Chapter 23 Anthraquinones, Quinones, and Polyhydric Phenols

460 CHAPTER 23

ANTHRAQUINONES , QUINONES , AND POLYHYDRIC PHENOLS

A.

9,lO-Anthraquinones

A large number of naturally occurring and synthetic anthraquinones have been widely employed a s dyestuffs and coloring agents in textiles, foods, drugs, cosmetics, and hair dyes1. Table 1 lists the mono- to hexa- hydroxyanthraquinones and their respective common names.

Table 1.

Hydroxyanthraquinones P o s i t i o n of

Name

OH g r o u p

Erythrohydroxyanthraquinone

1-

21,2-

A1i zar in

Purpuroxanthin, xanthopurpurin Quinizarin Anthrarufin

Chrysazin Hys t a m r i n Anthraflavin Isoanthraflavin A n t h r a c e n e Brown; A n t h r a g a l l o l Purpur i n A l i z a r i n B r i l l i a n t Bordeau R Flavopurpurin Anthrapurpurin A l i z a r i n Cyanine R A n t h r a c e n e Blue WR

1,3-

1,4-

1,5-

1,6-

(

1,71,82832,52,71,2,3-

1,2,41,2,51,2,61,2,7-

1,2,4,5,8-

1,2,4,S86,8-

Alizarin (1,2-dihydroxy-) (I); quinizarin (1.4-dihydroxy-) (11); anthragallol (1,2,3-trihydroxy-) (111) and purpurin (1,2,4-trihydroxy-) (IV) anthraquinones a r e among the best known of the hydroxylated derivatives and have achieved importance as mordant dyestuffs and a s intermediates for the manufacture of a number of important anthraquinone intermediates and a s intermediates for the production of dyes for wool and synthetic f i b e r s l . Because of their rather unique ability to form lakes with metallic ions, many hydroxyanthraquinones are also used for the detettion and estimation of metals. Other areas of utility of the 1,4- and 1,5-dihydroxyanthraquinones and 1,2,4trihydroxyanthraquinones a r e in the production of acrylate-ethylene polymers for

461 hot-melt adhesives and laminates2 a s light stabilizers for polystyrene3 and in the case of the 1,4-dihydroxy derivative (quinizarin) , a s lubricants for pneumatic tools4.

(1)

(11)

(111)

(IV)

Among the nitroanthraquinones that have utility in the preparation of aminoanthraquinones for dyestuffs a r e the 1-nitro-, 1,5-dinitro-, and 1,8-dinitro anthraquinones

.

In general, anthraquinone per s e is a relatively inert compound. In spite of its quinone structure, many reactions characteristic of quinone compounds, either do not occur, o r if so, only with difficulty. However, it is the base material for the manufacture of a group of d y e s . The carcinogenic activity of the anthraquinones have been sparsely examined. 1-Amino anthraquinone has been reported to be carcinogenic in r a t s 5 . 1-Methyl amino anthraquinone fed intragastrically was carcino enic in r a t s , while 2-amino anthraquinone induced cystic changes in the kidneys . 2.6-Diamino anthraquinone was also tested in this study and found negative6.

%

/

Brown and Brown7 recently described the screening of ninety 9,lO-anthraquinone derivatives and related anthracene derivatives for mutagenicity with 5 s_l typhimurium tester strains, TA 1535, TA 100, TA 1537, TA 1538, and TA 9 8 , with and without mammalian microsomal activation. Three patterns of mutagenesis were apparent in the approximately 35%of the compounds considered to be mutagenic. These are: (1) direct frameshift mutagenesis by certain derivatives bearing free hydroxyl groups. The most potent were anthragallol (1,2,3-trihydroxy-); purpurin (1,2,4-trihydroxy-) and anthrarufin (l15-dihydroxy-) anthraquinones While some hydroxy anthraquinones particularly at lower concentrations, exhibited activation by mammalian microsomal preparations, the majority of mutagenic hydroxy anthraquinones appeared to revert strain TA 1538 (his 3076) specifically. (2) Frameshift mutagenesis by certain derivatives with primary amino groups, a n d , in a few cases, with secondary amino groups. Frameshift mutagenesis was potentiated with mammalian microsomes, and activity with strain TA 100 (sensitive to base-pair substitution) was observed in a few cases, e . g , 1,2-diamino anthraquinone. (3) Anthraquinones with one or more nitro groups exhibited the least specificity with regard to tester strain reverted and to microsomal activation; all 7 nitro anthraquinones tested were mutagenic. In anthraquinones containing mixed "mutagenic" functional groups, the type c~fmutagenesis observed was usually NO2 > OH > NHZ. Table 2 illustrates the screcxiing of a number of anthraquinone derivatives and related compounds with S typhimurium tester strains TA 1535, TA 100, TA 1537, TA 1538, and TA 98/mammalian microsomal test.

