several new aspects of indigo chemistry

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The dark blue color indigo, and the dye of the same name and color , are surely quite familiar to

the reader . Intense colors in materials indicate a high degree of light absorption by their

component atoms or molecules . That in turn implies an extensive electron resonance and

delocalization in their molecular orbitals . Such a widespread electron resonance anddelocalization is found in metallic solids, a topic of particular interest to me . Thus , new types

of metallic compounds will be more likely derived from highly colored compounds like indigo ,

rather than from colorless ones like the saturated hydrocarbons , for example . Possible

electrically-conductive indigo derivatives are examined further on in this web page .

The terms indigoand indigotinare generally considered to refer to the same chemical substance ,

2,2'-bis(2,3-dihydro-3-oxoindolyliden) [underlinedblue hyperlinkscan be clicked when online

to download the referenced document , which will open in a new window]. Sometimes the term

indigo is applied only to the color and the natural product (which invariably contains a number

of chemical compounds) , while the word indigotin is reserved for the single pure compound of

indigo . However , Farris apparently uniquely has made an important distinction between the

two terms [thereferencesare presented at the end of the text , below], as illustrated in the

following sketch :

al New Aspects of Indigo Chemistry http://www.chemexplore.net/i

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As pointed out by Golding and Pierpoint, the indigo molecule (trans , E) is energetically

stabilized by intramolecular hydrogen bonding . Conversely , the indigotin molecule (cis , Z) is

destabilized by repulsion between the lone pairs of electrons on its carbonyl groups , and so far

has never been either isolated from natural sources nor synthesized in a pure form . As will be

discussed later on , it might be possible to obtain the indigotin isomer , but only bonded (via its

nitrogen atoms) to a suitable Transition metal cation such as Cu2+to form the compoundcopper(II) bis(indigotin) . The distinction made by Farris between indigo and indigotin will be

observed in this web page .

Indigo is chemically related to the heterocyclic compound indole:


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This relationship is also shown in the structure of the natural product indican (mainly from

Indigofera plants) , from which indigo dye was produced in Asia for centuries , before being

displaced by synthetic product from European (mainly German) chemical companies :

Indigo is also biosynthesized in the human body from tryptophan, an amino acid humans share


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with plants . Tryptophan is degraded by intestinal bacteria to the smelly indole . Some of the

indole is converted into indoxyl , which is eliminated via the kidneys . In rare cases certain

people are unable to process the indoxyl properly , and it's oxidized and dimerized into indigo

and indirubin (a red dye) . Traces of the indigo are excretedin their urine . King George III

(1738-1820) of Great Britain apparently was affectedby this peculiar syndrome . A related

medical condition , PUB (purple urine bag syndrome) , is thought to occur by the presence of

indigo (blue) and indirubin (red) in the urine . Their combination produces its striking purple

color . PUB is graphically illustrated in the color photo in the medical report on the topic byKhan and co-workers.

The chromophoreis the atomic grouping within a dye molecule responsible for its light

absorption properties . Indigo's chromophorehas been shown to be its central part , without the

phenyl groups :

In this web page we'll survey how indigo has been (and still is) chemically produced , and we'll

try to devise new methods to synthesize this remarkable molecule . These new synthetic

strategies may in some cases permit the design of novel analogues of the original molecule ,

having varying degrees of electron resonance and delocalization . Such indigo analogues would

be interesting new dyes to prepare and study , and could provide additional insight into the

electronic structure and functioning of the indigo chromophore .

The prominent German chemist Adolph von Baeyer (1835-1917) was the first person to

determine the molecular structure of indigo (1865-70) and to synthesize itfor the first time (in


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1870 , from isatin) . He also prepared it from cinnamic acid , but neither synthesis route was

economically feasible for large scale production :

His third indigo synthesis , from 2-nitrobenzaldehyde (1882) , was simple and gave a good yield

of product , but again was economically impractical due to the high cost of the starting material ,

2-nitrobenzaldehyde . Because of its simplicity and easiness to carry out , this route to indigo ,

now commonly called the Baeyer-Drewson process [von Baeyer's partner's name in this work

was actually spelled Drewsen , but somehow got changed along the way], is frequently found as

a semi-micro organic chemistry experiment in undergraduate laboratory manuals:


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Adolph von Baeyer was awarded theNobel Prize for chemistryin 1905 in recognition of his

work on indigo , among his many other chemical accomplishments . However , economically

practical syntheses of indigo were later developed by a Swiss-German chemistry professor , Karl


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Heumann(1850-1894) , and a German industrial chemist , Johannes Pfleger(1867-1957) .

