Recent Advances in 1 , 4-Benzoquinone Chemistry

They are widely distributed in the natural world, being found in bacteria, plants and arthropods and hence quinones are ubiquitous to living systems. Quinones play pivotal role in biological functions including oxidative phosphorylation and electron transfer. Their role as electron transfer agents in primary metabolic processes like photosynthesis and respiration is vital to human life. A large number of chemical derivatives with 1,4-benzoquinone as the basic subunit exhibit prominent pharmacological applications such as antibiotic, antitumor, antimalarial, antineoplastic, anticoagulant and herbicidal activity. Wide applications of quinones can also be found in the field of synthetic organic chemistry. Coordination chemistry of quinones is also quite rich from the perspective of designing magnetic materials and understanding photophysical properties. The studies of quinonoid compounds have focused on a broad spectrum of topics viz occurrence in nature, syntheses, cycloaddition reactions, photochemistry and pulse radiolysis, computational chemistry, etc. The copiousness of articles describing the aforementioned multi-functional aspects serves as a grand testimonial to the contemporary interest in quinone chemistry. Hence a comprehensive review has been carried out to explore various scientific reports on 1,4-benzoquinones covering their chemical and biological significance.


Introduction
Quinones are a large class of compounds endowed with rich and fascinating chemistry. 11,4-Benzoquinone or p-benzoquinone (1) is the basic structure of quinonoid compounds.
They are widely distributed in the natural world, 2 being found in bacteria, plants and arthropods and hence quinones are ubiquitous to living systems.Quinones play pivotal role in biological functions including oxidative phosphorylation and electron transfer. 3Their role as electron transfer agents in primary metabolic processes like photosynthesis and respiration is vital to human life.A large number of chemical derivatives with 1,4-benzoquinone as the basic subunit exhibit prominent pharmacological applications such as antibiotic, 4,5 antitumor, [6][7][8][9] antimalarial, 7,10 antineoplastic, 11 anticoagulant 12 and herbicidal activity. 13][16][17][18][19][20] Coordination chemistry of quinones is also quite rich from the perspective of designing magnetic materials 21 and understanding photophysical properties. 22The studies of quinonoid compounds have focused on a broad spectrum of topics viz occurrence in nature, 2 syntheses, 23 cycloaddition reactions, 24 photochemistry and pulse radiolysis, 1,25,26 computational chemistry, etc. 27 The copiousness of articles describing the aforementioned multi-functional aspects serves as a grand testimonial to the contemporary interest in quinone chemistry.Hence a comprehensive review has been carried out to explore various scientific reports on 1,4-benzoquinones covering their chemical and biological significance.
Pigments of various colors isolated from different sources have been identified as quinonoid compounds.Crude preparations of plants presently known to contain quinones as active ingredients were prescribed for more than 4000 years as purgatives or drugs. 29Throughout history several other medicinal benefits have been added to the list every year.The discoveries of antibiotic and antitumor properties of several naturally occurring quinones have raised interest among scientists to explore their use as pharmaceuticals. 30,31or instance, streptonigrin (STN) 32 (2) is a natural quinone with antitumor and antibiotic activity.
Polyhalogenated benzo-and naphthoquinones were found to be potent inhibitors of plant and bacterial ureases.Ashiralieva and Kleiner 50 showed that the inhibitory power decreased considerably when halogens were replaced by −OH, −CN, alkoxy or alkyl groups.The polyhalogenated quinones can be used for treatment of infections caused by urease producing bacteria.Polygonatum alte-lobatum Hayata is a Formosan endemic plant.The rhizome of this plant has been used as a tonic drug in Taiwan.Huang et al. 51 isolated two new series of quinones named polyanoquinones A (14) and B (15) from the rhizomes of Polygonatum alte-lobatum.
El-Feraly and co-workers 52 isolated five new alkylated benzoquinones (16-20) as methyl ether derivatives from a complex mixture of alkylated hydroxy benzoquinones obtained from the fruits of Maesa lanceolata.
A new benzoquinone named alopecuquinone (21) was isolated from the ethanol extract of the inflorescences of Cyperus alopecuroids by Nasser et al. 53 The ethanol extract of the plant material showed moderate estrogenic activity using a strain of Saccharomyces cerevisiae.It has also been reported that Cyperus species have medicinal effects such as pectoral emmolient, analgesic and anti-helmintic.
Hosttetman and co-workers 54 isolated two novel benzoquinones heliotropinones A (22) and B (23), from the aerial parts of Heliotropium ovalifolium.These two quinones demonstrated antifungal activities against Cladosporium cucumerinum and Candida albicans as well as antibacterial activity against Bacillus subtilis.Kaul and co-workers 55 isolated six novel alkylated benzoquinone irisoquins A-F (24-29) and a known cytotoxic quinone, irisoquin (30) from the rhizomes of Iris kumaonensis.These classes of compounds have attracted considerable attention because of their antioxidant and cytotoxic properties.