.

.

.

At present, it is not known whether hydroxy anthraquinones r e v e r t TA 1537 by simple intercolation o r a more reactive process7. It was suggested that possible oxidative metabolites o r chemical oxidation products involved in the latter process might include cyclic peroxides a s precursors to cA-dihydrodiol-anthraquinones8 o r phenoxide free radicalsl0I l l .

TABLE 11 SCREENING OF ANTHRAQUINONE DERIVATIVES AND RELATED COMPOUNDS F O R M U T A GENICITY WITH S A L M O N E L L A TYPHIMURIUMIMAMMALIAN MICROSOMAL TEST Test c o m p o u n d

S-9

Pg

Number of HU' rcvcrtantslplate a T A 1 5 3 5 TAlOO

Control

X

t

SD (N) d

-

(a) Hydroxylated m t h r a -

quinoner and related compounds

1.8.9-Trihydrox yanthracene

(Anthralin) (1)

10 20

982 28 (114) 922 25

TA1537 TA1538 TA98

1 0 +5 (121) 12t4 (112)

++

+

+++ ++

100 f

500 20(10

1.2-Dihydroxymthraquinone (Alizarin) ( 0 )

100 500

lo00

2o00

1.4-Dihydroxy~thraquinone (Quiniznrin) (1)

1.5-dihydroxyanthraquinonc (Anthrsrufin) (1)

++

++ +

+

+ -

+

100

++++

500

++++ + ++++ +

50 100

2000

1.8-DihydroxyMthraqulnonc (Chryuzin. Danthron) (2)

-

100

500 1000

-

++

++ ++

++++ ++ ++++ ++ ++++ +

+ * +

463 TABLE 11 (continued)

Test compound

'

S-9

Irl

Number of His' revertantslpiatr a TA1535 TAlOO

TA1537 TA1538 TA98

~

1.5-Dihydroxy-4.8 diaminoanthraquinone (1)

50 100 500

Leuco-1.4.5.&tetrahydroxyanthraquinone ( 2 )

100

500

1.2.4-Trihydroxyanthraquinone (Pulpurin) (1)

10 50 100

1 -1iydrox y-4-amino-anthra.

++++ + ++++

++ +++

100

+++

2000

50

quinone (2) 100

500

++ +++ ++++ +++ ++++

-

.

500

+

+++ ++ ++

500

quinone (Disperse Red 15) ( 2 )

1 -S-Aeetyl-4-hydrox yanthra-

+++ + +++++ +++ ++++++

++ f

++ +++ ++ +++ + ++ +++ +++

(b) Aminaled anthraquinones 1.2-Dismosnthraquinone (3)

100

500 2000

1.4-Diaminosnlhraquinone (1)

100 500

1000 2000

++++ +++ +++ ++++ +++ ++++ +++ ++

++ +++ + ++ ++

+ ++ ++ ++

+

++++

+++ ++

-

+++ -

++ ++++ ++

++++ ++ ++++++

-

++++ ++

+++ +++

464 TAI3I.E I I (continurd) Trsl coinpound

pg b

S-9

Number of His'revertantr/plate

TA1535 TAlOO 2.ti-1)iaminoanthraauinone ( 0 )

a

TA1537 TA1538 TA98

100 500 2000

1.4.5.8-Trtraaminoanthra-

100

quinone (Disperse Blue 1 ) (0)

