid at room temperature for 2 h, leading to 2,6-naphthalenediol in 81% yield along with 6isopropyl-2-naphthol (18%).

6.2.5.1. General procedure for the oxidation of diisopropylanphthalenes with NHPI/AIBN system (131) An acetonitrile (5 mL) solution of diisopropylnaphthalene (3 mmol), AIBN (3 mmol %), and NHPI (10 mmol %) was placed in a two-necked flask equipped with a balloon filled with O2. The mixture was stirred at 75uC for 21 h. The reaction mixture was treated with 0.3 M H2SO4 in CH3CN (1 mL) at 25uC for 2 h. Removal of the solvent under reduced pressure afforded a cloudy solution, which was purified by column chromatography on silica gel (n-hexane) to give the corresponding product.

6.2.6. NHPI/Hexafluoroacetone (HFA) system, for the PINO radical generation Iwahama and coworkers, (138) employed a new strategy consisting of radical and ionic processes as key reactions, i.e., (i) in situ generation of H2O2 via a-hydroxy hydroperoxide A from an alcohol and O2 assisted by NHPI, and (ii) the epoxidation of olefins by 2-hydroperoxyhexafluoropropan-2-ol B derived from the formed H2O2 and hexafluoroacetone, Scheme 24, (138). Based on the preliminary results, Iwahama and coworkers (138), extended their research on the aerobic epoxidation of various olefins using benzhydrol in the presence of catalytic amounts of NHPI and HFA, Table 18 (138).

6.2.6.1. General procedure for the epoxidation of alkenes, catalyzed by NHPI/HFA system(138) A PhCN (6 ml) solution of alkene (3 mmol), NHPI (49 mg, 10 mol%), HFAN3H2O (66 mg, 10 mol%) and benzhydrol (15 mmol) was placed in a twonecked flask equipped with a balloon filled with O2. The mixture was stirred at



Scheme 24: NHPI/HFA system, for the PINO radical generation (138).

80 C for 15 to 24 h, and then extracted with Et2O. The organic layer was dried over MgSO4 and analyzed by GLC. The products were separated from the solvent under reduced pressure and purified by column chromatography on silica gel (n-hexane-ethyl acetate 5 20:1) to give the corresponding epoxides.

6.2.7.

NHPI/Antraquinone derivatives system, for the PINO radical generation

Mimicry for biological oxygenation may be an inspirational approach for selective oxyfunctionalization of hydrocarbon with O2, because biologic oxygenation exhibits high selectivity under mild conditions. On the evolution of enzyme mimicry (139, 140), the biomimetic oxygenation model should encompass three elementary factors: a redox center, a one-electron transfer chain, and multiple binding sites similar to the surrounding protein environment of the enzyme.

265

Yield (%)

Selectivity (%) (trans: cis)

93

87

93 (99:1)

24

90

72

80 (99:1)

3

16

94

81

86 (98:2)

4

16

96

80

83 (99:1)

5

15

90

74

82

6

20

88

71

81

No.

Substrate

t/h

Conversion (%)

1

18

2b

Product

S. Coseri


266

Table 18: Epoxidation of various alkenes with O2 catalyzed by NHPI and HFA in the presence of benzhydrol.a

No.

Continued.

Product

Yield (%)

Selectivity (%) (trans: cis)

t/h

Conversion (%)

7

20

89

74

83

8c,d

24

80

72

90

9d,e

24

83

70

84

10d,f

24

78

63

80

11d,e

20

72

60

83 (75:25)

a

Substrate

Substrate (3 mmol) was allowed to react under dioxygen (1 atm) in the presence of NHPI (0.3 mmol), HFA (0.3 mmol) and benzhydrol (15 mmol) in PhCN (6 ml) at 80uC. bMePhCHOH was used in place of benzhydrol. cReaction was carried out at 90uC. da,a,a-Trifluorotoluene was used as solvent. e NHPI (0.6 mmol) was used. fCyclohex-2-en-1-one (8%), cyclohex-2-en-1-ol (2%) and cyclohexane-1,2-diol (1%) were obtained. gRatio a : b.



Table 18:

267


268

S. Coseri

Scheme 25: Catalytic Cycle of Anthraquinone and NHPI (146).

