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Brazilin and Haematoxylin*
Chapter 22
Brazilin and Haematoxylin * SIR ROBERT ROBINSON
Brazilin and haematoxylin constitute a small group related to the catechins. Their study brought to light a series of molecular rearrangements of interest comparable with those encountered among camphor or morphine derivatives. The sources of these substances are hard-woods of species of Caesalpinia which are disintegrated and then extracted with hot water. These extracts may be concentrated and then used directly for commercial purposes. Pernambucu redwood, C. crista, is the richest in brazilin content; the true Brazilwood, C. braziliensis, contains about half as much. Some kind of redwood was employed in India before the discovery of America and was imported into Europe from the East Indies for use as a dye. Kimichi mentioned the name bresil (braza --- fiery red) in II9O, so that brazilin is not so named because it was found in Brazil. The converse is true; the Spaniards named the country Brazil because the already known dye-wood was abundant there. Logwood extract (campeachy wood) is obtained from Haernatoxylon campechianum (Central America and Caribbean). Though not as important as formerly it is still used, especially for dying silk and furs. The actual adjective dye is haematein (q.v.) which is a polygenetic lnordant dye. The most favoured shades are grey to black obtained with chromium, and especially iron, mordants. 1. The brazilin group The wood extracts deposit crusts on standing and from these Chevreul (Ann. chim., 18o8, [i], 66, 225) first obtained brazilin by recrystallisation from aqueous alcohol. The formula, C16H140 5, was proposed by C. Liebermann and O. Burg (Ben, 1876, 9, 1883). On dry distillation, brazilin affords resorci* No significant new material on the chemistry of these two substances has been published since 1960. Chapter IX of the original edition is reproduced here as a tribute to Sir Robert Robinson's memory, and his long connection with Rodd's Chemistry of Carbon Compounds as Chairman of the Advisory Board from its inception over 25 years ago, particularly as it describes in his own words one of his many elegant contributions to organic chemistry. [4271
428
BRAZILIN
AND HAEMATOXYLIN
22
nol in not inconsiderable yield and this process, due to Kopp (Ber., 1873, 6, 446), was acutally used for many years for the preparation of resorcinol. The action of nitric acid on brazilin gave rise to styphnic acid (F. Reim, Ber., 1871, 4,332; 1879, i2, 1392). Liebermann and Burg (loc. cit. " also K. Buchka and A. Erck, Ber., 1885, 18, 1139) found that brazilin gives a tetra-acetyl derivative when heated with acetic anhydride and this was confirmed by G. Dralle (Ber., 1884, I7, 370). The latter chemist showed that brazilin gave a trimethyl ether, insoluble in aqueous alkali, which still contains a hydroxyl group (acetyl derivative); and a tetramethyl ether under very vigorous conditions. Brazilin was thus shown to be a trihydric phenol also containing an alcoholic hydroxyl group. Brazilin forms colourless needles (with I-5 H20) or prisms (with i .o H~O), m.p. circ. 25~ (optical rotation, see p. 445). Derivatives are: triacetate, needles, m.p. io5-6 o; tetra-acetate, needles, m.p. 149-1510; bromotetra-acetate, m.p. 203- 4 o; dibromotetra-acetate m.p. 185~ trimethyl ether, prisms, m.p. 138-9~ trimethyl ether acetate, m.p. 171-3~ tetrarnethyl ether, m.p. 137-9~ bromotetramethyl ether, prisms, m.p. 18o-181 ~ The first indication of a part of the molecular structure was given by C. G. Schall and G. Dralle (Ber., 1888, 21, 3o17; 1889, 22, 1559" 1892, 25, 19) who oxidized brazilin in alkaline solution by means of atmospheric oxygen. The first product is brazilein (see p. 435) but the red colour due to this substance disappeared and ~-resorcylic acid and a substance C9H604, needles m.p. 27 I~ were then isolated. The latter formed a diacetyl derivative and a dimethyl ether C9H40 2 (OMe) 9, which could be oxidized by means of permanganate to 2-hydroxy 4-methoxybenzoic acid. Schall (Ber., 1894, 27,528), suggested that the substance, C9H60 ,, was a dihydroxychromone (I)and W. Feuersteir~ and St. vo~ Koslar~ecki (Ber., 1899, 32, lO25) confirmed this view, since the dirnethyl ether (II)could be hydrolysed into formic acid and the fisetol dimethyl ether (III) already known as a degradation product of methylated fisetin (J. Herzig, Monatsh., 1891, i2, 187). .#~/O..
MeO . # ~ / O , .
0 (I)
MeO 1~/~ OH
o (II)
(III)
The synthesis of (II) was effected in 1924 (P. P / d y e r and J. Oberlin, Ber., 1924, 57, 208) from 7-methoxychromanone by way of its 3-oximino-derivarive. This was hydrolysed by means of sulphuric acid in aqueous acetic acid and the resulting mono-methyl ether of (I) was methylated.
I
BRAZILIN
GROUP
429
Oxidation o/ O-trimethylbrazilin by means o/ permanganate The investigations of W. H. Perkin, jun. in this field followed the model work of Goldschmidt on papaverine and his own studies of berberine. The oxidizing agent attacked various parts of the molecules and a variety of products was obtained. The information from the structures of the products, which sometimes had overlapping sections, was combined. It happened in this case that one of the fragments obtained in very small yield, namely brazilic acid, was found to be of exceptional importance. The investigation was started as long ago as 1883 and accounts were given in 1899 and 19oo (Proc. chem. Soc., 1899, 15, 27, 45, 241; 19oo; I6, lO6, lO7). The products were (i) brazilinic acid, C19H1809, a substance obtained from trimethylbrazilin without loss of carbon atoms, (2) an acid, C10H10Os, m.p. I74 ~ (3) an acid, C10H100s, m.p. 195 o and (4) brazflic acid, ClzHl~Os. The two acids, C10H100e, were identified as 2-carboxy-5-methoxyphenoxyacetic acid (IV) and metahemipinic acid (V) respectively. MeO 2"~ OCH2C02H ~C09H (IV)
MeO Q C02H Me0 C09H (v)
On heating, (IV) lost a carboxyl group and furnished m-meth0xyphenoxyacetic acid, which was synthesized. Later (Perkin and R. Robinson, J. chem., Soc., 19o8, 93, 504) (IV) was also synthesized from 2-hydroxy-4-methoxybenzaldehyde by introduction of the acetic residue and oxidation of the resulting aldehyde-acid. The isolation of metahemipinic acid led Perkin to suggest that the constitution of brazilin should be (VI). HO ~ / O , . ~ _ j ~ . OH
OH (vI)
The study of brazilic acid (Perkin, ibid., 19o2, 8I, 221) soon excluded one of the alternatives considered and the indane moiety of the formula received support from the later isolation of 4: 6-dimethoxyhomophthalic acid (vii) in small yield from among the permanganate oxidation products (ibid., 19o2, 8i, IO28;Perkin and Robinson, ibid., 19o 7, 9I, lO82). The yield of brazilic acid was only 0. 7 %; it furnished an oxime and a semicarbazone, and when reduced with sodium amalgam and the solution acidified it gave the lactone, CI~HI~Os, of dihydrobrazilic acid. On very gentle heating of brazilic acid with concentrated sulphuric acid, the solution acquired intense violet fluorescence, and was found to contain anhydrobrazilic acid (VIII). The constitution of this substance was deduced from its
430
BRAZILIN AND HAEMATOXYLIN
22
decomposition on boiling with barium hydroxide solution into fl-(6-hydroxy4-methoxybenzoyl) propionic acid (IX) and formic acid. MeO -~.....~ CO2H, MeO I ..~/ CH2-CO2H (vii)
MeO ..~'~O...[ 'CH 2" CO2H ~'~/ o (viii) . .
MeO [-~"'~ OH ' . % / C O 9CH 2. CHo9 CO2H (IX)
The methyl ether (IX) was synthesized. Later the acid (IX)was again obtained (idem, ibid., 19o8, 93, 502, 509) and its ester condensed with ethyl formate with the help of sodium and anhydrobrazilic acid isolated. This was the first example of a synthesis of a 3-substituted chromone, later applied by a number of workers to the synthesis of isoflavones. An alternative to (X) for brazilic acid can hardly be entertained in view of the simultaneous formation of (IV) in the oxidation process.
(X)
/C(OH) .CH2. COzH O Brazilic acid
In 19o4 Werner and P/eiBer (Chem. Zeitschr., 19o4, 3,421) suggested that brazilin has the structure (XI) but advanced no more experimental evidence in favour of this view and combined it with fallacious interpretations of other aspects of the chemistry of brazilin derivatives. Nevertheless the suggestion was an acute one and was eventually proved to be correct as the result of synthetic studies by Perkin and Robinson (Proc. chem. Soc., 19o6, 22, I6o; J. chem. Soc., 19o 7, 91, lO73). Apart from these an argument that gradually acquired force was that the CH~ groups marked with an asterisk in (IV) and (X) , were not likely to be produced from -Lri ~.T ./C" \C groups in the course of a permanganate oxidation. One of these CH, groups also survives in dimethoxyhomophthalic acid (VII). HO'~"~'/O'~cH2[ !l Z ,-,T
" ~ / ~ U\---/'~*'2 c/c:y~ / \ //
MeOS"HO'CH2"CO2H
"~/~'~o ~__CO,H /? k \__/
HO OH (XI)
Brazilin
MeO OMe (XII)
Brazilinic acid
Structure (XI), but not (VI), contains the two methylene groups which occur in the oxidation products.