500 2000

Anthraquinone-1-diaronium chloride (Fast Red A Salt) (0)

10 200

400

1 -Benzaniido-bchloro-

50

anthraauinone

100 500 I -N-AcetyI-4-0-acetylanthraauinone (4) I .4-Diamino 2.3 dihydroanthraquinone (4)

500

50

1 00 500

I -Anilino-brnethyl-

500

anthraquinone

1.5-Diamino-anthraquinone( 0 )

100 500 2000

( c ) Nitrated anthraquinone derivatives

I .8-I)ihydroxy-4.Cdinitroanlhraquinone ( 0 )

100

+

500

-

2000

+

+

-

+ +++

++ ++ -

+

++++++ +++++ ++++ ++++

-

-

++++

+++++

++++ +++

+++

++

+++

+++

465 TABLE 11 (continued) Teal compound

ug b

S-9

Number of Hi.* reverianls/plsle a TA1535 TAlOO

2.6-Dihy droxyanihraquinone (Anihraflavic Acid) ( 0 )

100

-

500

-

1000

1.8-Dihydrox Y-3-methylanthraquinone (Chryrophanic Acid)

100

500 2000

Leuco-l .I-dihydroxyanihraquinone (Leucoquinizuin)

100

500 2000

+

-

+ +++

++ ++

+++

++ ++

++

-

100

++

1.2-Dihydroxy-9-nnihronc (Anthinrobin) (2)

100

3-Methyl-l.8.9-trihydroxyMthracene (Chrysarobin) (1)

50

500

100

500

50 100 500

1.3.8-Trihy&ox~-6-me(hyIanihraquinone ( E m d i n )

*

20

500

1.2.5.8-Tetrahydrox yanihraquinone (Quiruliruin) ( 0 )

TA1537

50 250 2000

+++ +++ +++ ++ + + + ++ + +++ ++

+++ + +++ +++

+++

++++

_++ -

-

TA1538 TA98

466 TABLE I1 (continued) Test compound

S-9

Irg

Number ofHis' reverbntslplate a TA1535 TAlOO -

1-Nitro-2-methyl-anthra.

quinone ( 0 )

100

+

500

++

1270

+

500

1-Nitro-2-ethyl-anthraquinone 1000

>-

Diamino- 5 n itroanthraquinone ( 0 )

1-Amino-2-carboxylate-4nitro-anthraquinone ( 0 )

50

-

-

++

-

+

+

-

++

+

-

-

++

++

+ ++ ++

+

I

+

100

+++

500

++

-

+++ ++

-

50

7+

8+ 6+ 8+ 8+

8+ 5+ 8+ 8+

5+

100

I+ I+

500 l-Nitro-6(7)sulIonatoanthraquinone ( 0 )

TA1537 TA1538 TA9R

+++++ ++++

+++

-

+ +

++

+ ++

++ ++++ ++

+

100

500

I

++

t

50

+++

+

++

+++

++ + +++++ ++

(d) Miscellaneous including h o r n mutagem

500

-

1 Aminomthracene

20

-

2-Aminoanthmcene

1

1-Methoxy-anthraquinone

1-Aminopyrene

10

3-Aminopyrene

10

Benzo(a)pynne

5

+ +

+++++

+

++ +++

+ -

+

10

-

Benz(a)mthracene

20

-

5

9-Aminoacndine

12

++

+

-

Dibenzpyrene

6-Aminochrysene

++

+ +

-

+

-

+++++ ++

++

+++ 7+

+++

+++++ +++ ++++

461 B.

Quinones

Although the quinones and polyhydric phenols a r e normally very readily interconvertible, the quinones a r e considered a s conjugated cyclic diketones (dioxo derivatives) rather than aromatic compounds per se12-14. The most important and characteristic reaction of quinones is reaction to the corresponding dihydroxy aromatic compounds, viz , + 2e

.

.