][81] Thus, free radical scavengers have the potential as protective agents against various diseases.Lee et al. 82 isolated two such free radical scavenging quinones, betulinan A (67) and B (68) from the methanolic extract of Lenzites betulina.
Wang et al. 83 isolated two new benzoquinones, anserinone A (69), and B (70) with antifungal, antibacterial and cytotoxic activities from the liquid cultures of the coprophilous fungus Podospora anserina.
Ardisiaquinones are another interesting class of quinones derived from natural sources which are characterized by long carbon chains connecting two benzoquinone moieties.Ogawa et al. 85 first isolated ardisiquinones A-C (75-77) from the root bark of A. sieboldii.In 1995, Fukuyama et al. 86 reported the isolation of ardisiquinone D-F (78-80) from the same species and later published their total synthesis. 87In 2001, Yang et al. 88 extended the series to isolate ardisiaquinones G-I (81-83) from the leaves of Ardisia teysmanniana.All these quinones showed antimicrobial activity.
Carazza and co-workers 89 investigated the antibacterial activity of some new benzoquinones derivatives.The study points to the antibacterial activity of 2-aryl-3,5dimethoxy-1,4-benzoquinone derivatives.Cynanchum wilfordii Hemsley has been used as a tonic in Korea.A novel amino-substituted p-benzoquinone (84) has been isolated from this medicinally important plant by Yeo and Kim. 90Another potent antifungal benzoquinone (85) has been isolated from etiolated sorghum seedlings. 91anakubo and Isobe 92 reported the isolation of tetrabromo-1,4-benzoquinone from acorn worm.Structureactivity relationship of chemiluminescence activity of halogenated quinone derivatives reveals that a highly halogen substitution and 1,4-quinone skeleton are important for high chemiluminescence activity.Gentisyl quinone isovalerate, or blatellaquinone (BTQ) (86) has been reported 93 as a female sex pheromone produced by the German Cockroach, Blatella germanica.Bennet et al. 94 recently investigated the cytotoxic effects of BTQ in human lung adenocarcinoma cells.
Given its effectiveness to conjugate GSH, and possibly proteins, BTQ may be a potential chemical allergen  22, No. 3, 2011   contributing to allergic reactions in cockroach sensitized patients.
Pessoa et al. 95 isolated and characterized two significant quinones oncocalyxone A (87) and oncocalyxone C (88) from the ethanolic extract of heartwood of Auxemma oncocalyx.Later both oncocalyxones have been reported to exhibit antitumor activity. 96

Synthesis of 1,4-Benzoquinones
1,4-Benzoquinones are an important class of compounds, which serve as valuable building blocks in synthesis and are key moieties in the synthesis of biologically active compounds.A comprehensive report on various methodologies developed for the construction of benzoquinones and their derivatives is presented in this section.The immense interest on quinone chemistry has been observed from the middle of 19 th century.The most common quinone, benzoquinone (1) was the first synthesized quinone in the late 1830's in Liebig's laboratory as a result of the oxidation of quinic acid with manganese dioxide and sulfuric acid (Scheme 1). 29his reaction involves dehydration, decarboxylation and oxidation.
The same reagents can also react with aniline via a free radical condensation mechanism to afford benzoquinones.Succeeding these initial preparations of quinones, an array of reactions involving diverses starting compounds and efficient synthetic strategies have been reported in the literature till date for the synthesis of simple to highly complex benzoquinones.In general, quinones are being synthesized from phenols, 1,4-dihydroxybenzenes or hydroquinones and dimethoxybenzenes.Besides these traditional precursors some miscellaneous compounds also lead to benzoquinones.The commonly used oxidizing agents employed for quinone synthesis are silver oxide, 97 manganese oxide, 98 nitric acid, 99 salcomine/O 2 , 100 chromium oxidants, 101 benzene selenic anhydride, 102 ceric ammonium nitrate (CAN) 103 and DDQ. 104

Synthesis of 1,4-benzoquinones from phenols
Several techniques have been reported for the oxidation of phenols to benzoquinones.The Teuber reaction, 105  Teuber reaction is especially useful for the synthesis of heterocyclic quinones, where other oxidizing agents fail. 106Later on, several groups have developed direct and stepwise oxidation of phenols and their derivatives to p-quinones.Reinaud et al. 107 synthesized biologically active unsymmetrical alkyl-hydroxymethoxyquinone analogs (90) from p-methoxyphenol (89).The alkyl side chain was introduced regiospecifically ortho to the hydroxyl group via a Claisen rearrangement (Scheme 3).