I
BRAZILIN GROUP
431
Brazilinic acid, C19H1sO9, is a keto-dicarboxylic acid reducible to a dihydroderivative which formed a characteristic lactone. On the basis of (VI) it would be an aldehyde, hardly likely to be produced in a permanganate oxidation at 9o~ but the skeleton (XI) would be opened to (XlI). The lactone of dihydrobrazilinic acid would clearly be (XlV). A small yield of brazilinic acid was obtained by a Friedel-Crafts condensation of ethyl m-methoxyphenoxyacetate and metahemipinic anhydride. It was better to condense resorcinol dimethyl ether with metahemipinic anhydride under moderately vigorous conditions with hydrolysis of the o-MeO group and reduce to the lactone (XlII). Introduction of the acetic residue then afforded the desired lactone (XlV). MeO f~
MeO ,~,, OH I I ^ "~~lu\
CH CO
O" CH~. C09H
~fi~./O-. CH CO
/=~ MeO OMe
MeO OMe
(XlII)
(XlV)
The evidence thus available was consistent with the structure (xI) for brazilin but there was nothing to exclude (XV) which was the only possible alternative. HO [- .~. /~O~ "Cc/H~
H
MeO/~'~l/O'cH2 I II A~,
\ HO OH (xv)
/
MeO OMe (xvI) Trimethylbrazilone
Oxidation o/O-trimethylbrazilin by means o/chromic acid in acetic acid solution The pale greenish-yenow product of this oxidation, termed trimethylbrazilone, C19Hls06, was obtained at once in an almost pure condition. The composition change from trimethylbrazilin was + O and m 2H. The formula (XVI) was assigned to the substance in later years by Perkin and Robinson, consistent with the infra-red spectrum (R. E. Richards and M. L. Tomlinson, Natule, 1948, i62, 693 ) which shows a carbonyl band at 3,61o cm -1. There is no band round 1,72o cm -1 attributable to a hydroxyl group, excluding an earlier ketol structure.
432
BRAZILIN AND HAEMATOXYLIN
22
When heated with alcoholic potassium hydroxide, trimethylbrazilone loses the elements of water yielding the potassium salt of a-anhydrotrimethylbrazilone (XVlI). OH
~ . ~ OMe ONe a-Anhydrotrimethylbrazilone (XVII)
The acetyl-derivative of (XVlI) is obtained by treatment of trimethylbrazilone with acetic anhydride. The reactions of ~-anhydrotrimethylbrazilone indicated its character as a derivative of/~-naphthol, azo-couplings, colour reaction with chloroform and aqueous alcoholic alkali, etc. Conversion to a ~-naphthoquinone derivative, trimethoxy-~-brazanquinone, could be accomplished in stages as follows: OAc
OAc
OH
> "~NO 2 ~
OH
NO2 ~
O
NH~
"O
Trimethoxy-a-brazanquinone forms deep brown micro-crystals and condenses with o-tolylenediamine to a characteristic quinoxaline derivative. Furthermore, ferric chloride oxidizes a-anhydrotrimethylbrazilone to a very sparingly soluble dinaphthol derivative and from this the corresponding substituted dinaphthylene oxide can be obtained by the action of phosphoryl chloride. An independent synthesis of ~-anhydrotrimethylbrazilone was effected by P. C. Johnson and A. Robertson (J. chem. Soc., 195o, 2391). /~-
OH
MeO ./~-..~,/O.>, CO~H
\ ~_~/ MeO OMe
(XVlII)
%// MeO OMe
(XlX)
An improved synthesis of brazilinic acid was possible by reacting the known phenolic acid (XVlII)with ethyl bromacetate and potassium carbonate in an acetone medium. The ethyl brazilinate so produced was hydrolysed and the acid condensed with acetic anhydride and sodium acetate to the coumarone derivative {XlX). After eliminating the carboxyl in the coumatone ring, the Arndt-Eistert homologation was applied to the resulting mono-
I
BRAZILIN
GROUP
433
carboxylic acid and the product (XX) furnished a-anhydrotrimethylbrazilone on gentle heating with concentrated sulphuric acid.
~02H
MeO ~ - . . / O . .
(XVlI)
\__/ MeO OMe
(xx)
The action of sulphuric acid on trimethylbrazilone (XVI) was first studied by Hem@ Pollak and Galitzenstein (Ber., 19o4, 37, 631) and the course of the reaction elucidated by Perkin and Robinson (J. chem., Soc., 19o9, 95, 385; cf. idem, ibid., 19o8, 93, 5Ol). The product, called 7j-trimethylbrazilone, is isomeric with the starting material. It is an acid and gives a good yield of 4: 5-dimethoxyhomophthalic acid on oxidation by means of permanganate. When treated with dehydrating agents, 7j-trimethylbrazilone gives flanhydrotrimethylbrazilone. A smooth conversion is that of the y~-trimethylbrazilone to the acetyl-derivative of the anhydro-compound on heating with acetic anhydride. It transpires that the change may be represented as shown (XXI to XXII). Trimethyl- (XVI) brazilone
H.SO, CH9
(xxI) OH
0
I --vlvlo o (XXlI)
fl-Anhydrotrimethylbrazilone
(XXIII)
Oxidation of fl-anhydrotrimethylbrazilone by means of chromic acid furnishes a red quinone which is not a I : 2-quinone, but closely resembles the substance (XXlII) synthesised by reaction of 2: 3-dichloronaphthoquinone and resorcinol in alcoholic sodium ethoxide (Liebermann, Ber., 1899, 32,924). An independent synthesis of fl-anhydrotrimethylbrazilone was effected by K. W. Bentley and Robinson (J. chem. Soc., I95O, 1353). The processes are indicated in the following scheme:
434
BRAZlLIN AND HA:EMATOXYLIN
+ ~%/
=.sc CN- CH~
22
=o(bo=
OMe
CO. CH 2
OMe
Monomethyl ether / IBr.CH.,CO2Etin alcoholicNaOEt MeO ~ % O. CH 2.COoH CO'CH2 __ OMe OMe
MeO ./ acid chloride
2
-
AICl~ ->
( "-'- OMe
(XVI)
A noteworthy reaction occurs when trimethylbrazilone reacts with phenylhydrazine in hot alcoholic solution {cf. J. Herzig and J. PoUak, Ber., 19o5, 38, 2166; 19o6, 39, 265). Nitrogen is evolved and some benzene is produced whilst the diketone simply loses two atoms of oxygen, forming deoxytrimethylbrazilone (XXlV). The reaction is by no means smooth nor is the yield particularly favourable. Nevertheless it is substantial and the mechanism of the process is far from obvious. The constitution of deoxytrimethylbrazilone has been confirmed by synthesis (see below); the subMeO (2 ,'~O'-cH2
\
/
(XXIV) MeO OMe Deoxytrimethylbrazilone (anhydrotrimethylbrazilin)
stance could also be termed anhydrotrimethylbrazilin. The reaction mechanism remains obscure and needs further investigation. The action of concentrated nitric acid on trimethylbrazilone also led to remarkable results (A. W. Gilbody and Perkin, J. chem. Soc., 19o2, 81, lO48; cf. Perkin and Robinson, ibid., 19o 9, 95, 389; Herzig, Pollak and Vonk, Monatsh., 19o 4, 25, 871). The elements of HNO 3 were added and the crystalline product obtained in nearly quantitative yield was termed nitrohydroxydihydrotrimethylbrazilone. It was recognised as a ketol-lactone of the structure (XXV). When O MeOl.~ A ~ O "~,/CJ~H~)H CH2 NO2 '//'~' ~%) OMe
(xxv)
oMe
MeO (#"~ OH CH30 ~ COgH NO 2 NaOH aq. 7 /* ~'/CH2" MeO lit
OMe OMe
C H 2 ~ ~ " OMe
Ir
I
I
BRAZILIN GROUP
435
treated with aqueous sodium hydroxide it dissolved to a purple solution which gradually became yellowish brown and deposited a precipitate. The latter consisted of 3:4-dimethoxy-6-nitrotoluene along with a small proportion of the related dinitrotetramethoxydiphenylethane. The solution contained 2-hydroxy-4-methoxybenzoic acid. Permanganate oxidation of (XXV) afforded the known 2-carboxy-6-methoxyphenoxyacetic acid (IV). Furthermore, the action of phenylhydrazine on (XXV) gave rise to the osazone (XXVI). MeO M e O C > H 2 - C - C H " N2HPh N2HPh
(xxvi) The formation of (XXV) from trimethylbrazilone is in full accord with the diketonic structure advocated, being simply a displacement of a carbonyl accompanying nitration and fully analogous to known processes such as the following (V. J. Harding and C. Weizmann, J. chem. Soc., 191o, 97, 1131; cf. Harding, ibid., 1914 , lO5, 2790). MeO ~ / . CO-CH s
MeO
INO2
+ CHa.CO2H
The foregoing noteworthy series of transformations are due to different modes of attack by reagents, summarised in the following scheme: .~ 5IeO[
I]/
.(a)
/" ,'"l.-2(c)
"~ X;,";--CO._.~h~ (b)"OC~," . - \ C ~ " ' - ( d ) - ~ - - { *'" (XVI)
MeO OMe
Transformations of O-trimethylbrazilone (XVI) NaOH, Ac=O etc -+ a-Anhydrotrimethylbrazilone (XVII) Fission by H2SO4 -+ w-trimethylbrazilone (XXI) leading to fl-anhydrotrimethylbrazilone (XXII) (c) Phenylhydrazine -+ deoxytrimethylbrazilone (XXIV) (d) Fission by HNO a -+ nitrohydroxydihydrotrimethylbrazilone (XXV) (a) (b)
Brazilein, C16H1~O5, and its derivatives Brazilin is a colourless substance readily convertible by oxidation into the colouring matter, brazilein. An alkaline solution of brazilin quickly acquires an intense crimson colour in contact with air and this method can he em-
436
BRAZILIN
ANDHAEMATOXYLIN
22
ployed for the preparation of brazilein using ammoniacal solutions. A better method makes use of oxidation by means of iodine in alcoholic solution. Brazilein separates in small crystals which are browish yellow by transmitted light under the microscope and in mass present a metallic glance resembling that of gun metal. It has only comparatively recently been observed that brazilein is optically active and that it can be reduced to brazilin by means of borohydride in aqueous alkaline solution (F. Morsingh and Robinson, Int. Congress Pure and App1. Chem., Ztirich, 1953). Brazilin is obviously the leuco-compound of the quinonoid brazilein which could be formulated as (XXVlI), (XXVlII) or (XXlX) on the basis of (XI) for brazilin. We can proceed to eliminate the possibility (XXlX) and in the section on the synthesis of brazylium salts (below) it is shown that (xxvIII) is the correct structure.