Biologic oxygenations of C-H bonds stem from the abstraction of hydrogen from organic compounds by the redox centers (141). PINO radical can be a nonmetallic redox center in catalytic hydrocarbon oxygenation, due to its highly electrophilic character. The action of the redox center in biologic oxygenation relies on a chain of one-electron transfers, resulting in formation of radicals (142). A ubiquitous quinine derivative (i.e., coenzyme) is often one of the units of the electrontransfer chain (143, 144). The essence of biosynthesis is the control of selectivity by some noncovalent binding of the substrate to the enzymatic protein domain. This suggests that porous zeolites could be used as host materials for host-guest composites with sequestered organic molecules, analogous to enzyme-substrate complexes in biooxidation, and enhances molecular orientation for chemical reactions (145). It was proposed that the quinones can make NHPI convert to PINO via one-electron transfer and subsequently facilitate hydrocarbon oxidation, in which zeolite is used to promote reaction selectivity (146). The catalytic redox cycle is presented in Scheme 25, (146). It is known that the surrounding organic environment of an enzyme is critical for high selectivities of products in biological processes, and the product orientation of reported organocatalytic reactions comes from the actions of substituents on the backbones of organocatalysts toward the reactants (147– 149). Yang et al. (150) by modification the substituents on antrachinone and then combining with NHPI reported the great potential of this organocatalytic system for selective oxygenation of different hydrocarbons. Anthraquinone (1.25 mol %) was first used in combination with NHPI (5.0 mol %) to catalyze the oxygenation of fluorene, which is shown in Table 19 as a model reaction. As we can see from Table 19, it could be concluded that the groups with an acidic proton decreased the catalytic activity of anthraquinone. The electronic

Phthalimide-N-oxyl (PINO) Radical, a Powerful Catalytic Agent Table 19: Oxygenation of Fluorene catalyzed by NHPI and different anthraquinone derivativesa (150).


Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14e 15f 16g 17h

X H 2-chloro 2-ethyl 1-amino 2-amino 1-nitro 1,4-diamino 1,4-dihydroxyl dinitrod 1-amino-2,4-dibromo 1-amino-2-bromo-4-hydroxyl 1,4-dihydroxyl-2-sulfonic acid 1,4-diamino-2,3-dichloro 1,4-diamino-2,3-dichloro 1,4-diamino-2,3-dichloro

Conversionb (%) Yield of 2c (%) 50 53 50 46 41 56 42 43 47 39 31 16 59 85 0 25 2

34 45 43 29 25 45 27 24 28 23 15 6 57 (54)i 85 (82)i 0 11 0.4

a Fluorene (5mmol) was oxygenated by O2 (( 0.3 MPa) in the presence of NHPI (5 mol%) and various anthraquinone derivatives (1.25 mol%) at 80uC for 5 h in 10 mL of acetonitrile. b Conversions of 1 were calculated from GC measurements using 1,2-dichlorobenzene as internal standard. cGC measurements after treatments of reaction mixture with Ph3P. dA mixture of 1,5- and 1,8-dinitro anthraquinone. eFor 25 h. fNHPI-free. gIn the absence of any anthraquinone derivatives. hIn the absence of both NHPI and anthraquinones. iIsolated yield.

effect of substituents on the anthraquinone seems nonessential, since there were not clearly different actions between electron-withdrawing and electrondonating groups. However, 1,4-diamino-2,3-dichloro-anthraquinone exhibits the highest yield (57%) and selectivity (59%) among the all anthraquinone derivatives. 1,4-Diamino-2,3-dichloro-anthraquinone and NHPI were further employed to catalyze oxygenations of various hydrocarbons under 0.3 MPa of O2 at 80uC, Table 20, (150). Tetralin was oxygenated with high conversion (91%) and converted selectively to tetralone with 88% isolated yield. Acenaphthene, ethylbenzene, adamantane, and indane were oxidized at good conversions (59–94%). The major oxidation product of toluene was benzoic acid, because as demonstrated before aldehyde can be used as radical-initiator for NHPI-based oxygenation (151) and is not stable in such radical reaction. At 80uC for 5 h, 2% cyclohexane

269

270

S. Coseri Table 20: Oxygenation of Different Hydrocarbons Catalyzed by 1,4-Diamino-2,3dichloro-anthraquinone and NHPIa(150).