2,3,6-Trimethyl-1,4-benzoquinone, TMQ (97)  synthesized by the oxidation of 2,3,6-trimethylphenol, TMP (96), is used as a precursor in the synthesis of vitamin E. 111,112 Molecular oxygen, hydrogen peroxide or t-butyl hydroperoxide are being used as common oxygen sources and different catalytic systems metallophthalocyanins, 113,114 heteropolyoxometallates, 115,116 spinel CuCo 2 O 4 , 117 copper hydroxyl phosphate, 118 iron halides, 119 copper (II) chloride, 120,121 metal acetylacetonates 122 and titanium silicates. 123,124Kholdeeva et al. 125 reported the TMP oxidation to TMQ with aqueous hydrogen peroxide.Later they modified the oxidation process using aqueous H 2 O 2 over titanium (IV) grafted on commercial mesoporous silica catalyst produced TMQ in nearly quantitative yield (Scheme 7). 126 125men et al. 127 have recently reported TMP to TMQ oxidation with potassium peroxomonosulfate, KHSO 5 , present in oxone catalysed by either iron phthalocyanin tetrasulfonate, [FePcTS] or cobalt phthalocyanin tetrasulfonate, [CoPcTS] in methanol-water mixture.The proposed mechanism for this oxidation involves, first the hydrogen abstraction from TMP by [Fe IV (O)PcTS] generating the 2,3,6-trimethylphenoxy radical.This radical is attacked by [Fe IV (O)PcTS] at the carbon para to the phenoxide oxygen resulting in the formation of an intermediate.Then proton mediated elimination produces catalyst and TMQ (Scheme 8).

OH
The highlight of the above strategy is that the reaction proceeded with 100% yield when the oxidant:substrate:catalyst molar ratios were 1200:300:1.Phenols with bulky substituents can also be converted to corresponding benzoquinones.Barton and Gloahec 128 reported a convenient high yield synthesis of 2,6-di-t-butyl-1,4-benzoquinone (100) from the iron catalysed oxidation of 2,4,6-tri-t-butyl phenol (98)   (105) have been oxidized to their p-quinones 102, 104 and 106 and respectively (Scheme 10). 129annabidiol (101) has been oxidized by air in an alcoholic solution in the presence of 5% KOH over 24 h at 0 °C to hydroxyquinone (102) at ca. 20% yield.][132][133][134] The nitric acid oxidation of phenols into the corresponding quinones has been known for a century.Nakao et al. 135 used such a protocol in the synthesis of antileukemic agents.Such a protocol has also been used by Cohen et al. 136 in the total synthesis of vitamin E (tocopherol).Heasely and co-workers 137 designed a twostep synthetic strategy for substituted quinones (109) from 2,4,6-trichlorophenol (107) (Scheme 11).A dimer type ketal (108) is formed in the first step which was easily hydrolyzed to respective quinones.
Polymer supported vanadium complexes have been reported as catalysts for the t-butyl hydroperoxide oxidation of phenols to 1,4-benzoquinoes in 69-95% yield. 140Yet in another method a mixture of cobalt and manganese salts of p-aminobenzoic acid supported on silica gel catalyses the oxidation. 141Recently, Brocksom and co-workers 142 undertook a comparative study on the oxidation of monophenols to p-benzoquinones.They used a range of oxidants such as cobalt, nickel, copper and vanadyl with different salen type ligands.Besides, the study also reported the use of hydrogen peroxide, oxone, dimethyl oxirane and iodoxybenzoic acid.
The electrosynthesis of benzoquinone is also reported. 143t is done by the anodic oxidation of phenol in acetonitrilewater mixtures on a-PbO 2 and b-PbO 2 electrodes.Conversion of 61-74% has been achieved by this method.The phenol oxidation mechanism 144,145 is shown in Scheme 13.
The recent advancement in the synthesis of quinone from phenol is the green chemistry route.Oelgemoller and co-workers 146 described the solar chemical synthesis of quinones by the photo-oxygenation of phenols.The yields were high when the reactions were performed in sunlight rather than artificial light.
Simple air-oxidation also is a successful method if the hydroquinone is sufficiently activated towards oxidation.An example of this is reported by Kelly et al. 158 in a short synthesis of diazaquinomycin A (115) from hydroquinone (114) (Scheme 14).
Nitric acid-impregnated manganese dioxide 159 in methylene chloride is also used as an oxidant.Tapia and co-workers 160 158 by stirring the solution at 0 °C for 30 min.About three decades back we applied MnO 2 as an effective oxidizing agent for the preparation of 1,4-benzoquinones from their hydroquinones. 161The oxidation reactions of hydroquinones (116) occur efficiently by catalysis with alumina-supported copper (II) sulfate, the supported catalyst (SCAT), to give benzoquinones (117) in good yield (Scheme 15). 148e synthetic potentiality of the above kind of catalytic reactions has been amply demonstrated by easy isolation of the final products using only filtration and solvent evaporation as well as by application to large scale syntheses.Other interesting oxidation of hydroquinones to benzoquinones has been reported by Shi et al. 162 in which 2-alkylhydroquinones (118) were converted to 2-alkyl-3,5,6-trichloro-1,4-benzoquinones (119) in low yield by reaction with chlorine gas in refluxing acetic acid (Scheme 16).