~_// HOOH
(XXVII)
~_/
k__//
HO 6
60H
(XXVIII) Brazilein
(XXIX)
\_// 60H
(XXIXa)
It should be noted that the quinoid pattern of (XXIX) as in (XXIXa) would be derived from the alternative structure (XV~XXIXa) for brazilin which, however, could not give rise to (XXVII)or (XXVIII). The exclusion of X X I X (XXIXa) accordingly also excludes this alternative and for the first time. The methylation of brazilein by means of methyl sulphate and aqueous potassium hydroxide furnishes trimethylbrazilein and tetramethyldihydrobrazileinol as the main products (Engels, Perkin at. ~ Robinson; J. chem., Soc., I9O8, 93, III5). Less highly methylated products which are also obtained have been little investigated. Trimethylbrazilein forms a magnificent scarlet formate and when recovered from this derivative may be crystaUised in large orange-yellow prisms. When treated with boiling sodium hydroxide it adds the elements of water affording the colourless trimethyldihydrobrazileinol which on the one hand is easily dehydrated to trimethylbrazilein (e.g. on warming with formic acid) and on the other hand can be methylated to the above mentioned tetramethyldihydrobrazileinol. The relat iola of these substances is clearly as shown in the following part structures:
I
B R A Z I L I N GROUP
Trimethylbrazilein
Dihydrotrimethylbrazileinol
437
Tetramethyldihydrobrazileinol
The important result that excludes the structure (XXIX) and XXlXa) for brazilein is that oxidation of tetramethyldihydrobrazileinol with chromic acid in acetic acid solution affords trimethylbrazilone (XVI). Hence tetramethyldihydrobrazileinol must be (XXX) derived from (XXVII) or (XXVIII) for brazilein. These considerations serve to determine the position of the alcoholic hydroxyl of brazilin (Engels et al., loc. cir.). An interesting decomposition of brazilein and its derivatives occurs when these quinones are treated with hydrogen peroxide, best in acetic acid solution (Engels et al.). Oxidation takes place round the central carbon atom of the diphenylmethane structure and with formation of hydroxyquinol derivatives. An appropriate model was later found in the behaviour of aurine (XXXI) under similar circumstances.
MeO OMe
(xxx) HO- C~H4..c/C6H 49OH /Jk..
HO. C~H4..CO .~ ~
H,O,
'l~i;o
'
(XXXI)
HO.C6H,.OH HO. CsH ," COgH
"~OH~ + HO'CsH4.OH
MeO . ~ / 0 . .
1~'~ HO' CsH4" OH +CO9
MeO - # ~ / O " C H ~ CH 2
~
HO2C/"CHa HO /
/-\
MeO OH (XXXII) Trimethylbrazilein
(XXXIII)
438
BRAZILIN AND HAEMATOXYLIN
22
Thus trimethylbrazilein ( X X X l I anticipating a sequel) is readily converted into (XXXIII). A significant reaction of brazilein and its derivatives is mentioned immediately in the next section.
The isobrazilein or brazylium salts So long ago as 1882 J. J. Hummel andA. G. Perkin (J. chem. Soc., 1882, 41, 367) studied the action of mineral acids on brazilein and discovered the so called isobrazilein salts. These are produced from their generators with loss of a molecule of water and are of the form B, HX. Thus the intense crimson solution of brazilein in concentrated sulphuric acid develops on gentle warming an orange brown and then exhibits a strong green fluorescence. On addition to water the orange isobrazilein hydrogen sulphate is precipitated. C16H1205 + H2SO4
> CxsHnO a, HSO 4 + H 2 0
This work was carried out before the theory of oxonium salts was established and long before the analogy of pyrylium with pyridinium was understood. Since 19o 7 the isobrazilein salts have been recognised (Engels et al., loc. cir., cf. J. chem. Soc., 19o8, 93, 49 o) as pyrylium salts and the skeleton of the cation may be termed "brazylium". Thus isobrazilein hydrogen sulphate can be formulated as (XXXlV). When tetramethyldihydrobrazileinol is warmed with sulphuric acid, the elements of methanol and 6f water are eliminated and O-trimethylbrazylium hydrogen sulphate is produced. This HSO 4
FeC14
| l /=k ~_// HO OH
(XXXlV)
/=\ ~_// MeO OMe
(xxxv)
dissolves in water to a yellow solution exhibiting a striking green fluorescence. The corresponding /errichloride (XXXV) can be readily recrystallized, possesses a definite melting point and is a suitable reference compound in the series. A second method of formation of (XXXV) is from deoxytrimethylbrazilone (XXIV) by oxidation in acid solution. Thus treatment of deoxytrimethylbrazilone with bromine in acetone solution is an especially convenient process giving O-trimethylbrazylium bromide in quantitative yield. The ferrichloride (XXXV) is then produced by treatment with a solution of solid ferric chloride in concentrated hydrochloric acid and may be crystallized from acetic acid.
I
BRAZILIN
GROUP
439
Synthesis o/ brazylium and other indenobenzopyrylium salts In the course of synthetical experiments designed in relation to the older brazilin structure, Perkin and Robinson (ibid., I9o7, 9I, lO73) had occasion to study the course of the condensation of salicylaldehyde and its derivatives with ketones such as indan-I-one and its dimethoxy-derivatives. In most cases basic catalysts were employed but these were unsatisfactory when ,~-resorcylaldehyde was used as the aldehyde component of the system. Turning to hydrogen chloride, for example in acetic acid solution, the formation of stable hydrochlorides was observed and these were equated with Btilow's pyranol salts (C. Biilow and W. von Sicherer, Ber., 19Ol, 34, 2368) and soon proved to be anhydro-pyranol salts. An early preliminary communication (Perkin and Robinson, Proc. chem. Soc., 19o 7, 23, 149) described the identity of the salts made on the one hand from resorcinol and benzoylacetaldehyde and on the other from fl-resorcylaldehyde and acetophenone. H-.._ C1 ~'~1 OH COPh HCI HO/~"~t/O~cPh "~ t ---+ I ,, I-~'/E-.CH..-CH U,O CHo/CH9 I OH I identical salts C1 CHO
CH3
2H20
The salicylaldehyde-ketomethylene synthesis was generalised (ibid., 19o8, 93, lO86) ; parallel work by H. Decker and T. yon Fellenberg was published at about the same time (Ber., 19o7, 40, 3815). The method was later elaborated for the syntheses of anthocyanidins and anthocyanins (See this vol., 84). FeC14 MeO i~'~ OH CO ~/~- OMe CHO + CH2-..CH2/~//" t ii tOMe
HC1 Fee13
~'~/O~~~. (XXXVI) C1
MeO ~'nlJ OH "%/ CO
H,
2~CH2
HC1,HCO2H_._
Moo( Jo
FeCla__~ (XXXV)
/
/CHg. MeO OMe (xxxvli)
MeO OMe
440
BRAZlLIN AND HAEMATOXYLIN
22
In 19o7 it was of interest as helping to disprove the earlier brazilin formulations. The salt (XXXVI) prepared from p-methoxysalicylaldehyde and 5:6,dimethoxyindan-I-one with the help of hydrogen chloride, and conversion to ferrichloride (Perkin and Robinson, J. chem. Soc., 19o8, 93, IIO6), was quite different from O-trimethylbrazylium ferrichloride (XXXV). The first synthesis of a substance containing the brazilin skeleton was that of O-trimethylbrazylium ferrichloride (XXXV) (H. G. Crabtree and Robinson J. chem. Soc., 1918, 113, 859). Veratrylidenepaeanol was catalytically hydrogenated to its dihydro-derivative (XXXVII). On treatment with boiling absolute formic acid and zinc chloride and subsequently with ferric
ooo.y" /~ Me CH~
eOj-~
OH
" ~ / ~ ' C "~
,~__//
"~CH2
,~ //
MeO OMe (xxxvIII)
MeO OMe (XXXlX)
chloride dissolved in hydrochloric acid, the ferrichloride (XXXV) identical with O-trimethylbrazylium ferrichloride, was obtained. In other experiments it has not been found possible to convert the chromone (xxxvIII) into a brazylium salt and hence the mechanism probably involves ring-closure of ( x x x v l I ) to an indene (XXXIX)followed by O-formylation and further ring-closure.
Synthesis o/deoxytrimethylbrazilone and trimethylbrazilone The synthesis of deoxytrimethylbrazilone (XXIV) was effected by Perkin and Robinson (J. chem. Soc., 1926, 941; 1927, 2o94; 1928, 15o4) and by Pfeiffer and his collaborators virtually simultaneously and by the same methods (cf. P. PleiBer, O. Angern et al., Ber., 1928, 61,839). The synthesis of veratrylidene-7-methoxychromanone (XL) was earlier described by Perkin and Robinson (Proc. chem. Soc., 1912, 28, 7). This substance was MeO .#N/O-.
MeO .#N/ON
i
P~.05_+
__+
6
/=\
OH
/
MeO OMe (XL)
6
/=\
/
CH2
MeO OMe (XLI)
(XXlV)
I
B R A Z I L I N GROUP
441
catalytically hydrogenated to a dihydro-derivative (XLI)which afforded deoxytrimethylbrazilone on cyclodehydration with phosphoric anhydride. Catalytic hydrogenation of deoxytrimethylbrazilone affords its dihydro derivative (XLII) which is described as O-trimethylbrazilane-a. The pyran and cyclopentene rings of (XLII) can be fused in cis- or trans- configuration. Actually, an isomeric O-trimethylbrazilane-b which is possibly the transform is known (Chatterjea and Robinson, unpublished). The chief reason for this assumption is that the catalytic reduction of (XXlV) would be likely to yield the cis form. Oxidation of (XLII) with chromic acid in acetic acid solution furnished trirnethylbrazilone (XVI). MeO - # ' ~ l / O ~ c H 2
'~-..~
CU
"C H / " - C H 2
\ / /~\
(XLII)
CrOa
--~
(XVI)
MeO OMe
"l'he constitution o/brazilein
It has been pointed out that addition of water to the quinonoid group of O-trimethylbrazilein produces a new phenolic hydroxyl. This marks the position of the quinone group and in order to label it this phenolic hydroxyl was ethylated. The O-ethyl-trimethyldihydrobrazileinol so obtained was converted by the method already described for the tetramethyl compound into an O-ethyldimethylbrazylium ferrichloride (XLIII or XLIV, dependent on the position of the quinonoid group of trimethylbrazilein). FeC14 EtO , ~ / O . - .