Heumann's first synthesis , in 1890 , used the industrial chemical aniline as a starting material . It

was converted into N-phenylglycine , which was internally condensed into indoxyl in molten

alkali at ~ 300 C . The indoxyl was quickly oxidized by atmospheric oxygen , dimerizing into

indigo . Unfortunately , the yield of product was too low by this route to make it commercially

attractive .

His second synthesis at the same time used the more expensive fine organic chemical anthranilic

acid as the starting material . In the same sort of reactions utilized by his first route , Heumann

obtained a high yield of indigo in this alternate procedure . It was actually scaled up to an

industrial level (several thousands of tonnes per annum , TPA) by BASF and Hoechst :


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Several years later (in 1901) , Pfleger working for Hoechst modified Heumann's first method


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by adding sodamide(sodium amide , NaNH2) to the alkaline flux . Sodamide is a very powerful

dehydrating agent , and it drove the ring closure reaction , to form indoxyl , to completion . Use

of the relatively cheap aniline as the starting material , and of sodamide as the condensation

agent , were the two key factors in the economic success of the BASF-Hoechst industrial indigo

synthesis . In 1925 BASF researchers devised an improved synthesis of N-phenylglycine from

the N-methylolation of aniline with formaldehyde and hydrogen cyanide , followed by

saponification of the resulting nitrile intermediate . This modification provided an additional

economy in the overall indigo production method . The BASF-Hoechst chemical synthesis ofindigo has entirely supplanted its original agricultural source at this time . About 17,000 TPA of

indigo are currently manufactured, virtually all of which is used for dyeing the cotton fibers of

denim , used in blue jeans .

All of the above indigo syntheses , while perfectly functional and you really can't argue with

success , can you ? seemed to me to be unintuitive, that is , with little if any connection to

conventional organic synthesis . And let's be honest : fusion of your intermediate in molten alkali

at 200300 C is definitely not part of the standard organic synthesis repertoire ! Those sorts of

conditions are fully the consequence of industrial expediency . Although indigo (its

chromophore in particular) has a somewhat unusual molecular structure , its synthesis should

nevertheless be amenable to more ordinary organic chemistry procedures than current industrial

processes might suggest . In the following sections of this web page several proposals for a

simpler , more intuitive synthesis of indigo will be outlined . In his review of indigo Farris

mentions ,

There are over thirtydifferent synthetic routes to indigo reported in the chemical literature (p.

367) .

I believe the following proposed methods are novel , but without a thorough literature search in

either Chemical Abstracts or SciFinder Scholar which are no longer available to me I can't

guarantee they actually are .

The two starting materials , as with the commercial processes outlined above , are anthranilic

acid(2-aminobenzoic acid) and aniline . The former is considered to be a fine chemical and isconsiderably more expensive than aniline , which is a high tonnage bulk chemical . Nevertheless

, I'll disregard the economic considerations in this study of indigo , in which the chemical aspects

of the compound are emphasized , and open the discussion with synthesis routes to it from

anthranilic acid .

Two points of practical significance must be raised , however . First , the commonest precursor

to indigo is indoxyl(see the sketch near the top of this web page) . Thus , all conventional indigo

syntheses are really indoxyl syntheses , since the latter intermediate is very easily converted into


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indigo by air oxidation . Throughout this essay I present the indoxyl structure in its keto form ;

its enol form is the heterocyclic molecule 3-hydroxyindole (as the aglycon in the indican

molecule , sketched above) .

The second point is also quite relevant to any indigo synthesis . Indigo is a remarkably robust

molecule , chemically speaking . For example , it can be dissolved in concentrated sulfuric acid ,

with the subsequent sulfonation of its aromatic rings (to produce indigo carmine , another useful

dyestuff) . Note that the chromophore is unaffected by this severe treatment . I suspect that theentire indigo molecule , not only its phenyl rings , are (4n+2) p aromatic (n = 1) , and thereby is

stabilized electronically to a certain extent :

The five-membered rings would have an aromatic stabilization somewhat like the pyrrole

molecule , for example . This energetic stabilization can assist us in the synthesis of indigo . In

fact , aromatic stabilization in the indigo product may be the main reason why the oxidation of

indoxyl and its dimerization into indigo is such an extraordinarily facile process . We can utilize

this energetic driving force in the syntheses described in the following sections to promote the

formation of the unusual chromophore section of the indigo molecule .