Owsik and Kolarez 163 carried out the catalytic oxidation of hydroquinone and studied the influence of surface properties of polymeric catalysts with aminoguanidyl ligand.They reported that under optimal conditions only  162 the main product, i.e., p-benzoquinone was obtained after 60 min.

Synthesis of benzoquinones from dimethoxybenzenes
The synthesis of 1,4-benzoquinones by the oxidative demethylation of dimethoxybenzenes or hydroquinonedimethyl ethers had been reported in the literature about five decades back.Nitric acid 164 and silver oxide 165 were used as oxidants for the synthesis of benzoquinones.Although nitric acid worked well for highly substituted 1,4-dimethoxybenzene derivatives, in some instances nitration of the aromatic ring occurs in addition to demethylation.Also both nitric acid and silver oxide required strong acidic media which the acid labile functional group could not tolerate.Subsequently Castagnoli and co-workers 166 introduced a facile and efficient oxidizing agent ceric ammonium nitrate, [Ce(NH 4 ) 2 (NO 3 ) 6 ] or CAN in acetonitrile for the oxidative demethylation of a variety of hydroquinone dimethyl ether (120) to corresponding quinone (1) in high yield (Scheme 17).The reaction can be carried out in the absence of a strong acid and is generally quite fast requiring only a few minutes of reaction time at room temperature.The selectivity and mildness of the reaction is illustrated by the fact that a variety of functional groups are tolerated.CAN in acetonitrile [167][168][169][170][171] then became the most versatile oxidizing agent for the dimethoxybenzene-benzoquinone transformation.For instance, the total syntheses of various biologically important short-chain ubiquinones (121) were accomplished via oxidative demethylation using CAN in good yield by Keinan et al. 172 (Scheme 18).
Hart and Huang 173 employed CAN oxidation in the penultimate step of the synthesis of an antitumor, antibiotic, pleurotin 122 (Scheme 19).
Besides CAN in MeCN-H 2 O, THF-water 179 is also used for the oxidative demethylation of 1,4-benzoquinones.
Multistep synthesis of quinones from dimethoxybenzene has also been reported.In a two step procedure, Shi et al. 162 first demethylated dimethoxy compounds (131) using BBr 3 to yield hydroquinones (132) and then carried out oxidation with Cl 2 /AcOH-H 2 O resulting in the formation of chlorinated quinones (133) (Scheme 26).
1,4-Benzoquinones have also been prepared from 1,3-dimethoxybenzenes where only one methoxy group converts to the keto group while other methoxy functionality remains intact in the resulting quinone.Singh and co-workers 183 synthesized 2,3-dimethoxy-5methyl-1,4-benzoquinone (ubiquinone Q 0 ) (135) by a reaction sequence starting form gallic acid present in mango kernel.In the final step of this synthetic sequence 3,4,5-trimethoxytoluene ( 134) is oxidized to ubiquinone Q 0 by 30% H 2 O 2 , HCOOH and phosphomolybdic acid in 57% yield (Scheme 27). 184When 50% H 2 O 2 is used in this conversion the yield of product is improved to 80%.
Recently a strategy for the eco-friendly and high yielding syntheses of ubiquinones starting from simple precursors and mild conditions was reported. 1853,4,5-Trimethoxytoluene ( 134) is treated with various reagents sequentially to obtain the final product, ubiquinones (137).The final oxidation of the 1,3-dimethoxybenzene ( 136) is carried out using ferric chloride, FeCl 3 (Scheme 28).
Oxidation of catechin (flavan-3-ols) is an important route to new potential bioactive p-benzoquinones.Bernini et al. 186 described the first catalytic benign methodology to obtain a new series of p-benzoquinones (139) by oxidation of catechin (138) and epicatechin derivatives with the hydrogen peroxide/methyltrioxo rhenium catalytic system (Scheme 29).Reactions were carried out both in homogenous and heterogeneous conditions and proceded with high conversion and moderate yields.Polymer supported methyltrioxorhenium systems were used as heterogeneous catalysts.After the first oxidation, the catalytic systems can be removed and reused for five consecutive times without loss of stability and efficiency.
Imparting new dimension to the synthesis of 1,4-benzoquinones a "telescoped process" for the preparation of 2-methoxy-3-methyl-1,4-benzoquinone (141) from 1,3-dimethoxytoluene (140) was disclosed by Bjorsvik and colleges. 187The compound 141 is produced selectively in high yield (95%) by a single pot telescoped oxidation process composed of three partial steps: Scheme 29.Synthesis of bioactive p-benzoquinones by Bernini et al. 186 i) oxidation using hydrogen peroxide and in the presence of a Brönsted acid, HNO 3 as a catalyst; ii) elimination of excess oxidant using sodium metasulfite and then iii) oxidation using concentrated nitric acid (Scheme 30).
A telescoped process implies that two or more steps are conducted without isolation or workup of the intermediate synthesized compounds.This telescoped process constitutes a green and environmentally benign alternative suitable for large scale use.