/=\ ~_//
MeO OMe (XLIII)
FeC14 MeO . # ~ / O ~
/=\ ~J
MeO OEt (XLIV)
These two O-ethyldimethylbrazylium ferrichlorides were synthesized: (XLIII) was made by the Crabtree and Robinson method from veratrylidene2-hydroxy-4-ethoxyacetophenone whilst (XLIV) was made from 3'ethoxy-4'-methoxybenzylidene-7-methoxychromanone by conversion to the related deoxy-ethyldimethylbrazilone and thence to the brazyliuxn salt. The synthesised salts proved to be sufficiently divergent in properties and a mixture showed a depressed melting point; (XLIV) was identical with the
442
B R A Z I L I N AND H A E M A T O X Y L I N
22
salt derived from trimethylbrazilein (V. M. Mi~ovi~ and Robinson, J. chem. Soc., 1937, 43). This proves that trimethylbrazilein is (XXXlI) and hence brazilein is probably (XXVIII).
Synthesis o/brazilin The most obvious route to the synthesis of trimethylbrazilein was by way of deoxytrimethylbrazilone but all attempts to hydrate the double bond of this substance met with failure. In presence of strong acids oxidation to the brazylium salt occurred and even under oxygen-free conditions disproportionation was noted, the case being analogous to that of certain dihydroquinoline derivatives. MeO ~ - . ~ / O . . I...~?N/~.~ H HO/t ? H2
FeCla
HC1
(XXXV)
/--\ (XLV) MeO OMe
Several years before the synthesis was achieved it had been shown (Perki~, W. N. Rdy and Robinson, J. chem. Soc., 1928, 15o4) that reduction of trimethylbrazilone by means of zinc and acetic acid gave the pinacol (XLV) characterised by ready conversion into O-trimethylbrazylium ferrichloride. AcO ~ / O " c H ~
AcO ~"~t,/O"cH2
CO \ /CH 2 ~AcOH-+ HO.C\
/--\ (XLu
/// AcO OAc
Triacetylbrazilone
HO ~ ' ~ l / O " c H 2
"CH / 2 --~
/z\ ~ //I AcO OAc (XLVII)
"~J~/ " ----~ -~ d/-brazilein HO.C\ "CH / 2 (XXVlII)
/-~\ ~ /// HO OH
dl-brazilin d-brazilin
The synthesis depends on the preparation of a similar pinacol in the unmethylated series (Morsingh and Robinson, loc. cir.). O-Triacetylbrazilone (XLVI) could be obtained by the chromic acid oxidation of O-tetra-acetylbrazilin and reduction of this substance by means of zinc and alcoholic acetic acid gave the pinacol (XLVII)in moderate yield. The conversion to dl-brazilein was realised when this pinacol was subjected to hydrolysis by means of alkalis and the solution acidified. In order to synthesize triacetylbrazilone (XLVI) dihydrodeoxytrimethylbrazilone-a (XLII), already synthesized, was demethylated, the resulting trihydric phenol acetylated and the O-triacetylbrazilane oxidized by means of chromic acid. Triacetylbrazilone (XLVI), identical with the product from
2
HAEMATOXYLIN
GROUP
443
triacetylbrazilin, was obtained. This made d/-brazilein a synthetic compound. It was reduced by borohydride to d/-brazilin and the optical resolution effected by repeated crystaUisation of the tetra-d-menthyloxyacetyl derivative. After hydrolysis of the resolved material, d-brazilin was obtained (not yet published). It is not known with certainty that naturally occurring brazilin is a member of the brazilane-a (cis-junction) series but this is probably the case in view of the fact that O-tetra-acetylbrazilin can be induced to lose the elements of acetic acid, in a catalysed pyrolysis, with formation of deoxy-O-triacetylbrazilone (XLVIII) (private communication, Ollis). The latter substance has been identified as the product (Herzig) of the acetylating zinc dust reduction of brazilein.
/
CH z
/=~
/=\
AcO OAc
AcO OAc (XLVIII) 2. The haematoxylin group
In general, progress in the haematoxylin group followed closely the brazilin developments but the various compounds are not quite so attractive physically, being usually more soluble in solvents, with less power to crystallise and the colours and fluorescences are not so bright as is the case with the brazilin derivatives. Haematoxylin can be obtained from logwood extract in colourless crystals; the empirical formula is CleH140 e. This contains one oxygen atom more than the formula of brazilin, due to the presence of an additional hydroxyl group, located in the 8 position of the benzopyran moiety of the structure by the synthesis of haematoxylinic acid from pyrogallol and by the formation of pyrogallol when haematoxylin is fused with potassium hydroxide. X~qth four phenolic and an alcoholic hydroxyl group, haematoxylin forms a pentacetate, m.p. 165-166~ a tetramethyl ether, m.p. 139-14o~ (acetate, m.p. 178-18o~ and a pentamethyl ether, m.p. 144-1470. Optical rotation, see p. 445.
Permanganale bxidalio~ o/d-tetramethylhaernatoxylin, The analogue of brazilic acid was not isolated but haematoxylinic acid corresponded to brazilinic acid (Perki~, and J. Yates, J. chem. Soc., 19o2, 81, 235). On reduction this gave the lactone of dihydrohaematoxylinic acid (XLIX) which was s~mthesized (Perkin and Robinson, ibid., 19o8, 93, 515) 9
444
B R A Z l L I N AND H A E M A T O X Y L I N
22
Condensation of metahemipinic anhydride and pyrogallol trimethyl ether with the help of aluminium chloride could be managed so as to hydrolyse only the o-methoxyl group. Reduction of the product and introduction of the -CH2.CO~H group furnished the required lactone (XLIX). MeO MeO ,/~"~,~ O" CH2"CO2H
MeO MeO I~ ' ~ ' II/ O ' C H! 2
I'~..~-~...0..
~-~J~ CO
CH CO
OC
MeO OMe
~CH~
MeO OMe
(XLIX)
(L)
Tetramahylhaematoxylone and diethylenehaematoxylone. Oxidation of tetramethylhaematoxylin by means of chromic acid in acetic solution gave tetramethylhaematoxylone (L) (Perkin, J. chem. Soc., 19o2, 8i, lO57) Which is a substance entirely analogous to trimethylbrazilone. For example its behaviour with alkalis, acetic anhydride (a-anhydrotetramethylhaematoxylone and its acetyl derivative), nitric acid and phenylhydrazine corresponded to that of trimethylbrazilone. The ~-tetramethylhaematoxylone series has been little investigated. Deoxytetramethylhaematoxylone (P/eiu~r) and deoxydiethylenehaematoxylone (LI) were synthesized by applications of the method already described in connection with deoxytrimethylbrazilone (Perkin, A. Pollard and Robinson, J. chem. Soc., 1937, 49). /CH2.. H2C O
'
/=~ O (LI)
O
HgC-CH 2
The properties of these substances closely resembled those of deoxytrimethylbrazilone. Thus oxidation in acid solution gave the respective haematoxylium salts.
Haematein and its derivatives The technically important point here is that haematein is a much better adjective dye than brazilein; otherwise the two series go in step together. The
2
HAEMATOXYLIN
GROUP
445
methylation of haematein gave a high yield of pentamethyldihydrohaemateinol (LII) which was exceptional in this series in that it had a considerable power of crystallisation (Engels et al., ibid., 19o8, 93, 1115). Tetramethylhacmatoxylium ferrichloride (LIII) was synthesized by H. G. Crabtree and Robinson (ibid., 1922, I2I, lO33). FeC14 MeO
MeO
/=\ ~_// (LII)
MeO OMe
/=\ ~J (LIII)
MeO OMe
Synthesis o/ d-haematoxylin The stages and methods followed the brazilin model closely (Morsingh and Robinson, Internatl. Congress of Pure and Applied Chem., Ztirich, 1953).
Possible natural occurrence o/a haematoxylin methyl ether Haematoxylon a/ricanum, a South African member of the family Caesalpiniaceae, afforded an extract, the colour reactions and dyeing properties of which clearly indicated that it contained a substance similar to brazilin and to haematoxylin, but identical with neither. A. G. Perkin has suggested that this may be a methoxy-brazilin (O-methylhaematoxylin) (Perkin and Everest, The Natural Organic Colouring Matters, Longrnans, Green and Co., London, 1918, p. 382; A. G. Perkin, J. Soc. Dy. Col., 1918, 34, 99). If, on the other hand, the substance is brazilin, modified in properties by impurities, there is an interest of a different kind, namely the occurrence of brazilin in a botanical group in which only haematoxylin has previously been identified.
Optical rotatory powers o/brazilin and haematoxylin and their derivatives Brazilin (natural), (a) ~ "5~+ 121.50. brazilin (reduction of brazilein), (a) ~x'5~+ I23.4 ~ both in methanol (Morsingh and Robinson, loc cit.). O-tetra-acetylbrazilin, (a)D + 76-4 ~ O-acetyltrimethylbrazilin, (a)~)~176 + 128.2 (Herzig et al., Monatsh., 19~ 27, 753)-Haematoxylin (natural), (a)D + 99-6 ~ (Hesse, Ann. chim., 1859, Io9, 532)" haematoxylin (reduction of haematein), (a)~~176 + 98.4 ~ (M. and R.). O-Acetyltetmmethylhaematoxylin (a)~)~176 + 151. 5 o (Herzig et al., loc. cir.). Brazilinic acid and trimethylbrazilone are optically inactive, but brazilic acid, which should be optically active, was not examined for this property. The stereochemical correspondence of brazilin and haematoxylin is probable but has not been directly demonstrated, for example, by X-ray crystallography.
