2- Acetyl-p-benzoquinone

This orientation reversal is noted also with 2,5-dimethyl-p-benzoquinone and 2-acetyl-p-benzoquinone, but not with 6-methoxy-p-toluquinone. The orientation observed in the thermal reactions is unexpected, since Diels-Alder reactions with simple ilicnophilcs give the two possible adducts in approximately equal amounts. 

As an example, acetaminophen (APAP) in overdose has been used by several groups to identify hepatotoxicity biomarkers in mice. APAP-induced hepatotoxicity is characterized by hepatic centrilobular necrosis and hepatitis. APAP biotransformation by Phase I enzymes leads to the formation of the reactive metabolite N-acetyl-p-benzoquinone (NAPQI), which can deplete glutathione and form adducts with hepatic proteins (see Section 15.2). Protein adduction primes the hepatocytes for cytokines released by activated macrophages (Kupffer cells) and/or destructive insults by reactive nitrogen species. Although necrosis is recognized as the mode of cell death in APAP overdose, the precise mechanisms are still being elucidated [152]. 

The formation of the substituted dibenzofuran-l,4-dione (405) from 5,5 -dimethyl-2,2 -di-p-benzoquinone (406) can be achieved thermally or by photolysis in hydroxylic solvents such as methanol or acetic acid,421 and a related cyclization has been observed in dinaphtha-quinones.422 A dibenzofuran derivative (407) is also obtained on irradiation of the conjugated dione (408) the intermediate (409) can be isolated by maintaining a temperature of 6° in the reaction flask.423 A mechanism for the photorearrangement of 2-acetyl-3-furyl-p-benzoquinones to derivatives of isobenzofuran has been proposed424 [Eq. (109)]. 

FIGURE 10-2. Pathway of acetaminophen metabolism and basis for hepatotoxicity. (NAPQI, N-acetyl-p-benzoquInone-lmlne, a reactive acetaminophen metabolite.)... 

ALT alanine aminotransferase AST aspartate aminotransferase CYP cytochrome P450 liver enzyme system NAPQI V-acetyl-p-benzoquinone imine NAT2 N-acetyltransferase 2 genotype... 

Fig. 3 Mechanistic determinants in acetaminophen-induced hepatic necrosis. APAP Acetaminophen, iVAFg/N-Acetyl-p-benzoquinone imine, CYP cytochrome P-450, G5//reduced glutathione, ROS reactive oxygen species, RNS reactive nitrogen species, om outer membrane, im inner membrane, MPT mitochondrial permeability transition, BAX Bcl-2-associated X protein...

Acetaminophen (paracetamol) is a commonly used analgesic which is hepatotoxic at high doses in humans and in laboratory animals. Toxicity is believed to be mediated by the reactive metabolite N-acetyl-p-benzoquinone imine which binds to protein thiols as 3-(cystein-S-yl)acetaminophen adducts. Ultrasensitive immimoassays for 3-(with parallel elevations in serum adducts and serum levels of the liver-specific transaminase ALT. This suggested that the serum adducts were of hepatic origin and could be monitored as a biomarker of acetaminophen toxicity. Analysis of serum samples from acetaminophen overdose patients demonstrated a positive correlation between immunochemically detectable serum adducts and hepatotoxicity. 

Syntheses of 4,5-Unsaturated Cyclic Compounds - Swem oxidation of methyl 2,3,4-tri-C>-acetyl-a-D-glucopyranoside followed by base-induced elimination of acetic acid afforded unsaturated aldehyde 33. Further transformation of the aldehyde group into a methylene unit by way of a Wittig olefination and replacement of the acyl groups with benzyls or methyls yielded 34 which underwent a Diels-Alder reaction (the acyl protected variant of 34 was unreac-tive) with 2-methoxycarbonyl-p-benzoquinone, followed by acid-catalysed double... 