In the first suggested new synthesis of indigo from anthranilic acid , the CH2 group in the

indoxyl intermediate would be derived from the N-methylolation of the anthranilic NH2group

by formaldehyde (as in the 1925 BASF synthesis of N-phenylglycine) . In the first variation of

this route a phosphorus(III) compound would be attached to the CH2 group . Phosphorus has

a powerful affinity for oxygen , and the phosphorus(III) center might bond to one of the oxygen

atoms of the anthranilic COOH group and tear it off the carbon . An analogous reaction is the

Wittig olefination reaction , and in particular the Horner-Wadsworth-Emmons modificationof


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the Wittig reaction , in which the phosphite group extracts the aldehyde or ketone oxygen atom :


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Triethyl phosphite , (EtO)3P (b.p. 156 C) , is a deoxygenating reducing agent , as are all

phosphorus(III) compounds . Triphenylphosphine is an even stronger deoxygenating agent than

the phosphite esters , but its reaction by-product , triphenylphosphine oxide , is only slightly

soluble in water and thus might be difficult to separate from the insoluble indigo product . On

the other hand , triethyl phosphate is water-soluble and so wouldn't interefere with the filtration

of the indigo . The chemically reducing and deoxygenating acids , phosphorus (H3PO3) and

hypophosphorus (H3PO2) , are commercially available and might also be successfully used in the

N-methylolation reaction and subsequent deoxygenation reaction . Anthranilic acid is sparingly

soluble in cold water , more so in hot water , so the entire one pot reaction might be carried out

in aqueous solution , possibly with some warming . It could be as simple and easy to do as the

Baeyer-Drewson reaction with 2-nitrobenzaldehyde .

The intermediate methylol-lactone could also be prepared and isolated pure in one step , then

cooked with triethyl phosphite to remove the lactone oxygen , forming indoxyl in the second

step . This intermediate could be isolated pure (under an inert atmosphere such as nitrogen) , or

converted to indigo without any attempted purification .

Noting that in these reactions the methylol-lactone undergoes first a deoxygenating reduction ,then an oxidizing dehydration , the question arises : could it be dehydrated directly to indigo ?

As mentioned above , formation of the remarkably stable aromatic chromophore system in the


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indigo product might energetically assist the reaction to completion . I may be optimistically

daydreaming here , butjust cooking anthranilic acid with formaldehyde under dehydrating

conditions might produce indigo in a good yield !Now , wouldn't that be a nice improvement

over the BASF-Hoechst process ! The formaldehyde would certainly N-methylolate the

anthranilic acid ....... then what would happen ?

In a second series of experiments the ester , methyl anthranilate , would be the starting material .

Methyl anthranilate is used extensively as a flavoring agent (grape flavor) and perfumeryingredient (it's a component of bergamot , jasmine , neroli , and ylang-ylang oils , and is found in

grape juice) . Examining Heumann's version 2 industrial synthesis of indigo (sketch above), we

see that it's a rather severe , forcible type of ring condensation reaction , somewhat like the

well-known Dieckmann reaction(1894-1901 , later than Heumann's indigo synthesis in 1890) .

So the question naturally arises : why not use the genuine Dieckmann reaction to prepare

indoxyl ?


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The same sort of reactions might be applied to the syntheses of thioindigo , a well-known indigo


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analogue , and its oxygen analogue I've dubbed oxyindigo. This latter compound might be

derived from methyl salicylate , which is commonly known as oil of wintergreen , a fragrant

flavoring and scenting chemical . Electron resonance in the oxyindigo chromophore is expected

to be less strong than in either of indigo or thioindigo , as the heteroatom basicity decreases in

the order N > S > O . Thioindigois actually a reddye (its industrial name is Vat Red 41) , so

oxyindigo could conceivably be colorless !


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In the two sketches above the strong base sodium methoxide (in anhydrous methanol) was

suggested for use in the Dieckmann condensations with the methyl esters . However , the


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extraordinarily powerful , non-nucleophilic basepotassium hydride, KH , would probably be

the optimum reagent for these cyclizations . Brownhas described the kaliation of esters with

KH , resulting in their condensation into b-ketoesters in very high yields , typically > 95% . The

KH reagent was used in the form of a 40% suspension (by weight) in mineral oil , with

anhydrous THF as the reaction solvent .

As outlined above , the modern industrial syntheses of indigo are based on the economical

aniline feedstock , rather than on the more expensive anthranilic acid . Another good reason to

use aniline as a starting material for any new indigo synthesis is that many substituted anilines

are commercially available , and might be used to prepare their corresponding indigo analogues

for study . Such is not the case for anthranilic acid derivatives , which can be challenging to

obtain .