0

OH

The 1,2- and 1,4-quinones a r e the most common of a variety of quinone-like compounds that have been prepared. Benzene derivatives which a r e most susceptible or para positions to oxidation to quinones a r e those that a r e disubstituted in the& o with hydroxyl or amino groups. A s a, P-unsaturated ketones, quinones readily form 1,4-addition products (e .g , addition of hydrogen chloride and acid-catalyzed addition of acetic anhydride) Quinones with one-double-bond that analogously a s their open chain is not part of an aromatic ring also readily undergo Diels-Alder additions12-14. 1. para-Quinone (1,4-benzo uinone; benzoquinone; 2,5-cyclohexadiene-l,4-dione; =O) can be prepared by the oxidation of 1,4-cyclohexadiene dioxide; O=

.

benzene or a variety of benzene derivatives. A widely used process involves the oxidation of aniline with manganese dioxide and sulfuric acidl4, viz. ,

Other oxidizing agents that have been employed a r e sodium dichromate or lead dioxide and sulfuric acid and sodium chlorate in very dilute sulfuric acid with a trace of vanadium pentoxide. The major applications of para-quinone i n ~ l u d e ' ~ - ' ~ :(a) as an intermediate in the production of hydroquinone; (b) the preparation of quinhydrone (a complex of paraquinone and hydroquinone used in an electrode for pH determinations); (c) preparation of 2,3-dichloro-5,6-dicyanobenzoquinonefor use as a selective oxidizing agent in steroid synthesis; (d) the preparation of its dioxime and the dibenzoate of the dioxime for use a s rubber accelerators; (e) a s a polymerization inhibitor; (f) in photography a s a hydroquinone-quinone oxidation-reduction system; (g) as a tanning agent; (h) in the manufacture of dyes; (i) as a chemical reagent; ( j ) degradation inhibitor for acrylonitrile-vinylidene chloride polymersl6; )k) stabilizer for acrylic acid17; (1) vulcanization agent for fluoro rubbers18; (m) polymerization catalyst for linseed oill9; (n) catalyst in the manufacture of polyalkenamenes20; (0)a constituent in thermographic copying material2I; and (p) as a fixative for immunohistochemistry22. para-Quinone has been found as a pollutant in filtered surface and ground water at a water-works in the Federal Republic of GermanyZ3.

468

Data on the carcinogenicity of para-quinone a r e extremely limited. An increased incidence of skin tumors and lung tumors were found in mice treated with 0.1% paraquinone by skin applicationz4. Injection site fibrosarcomas were found among r a t s of Saitama mixed strain receiving 32 subcutaneous injections propylene glycol solution of para-quinone 25 (81 mg paraquinone and 1 6 . 5 ml propylene glycol)

.

Two lung adenocarcinomas were observed i n 25 mice exposed to 5 mg quinone for 1 h r 6 times/week compared to 1 adenoma in 25 untreated controls

?Gl

.

para-quinone is similarly limited. para-Quinone was nona t toxic concentrations27 and did not induce dominant lethal mutations &hen administered i . p a s a single dose of 6 . 2 5 mg/kg i n male miceZ8 C.

Polyhydric Phenols

Polyhydric phenols (benzene diols and triols) compose a group of compounds that have had a n extensive spectrum of utility in the production of dyes, pharmaceuticals, plasticizers, textile and leather chemicals29for a n extensive period of time. The structures of these agents, with their respective common names with which they a r e generally associated with a r e shown below:

Catechol

Resorcinol

Hydroquinone

Pyrogallol

Phloroglucinol

These derivatives react typically a s phenols hence undergoing ring electrophilic substitutions via halogenation, sulfonation, alkylation, nitration, Friedel-Crafts acylation, Kolbe and Reimer-Tiemann reactions or condensations with aldehydes, or para ketones or e s t e r ~ ~ 9 - ~Polyhydric O. phenols with the hydroxyls in the& o relationship a r e normally readily oxidized to quinonesZ9* 3 0 .