Brazilin and Haematoxylin * SIR ROBERT ROBINSON
Brazilin and haematoxylin constitute a small group related to the catechins. Their study brought to light a series of molecular rearrangements of interest comparable with those encountered among camphor or morphine derivatives. The sources of these substances are hard-woods of species of Caesalpinia which are disintegrated and then extracted with hot water. These extracts may be concentrated and then used directly for commercial purposes. Pernambucu redwood, C. crista, is the richest in brazilin content; the true Brazilwood, C. braziliensis, contains about half as much. Some kind of redwood was employed in India before the discovery of America and was imported into Europe from the East Indies for use as a dye. Kimichi mentioned the name bresil (braza --- fiery red) in II9O, so that brazilin is not so named because it was found in Brazil. The converse is true; the Spaniards named the country Brazil because the already known dye-wood was abundant there. Logwood extract (campeachy wood) is obtained from Haernatoxylon campechianum (Central America and Caribbean). Though not as important as formerly it is still used, especially for dying silk and furs. The actual adjective dye is haematein (q.v.) which is a polygenetic lnordant dye. The most favoured shades are grey to black obtained with chromium, and especially iron, mordants. 1. The brazilin group The wood extracts deposit crusts on standing and from these Chevreul (Ann. chim., 18o8, [i], 66, 225) first obtained brazilin by recrystallisation from aqueous alcohol. The formula, C16H140 5, was proposed by C. Liebermann and O. Burg (Ben, 1876, 9, 1883). On dry distillation, brazilin affords resorci* No significant new material on the chemistry of these two substances has been published since 1960. Chapter IX of the original edition is reproduced here as a tribute to Sir Robert Robinson's memory, and his long connection with Rodd's Chemistry of Carbon Compounds as Chairman of the Advisory Board from its inception over 25 years ago, particularly as it describes in his own words one of his many elegant contributions to organic chemistry. [4271
428
BRAZILIN
AND HAEMATOXYLIN
22
nol in not inconsiderable yield and this process, due to Kopp (Ber., 1873, 6, 446), was acutally used for many years for the preparation of resorcinol. The action of nitric acid on brazilin gave rise to styphnic acid (F. Reim, Ber., 1871, 4,332; 1879, i2, 1392). Liebermann and Burg (loc. cit. " also K. Buchka and A. Erck, Ber., 1885, 18, 1139) found that brazilin gives a tetra-acetyl derivative when heated with acetic anhydride and this was confirmed by G. Dralle (Ber., 1884, I7, 370). The latter chemist showed that brazilin gave a trimethyl ether, insoluble in aqueous alkali, which still contains a hydroxyl group (acetyl derivative); and a tetramethyl ether under very vigorous conditions. Brazilin was thus shown to be a trihydric phenol also containing an alcoholic hydroxyl group. Brazilin forms colourless needles (with I-5 H20) or prisms (with i .o H~O), m.p. circ. 25~ (optical rotation, see p. 445). Derivatives are: triacetate, needles, m.p. io5-6 o; tetra-acetate, needles, m.p. 149-1510; bromotetra-acetate, m.p. 203- 4 o; dibromotetra-acetate m.p. 185~ trimethyl ether, prisms, m.p. 138-9~ trimethyl ether acetate, m.p. 171-3~ tetrarnethyl ether, m.p. 137-9~ bromotetramethyl ether, prisms, m.p. 18o-181 ~ The first indication of a part of the molecular structure was given by C. G. Schall and G. Dralle (Ber., 1888, 21, 3o17; 1889, 22, 1559" 1892, 25, 19) who oxidized brazilin in alkaline solution by means of atmospheric oxygen. The first product is brazilein (see p. 435) but the red colour due to this substance disappeared and ~-resorcylic acid and a substance C9H604, needles m.p. 27 I~ were then isolated. The latter formed a diacetyl derivative and a dimethyl ether C9H40 2 (OMe) 9, which could be oxidized by means of permanganate to 2-hydroxy 4-methoxybenzoic acid. Schall (Ber., 1894, 27,528), suggested that the substance, C9H60 ,, was a dihydroxychromone (I)and W. Feuersteir~ and St. vo~ Koslar~ecki (Ber., 1899, 32, lO25) confirmed this view, since the dirnethyl ether (II)could be hydrolysed into formic acid and the fisetol dimethyl ether (III) already known as a degradation product of methylated fisetin (J. Herzig, Monatsh., 1891, i2, 187). .#~/O..
MeO . # ~ / O , .
0 (I)
MeO 1~/~ OH
o (II)
(III)
The synthesis of (II) was effected in 1924 (P. P / d y e r and J. Oberlin, Ber., 1924, 57, 208) from 7-methoxychromanone by way of its 3-oximino-derivarive. This was hydrolysed by means of sulphuric acid in aqueous acetic acid and the resulting mono-methyl ether of (I) was methylated.
I
BRAZILIN
GROUP
429
Oxidation o/ O-trimethylbrazilin by means o/ permanganate The investigations of W. H. Perkin, jun. in this field followed the model work of Goldschmidt on papaverine and his own studies of berberine. The oxidizing agent attacked various parts of the molecules and a variety of products was obtained. The information from the structures of the products, which sometimes had overlapping sections, was combined. It happened in this case that one of the fragments obtained in very small yield, namely brazilic acid, was found to be of exceptional importance. The investigation was started as long ago as 1883 and accounts were given in 1899 and 19oo (Proc. chem. Soc., 1899, 15, 27, 45, 241; 19oo; I6, lO6, lO7). The products were (i) brazilinic acid, C19H1809, a substance obtained from trimethylbrazilin without loss of carbon atoms, (2) an acid, C10H10Os, m.p. I74 ~ (3) an acid, C10H100s, m.p. 195 o and (4) brazflic acid, ClzHl~Os. The two acids, C10H100e, were identified as 2-carboxy-5-methoxyphenoxyacetic acid (IV) and metahemipinic acid (V) respectively. MeO 2"~ OCH2C02H ~C09H (IV)
MeO Q C02H Me0 C09H (v)
On heating, (IV) lost a carboxyl group and furnished m-meth0xyphenoxyacetic acid, which was synthesized. Later (Perkin and R. Robinson, J. chem., Soc., 19o8, 93, 504) (IV) was also synthesized from 2-hydroxy-4-methoxybenzaldehyde by introduction of the acetic residue and oxidation of the resulting aldehyde-acid. The isolation of metahemipinic acid led Perkin to suggest that the constitution of brazilin should be (VI). HO ~ / O , . ~ _ j ~ . OH
OH (vI)
The study of brazilic acid (Perkin, ibid., 19o2, 8I, 221) soon excluded one of the alternatives considered and the indane moiety of the formula received support from the later isolation of 4: 6-dimethoxyhomophthalic acid (vii) in small yield from among the permanganate oxidation products (ibid., 19o2, 8i, IO28;Perkin and Robinson, ibid., 19o 7, 9I, lO82). The yield of brazilic acid was only 0. 7 %; it furnished an oxime and a semicarbazone, and when reduced with sodium amalgam and the solution acidified it gave the lactone, CI~HI~Os, of dihydrobrazilic acid. On very gentle heating of brazilic acid with concentrated sulphuric acid, the solution acquired intense violet fluorescence, and was found to contain anhydrobrazilic acid (VIII). The constitution of this substance was deduced from its
430
BRAZILIN AND HAEMATOXYLIN
22
decomposition on boiling with barium hydroxide solution into fl-(6-hydroxy4-methoxybenzoyl) propionic acid (IX) and formic acid. MeO -~.....~ CO2H, MeO I ..~/ CH2-CO2H (vii)
MeO ..~'~O...[ 'CH 2" CO2H ~'~/ o (viii) . .
MeO [-~"'~ OH ' . % / C O 9CH 2. CHo9 CO2H (IX)
The methyl ether (IX) was synthesized. Later the acid (IX)was again obtained (idem, ibid., 19o8, 93, 502, 509) and its ester condensed with ethyl formate with the help of sodium and anhydrobrazilic acid isolated. This was the first example of a synthesis of a 3-substituted chromone, later applied by a number of workers to the synthesis of isoflavones. An alternative to (X) for brazilic acid can hardly be entertained in view of the simultaneous formation of (IV) in the oxidation process.
(X)
/C(OH) .CH2. COzH O Brazilic acid
In 19o4 Werner and P/eiBer (Chem. Zeitschr., 19o4, 3,421) suggested that brazilin has the structure (XI) but advanced no more experimental evidence in favour of this view and combined it with fallacious interpretations of other aspects of the chemistry of brazilin derivatives. Nevertheless the suggestion was an acute one and was eventually proved to be correct as the result of synthetic studies by Perkin and Robinson (Proc. chem. Soc., 19o6, 22, I6o; J. chem. Soc., 19o 7, 91, lO73). Apart from these an argument that gradually acquired force was that the CH~ groups marked with an asterisk in (IV) and (X) , were not likely to be produced from -Lri ~.T ./C" \C groups in the course of a permanganate oxidation. One of these CH, groups also survives in dimethoxyhomophthalic acid (VII). HO'~"~'/O'~cH2[ !l Z ,-,T
" ~ / ~ U\---/'~*'2 c/c:y~ / \ //
MeOS"HO'CH2"CO2H
"~/~'~o ~__CO,H /? k \__/
HO OH (XI)
Brazilin
MeO OMe (XII)
Brazilinic acid
Structure (XI), but not (VI), contains the two methylene groups which occur in the oxidation products.