The following proposed synthesis of indigo and its analogues starts with an acetylene chemical ,

dimethyl acetylenedicarboxylate . This material is a moderately priced commercial reagent (eg.

Aldrich Chemical Co.) . Interestingly , BASF produces certain related acetylene chemicals such

as 2-butyne-1,4-diol by the methylolation of acetylene with formaldehyde under alkaline

conditions . It's therefore conceivable that dimethyl acetylenedicarboxylate could also be

manufactured in bulk quantities from acetylene should the demand ever arise for it .

Aniline is used in this acetylene route instead of anthranilic acid . Unlike previous syntheses of

indigo , this proposed procedure does not involve indoxyl as an intermediate . If successful , thisapproach could be used to synthesize many other indigo analogues as well :


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NB :Caution! The intermediate dimethyl E-2,3-dibromofumarate is probably a very hazardous

, lachrymatory , vesicant , corrosive material , and should NOT be isolated . All necessary safety

precautions should be observed (gloves , goggles , efficient fume hood , etc.) when handling its

solutions . I would ask any reader attempting this reaction to please be very careful with it !

In the above synthesis scheme the Friedel-Crafts acylation of the aniline rings is done by the

carbomethoxy ester groups . Acid chlorides , anhydrides , carboxylic acids , and esters can all beused to acylate aromatic rings ; of course , the acid chlorides are the best known of these

acylating reagents . An interesting example of the acylation/alkylation of an aromatic ring by an

ester function is provided by the synthesis of a-tetralone, by the combination of benzene with

g-butyrolactone . A large (~ 4:1) molar ratio of AlCl3to g-butyrolactone was used in this

preparation , since the Al3+acted both as a catalyst in the acylation and as a reagent in the

alkylation , bonding with the alcohol (lactone) oxygen .

In a variation of this proposed reaction , acetylene dicarboxylic acidcould be used as the starting


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material , with the COOH groups acylating the aniline rings . Hartoughhas demonstrated the

acylation of thiophenes and furans with carboxylic acids , using phosphoric acid and phosphorus

pentoxide as the dehydrating agents (presumably the reactive acylium cation is the actual

acylating agent) . Even concentrated sulfuric acid can be an effective dehydrating agent for

acylations by carboxylic acids , for example in the preparation of acridone. As suggested above ,

formation of the energetically stabilizing aromatic indigo chromophore might help to drive these

ring acylations to completion in a good yield .

The highly reactive dimethyl E-2,3-dibromofumarate intermediate could be combined with a

wide variety of aliphatic and aromatic amines (triethylamine is added to the aniline or other

amine to absorb the by-product HBr) . For example , an aliphatic version of the indigo

chromophore could be produced using dimethylamine as the amine reactant :

The resulting adduct , dimethyl 2,3-bis-E-(dimethylamino)fumarate , might have a deep blue

color . However , it might equally be colorless , since the chromophore in this case isn't part ofan aromatic ring system , as with indigo .

The hypothetical compound pseudo-indigo (for lack of a better term)has the indigo

chromophore andit should also be aromatic . Its rings have six p electrons each , even though it

lacks the phenyl groups . The following scheme is suggested for the synthesis of pseudo-indigo .

Its key step is the Mannich condensationof 3-hexyne-2,5-dione with two equivalents of

formaldehyde and ammonium cation (in effect , the transient methylol intermediate

HOCH2NH3+) , followed by the a,b-addition of the neutral amino groups to the reactive triple


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bond :

As an alternative to bromination / dehydrobromination to achieve aromaticity in the pseudo-

indigo , dehydrogenation of the bis-aminoketone intermediate might be accomplished with

palladium on charcoal , or with sulfur or selenium . All three reagents are well known


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dehydrogenation agents used in organic syntheses .

I suspect that 4n+2 p aromaticity is required for the indigo chromophore , even though the

phenyl groups are unnecessary . Thus , pseudo-indigo will likely have a dark blue color like

indigo itself , while dimethyl 2,3-bis-E-(dimethylamino)fumarate will be colorless .

The readily available fine chemical 3-bromoaniline (b.p. 251 C) might serve as the precursor to

the legendary Tyrian Purpledye , 6,6'-dibromoindigo :

If successful , this acetylene route to Tyrian Purple would be very simple and straightforward ,

much more so than the many lengthy and convoluted syntheses of the compound reported in the

literature (see the refs. in Tyrian Purple) . And , given the dozens of substituted anilines

commercially available , the acetylene route would make many other interesting indigo

analogues readily available for study .