Later Xiong and Moore 191 also carried out the ring expansion of 4-alkylcyclobutenones by thermolysis to furnish a variety of N-heterocyclic quinones.
Moody and co-workers 195 reported a microwave-mediated Claisen rearrangement followed by phenol oxidation to yield many naturally occurring 1,4-benzoquinones from readily available precursors.Our group has been involved in the synthesis of a wide range of 1,4-benzoquinones (163) applying a three step synthetic strategy from readily available precursors (Scheme 39).
Gan et al. 202 developed a new, convergent and versatile synthetic strategy for efficient synthesis of 2,5-disubstituted-3,6-dimethoxy-1,4-benzoquinones (167)  from readily available molecules (Scheme 41).By two sequential Suzuki couplings, aromatic components can be selectively introduced into the dihalogenated benzoquinone scaffolds (166).This method serves as a key step in the total synthesis of leucomelone (168) in three steps and in 61% overall yield.
Another method was also reported by Pirrung et al. 203 which sequentially adds indole-3-mercurials to dichlorinated quinones using palladium catalysis.These reactions can be used in the modular assembly of bis(indol-3-yl)-benzoquinones, a significant natural product family.
Zora et al. 208 demonstrated a concise and synthetically flexible cyclobutenedione based approach to highly substituted ferrocenyl quinones (175) which relies on the versatility of cyclobutene diones as scaffolds for the construction of a diverse range of molecular structures.
R e c e n t l y s o m e n o n -t r a d i t i o n a l a p p r o a c h e s to the synthesis of biologically active substituted 1,4-benzoquinones were reported by Batra et al. 209 The synthesis has been accomplished using anhydrous K 2 CO 3 both as catalyst and solid support under thermal heating, solvent free grinding and solid-phase microwave irradiation

Computational Investigations on 1,4-Benzoquinones
One of the main areas where computational techniques are often applied is the characterization of the geometry of molecules.This can be achieved by the optimization of energy and geometry of molecules at various levels of theory.Novak and Kovak 210 studied the electronic structure of substituted benzoquinones and quinonechlorimides using the DFT method at the B3LYP/6-31G* level.A single point Green's functions (GF) 211 type calculation was performed in order to obtain vertical ionization energies.The computational results validated the theoretically predicted geometries with measured ones obtained by X-ray or electron diffraction.An ab initio molecular orbital study of different pyridoquinones (177 and 178) was reported by Yavari and Zabrijad-Shiraz. 212The structures of both classical and non-classical benzoquinones and pyridoquinones were optimized at HF/6-31G* and B3LYP/6-31G** levels.MP2 level calculations have been performed to calculate the single point energy (SPE).Among the possible isomers of pyridoquinones the 2,5-isomer was calculated to be the most stable.Apart from pyridoquinones, Yavari et al. 213 also modelled another interesting group of quinones, pentaloquinones (PQ) (179-184).
The geometry of the PQs were optimized at HF and B3LYP levels and single point energies calculated at QCISD level.1,5-Pentalenequinone was reported to be the most stable isomer.
Recently Atalar et al. 214 extended the investigation on pentalenoquinones (PQs) to bromopentalenoquinones (185-189) to reveal the stability and aromatic character.
The stability was determined by comparing the relative energy and the HOMO-LUMO energy gap, while the Baik et al. 215 accomplished the reactivity and stability studies of benzoquinones methides by ab initio calculations.The relative stabilization energies of differently substituted benzoquinone methides were calculated at the B3LYP/6-31G//B3LYP/6-31G* level by means of isodesmic equation 216 (Scheme 44) shown below.
The outcome of the theoretical analysis revealed that the symmetrically hindered benzoquinones methides are found to be more stable owing to the effective hyperconjugation of the dialkyl groups with the ring.
Hartree-fock and density functional studies on the structure and vibrational frequencies of quinone derived Schiff's base ligand, 1-imino-(ethyl-2'-pyridine)-2hydroxynaphthoquinone, have also been reported. 217The syn and anti conformers of the aforesaid ligand have been obtained as the local minima on the potential energy surface with the syn conformer as more stable than the anti conformer due to intramolecular hydrogen bonding.
The HOMOs and the LUMOs shifted to higher energies as the number of silyl groups increased whereas the calculated vibrational frequencies shifted to lower frequencies.The LUMO energy levels of the silyl-1,4benzoquinones were quantitatively proportional to the first half-wave reduction potentials.
0][221][222] Recently Min et al. 223 applied theoretical calculation to assign individual THz absorption spectra of the p-quinones with semiempirical AM1, hartreefock (HF) and density functional theory (DFT) method.The results with DFT method at B3LYP/6-311G produced better simulation with the experimental data.The molecular property of a compound is controlled by its molecular geometry.5][226] Song et al. 227 carried out an exhaustive DFT and ab initio hartree-fock studies on the structural parameters and chemical reactivity of all the free radicals generated by benzoquinones and hydroquinone.The highlight of this study is that the free radicals can be easily generated in aqueous solution and are more reactive.