Hepatotoxicity does not occur at recommended doses of acetaminophen. Administration of 2 g, or twice the recommended dose, of intravenous paracetamol in healthy subjects has been shown to stay far below the threshold of hepatotoxicity. When ingested at high doses, acetaminophen is metabolized to JV-acetyl-p-benzoquinone-imine (NAPQI). NAPQI is rapidly conjugated with glutathione to a nontoxic compound. The depletion of glutathione results in the accumulation of NAPQI that is responsible for liver injury. Acetaminophen has a narrow therapeutic window and even minor overdoses may cause severe hepatic injury. Liver necrosis occurs at 7.5-10 g of acetaminophen. 

When the hepatic capacity for protective metabolism by glucuronidainn is exceeded, acetaminophen undergoes N-hydroxylation followed by the spontaneous formation of N-acetyl-p-benzoquinone. 

The behaviour of p-benzoquinone on reaction with acetic anhydride in the presence of sulphuric acid is of interest. The eventual product is 1,2,4-triacetoxybenzene (the Thiele acetylation), which is formed by the following... 

Conversion of p-benzoquinone into 1,2,4-triacetoxybenzene (Thiele acetylation). Add 11 g (0.1 mol) of p-benzoquinone in small portions to a mechanically stirred mixture of 33 g (0.32 mol) of acetic anhydride and 0.25 ml of concentrated sulphuric acid. The temperature of the mixture rises to 40-50 °C and is kept within this range by regulating the rate of addition of the quinone. When the addition is complete allow the solution to cool to about 25 °C and pour into 150ml of cold water. Collect the precipitated triacetate and recrystallise it from about 50 ml of rectified spirit the yield is 22 g (86%), m.p. 97 °C. 

Benzene, phenol, and hydroquinone are metabolized in vivo to benzoquinone and excreted as the mer-capturate, N-acetyl-S-(2,5-dihydroxyphenyl)-L-cy-steine. Hydroquinone is a reducing cosubstrate for peroxidase enzymes, and the resultant semiquinone and p-benzoquinone may bind to DNA. 

This type of cyclocondensation is represented only by a somewhat specialized example. Thus methyl p-benzoquinone-2-carboxylate (121) with A-acetonylidene-M-methyDiydrazine (122) gave 4-acetyl-5,8-dihydroxy-2-methyl-l(2Ff)-phthalazi-none (123) [or its tautomer, 4-acetyl-8-hydroxy-2-methyl-l,5(2H,3fl) phthalazine-dione] (MeOH, 20°C, 12 h 50%). °... 

Towers, M. D. K. N., Woodgate, P. D. and Brimble, M. A. 2003. Addition of 2-[(trimethylsi-lyloxy)]furan to 2-acetyl-1,4-benzoquinone using chiral non-racemic copper(II)-pybox catalysts. Arfa voc (i) 43-55. 

Preparation by adding an aqueous solution of sodium hydrosulfite to an ethereal solution of 2-acetyl-3-(3-acetyl-4-hydroxyphenoxy)-l, 4-benzoquinone (m.p. 120-121°) and stirring the mixture at r.t. for 30 min (80%) [5916]. 

Polyquinolines form another class of heteroaromatic polymers exhibiting photoconductivity. The interest in the synthesis of polyquinolines has increased rapidly during the last decade because of their excellent oxidative and thermal stability. When doped with alkali metal donor compounds like sodium naphthalide or sodium anthracide, several polyquinolines show electrical conductivity as high as 10 S/cm [336,337], When doped with electron-donor compounds such as TNF or 2,3-dichloro-5,5-dicyano-l,4-benzoquinone some poly-quinolines show distinct photoconductivity. One such polyquinoline is poly(4-phenyl-2,6-(p-phenoxy)-quino-line) (54b) [338,339]. It is obtained by the acid catalysed self-condensation reaction of 4-amino-4 -acetyl-3-benzoyl diphenyl ether (54a). 

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