Substrates

Time (h) Conv. (%)

Products and yields (%)

5

85

54

22

10

91

88c

2

6

94

64c

15

10

92

54c

25

4b

15

12

2

9

17

11

5



Substrates

Continued. Time (h) Conv. (%)

Products and yields (%)

11

59

45c

7

7

82

55

18

a The reactions were carried out in 10 mL of CH3CN, using 5 mmol of solid substrates and 2 mL of liquid; 1.25 mol % of 1,4-diamino-2,3-dichloro-anthraquinone and 5.0 mol % of NHPI were used in all cases. bReaction at 100uC. cIsolated yields.

was converted, but a significant conversion (15%) of cyclohexane was obtained at 100uC during 4 h. In comparison with the current industrial processes (about 3–7% conversion at 160uC) the results for cyclohexane oxygenation indicate that the catalytic activity of this system increased as the temperature was raised and was applicable even to inactive alkanes. 6.2.7.1. General procedure for the hydrocarbon oxygenation by using NHPI/ anthraquinone system (150) The hydrocarbon (5.0 mmol), anthraquinone (1.25 mmol), NHPI (5 mmol), and acetonitrile (10 mL) were added into a Teflon-lined 70-ml stainless steel autoclave. After closing the autoclave, the air inside was replaced with O2 for three times. Under stirring, preheated at 80uC, and then charged O2 to 0.30 MPa to start the reaction. During the reaction, if the pressure of O2 decreased to 0.25 MPa, charged O2 to 0.30 MPa again. Stop the reaction at the predetermined time.

6.2.8.

NHPI – o-Phenanthroline system

O-Phenanthroline (Phen) or bipirydine (or analogues) in combination with a metal has been employed to the electron-transfer process or to some oxidation processes, (152, 153) but has rarely employed for hydrocarbon

271

272

S. Coseri


Scheme 26: Oxidation of ethylbenzene with molecular oxygen (154).

oxidation in the absence of metal complexes. Tong et al., (154) reported a new o-phenanthroline (or analogues)-mediated, metal free catalytic system for the oxidation of hydrocarbons in the presence of NHPI and a cocatalyst. Molecular bromine (Br2), which has shown a particular promotion effect in some oxidation processes (155), was chosen as a cocatalyst. To test the efficiency of their new proposed catalytic system, Tong et al. (154) used ethylbenzene as a model substrate, Scheme 26, (154). The reaction was carried out under 0.3 MPa of O2 at 353 K for 2 h. Table 20 shows the results of oxidation using Phen or different analogues as catalyst mediators in the presence of NHPI and Br2. When Phen was employed, a 76% conversion and 97% selectivity for acetophenone (Scheme 26, 1) was obtained (Table 21, entry 1). The conversion decreases (67 or 65 %) and the selectivity for 1 (Scheme 26) was almost unchanged when 2, 29-bipyridine or bathophenanthroline replaced Phen as catalyst mediators (Table 21, entries 2 and 3). However, when neocuproine, bathocuproin, or, 2, 29-bichinolin was employed, the conversion (35–49%) and selectivity (75–88%) for 1 (Scheme 26) were evidently reduced (Table 21, entries 4–6). The lowest conversion (only 28 %) and selectivity (67%) was obtained when 4,49-bipyridine replaced Phen (Table 21, entry 7). Among all the used mediators, Phen is a most efficient catalyst, and differences in the oxidation mediated by different analogues are probably ascribed to effects of conjugated structures and substituents. Tong et al. (154) carried out another set of experiments in order to clearly reveal the function and character of catalyst components. When 7.5 mol % (1, 10) phenanthroline was used individually (Table 22, entry 1), only 3 % of ethylbenzene was oxidized, no oxidation occurred when 2.5 mol % Phen was solely employed (Table 22, entry 2). On the contrary, when Phen and NHPI were coupled as a catalytic system, the conversion was improved to 9 % with 71 % selectivity for 1-phenylethyl hydroperoxide was obtained (Table 22, entry 3). 1%, 3%, or 2% of ethylbenzene was respectively oxidized (Table 22, entries 4–6) by Br2, 1%, 3%, or 2% of ethylbenzene was respectively oxidized (Table 22, entries 4–6) by Br2, NHPI-Br2 or Phen-Br2, under the same reaction conditions. Furthermore, when bromine ion was used as a cocatalyst in the presence of Phen and NHPI, a promising result (43% conversion and 75% selectivity for product 1) (see Scheme 26) was obtained. The control experiments were carried out with larger contents of Phen-Br2 and the

Phthalimide-N-oxyl (PINO) Radical, a Powerful Catalytic Agent Table 21: Oxidation of ethylbenzene by Phen (or analogues)-mediated catalysisa (154). Product selectivity [%]