Bangal 228 studied the proton coupled charge transfer in the formation of charge transfer complexes between 1,4-benzoquinone and 2,6-dimethoxyphenol by DFT-B3LYP/6-311G(d,p) level.The strength of the charge transfer complex formation ability depended on the HOMO-LUMO energy gap which in turn was influenced by the H-bond formation.
Tormena et al. 229 carried out a detailed theoretical analysis of the relative stability of endo/exo Diels-Alder adducts formed by the reaction between cyclopentadiene and 1,4-benzoquinone.The energies of both endo and exo adducts were obtained at CBS-Q level of theory, which showed that endo adduct is more stable than exo.An NBO electronic structure analysis indicated that the attractive delocalization interaction predominates over the steric repulsive interaction in the endo adducts.
Patil and Sunoj 230 reported the substituent effects of retro Diels-Alder reaction in benzoquinones.A systematic study has been carried out on the retro Diels-Alder reaction of cycloadducts (198) formed between substituted cyclopentadiene (199) and p-benzoquinone (1) based on the hybrid HF-DFT method (Scheme 45).
The transition state study on the cycloreversion reaction demonstrated that -SiMe 3 substituents are most effective in lowering the activation barrier.
The influence of hydrogen bonds to nearby molecules direct the quinones to perform a desired function. 231This principal is verified by the ab initio studies of neutral and anionic 1,4-benzoquinone-water clusters by Manojkumar et al. 232 They observed that when two water molecules are complexing with 1,4-benzoquinone, a conformer exhibiting a H-bond between two water molecules (W 2 Q) is energetically more favoured than the conformer WQW in which there is no direct interaction between the water molecules.The geometry of the structures were optimized at MP2 and B3LYP level using the 6-311++G** basis set.
The reaction of quinone mediated reduction of oxygen to peroxide (Scheme 46) has been investigated in detail by Wass et al. 233 through quantum chemical modeling.
DFT-B3LYP level study was done to map the course of the reaction constituting the above steps.
in organic synthesis. 234The hydride affinity of quinones is a measure of their oxidizing power.
Based on this principle, Zhu et al. 235 predicted the hydride affinities of a variety of eighty quinones in DMSO solution so as to prepare large and useful library of organic oxidants.They defined hydride affinity of quinone in solution as the free energy change in the reaction of quinone with free hydride ion to form the corresponding hydroquinone anion at 25 °C in solution (Scheme 47).
A similar study to predict the electron affinities of various methylated and halogenated derivatives of p-benzoquinones has been undertaken by Wheeler and co-workers. 236][239][240] Very recently the characterization of semiquinones and quinones formed as intermediates in the oxidation of flavonoid epicatechin has been studied by means of computational chemistry. 241The antifungal and antioxidant activities of flavonoids depend on the stability of these semiquinones and quinones. 242The antioxidant activity is directly related to the ease of deprotonation of its OH groups.Consequently the structural properties, the bond dissociation energy and total energy of these compounds from epicatechin was determined using B3LYP/6-31G** level of calculation.The results showed that the 4'-OH of the catechol group represents the primary site of deprotonation (the most oxidizable), which gives both the most stable and the easiest formed semiquinones.
By this model, the computed electrode potentials are within at most ± 0.087 V and an average error of 0.043 V with experimental values.Namazian and Almodarresieh 256 extended their study to improve the reduction potential values by including the frequency calculations and relaxation of salvation energy.Recently Pakiari et al. 257 further modified the computational techniques and carried out the evaluation of standard twoelectron reduction potentials of some quinones at B1B95 level of density functional theory methods.Polarized continuum models, CPCM and DPCM are employed for considering the solvent contribution.In comparison with other methods DFT-B1B95 is a reliable level of theory and less computer time demanding, which gives moderate accuracy even when ordinary sized basis sets are used.
Quinones lead to the generation of reactive oxygen species, through redox cycling in the presence of oxygen.][260] The potential of quinone compounds to participate in redox cycling is mainly dependent on the stability of the semiquinone radical relative to the quinone and the quinol forms.A simple and practical method for calculating thermodynamic parameters necessary to estimate semiquinone stability constants and redox potentials for quinone natural products has been reported by Cape et al. 261 utilizing DFT-B3LYP method.Accurate calculation of absolute one-electron redox potentials of some p-quinone derivatives in acetonitrile was done by Namazian and Coote. 262A thermodynamic cycle is designed to calculate ∆G 0 (t) of reaction from its components (Scheme 49).
An ONIOM method in which the core is studied at G3(MP2)-RAD is used for calculating the thermodynamic properties.
Tetrafluoro-p-benzoquinone (TFBQ) has many applications in chemical synthesis [263][264][265] owing to the presence of four highly electronegative F atoms.The electron affinity and redox potential of TFBQ has recently been computed by Namazian et al. 266 via standard ab initio molecular orbital theory at the G3(MP2)-RAD level of theory.Natural bond orbital (NBO) method is used to predict the charge distribution at TFBQ and BQ anions.They correlated the charge distribution with the electron affinity.