Wurtster Blue compoundsalso have a deep , sapphire blue color , caused by the molecule-wideresonance of their unpaired singlet electron , formally located on their aminium nitrogen atom :

It might be possible to synthesize an indigo Wurster Blue compound from the intermediate

5,5'-bis(dimethylamino)indigo by treating it with a suitable one-electron oxidizer such as

antimony pentachloride:


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A powerful one-electron oxidizer , the nitrosonium cationNO+(as its stable salt NO+PF6-) ,

could be used to form the corresponding Wurster Blue compound ,

5,5'-bis(dimethylaminium)indigo hexafluorophosphate . The extreme degree of electron

resonance in these hypothetical Wurster Blue molecules might cause them to appear black!

They might also be electrically conducting to a certain extent , conceivably having the electron

transport properties of a moderately conductive semiconductor . If so , their synthesis and study

would be a promising venture into the fascinating realm of the metallic solids .

The unusual indigo chromophore with its combination of two electron-donating nitrogen atoms

and two electron-withdrawing carbonyl groups suggests that indigo could form charge transfer

compoundswith either electron acceptor or electron donor molecules . Examples of both types

of compounds are illustrated as follows :


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In an undergraduate analytical chemistry course I had to prepare crystalline derivatives of an

unknown organic compound , so I made its charge transfer complexes with trinitrobenzene and


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picric acid , which together with its various spectroscopic analyses (IR , UV/VIS , NMR)

confirmed its identity as naphthalene . Of course , it also smelled like mothballs , which was an

immediate olfactory clue !

Tetrakis(dimethylamino)ethylene [TDAE] and tetrathiofulvalene [TTF] belong to the class of

electron-rich olefins, and are remarkably powerful one- and two-electron reducers . In fact ,

TDAE is said (Hoffmann , electron-rich olefins, p. 756) to be a reducing agent comparable to

zinc metal (Eox0 = 0.76 V) . It can form electrically-conducting charge transfer compounds withvarious acceptors :

TTF forms a mixed-valentcharge transfer compound with TCNQ (above sketch) in which there

are both TTF0molecules (41%) and TTF1+cations (59%) . TTF-TCNQis a molecular metal,

with an ambient electrical conductivity of ~ 9000 ohm-1-cm-1at 58 K ; below that temperature


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the conductivity plummits , and the material becomes an insulator . Above 58 K TTF-TCNQ

behaves like a conventional metal :

As mentioned , the indigo chromophore appears to be electrically amphoteric , with electron-donating N atoms (S atoms in thioindigo) and electron-accepting C=O groups . It's interesting to

speculate that indigo might form electrically-conductive charge transfer compounds with TDAE ,

TTF , TCNQ , TCNE , and other such electron donor and acceptor molecules . If they had a

significantly high electrical conductivity they might even be classified as molecular metals !

One of the challenges presented by the synthesis of such charge transfer compounds is the

notorious insolubility , or low solubility , of indigo in water and most common organic solvents .

It will dissolve to a certain extent in chloroform , dimethyl sulfoxide , and nitrobenzene . The

metallic TTF-TCNQ charge transfer complex was prepared by mixing solutions of the TTF and

TCNQ components in acetonitrile . I wonder if the common paint solvent acetone would

dissolve indigo to any extent . The verypolar solventpropylene carbonate, which has been used

to dissolve various inorganic salts in electrochemical studies , might also be tried as an indigo

solvent .


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The nucleophilic N [NH] and O [C=O] sites on the indigo molecule might be used to form

coordinate covalent bonds with suitable electrophilic acceptors such as metal cations ,

particularly those from the Transition metal families . The first Transition metal complexes with

indigo as a ligand were prepared by Beck and co-workersaround 1989 . More recently ,

Professor R.G. Hicks and his students at the University of Victoria , British Columbia , Canada ,

have developed a new series of indigo-based ligands for complexation with Transition metalcations . These so-called nindigos, which are bi-funcionalized ketimines , were prepared by

the rather forceful condensation of indigo with anilines : 2 RNH2+ 2 (indigo)C=O --------> 2

RN=C(indigo) + 2 H2O . The nindigo reagents are more soluble in organic solvents than indigo

, they are more reactive and versatile as ligands than it , and their metal cation complexes are

easier to analyse and characterize than are those of indigo .