Entry

Mediator

Conversionb [%]

1

76

97

3

,1

2

67

96

3

1

3

65

97

2

1

4

35

75

20

5

5

45

87

11

2

273

274

S. Coseri Table 21:

Continued. Product selectivity [%]


Entry

Mediator

Conversionb [%]

6

49

88

11

1

7

28

67

17

17

a

Reaction conditions: the reaction of ethylbenzene was performed on a 1 mL scale, in the presence of NHPI (7.5 mol %), Phen hydrate or analogues (2.5 mol %), Br2 (3.0 mol %), in 10 mL acetonitrile, pressure 5 0.3 MPa, time 5 2 h, temperature 5 353 K. bThe data were obtained by GC and GC-MS analysis using 1,3-dichlorobenzene as an internal standard.

Table 22: (154).

Oxidation of ethylbenzene by Phen (or analogues)-mediated catalysisa

Product selectivity [%]

Entry 1 2 3 4 5 6 7b 8c 9d a

Catalyst NHPI Phen Phen + NHPI Br2 NHPI + Br2 Phen + Br2 Phen + NHPI + Br2 Phen + Br2 Phen + Br2 + NaBr

Conversiona [%] 3 0 9 1 3 2 43 4 6

9 – 11 28 18 86 75 72 71

12 – 18 47 80 13 12 25 14

79 – 71 25 2 1 13 3 15

Reactions conditions and analytical methods were similar with the situation in Table 21. 5.0 mol % was employed. c12.5 mol % Phen and 15.0 mol % Br2 were employed. d5.0 mol % Phen, 3.0 % mol Br2 and 5.0 % mol NaBr were employed. b



Scheme 27: Proposed mechanism for hydrocarbon oxidation using Phen-mediated catalytic system (154).

combination of Phen-Br2-Br- (Table 22, entries 8 and 9), only 4% and 6% conversion were obtained, which showed that the bromine radical could rarely exist and PINO radical could mainly perform activation of C-H bond in this organocatalytic oxidation. Several parameters have been investigated in order to accurate establish a reaction mechanism of this process. The authors (154) showed that no oxidation occurred in the presence of hydroquinone, which confirmed the free radical pathway of the reaction. In addition, after Phen, NHPI and Br2 were mixed together in acetonitrile, the solution’s color gradually changed from brown-red (color of Br2) to yellow (color of PINO), which visually proved the production of PINO radicals. Moreover, PINO signals could be found by means of in situ FT-IR spectroscopy. A proposed mechanism for hydrocarbon oxidation using Phen-mediated catalytic system is showed in Scheme 27 (154). In the beginning of the reaction, Phen is converted to cation radicals through single-electron oxidation of the nitrogen, then the cations radicals promote the generation of PINO radical under the metal-free conditions, via electron and proton transfer between cation radicals and NHPI (Equation 1, Scheme 27). The next step involves the hydrogen atom abstraction from the hydrocarbon by PINO, and the resulting hydrocarbon radical being trapped by dioxygen provides the peroxy radicals, which are eventually converted into products through hydroperoxide (Equation 2, Scheme 27).

6.2.8.1. General procedure for the ethylbenzene oxidation using the PhenNHPI catalytic system (154) An acetonitrile (10 mL) solution of ethylbenzene (1mL, 8.3 mmol), NHPI (7.5 mol %), Phen (2.5 mol %), and bromine (3.0 mol %) was charged into 100 mL autoclave equipped with magnetic stirring and automatic temperature control. The atmosphere inside were replaced with oxygen before the reactor was sealed. Under stirring, the autoclave was preheated to 353 K, and then

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the oxygen was charged to 0.3 MPa and kept for 2 h. After the reaction, the autoclave was cooled, and the excess gas was purged.