Our group carried out a semiempirical (AM1) computational study on the modeling of Diels-Alder cycloadditions at the beginning of this decade. 267A number of model quinones with both electron donor and acceptor substituents have been studied and the energy gaps to both electron-rich and electron-deficient dienes have been calculated.Then we extended the study to quinoxalin quinones (128). 268sults of the computational study revealed that by choosing appropriate diene such as electron-withdrawing diene, it is possible to reverse the course of Diels-Alder cycloaddition from quinonoid ring to the heterocyclic moiety.
Very recently an interesting DFT study in understanding the influence of Lewis acid in the regioselectivity of the Diels-Alder reactions of 2-methoxy-5-methyl-1,4benzoquinone (203) (Scheme 50) has been reported by Soto Delgado and co-workers. 269he theoretical results obtained by DFT-B3LYP level calculation provided a useful tool for the interpretation of the reaction mechanisms.Transition state studies showed that there is a larger activation barrier associated with the uncatalyzed processes.
Zhou and Corey 289 reported a novel enantioselective [3+2] addition of 1,4-benzoquinones with vinyl ethers catalyzed by the chiral oxazaborolidinium ion (Scheme 52).This methodology has been applied to a short enantioselective synthesis of the potent naturally occurring mutagen aflatoxin B 2 (205).
The synthetic utility of these cycloaddition reactions has been demonstrated by the synthesis of different antimicrobial pterocarpan phytoxalexins (210).
The hydride transfer reaction from 211 to 1 also occurs besides the cycloaddition when the Lewis acidity of metal ion decreases.A change in the type of reaction from a cycloaddition to a hydride transfer depends on the Lewis acidity of metal ions.Another noteworthy [3+2] cycloaddition involves reaction of naphthoquinones with nitrile oxides to generate regiodefined type II polyketide building blocks. 293he extreme enthusiasm in the [3+2] cycloaddition reactions led to the emergence of very interesting pseudo-1,3-dipolar cycloaddition chemistry.Passmore and coworkers 294 identified this pseudo-1,3-dipolar cycloaddition as a powerful tool for accessing a variety of mono-and bifunctional 6p heterocyclic 1,3-dithiazolium cations.They reported the unprecedented formation of a benzo-fused 1,3,2-dithiazolium [AsF 6 -] salt by a one step quantitative cycloaddition of SNSAsF 6 with 1,4-benzoquinone (1) (Scheme 55).
Another glorious achievement of this group using the chiral catalyst (214) has been the transformations of some of the classical synthesis of racemic natural products. 307Hence the enantioselective versions of the Sarett's total synthesis of cortisone, Kende's total synthesis of dendrobine, Chu-Moyer/Danishefsky synthesis of (±)-myrocin C and Mehta's synthesis of (±)-triquinanes have been accomplished with excellent yields.Later Corey and co-workers 308  White and Choi 310 demonstrated the synthetic utility of Diels-Alder reaction of benzoquinone (1) through the asymmetric synthesis of the indole alkaloid (-)-ibogamine (220).The key step in this synthesis is the Diels-Alder addition of (1) to an achiral diene (218) in the presence of a chiral catalyst, (S)-BINOL-TiCl 2 to give for the adduct (219), which on subsequent reactions yielded (220) (Scheme 58).
Masked 1,4-benzoquinones (221) are quinones in which a carbonyl group is masked by converting into monoketals.2][313] March et al. 314 reported that phenylthiomonoketal (222) works efficiently as a masked p-benzoquinone in Diels-Alder reactions.These cycloadditions may be performed with certain Lewis acid catalyst like ZnBr 2 and give rise exclusively to endo adducts with a good to excellent anti-facial selectivity (Scheme 59).Carreno et al. 315 studied the effect of aryl substitution on reactivity, chemoselectivity and p-facial diastereoselectivity of Diels-Alder reactions of various 2-(arylsulfinyl)-1,4-benzoquinones (223-226) with cyclopentadienes.The reactivity and selectivity of the process proved to be dependent on the electron density of the arylsulfinyl group.
Later Carreno and colleges 316 observed that the dienophilic reactivity of the 2-methyl substituted quinones have been increased upon boronic acid substitution.The Diels-Alder reaction of this substrate (227) followed by a spontaneous and stereoselective protodeboronation to give the trans-fused cycloadduct, 228 (Scheme 60).
The role of boron group in this typical cycloaddition is to act as a temporal regiocontroller and leads to the uncommon meta-regioisomer of the cycloadduct.Trauner and colleges 317 demonstrated the viability of vinyl quinones in Diels-Alder reactions.They utilized this strategy to synthesize medicinally significant (-)-halenaquinone (229).