I
BRAZILIN GROUP
431
Brazilinic acid, C19H1sO9, is a keto-dicarboxylic acid reducible to a dihydroderivative which formed a characteristic lactone. On the basis of (VI) it would be an aldehyde, hardly likely to be produced in a permanganate oxidation at 9o~ but the skeleton (XI) would be opened to (XlI). The lactone of dihydrobrazilinic acid would clearly be (XlV). A small yield of brazilinic acid was obtained by a Friedel-Crafts condensation of ethyl m-methoxyphenoxyacetate and metahemipinic anhydride. It was better to condense resorcinol dimethyl ether with metahemipinic anhydride under moderately vigorous conditions with hydrolysis of the o-MeO group and reduce to the lactone (XlII). Introduction of the acetic residue then afforded the desired lactone (XlV). MeO f~
MeO ,~,, OH I I ^ "~~lu\
CH CO
O" CH~. C09H
~fi~./O-. CH CO
/=~ MeO OMe
MeO OMe
(XlII)
(XlV)
The evidence thus available was consistent with the structure (xI) for brazilin but there was nothing to exclude (XV) which was the only possible alternative. HO [- .~. /~O~ "Cc/H~
H
MeO/~'~l/O'cH2 I II A~,
\ HO OH (xv)
/
MeO OMe (xvI) Trimethylbrazilone
Oxidation o/O-trimethylbrazilin by means o/chromic acid in acetic acid solution The pale greenish-yenow product of this oxidation, termed trimethylbrazilone, C19Hls06, was obtained at once in an almost pure condition. The composition change from trimethylbrazilin was + O and m 2H. The formula (XVI) was assigned to the substance in later years by Perkin and Robinson, consistent with the infra-red spectrum (R. E. Richards and M. L. Tomlinson, Natule, 1948, i62, 693 ) which shows a carbonyl band at 3,61o cm -1. There is no band round 1,72o cm -1 attributable to a hydroxyl group, excluding an earlier ketol structure.
432
BRAZILIN AND HAEMATOXYLIN
22
When heated with alcoholic potassium hydroxide, trimethylbrazilone loses the elements of water yielding the potassium salt of a-anhydrotrimethylbrazilone (XVlI). OH
~ . ~ OMe ONe a-Anhydrotrimethylbrazilone (XVII)
The acetyl-derivative of (XVlI) is obtained by treatment of trimethylbrazilone with acetic anhydride. The reactions of ~-anhydrotrimethylbrazilone indicated its character as a derivative of/~-naphthol, azo-couplings, colour reaction with chloroform and aqueous alcoholic alkali, etc. Conversion to a ~-naphthoquinone derivative, trimethoxy-~-brazanquinone, could be accomplished in stages as follows: OAc
OAc
OH
> "~NO 2 ~
OH
NO2 ~
O
NH~
"O
Trimethoxy-a-brazanquinone forms deep brown micro-crystals and condenses with o-tolylenediamine to a characteristic quinoxaline derivative. Furthermore, ferric chloride oxidizes a-anhydrotrimethylbrazilone to a very sparingly soluble dinaphthol derivative and from this the corresponding substituted dinaphthylene oxide can be obtained by the action of phosphoryl chloride. An independent synthesis of ~-anhydrotrimethylbrazilone was effected by P. C. Johnson and A. Robertson (J. chem. Soc., 195o, 2391). /~-
OH
MeO ./~-..~,/O.>, CO~H
\ ~_~/ MeO OMe
(XVlII)
%// MeO OMe
(XlX)
An improved synthesis of brazilinic acid was possible by reacting the known phenolic acid (XVlII)with ethyl bromacetate and potassium carbonate in an acetone medium. The ethyl brazilinate so produced was hydrolysed and the acid condensed with acetic anhydride and sodium acetate to the coumarone derivative {XlX). After eliminating the carboxyl in the coumatone ring, the Arndt-Eistert homologation was applied to the resulting mono-
I
BRAZILIN
GROUP
433
carboxylic acid and the product (XX) furnished a-anhydrotrimethylbrazilone on gentle heating with concentrated sulphuric acid.
~02H
MeO ~ - . . / O . .
(XVlI)
\__/ MeO OMe
(xx)
The action of sulphuric acid on trimethylbrazilone (XVI) was first studied by Hem@ Pollak and Galitzenstein (Ber., 19o4, 37, 631) and the course of the reaction elucidated by Perkin and Robinson (J. chem., Soc., 19o9, 95, 385; cf. idem, ibid., 19o8, 93, 5Ol). The product, called 7j-trimethylbrazilone, is isomeric with the starting material. It is an acid and gives a good yield of 4: 5-dimethoxyhomophthalic acid on oxidation by means of permanganate. When treated with dehydrating agents, 7j-trimethylbrazilone gives flanhydrotrimethylbrazilone. A smooth conversion is that of the y~-trimethylbrazilone to the acetyl-derivative of the anhydro-compound on heating with acetic anhydride. It transpires that the change may be represented as shown (XXI to XXII). Trimethyl- (XVI) brazilone
H.SO, CH9
(xxI) OH
0
I --vlvlo o (XXlI)
fl-Anhydrotrimethylbrazilone
(XXIII)
Oxidation of fl-anhydrotrimethylbrazilone by means of chromic acid furnishes a red quinone which is not a I : 2-quinone, but closely resembles the substance (XXlII) synthesised by reaction of 2: 3-dichloronaphthoquinone and resorcinol in alcoholic sodium ethoxide (Liebermann, Ber., 1899, 32,924). An independent synthesis of fl-anhydrotrimethylbrazilone was effected by K. W. Bentley and Robinson (J. chem. Soc., I95O, 1353). The processes are indicated in the following scheme:
434
BRAZlLIN AND HA:EMATOXYLIN
+ ~%/
=.sc CN- CH~
22
=o(bo=
OMe
CO. CH 2
OMe
Monomethyl ether / IBr.CH.,CO2Etin alcoholicNaOEt MeO ~ % O. CH 2.COoH CO'CH2 __ OMe OMe
MeO ./ acid chloride
2
-
AICl~ ->
( "-'- OMe
(XVI)
A noteworthy reaction occurs when trimethylbrazilone reacts with phenylhydrazine in hot alcoholic solution {cf. J. Herzig and J. PoUak, Ber., 19o5, 38, 2166; 19o6, 39, 265). Nitrogen is evolved and some benzene is produced whilst the diketone simply loses two atoms of oxygen, forming deoxytrimethylbrazilone (XXlV). The reaction is by no means smooth nor is the yield particularly favourable. Nevertheless it is substantial and the mechanism of the process is far from obvious. The constitution of deoxytrimethylbrazilone has been confirmed by synthesis (see below); the subMeO (2 ,'~O'-cH2
\
/
(XXIV) MeO OMe Deoxytrimethylbrazilone (anhydrotrimethylbrazilin)
stance could also be termed anhydrotrimethylbrazilin. The reaction mechanism remains obscure and needs further investigation. The action of concentrated nitric acid on trimethylbrazilone also led to remarkable results (A. W. Gilbody and Perkin, J. chem. Soc., 19o2, 81, lO48; cf. Perkin and Robinson, ibid., 19o 9, 95, 389; Herzig, Pollak and Vonk, Monatsh., 19o 4, 25, 871). The elements of HNO 3 were added and the crystalline product obtained in nearly quantitative yield was termed nitrohydroxydihydrotrimethylbrazilone. It was recognised as a ketol-lactone of the structure (XXV). When O MeOl.~ A ~ O "~,/CJ~H~)H CH2 NO2 '//'~' ~%) OMe
(xxv)
oMe
MeO (#"~ OH CH30 ~ COgH NO 2 NaOH aq. 7 /* ~'/CH2" MeO lit
OMe OMe
C H 2 ~ ~ " OMe
Ir
I
I
BRAZILIN GROUP
435
treated with aqueous sodium hydroxide it dissolved to a purple solution which gradually became yellowish brown and deposited a precipitate. The latter consisted of 3:4-dimethoxy-6-nitrotoluene along with a small proportion of the related dinitrotetramethoxydiphenylethane. The solution contained 2-hydroxy-4-methoxybenzoic acid. Permanganate oxidation of (XXV) afforded the known 2-carboxy-6-methoxyphenoxyacetic acid (IV). Furthermore, the action of phenylhydrazine on (XXV) gave rise to the osazone (XXVI). MeO M e O C > H 2 - C - C H " N2HPh N2HPh
(xxvi) The formation of (XXV) from trimethylbrazilone is in full accord with the diketonic structure advocated, being simply a displacement of a carbonyl accompanying nitration and fully analogous to known processes such as the following (V. J. Harding and C. Weizmann, J. chem. Soc., 191o, 97, 1131; cf. Harding, ibid., 1914 , lO5, 2790). MeO ~ / . CO-CH s
MeO
INO2
+ CHa.CO2H
The foregoing noteworthy series of transformations are due to different modes of attack by reagents, summarised in the following scheme: .~ 5IeO[
I]/
.(a)
/" ,'"l.-2(c)
"~ X;,";--CO._.~h~ (b)"OC~," . - \ C ~ " ' - ( d ) - ~ - - { *'" (XVI)
MeO OMe
Transformations of O-trimethylbrazilone (XVI) NaOH, Ac=O etc -+ a-Anhydrotrimethylbrazilone (XVII) Fission by H2SO4 -+ w-trimethylbrazilone (XXI) leading to fl-anhydrotrimethylbrazilone (XXII) (c) Phenylhydrazine -+ deoxytrimethylbrazilone (XXIV) (d) Fission by HNO a -+ nitrohydroxydihydrotrimethylbrazilone (XXV) (a) (b)
Brazilein, C16H1~O5, and its derivatives Brazilin is a colourless substance readily convertible by oxidation into the colouring matter, brazilein. An alkaline solution of brazilin quickly acquires an intense crimson colour in contact with air and this method can he em-
436
BRAZILIN
ANDHAEMATOXYLIN
22
ployed for the preparation of brazilein using ammoniacal solutions. A better method makes use of oxidation by means of iodine in alcoholic solution. Brazilein separates in small crystals which are browish yellow by transmitted light under the microscope and in mass present a metallic glance resembling that of gun metal. It has only comparatively recently been observed that brazilein is optically active and that it can be reduced to brazilin by means of borohydride in aqueous alkaline solution (F. Morsingh and Robinson, Int. Congress Pure and App1. Chem., Ztirich, 1953). Brazilin is obviously the leuco-compound of the quinonoid brazilein which could be formulated as (XXVlI), (XXVlII) or (XXlX) on the basis of (XI) for brazilin. We can proceed to eliminate the possibility (XXlX) and in the section on the synthesis of brazylium salts (below) it is shown that (xxvIII) is the correct structure.