In Beck and co-workers' indigo-Pd/Pt complexes the indigo served as a monodentate ligand ,

with the Pd/Pt bonded by the carbonyl oxygen and the amine nitrogen . Tributylphosphine and

chloride ligands on the Pd/Pt improved the solubility of the complex in organic solvents [the

bis(indigo) complex was very insoluble] . A similar sort of metal-indigo complex might beformed with Cu(II) :

The copper(II) cation in this hypothetical complex would have a tetrahedral (sp3) coordination .

These Transition metal coordinate covalent compounds of indigo are reminiscent of the

phthalocyanine-metal complexes , which are highly insoluble in water and organic solvents , and

are accordingly used as dyes and pigments in many applications . Copper(II) phthalocyanine is a

dark blue solid ; its trade name is Monastral Blue (ICI) :


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The corresponding bis-indigo complex with copper(II) might be prepared via the leuco forms of

indigo and indigotin . The complexation would take advantage of the powerful bonding affinity

between the copper(II) cation and four amine nitrogen atoms (overcoming the destabilizing

carbonyl oxygen lone pairs repulsion) :


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The resulting compound , copper(II) bis(indigotin) , could well be a deep blue , highly insoluble

, microcrystalline solid like copper(II) phthalocyanine , and might find the same industrial uses

as it . On a practical note , copper(II) bis(leucoindigotin) and copper(II) bis(indigotin) might be

tried as the insoluble blue pigment for dying cotton and other textiles . In effect , the copper(II)

salt would be used in the conventional indigo dying process as a mordant, to permanently bond


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the dye molecules onto the fiber surfaces . Such copper(II) indigo complexes might deposit a

deeper , more intense shade of blueon the textile than ordinary indigo , and be more resistant to

oxidation and fading than it .

The corresponding nickel(II) bis(indigotin) , with square planar , low spin , diamagnetic Ni2+

(3d8) , could be prepared in a similar manner . I'm guessing it would have a deep greencolor .

These examples will give the reader a glimpse into the new research area of indigometal cation

complexes .

I hope this web page has shown that there's a lot more to indigo chemistry than just blue jeans !

A comprehensive bibliography of the literature of indigo has been compiled by : C.J. Cooksey ,Indigo : An Annotated Bibliography, Biotechnic and Histochemistry 82 (2) , pp. 105-125

(2007) . It contains a wealth of information about indigo from natural sources , and of the many

syntheses and physical and chemical properties of the compound . Update(August 14th, 2012) :

a revised version of this bibliography has just been published : C.J. Cooksey , An Annotated

Bibliography of Recent Significant Publications on Indigo and Related Compounds, Biotechnic

and Histochemistry 2012 , Early Online , pp. 1-25 . Complimentary PDF copies of these

bibliographies can be obtained via email by writing toDr. Cooksey .

Farris: R.E. Farris , Dyes , Natural, pp. 351-373 in the Kirk-Othmer Encyclopedia of

Chemical Technology , 3rdedition , vol. 8 , M. Grayson and D. Eckroth (eds.) , John Wiley ,

New York , 1979 . Indigo is discussed on pp. 364-368 . Indigotin is structure 46 , p. 367 .

Golding and Pierpoint: B.T. Golding and C. Pierpoint , Indigo Blue, Educ. Chem. 23 (3) , pp.

71-73 (May , 1986) .

indole: Y. Yamamoto , Y. Inoue , U. Takaki , and H. Suzuki , Development of a Practical

One-Pot Synthesis of Indigo from Indole, Bull. Chem Soc. Jpn. 84 (1) , pp. 82-89 (2011)

[HTML, 100 KB] .

apparently was affected: C. Cooksey and A.T. Dronsfield , George III , Indigo , and the Blue

Ring Test, Educ. Chem. 45 (2) , pp. 45-47 (March , 2008) [web page] .

Khan and co-workers: F. Khan , M.A. Chaudhry , N. Qureshi , and B. Cowley , Purple Urine

Bag Syndrome : An Alarming Hue ? A Brief Review of the Literature, Int. J. Nephrol. 2011 ,

Article ID 419213 , 3 pp. [PDF, 958 KB] .

Indigo's chromophore: C.J. Cooksey , Tyrian Purple : 6,6'-Dibromoindigo and Related

Compounds, Molecules 6 (9) , pp. 736-769 (2001) ; Figure 2 , p. 745 [PDF, 302 KB] .


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synthesize it: anon. (Web document) , The History of Indigo, Department of Chemistry ,

University of New Brunswick , Fredericton , New Brunswick , Canada [PDF, 314 KB] .

laboratory manuals: The History of Indigo (above), PDF p. 5 ; anon. (Web document) ,

Chemistry of Blue Jeans : Indigo Synthesis and Dyeing, p. 8 [PDF, 106 KB] ; B. English et al.