6.3. New Heterogeneous System for the PINO Radical Generation (NHPI/Sodium Periodate) The use of NHPI in organic chemistry is limited due to its low solubility in many organic solvents. A new approach to overcome this limitation is to take into account the possibility of the use of heterogeneous systems. Our very recent findings, in connection with the unexpected behavior of the NHPI/ cycloalkenes system, lead to a new way to generate PINO radical, using sodium periodate (156). Sodium periodate is a widely used reagent for the oxidative cleavage of 1,2-diols to carbonyl compounds (157). Unfortunately, the use of this highly selective reagent is also strongly restricted by its insolubility in organic solvents (158). There have been reported many attempts to overcome this inconvenient, that is, the use of quaternary alkyl ammonium periodate in organic solvents and the use of potassium metaperiodate under phase-transfer catalysis conditions (159–161). The concept of supported reagents (162, 163), either adsorbed on or bound to insoluble matrixes, also offered an attractive solutions. To accelerate the development and optimization of reaction conditions for solid-supported transformations, Krchnak and co-workers have designed and used dual linkers with a reference cleavage site (164). The key feature of dual linkers is their inherent ability to provide complete cleavage of all polymer-supported reaction components. A dual linker consists of a sequence of two linkers in series cleaved by the same reagent. The second linker is attached to the polymer-supported first linker and a reference cleavage site is formed between the first and second linkers. The second linker is always cleaved from the first linker, independent of the chemical transformations performed on the second linker. Krchnak, reported the use of a dual linker in ‘‘the discovery of an unexpected side reaction’’ that occurs during the Mitsunobu reaction of NHPI with polymer-supported alcohols (164), NHPI reaction with amines (165), and NHPI reaction with Wang or Sarsin resins (166). Silica gel supported metaperiodate was shown to oxidize smoothly 1,2diols and hydroquinones in dichloromethane and non polar organic solvents. Wet silica gel is an effective support for metaperiodate. The method consists in stirring suspensions of silica gel in dichloromethane, with a freshly prepared solution of sodium periodate in water, and then NHPI is added. The PINO radical is generating according with the Equation 17.



Scheme 28: The reaction mechanism of cyclooctene reaction with PINO generated by sodium periodate (156).

After 5 minutes, a cycloalkene/dichloromethane solution is added, at this point, the radical reaction between PINO and cycloalkene taking place. The reaction occurs by abstraction–addition and addition–abstraction competitive mechanisms, the final products being identical for the both mechanisms in the case of the symmetrical alkenes. The ratio between these two competitive reaction mechanisms was a major subject of our previous works (106, 107). Scheme 28 (156) shows the reaction mechanism of cyclooctene reaction with PINO generated by sodium periodate. Since it has been showed that cyclooctene yielded the highest percentage (61%) of the diadduct formation in the NHPI/Pb(OAc)4 system (107), among all the used alkenes, the probability to detect any trace of the diadduct formation, it is obvious to be the highest for the cyclooctene/NHPI/sodium periodate. 6.3.1.

General Procedure for the NHPI/NaIO4/Cycloalkene reaction (156)

To a vigorously suspension of chromatographic grade silica gel (15 g) in CH2Cl2 (100 mL) in a 250 mL Erlenmeyer flask, is added a 0.35 molar aq. solution of NaIO4 (10 mL) dropwise with stirring, and NHPI (7 mmol). After 5 minutes, the cycloalkene (70 mmol) in CH2Cl2 (20 mL) is added, and the reaction is monitored by TLC, until it is completed, generally less than 15 minutes. The mixture is then filtered on a sintered glass, and the silica gel is thoroughly washed with CH2Cl2 (3 6 30 mL). Evaporation of the solvent and cycloalkene excess affords the crude product pure enough for most purposes; yield: 88–92 %.GC and/or 1H NMR reveal no diadducts formation.

7. NHPI DERIVATIVES AND ANALOGS, AS CATALYSTS IN OXIDATION REACTIONS Once the NHPI has been recognized as a valuable catalyst for the aerobic oxidation of a wide range of organic compounds under mild conditions, the

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Scheme 29: NHPI and PINO derivatives used as catalysts in oxidation reactions.

researchers’ concern was next turned toward of the use of NHPI derivatives as catalysts for the oxidation reactions, since one the major drawback in the use of NHPI, is the self-decomposition of resulted PINO, thus requiring quite large amounts of NHPI (usually 10 mol%). Scheme 29 shows the most important NHPI/PINO derivatives used in organic catalysis.

Einhorn et al. (167) reported the synthesis and the catalytic activities of Nhydroxy-3,4,5,6-tetraphenylphthalimide (NHTPPI) (compound 6, Scheme 29) allowing highly efficient benzylic oxidation at mild temperatures, Equation 19. NHTPPI was prepared in a single step from commercially available tetraphenylphtalic anhydride and hydroxylamine hydrochloride in anhydrous pyridine (167). Notably, NHTPPI is more soluble than NHPI in most of the classical solvents, and the half life (t1/2) of its corresponding nitroxyl radical, is about 5 times longer than that of PINO, at 35uC.