~_// HOOH
(XXVII)
~_/
k__//
HO 6
60H
(XXVIII) Brazilein
(XXIX)
\_// 60H
(XXIXa)
It should be noted that the quinoid pattern of (XXIX) as in (XXIXa) would be derived from the alternative structure (XV~XXIXa) for brazilin which, however, could not give rise to (XXVII)or (XXVIII). The exclusion of X X I X (XXIXa) accordingly also excludes this alternative and for the first time. The methylation of brazilein by means of methyl sulphate and aqueous potassium hydroxide furnishes trimethylbrazilein and tetramethyldihydrobrazileinol as the main products (Engels, Perkin at. ~ Robinson; J. chem., Soc., I9O8, 93, III5). Less highly methylated products which are also obtained have been little investigated. Trimethylbrazilein forms a magnificent scarlet formate and when recovered from this derivative may be crystaUised in large orange-yellow prisms. When treated with boiling sodium hydroxide it adds the elements of water affording the colourless trimethyldihydrobrazileinol which on the one hand is easily dehydrated to trimethylbrazilein (e.g. on warming with formic acid) and on the other hand can be methylated to the above mentioned tetramethyldihydrobrazileinol. The relat iola of these substances is clearly as shown in the following part structures:
I
B R A Z I L I N GROUP
Trimethylbrazilein
Dihydrotrimethylbrazileinol
437
Tetramethyldihydrobrazileinol
The important result that excludes the structure (XXIX) and XXlXa) for brazilein is that oxidation of tetramethyldihydrobrazileinol with chromic acid in acetic acid solution affords trimethylbrazilone (XVI). Hence tetramethyldihydrobrazileinol must be (XXX) derived from (XXVII) or (XXVIII) for brazilein. These considerations serve to determine the position of the alcoholic hydroxyl of brazilin (Engels et al., loc. cir.). An interesting decomposition of brazilein and its derivatives occurs when these quinones are treated with hydrogen peroxide, best in acetic acid solution (Engels et al.). Oxidation takes place round the central carbon atom of the diphenylmethane structure and with formation of hydroxyquinol derivatives. An appropriate model was later found in the behaviour of aurine (XXXI) under similar circumstances.
MeO OMe
(xxx) HO- C~H4..c/C6H 49OH /Jk..
HO. C~H4..CO .~ ~
H,O,
'l~i;o
'
(XXXI)
HO.C6H,.OH HO. CsH ," COgH
"~OH~ + HO'CsH4.OH
MeO . ~ / 0 . .
1~'~ HO' CsH4" OH +CO9
MeO - # ~ / O " C H ~ CH 2
~
HO2C/"CHa HO /
/-\
MeO OH (XXXII) Trimethylbrazilein
(XXXIII)
438
BRAZILIN AND HAEMATOXYLIN
22
Thus trimethylbrazilein ( X X X l I anticipating a sequel) is readily converted into (XXXIII). A significant reaction of brazilein and its derivatives is mentioned immediately in the next section.
The isobrazilein or brazylium salts So long ago as 1882 J. J. Hummel andA. G. Perkin (J. chem. Soc., 1882, 41, 367) studied the action of mineral acids on brazilein and discovered the so called isobrazilein salts. These are produced from their generators with loss of a molecule of water and are of the form B, HX. Thus the intense crimson solution of brazilein in concentrated sulphuric acid develops on gentle warming an orange brown and then exhibits a strong green fluorescence. On addition to water the orange isobrazilein hydrogen sulphate is precipitated. C16H1205 + H2SO4
> CxsHnO a, HSO 4 + H 2 0
This work was carried out before the theory of oxonium salts was established and long before the analogy of pyrylium with pyridinium was understood. Since 19o 7 the isobrazilein salts have been recognised (Engels et al., loc. cir., cf. J. chem. Soc., 19o8, 93, 49 o) as pyrylium salts and the skeleton of the cation may be termed "brazylium". Thus isobrazilein hydrogen sulphate can be formulated as (XXXlV). When tetramethyldihydrobrazileinol is warmed with sulphuric acid, the elements of methanol and 6f water are eliminated and O-trimethylbrazylium hydrogen sulphate is produced. This HSO 4
FeC14
| l /=k ~_// HO OH
(XXXlV)
/=\ ~_// MeO OMe
(xxxv)
dissolves in water to a yellow solution exhibiting a striking green fluorescence. The corresponding /errichloride (XXXV) can be readily recrystallized, possesses a definite melting point and is a suitable reference compound in the series. A second method of formation of (XXXV) is from deoxytrimethylbrazilone (XXIV) by oxidation in acid solution. Thus treatment of deoxytrimethylbrazilone with bromine in acetone solution is an especially convenient process giving O-trimethylbrazylium bromide in quantitative yield. The ferrichloride (XXXV) is then produced by treatment with a solution of solid ferric chloride in concentrated hydrochloric acid and may be crystallized from acetic acid.
I
BRAZILIN
GROUP
439
Synthesis o/ brazylium and other indenobenzopyrylium salts In the course of synthetical experiments designed in relation to the older brazilin structure, Perkin and Robinson (ibid., I9o7, 9I, lO73) had occasion to study the course of the condensation of salicylaldehyde and its derivatives with ketones such as indan-I-one and its dimethoxy-derivatives. In most cases basic catalysts were employed but these were unsatisfactory when ,~-resorcylaldehyde was used as the aldehyde component of the system. Turning to hydrogen chloride, for example in acetic acid solution, the formation of stable hydrochlorides was observed and these were equated with Btilow's pyranol salts (C. Biilow and W. von Sicherer, Ber., 19Ol, 34, 2368) and soon proved to be anhydro-pyranol salts. An early preliminary communication (Perkin and Robinson, Proc. chem. Soc., 19o 7, 23, 149) described the identity of the salts made on the one hand from resorcinol and benzoylacetaldehyde and on the other from fl-resorcylaldehyde and acetophenone. H-.._ C1 ~'~1 OH COPh HCI HO/~"~t/O~cPh "~ t ---+ I ,, I-~'/E-.CH..-CH U,O CHo/CH9 I OH I identical salts C1 CHO
CH3
2H20
The salicylaldehyde-ketomethylene synthesis was generalised (ibid., 19o8, 93, lO86) ; parallel work by H. Decker and T. yon Fellenberg was published at about the same time (Ber., 19o7, 40, 3815). The method was later elaborated for the syntheses of anthocyanidins and anthocyanins (See this vol., 84). FeC14 MeO i~'~ OH CO ~/~- OMe CHO + CH2-..CH2/~//" t ii tOMe
HC1 Fee13
~'~/O~~~. (XXXVI) C1
MeO ~'nlJ OH "%/ CO
H,
2~CH2
HC1,HCO2H_._
Moo( Jo
FeCla__~ (XXXV)
/
/CHg. MeO OMe (xxxvli)
MeO OMe
440
BRAZlLIN AND HAEMATOXYLIN
22
In 19o7 it was of interest as helping to disprove the earlier brazilin formulations. The salt (XXXVI) prepared from p-methoxysalicylaldehyde and 5:6,dimethoxyindan-I-one with the help of hydrogen chloride, and conversion to ferrichloride (Perkin and Robinson, J. chem. Soc., 19o8, 93, IIO6), was quite different from O-trimethylbrazylium ferrichloride (XXXV). The first synthesis of a substance containing the brazilin skeleton was that of O-trimethylbrazylium ferrichloride (XXXV) (H. G. Crabtree and Robinson J. chem. Soc., 1918, 113, 859). Veratrylidenepaeanol was catalytically hydrogenated to its dihydro-derivative (XXXVII). On treatment with boiling absolute formic acid and zinc chloride and subsequently with ferric
ooo.y" /~ Me CH~
eOj-~
OH
" ~ / ~ ' C "~
,~__//
"~CH2
,~ //
MeO OMe (xxxvIII)
MeO OMe (XXXlX)
chloride dissolved in hydrochloric acid, the ferrichloride (XXXV) identical with O-trimethylbrazylium ferrichloride, was obtained. In other experiments it has not been found possible to convert the chromone (xxxvIII) into a brazylium salt and hence the mechanism probably involves ring-closure of ( x x x v l I ) to an indene (XXXIX)followed by O-formylation and further ring-closure.
Synthesis o/deoxytrimethylbrazilone and trimethylbrazilone The synthesis of deoxytrimethylbrazilone (XXIV) was effected by Perkin and Robinson (J. chem. Soc., 1926, 941; 1927, 2o94; 1928, 15o4) and by Pfeiffer and his collaborators virtually simultaneously and by the same methods (cf. P. PleiBer, O. Angern et al., Ber., 1928, 61,839). The synthesis of veratrylidene-7-methoxychromanone (XL) was earlier described by Perkin and Robinson (Proc. chem. Soc., 1912, 28, 7). This substance was MeO .#N/O-.
MeO .#N/ON
i
P~.05_+
__+
6
/=\
OH
/
MeO OMe (XL)
6
/=\
/
CH2
MeO OMe (XLI)
(XXlV)
I
B R A Z I L I N GROUP
441
catalytically hydrogenated to a dihydro-derivative (XLI)which afforded deoxytrimethylbrazilone on cyclodehydration with phosphoric anhydride. Catalytic hydrogenation of deoxytrimethylbrazilone affords its dihydro derivative (XLII) which is described as O-trimethylbrazilane-a. The pyran and cyclopentene rings of (XLII) can be fused in cis- or trans- configuration. Actually, an isomeric O-trimethylbrazilane-b which is possibly the transform is known (Chatterjea and Robinson, unpublished). The chief reason for this assumption is that the catalytic reduction of (XXlV) would be likely to yield the cis form. Oxidation of (XLII) with chromic acid in acetic acid solution furnished trirnethylbrazilone (XVI). MeO - # ' ~ l / O ~ c H 2
'~-..~
CU
"C H / " - C H 2
\ / /~\
(XLII)
CrOa
--~
(XVI)
MeO OMe
"l'he constitution o/brazilein
It has been pointed out that addition of water to the quinonoid group of O-trimethylbrazilein produces a new phenolic hydroxyl. This marks the position of the quinone group and in order to label it this phenolic hydroxyl was ethylated. The O-ethyl-trimethyldihydrobrazileinol so obtained was converted by the method already described for the tetramethyl compound into an O-ethyldimethylbrazylium ferrichloride (XLIII or XLIV, dependent on the position of the quinonoid group of trimethylbrazilein). FeC14 EtO , ~ / O . - .