, Synthesis of Indigo and Vat Dyeing , Exp. 863, p. 3 [PDF, 145 KB] ; anon. (Web document

from the Royal Society of Chemistry , UK) , The Microscale Synthesis of Indigo Dye, PDF p.

3 [PDF, 24 KB] ; C.J. Cooksey , Indigo Chemical Synthesis [web page] .

sodamide: the sodamide fusion process is described in some detail by W.C. Fernelius and E.E.

Renfrew , Indigo, J. Chem. Educ. 60 (8) , pp. 633-634 (1983) ; see esp. p. 634 .

anthranilic acid: P. Wiklund and and J. Bergman , The Chemistry of Anthranilic Acid, Current

Org. Syn. 3 (3) , pp. 379-402 (2006) ; B.S. Furniss et al. , Anthranilic Acid, Vogels Textbook

of Practical Organic Chemistry , 4thedition , Longman , London (UK) , 1978 ; p. 666 ; G.

Kilpper and J. Grimmer , Continuous Production of Anthranilic Acid, U.S. Patent 4,276,433

(to BASF , June 30th, 1981) [PDF, 185 KB .Note : this file can be opened only with Acrobat

Reader v. 6 or later. If desired , this application can be downloaded for free from

Oldversion.com] . The following sketch , abstracted from this patent , outlines the industrial

manufacture of anthranilic acid from phthalimide using the Hofmann reaction(or rearrangement

or degradation) :

Cooksey (web page) provides a broader perspective on this anthranilic acid route to indigo ,


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starting with the bulk industral chemical naphthalene .

Horner-Wadsworth-Emmons modification: W.S. Wadsworth Jr. and W.D. Emmons , The Utility

of Phosphonate Carbanions in Organic Synthesis, J. Amer. Chem. Soc. 83 (7) , pp. 1733-1738

(1961) ; web page(1) ; web page(2) .

Dieckmann reaction: J.P. Schaefer and and J.J. Bloomfield , The Dieckmann Condensation

(Including the Thorpe-Ziegler Condensation), Org. React. 15 , pp. 1-203 (1967) ; N. J. Leonardand C. W. Schimelpfenig Jr. , Synthesis of Medium- and Large-Ring Ketones via the Dieckmann

Condensation, J. Org Chem. 23 (11) , pp. 1708-1710 (1958) ; E.E. Royals , Claisen

Condensation of Methyl Esters, J. Amer. Chem. Soc. 70 (2) , pp. 489-491 (1948) [similar

reaction conditions are used in both the Claisen and Dieckmann condensations]; M.A.A. Amleh

, Dieckmann Condensation Reaction, Microsoft Powerpoint Slide Show [PPT, 259 KB] ; P.S.

Pinkney , 2-Carboethoxycyclopentanone, Org. Syn. Coll. Vol. 2 , pp. 116-119 (1943) [PDF,

140 KB] ; H.U. Daeniker and C.A. Grob , 3-Quinuclidone Hydrochloride, Org. Syn. Coll. Vol.

5 , pp. 989-993 (1973) [PDF, 142 KB] ; J. T. Mohr, M. R. Krout, and B. M. Stoltz ,

Preparation of (S)-2-Allyl-2-Methylcyclohexanone, Org. Syn. 86 , pp. 194 et seq. (2009)

[web page] ; Organic Chemistry Portal [web page] ; SynArchive [web page] ; Classic OrganicReactions [web page] .

Brown: C.A. Brown , Rapid , High Yield Condensations of Esters and Nitriles via Kaliation,

Synthesis , May , 1975 , pp. 326-327 . The extremely reactive KH can be safely and

conveniently handled as a 50% dispersion (by weight) in paraffin wax : D.F. Taber and C.G.

Nelson , Potassium Hydride in Paraffin : A Useful Base for Organic Synthesis, J. Org Chem. 71

(23) , pp. 8973-8974 (2006) [PDF, 35 KB] .

a-tetralone: C.E. Olson and A.R. Bader , a-Tetralone, Org. Syn. Coll. Vol. 4 , pp. 898-902

(1963) [PDF, 171 KB] .

Hartough: H.D. Hartough and A.I. Kosak , Acylation Studies in the Thiophene and Furan

Series . IV. Strong Inorganic Oxyacids as Catalysts, J. Amer. Chem. Soc. 69 (12) , pp.