Phthalimide-N-oxyl (PINO) Radical, a Powerful Catalytic Agent Table 23: Aerobic oxidation of indan using various NHPI derivatives (1 mol%) as catalysts in acetonitrile at 35uC (167). Run


1 2 3 4 5 6 7 8 9 10

Catalysta

Yieldb (%)

1 2 3 4 5 6 7 15 16 17

62 45 46 30 11 34 80 48 38 15

a

See Scheme 29. bDetermined by GC after 6 h.

The generation of corresponding nitroxyl radical from NHTPPI was achieved by using cerium (IV) ammonium nitrate. A maximum absorption band has been identified at 425 nm (167). Table 23 shows the yields of aerobic oxidation of indan using various NHPI derivatives. It can be observed from Table 23 that derivatives bearing electron donating or electron withdrawing substituents (168, 169) were less effective (runs 2–5), as well as the tetrachloro- and naphthalenic derivatives (runs 6 and 8). Espenson and coworkers (170) have used NHPI and its derivatives, compounds 8, 9, 10, 14 (Scheme 29) as promoters with Co(OAc)2 catalyst for the autooxidation of p-xylene and other methyl arenas. It has been found that the activity of the substituted NHPI promoters follows the order NHPI . 8 (see Scheme 29) . 9 (see Scheme 29), which can be interpreted in terms of kinetic stability of the corresponding nitroxyl radical. Sala et al. (20) recently reported the PINO radical formation at room temperature irradiation with filtered light (l . 300 nm) of a mercury lamp of an aerobic benzene solution containing N-triphenylmethyloxy- (11), and N-diphenymethyloxyphthalimde (12), (see Scheme 29). Interestingly, in the case of using of N- benzyloxyphthalimide (13) (see Scheme 29), after irradiation, the EPR does not show any signal, that suggest that the photostability of N-alkoxyphthalimides is strongly dependent on the nature of the alkyl moiety attached to the oxygen. Beside PINO, others non persistent nitroxyl radicals have continuously attracted the scientific community because they can act as efficient mediators in many various reactions. These unstable (transient) radicals are generated in situ from their parent hydroxylamines, some of them being presented in Scheme 30. Hydroxyl amines such as HBO, TFBT, HOAT, and VA have been reported to be effective mediators for the enzyme lacasse (171). By far, the most studied hydroxyl amines are N-hydroxysaccharin (NHS), and 1-hydroxybenzotriazole

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Scheme 30: Some hydroxylamines used for the nitroxyl radicals’ formation.

(HBT), with their corresponding nitroxyl radicals: succinimide N-oxyl (SINO) and benzotriazole-N-oxyl (BTNO) radicals, respectively. The use of NHS, in which, one carbonyl group in NHPI is replaced by the more strongly electron-withdrawing sulfonyl group, should provide a more effective catalyst activity in the cycloalkane’s autooxidation. Indeed, this hypothesis was proved by the Sheldon et al. works (172, 173). Table 24, (172, 173) shows the comparative results obtained in the autooxidation of cyclododecane in acetic acid at different temperatures, by using both NHPI and NHS. As expected, NHS proved its superior catalytic activity, allowing a lower reaction temperature. In contrast, at this temperature (50uC), NHPI failed to Table 24:

Oxidation of cyclododecane in AcOH in the presence of Co(acac)2.

Run

Co-catalyst

T (uC)

Time (h)

Conversiona (%)

None NHS NHPI NHS NHPI NHS NHPI

100 100 100 75 75 50 50

24 6 6 8 8 24 24

,4 64 58 47 36 42 0

1 2 3 4 5 6 7 a

Conversion is determined by GC using 1,2,4-trichlorobenzene as internal standard.