The construction of complex polycyclic frameworks has also been reported by a double domino Knoevenagel hetero Diels-Alder synthetic strategy.Jimenez-Alonso et al. 323 synthesized several bis-pyrano-1,4-benzoquinones (220) using this strategy for the first time (Scheme 65).Using microwave radiations these reactions proceeded more efficiently and rapidly.
Pardasani et al. 324 studied the base-induced benzoyl migrations in Diels-Alder adducts of benzoyl-1,4benzoquinones.Later, we carried out the Diels-Alder reaction of some fluorinated p-benzoquinones (221) with substituted dienes (222) furnishing the adducts 4a,5,8,8atetrahydro-1,4-naphthaquinones (223) in good yield (Scheme 66). 325he potential utility of such a cycloaddition reaction lies in the synthesis of a number of anthracyclinone analogues.Similar Diels-Alder reactions of numerous 1,4-benzoquinones have been subsequently reported by our group. 198,326,327 en et al. 328 achieved a typical cycloaddition reaction of zirconacyclopentadiene (224) to various quinones leading to a 6-membered adduct (Scheme 67).This is an efficient method for higher quinones by a zirconium/CuCl mediated cycloaddition reactions of two alkynes and quinone in a one-pot procedure.
Pirrung and Kaliappan 329 developed a cycloaddition strategy based on the dipolar cycloaddition reactions of rhodium-generated carbonyl ylides (225) with p-benzoquinones to synthesize biologically important compounds containing spirocyclopropyl group.This cycloaddition generated both the C=O (226) and C=C (227)  addition products (Scheme 68).
Photocycloaddition of cyclic conjugated enones with alkenes is a convenient method to construct a cyclobutane containing polycyclic system.6][337] Quinones occupy a very important position in the photoreactions with alkenes in which the conjugated C=C and C=O double bonds competitively take part in the [2+2] photocycloaddition to provide cyclobutane derivatives [338][339][340] and Paterno-Buchi adducts [341][342][343] respectively, depending on the identities of the quinone as well as the alkenes.We studied 344 the photocyclisation of benzoyl-1,4-benzoquinones leading to xanthones and phenyl gentisate esters while pursuing studies on the synthesis of anthracyclinones and heteroanthracyclinones.

Pulse Radiolytic Studies on 1,4-Benzoquinones
Pulse radiolysis is a method of studying fast chemical reactions in which a sample is subjected to a pulse of ionizing radiation, and the products formed by the resulting reactions are studied stereospecifically. 3480][351][352][353][354] Quinones participate in a range of biological redox processes owing to their efficiency in undergoing reduction.][357] Rao and Hayon 358 studied in detail the ionization constants, absorption spectra and extinction coefficients of numerous semiquinone radicals in aqueous solution and correlated their increased reduction potential with increased acidity.ey found that in acidic environment fluoranil can be a better electron acceptor than 1,4-benzoquinones.
They studied the kinetics of semiquinone disproportionation by pulse radiolysis and attributed lower rate of disproportionation of Q •-to outstanding antitumor activity of the corresponding quinone (Q).
A series of newly synthesized nine aroyl/heteroacyl-1,4-benzoquinones (RCO-BQ) undergoes one-electron  362 The radical centre is mainly located in the quinone ring, though a small probability exists for reduction at the carbonyl (CO) group.The intramolecular hydrogen bonding between the OH group of the semiquinone ring and the adjacent CO group makes the radical more stable as compared to the simple benzosemiquinone radical.A red-shifted absorption band arises mainly due to large conjugation in the semiquinone.The substitutions (R), thiophenyl, phenyl and furanyl groups at the keto position reduce their one electron reduction potential (E1) values from -30 mV for BQ to < -300 mV in some of these quinones.

Conclusion
The comprehensive literature survey pertaining to multiple aspects of quinone chemistry unveiled the sustaining importance of quinonoid compounds in many fields of science.The isolation of different quinones from plants and micro-organisms are still being carried out ambitiously.Synthetic organic chemists encouraged by the potential applications of quinones have devised a plethora of synthetic strategies which led to the explosion of articles reporting newer and interesting benzoquinone derivatives.With the advancement of computational methods in solving chemical problems, theoretical studies in various properties of quinones had also been started to report abundantly in the last decade.All these and other significant developments in the cycloaddition and pulse radiolysis of quinones are presented in this review.

Scheme 33 .Scheme 34 .Scheme 35 .
Scheme 33.Synthesis of quinone (149) by thermolysis of benzocyclobutenone.190 established based on the nucleus independent chemical shift (NICS) values.The calculations demonstrated that the insertion of Br atom decreased the HOMO-LUMO energy gap and NICS values.
Oxidation of TMP to TMQ using H 2 O 2 and grafted Ti (IV)/SiO 2 catalyst byKholdeeva et al.
with t-butylhydroperoxide (TBHP) (Scheme 9).Compound 99 is a useful synthetic intermediate.Earlier Muruhashi et al. 108 also reported a Mechanism proposed for the oxidation of TMP with KHSO 5 catalysed by [Fe III PcTS].