1. Catechol (ortho-hydroxypheonol; 1,2-benzenediol; ortho-hydroquinone; pyrocatechol) can be prepared by a variety of procedures including: (a) the alkali fusion of ortho-chlorophenol; (b) the oxidation of benzene with hydrogen peroxide; and (c) recovery from lignin-containing waste streams from wood pulping operations. The major a r e a s of utility of catechol include: (a) a s an antioxidant and polymerization inhibitor; ( b ) photographic developer; (c) a s an intermediate in the production of pharmaceuticals, pesticides, perfumes and resins; (d) as r u b b e r compounding aids; ( e l in the preparation of electron-sensitive copying papers; (f) a s a n additive i n metal plating baths and ( g ) in the synthesis of tert.buty1catechols which have been recommended as catalysts i n polyurethan formulations29. Catechol has been widely found i n drainage water from butaminous shale, coal, c r u d e wood t a r , cigarette smoke, and in the effluents resulting from the production of coal-tar chemicals in the U . S . S . R . 3 l .

469

2 . Hydroquinone (para-hydroxyphenol; 1,4-dihydroxybenzene; p-hydroquinone; hydroquinol) can be produced by a variety of methods including: (a) the oxidation of aniline with Mn02 and H2SO4 followed by reduction with iron dust and water; (b) the oxidation of benzene or numerous benzene derivatives followed by the reduction of the resulting para-quinone29; (c) the alkylation of benzene with propylene to produce a mixture of di-isopropyl benzene isomers then oxidation of the isolated paraisomer with oxygen to corresponding dihydroperoxide followed by treatment with acid to yield para-hydroquinone and acetone and ( d ) oxidation of phenol with H 2 0 2 to produce a mixture of products from which both para-hydroquinone and pyrocatechol a r e isolated. The major a r e a s of utility of hydroquinone29132 a r e : (a) as a photographic develope (b) a s a n antioxidant and polymerization inhibitor in materials such a s fats, oils, paints, vitamins, unsaturated monomers and gasoline; (c) a s a chemical intermediate in the preparation of hydroquinone ethers and diethers which a r e employed a s stabilizing agents, antioxidants, plasticizers and in perfume and cosmetic preparations; ( d ) a n intermediate for rubber-processing chemicals; (e) a s a dye intermediate; ( f ) a s a laboratory agent; and (g) a s a component of dermatological agents used to bleach hyperpigmented skin blemishes. Para-hydroquinone has been found in effluents resultin from the production of coal-tar chemicals i n the U.S.S.R.31 and in cigarette smoke5 9

.

The data on carcinogenicity and mutagenicity of the polyhydric phenols a r e very limited. Catechol in combination with benzo(a)pyrene enhanced the skin carcinogenic effects induced by benzo(a)pyrene alone in skin painting studies with female ICR/Ha Swiss mice33. Para-hydroquinone was inactive when tested a s an initiator of skin carcinogenesis using albino male mice of the " S " strain34. However, in bladder implantation studies, para-hydroquinone in cholesterol pellets increased the incidence of bladder carcinomas i n mice35. Resorcinol (meta-hydroquinol) showed no carcinogenic effect following skin application of 0 . 0 2 ml of a 5, 2 5 o r 50% solution in acetone to female Swiss mice36. The hydroquinones have induced chromosome aberrations or kariotypic effects in 38, Allium ~ e p a 3 ~ n Vicia faba39J40and Allium sativium40t41. Parahydroquinine was found to be less toxic to E. coli W3110 (pol A') P3478 (pol A-) which suggests that this agent can damage DNA.

than to

Resorcinol a t a dose of up to 1000 pg/plate was not mutagenic- in S,typhimurium TA 1535, TA 1537, TA 98 o r TA 1 0 0 in the presence o r absence of r a t liver microsomes42.

470 References

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21

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51

-

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1

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18

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.

1

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472

4 2 . McCann, J . , Choi, E . , Yamasaki, E . , and Ames, B . N . , Detection of Carcinogens a s mutagens i n Salmonella/microsome test: Assay of 300 chemicals, Proc. Natl Acad. S c i . , 72 (1975) 5135-5139 I