promote the oxidation reaction of cyclododecane. NHS/Co(acac)3 catalyzes the selective autooxidation of primary and secondary alcohols, to carboxylic acids and ketones, respectively (173). Interestingly in these transformations, NHS has a lower catalytic activity than NHPI. Moreover, the same result has been found for the ethylbenzene autooxidation (173). A plausible explanation for the contrasting behavior of cycloalkanes on the one hand (higher reaction rate with NHS) and alcohols and ethylbenzene on the other hand (higher reaction rates with NHPI) should be linked with the enthalpic consideration and the BDE values of the substrates (the BDE of the C-H bond in cycloalkanes is significantly higher than the a-C-H bond in alcohols and alkylbenzenes, 450 kJ/mol and 360 kJ/mol, respectively). The spectrophotometric, EPR and kinetic characterization of the BTNO radical from its parent hydroxyl amine HBT, was reported for the first time by Galli et al. (174). The BTNO species was generated in acetonitrile at 25uC by adding a solution of the one-electron CAN. The UV/Vis spectrum recorded immediately (15 ms) after the mixing of the HBT and CAN solutions, reveal a broad absorption band in the 400–600 nm region, with lMAX 5 474 nm. The decomposition of BTNO radical is faster than that reported for PINO radical (18) (half-life of 110 and 7900 s, respectively), thus suggesting a lower catalytic activity of BTNO. Subsequently, the BDE of the .NO-H bond in HBT calculated from the thermochemical cycle, was reported as 85 kcal mol21 (171) whereas the BDE value obtained by quantum chemical calculations by the Density Functional approach (DFT) has been found as 85.9 kcal mol21 (171). These values are significantly lower than the BDE value of the .NO-H in NHPI, which could imply a lower reactivity of the BTNO radical than PINO. Indeed, by the work of Galli et al. (175), the second-order rate constant of H-abstraction from H-donor substrates are lower in the case of using BTNO than in the case of using PINO, see Table 25 (175). It can be observed in Table 25, the rate values with the PINO radical are always higher.

8.

CONCLUSIONS AND OUTLOOK

Without any doubts, in our days, the use of NHPI in many and various organic transformations represent an intriguing subject, many research groups reporting new and spectacular application of NHPI. However the chemists’ interest in this area forwarded the knowledge of NHPI’s physicochemical properties. There are still disputes linked with the precise value of the BDE in NHPI, various research groups reporting different values for the experiments performed in the same conditions. Another point that can be improved is to carry out systematic studies of

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S. Coseri Table 25: Second-order rate constant, kH (M21 s21) of H-abstraction from H-donor substrates by BTNO and PINO at 25uC.


Substrate, RH (no. of equivalent removable H atoms) C6H5CH2OH (2) 4-MeO-C6H4CH2OH (2) 4-MeO-toluene (3) PhOH (1) fluorene (2) Ph3CH (1) Ph2CHOH (1) PhCH2 (2) p-xylene (6) PhCHO (1)

kH (M21 s21) at 25uC in kH (M21 s21) at 25uC in MeCN with BTNO radical MeCN with PINO radical 0.57 3.4 0.091 66 1.9 2.3 3.2 0.36 0.02 0.8

5.7 22 3.4 330 20 59 58 6.6 0.99 11

The better performance of NHPI in comparison with HBT has also been found in the case of amides’ oxidation by the laccase-generated aminoxyl radicals (176).

the NHPI stability under the same conditions as the reaction implying NHPI are usually carried out (especially in acidic media and high temperatures, when the possibility of the decomposition becomes much more favorable). Other issue, which need to be addressed, concern the metal catalyst used with NHPI in the reactions. There are reported several metal types used as cocatalyst with NHPI, alone with in different mixture combinations. Deeper investigations of the metal activity correlate with its electronic structure and metal’s ability to be bonded into ligands complex network can afford the obtaining of the new catalytic systems with a better activity. However, the global concerns liked with the pollution issues, persuade the researchers to rethink the opportunity of the use of metal cocatalysts with NHPI. From this point of view, new systematic research should be directed toward identifying new ‘‘metal free’’ cocatalyst to be used with NHPI, and to optimize the conditions for the already reported systems. The use of NHPI as a catalyst agent is very limited to the best of my knowledge under unconventional media: ionic liquids (177), microwaves, and under ultrasound irradiation (178). In ionic liquids, similar with many other transformations, we can expect better performance than in the conventional organic solvents for the aerobic oxidation. The microwave reactions using NHPI can bring new findings to develop the understanding of the powerful activity of the NHPI. Solving the majority of these questions, we can expect afterwards to extent the use of the catalytic role played by NHPI in many different relevant systems, including oligosaccharides, polysaccharides, amino acids, and many others.


ACKNOWLEDGMENTS The author thanks NATO, for the ‘‘NATO Reintegration Grant,’’ CBP.EAP.RIG 982044. Thanks are also due to Prof. Bogdan C. Simionescu for his full support and helpful discussions.


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