/=\ ~_//
MeO OMe (XLIII)
FeC14 MeO . # ~ / O ~
/=\ ~J
MeO OEt (XLIV)
These two O-ethyldimethylbrazylium ferrichlorides were synthesized: (XLIII) was made by the Crabtree and Robinson method from veratrylidene2-hydroxy-4-ethoxyacetophenone whilst (XLIV) was made from 3'ethoxy-4'-methoxybenzylidene-7-methoxychromanone by conversion to the related deoxy-ethyldimethylbrazilone and thence to the brazyliuxn salt. The synthesised salts proved to be sufficiently divergent in properties and a mixture showed a depressed melting point; (XLIV) was identical with the
442
B R A Z I L I N AND H A E M A T O X Y L I N
22
salt derived from trimethylbrazilein (V. M. Mi~ovi~ and Robinson, J. chem. Soc., 1937, 43). This proves that trimethylbrazilein is (XXXlI) and hence brazilein is probably (XXVIII).
Synthesis o/brazilin The most obvious route to the synthesis of trimethylbrazilein was by way of deoxytrimethylbrazilone but all attempts to hydrate the double bond of this substance met with failure. In presence of strong acids oxidation to the brazylium salt occurred and even under oxygen-free conditions disproportionation was noted, the case being analogous to that of certain dihydroquinoline derivatives. MeO ~ - . ~ / O . . I...~?N/~.~ H HO/t ? H2
FeCla
HC1
(XXXV)
/--\ (XLV) MeO OMe
Several years before the synthesis was achieved it had been shown (Perki~, W. N. Rdy and Robinson, J. chem. Soc., 1928, 15o4) that reduction of trimethylbrazilone by means of zinc and acetic acid gave the pinacol (XLV) characterised by ready conversion into O-trimethylbrazylium ferrichloride. AcO ~ / O " c H ~
AcO ~"~t,/O"cH2
CO \ /CH 2 ~AcOH-+ HO.C\
/--\ (XLu
/// AcO OAc
Triacetylbrazilone
HO ~ ' ~ l / O " c H 2
"CH / 2 --~
/z\ ~ //I AcO OAc (XLVII)
"~J~/ " ----~ -~ d/-brazilein HO.C\ "CH / 2 (XXVlII)
/-~\ ~ /// HO OH
dl-brazilin d-brazilin
The synthesis depends on the preparation of a similar pinacol in the unmethylated series (Morsingh and Robinson, loc. cir.). O-Triacetylbrazilone (XLVI) could be obtained by the chromic acid oxidation of O-tetra-acetylbrazilin and reduction of this substance by means of zinc and alcoholic acetic acid gave the pinacol (XLVII)in moderate yield. The conversion to dl-brazilein was realised when this pinacol was subjected to hydrolysis by means of alkalis and the solution acidified. In order to synthesize triacetylbrazilone (XLVI) dihydrodeoxytrimethylbrazilone-a (XLII), already synthesized, was demethylated, the resulting trihydric phenol acetylated and the O-triacetylbrazilane oxidized by means of chromic acid. Triacetylbrazilone (XLVI), identical with the product from
2
HAEMATOXYLIN
GROUP
443
triacetylbrazilin, was obtained. This made d/-brazilein a synthetic compound. It was reduced by borohydride to d/-brazilin and the optical resolution effected by repeated crystaUisation of the tetra-d-menthyloxyacetyl derivative. After hydrolysis of the resolved material, d-brazilin was obtained (not yet published). It is not known with certainty that naturally occurring brazilin is a member of the brazilane-a (cis-junction) series but this is probably the case in view of the fact that O-tetra-acetylbrazilin can be induced to lose the elements of acetic acid, in a catalysed pyrolysis, with formation of deoxy-O-triacetylbrazilone (XLVIII) (private communication, Ollis). The latter substance has been identified as the product (Herzig) of the acetylating zinc dust reduction of brazilein.
/
CH z
/=~
/=\
AcO OAc
AcO OAc (XLVIII) 2. The haematoxylin group
In general, progress in the haematoxylin group followed closely the brazilin developments but the various compounds are not quite so attractive physically, being usually more soluble in solvents, with less power to crystallise and the colours and fluorescences are not so bright as is the case with the brazilin derivatives. Haematoxylin can be obtained from logwood extract in colourless crystals; the empirical formula is CleH140 e. This contains one oxygen atom more than the formula of brazilin, due to the presence of an additional hydroxyl group, located in the 8 position of the benzopyran moiety of the structure by the synthesis of haematoxylinic acid from pyrogallol and by the formation of pyrogallol when haematoxylin is fused with potassium hydroxide. X~qth four phenolic and an alcoholic hydroxyl group, haematoxylin forms a pentacetate, m.p. 165-166~ a tetramethyl ether, m.p. 139-14o~ (acetate, m.p. 178-18o~ and a pentamethyl ether, m.p. 144-1470. Optical rotation, see p. 445.
Permanganale bxidalio~ o/d-tetramethylhaernatoxylin, The analogue of brazilic acid was not isolated but haematoxylinic acid corresponded to brazilinic acid (Perki~, and J. Yates, J. chem. Soc., 19o2, 81, 235). On reduction this gave the lactone of dihydrohaematoxylinic acid (XLIX) which was s~mthesized (Perkin and Robinson, ibid., 19o8, 93, 515) 9
444
B R A Z l L I N AND H A E M A T O X Y L I N
22
Condensation of metahemipinic anhydride and pyrogallol trimethyl ether with the help of aluminium chloride could be managed so as to hydrolyse only the o-methoxyl group. Reduction of the product and introduction of the -CH2.CO~H group furnished the required lactone (XLIX). MeO MeO ,/~"~,~ O" CH2"CO2H
MeO MeO I~ ' ~ ' II/ O ' C H! 2
I'~..~-~...0..
~-~J~ CO
CH CO
OC
MeO OMe
~CH~
MeO OMe
(XLIX)
(L)
Tetramahylhaematoxylone and diethylenehaematoxylone. Oxidation of tetramethylhaematoxylin by means of chromic acid in acetic solution gave tetramethylhaematoxylone (L) (Perkin, J. chem. Soc., 19o2, 8i, lO57) Which is a substance entirely analogous to trimethylbrazilone. For example its behaviour with alkalis, acetic anhydride (a-anhydrotetramethylhaematoxylone and its acetyl derivative), nitric acid and phenylhydrazine corresponded to that of trimethylbrazilone. The ~-tetramethylhaematoxylone series has been little investigated. Deoxytetramethylhaematoxylone (P/eiu~r) and deoxydiethylenehaematoxylone (LI) were synthesized by applications of the method already described in connection with deoxytrimethylbrazilone (Perkin, A. Pollard and Robinson, J. chem. Soc., 1937, 49). /CH2.. H2C O
'
/=~ O (LI)
O
HgC-CH 2
The properties of these substances closely resembled those of deoxytrimethylbrazilone. Thus oxidation in acid solution gave the respective haematoxylium salts.
Haematein and its derivatives The technically important point here is that haematein is a much better adjective dye than brazilein; otherwise the two series go in step together. The
2
HAEMATOXYLIN
GROUP
445
methylation of haematein gave a high yield of pentamethyldihydrohaemateinol (LII) which was exceptional in this series in that it had a considerable power of crystallisation (Engels et al., ibid., 19o8, 93, 1115). Tetramethylhacmatoxylium ferrichloride (LIII) was synthesized by H. G. Crabtree and Robinson (ibid., 1922, I2I, lO33). FeC14 MeO
MeO
/=\ ~_// (LII)
MeO OMe
/=\ ~J (LIII)
MeO OMe
Synthesis o/ d-haematoxylin The stages and methods followed the brazilin model closely (Morsingh and Robinson, Internatl. Congress of Pure and Applied Chem., Ztirich, 1953).
Possible natural occurrence o/a haematoxylin methyl ether Haematoxylon a/ricanum, a South African member of the family Caesalpiniaceae, afforded an extract, the colour reactions and dyeing properties of which clearly indicated that it contained a substance similar to brazilin and to haematoxylin, but identical with neither. A. G. Perkin has suggested that this may be a methoxy-brazilin (O-methylhaematoxylin) (Perkin and Everest, The Natural Organic Colouring Matters, Longrnans, Green and Co., London, 1918, p. 382; A. G. Perkin, J. Soc. Dy. Col., 1918, 34, 99). If, on the other hand, the substance is brazilin, modified in properties by impurities, there is an interest of a different kind, namely the occurrence of brazilin in a botanical group in which only haematoxylin has previously been identified.
Optical rotatory powers o/brazilin and haematoxylin and their derivatives Brazilin (natural), (a) ~ "5~+ 121.50. brazilin (reduction of brazilein), (a) ~x'5~+ I23.4 ~ both in methanol (Morsingh and Robinson, loc cit.). O-tetra-acetylbrazilin, (a)D + 76-4 ~ O-acetyltrimethylbrazilin, (a)~)~176 + 128.2 (Herzig et al., Monatsh., 19~ 27, 753)-Haematoxylin (natural), (a)D + 99-6 ~ (Hesse, Ann. chim., 1859, Io9, 532)" haematoxylin (reduction of haematein), (a)~~176 + 98.4 ~ (M. and R.). O-Acetyltetmmethylhaematoxylin (a)~)~176 + 151. 5 o (Herzig et al., loc. cir.). Brazilinic acid and trimethylbrazilone are optically inactive, but brazilic acid, which should be optically active, was not examined for this property. The stereochemical correspondence of brazilin and haematoxylin is probable but has not been directly demonstrated, for example, by X-ray crystallography.