3093-3096 (1947) ; idem. , Acylation Studies in the Thiophene and Furan Series . VI. Direct

Acylation with Carboxylic Acids and Phosphorus Pentoxide, J. Amer. Chem. Soc. 69 (12) , pp.

3098-3099 (1947) ; A.I. Kosak and H.D. Hartough , 2-Acetothienone, Org. Syn. Coll. Vol. 3 ,

pp. 14-16 (1955) [PDF, 115 KB] .

acridone: C.F.H. Allen and G.H.W. McKee , Acridone, Org. Syn. Coll. Vol. 2 , pp. 15-17

(1943) [PDF, 129 KB] .

Tyrian Purple: the best review I've read of Tyrian Purple is undoubtedly that by Cooksey

(Indigo's chromophore, above) ; it's highly recommended . The synthesis of Tyrian Purple has

attracted a great deal of attention over the years . Various publications on this topic : P.F. Schatz

, Indigo and Tyrian Purple In Nature and in the Lab, J. Chem. Educ. 78 (11) , pp.

1442-1443 (2001) ; J.M. Pinkney and J.A. Chalmers , Synthesizing Tyrian Purple, Educ.

Chem. 16 (5) , pp. 144-145 (September , 1979) ; J.L. Wolk and A.A. Frimer , Preparation of

Tyrian Purple (6,6'-Dibromoindigo) : Past and Present, Molecules 15 (8) , pp. 5473-5508


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(2010) [PDF, 303 KB] ; idem. , A Simple , Safe and Efficient Synthesis of Tyrian Purple

(6,6-Dibromoindigo), Molecules 15 (8) , pp. 5561-5580 (2010) [PDF, 229 KB] ; Cooksey's

Tyrian Purple web page; Cooksey's synthesis (web page) ; historical syntheses (web page) ;

Wikipedia web page; Molecule of the Month web page.

Wurtster Blue compounds: See the discussion , photos , and video demonstration of the

formation of a Wurster Blue compound in solution on Peter Keusch's web page, Wurster's

Blue.

antimony pentachloride: SbCl5has been used to form the stable Wurster Blue aminium salt ,

tris-(4-bromophenyl)aminium hexachloroantimonate , in a quantitative yield : F.A. Bell , A.

Ledwith , and D.C. Sherrington , Cation-radicals : Tris-(p-bromophenyl)amminium Perchlorate

and Hexachloroantimonate , J. Chem. Soc. C 1969 (19) , pp. 2719-2720 ; see also G.W.

Cowell , A. Ledwith , A.C. White , and H.J. Woods , Electron-Transfer Oxidation of Organic

Compounds with Hexachloroantimonate [SbCl6] Ion , J. Chem. Soc. B 1970 (2) , pp. 227-231

. The standard reduction potential of SbCl5in a halide environment is ~ 0.8 V , indicating that it

is a moderately strong oxidizing agent .

nitrosonium cation: W.J. Plieth , Nitrogen, Ch. 5 , pp. 321-479 in Encyclopedia of

Electrochemistry of the Elements , Vol. 8 , A.J. Bard (ed.) , Marcel Dekker , New York , 1978 ;

p. 325 . The redox half-reaction (reduction) of the nitrosonium cation is :

NO++ e- --------------> NO (g) ; E0red = 1.45 V .

This standard reduction potential indicates that NO+is a rather powerful oxidizing agent .

electron-rich olefins: R.W. Hoffmann , Reactions of Electron-Rich Olefins, Angew. Chem.

Internat. Ed. Engl. 7 (10) , pp. 754-765 (1968) ; N. Wiberg , Tetraaminoethylenes as Strong

Electron Donors, Angew. Chem. Internat. Ed. Engl. 7 (10) , pp. 766-779 (1968) ; J. Hocker

and R. Merten , Reactions of Electron-Rich Olefins with Proton-Active Compounds, Angew.

Chem. Internat. Ed. Engl. 11 (11) , pp. 964-973 (1972) .

TDAE: R.L. Pruett et al. , Reactions of Polyfluoro Olefins. II. Reactions with Primary and

Secondary Amines, J. Amer. Chem. Soc. 72 (8) , pp. 3647-3650 (1950) ; the preparation of

TDAE is described on p. 3649 . TDAE is commercially available , eg. from Aldrich .

TTF-TCNQ: J. Ferraris , D.O. Cowan , V. Walatka Jr. , and J.H. Perlstein , Electron Transfer in

a New Highly Conducting DonorAcceptor Complex, J. Amer. Chem. Soc. 95 (3) , pp.

948-949 (1973) ; D. Dolphin , W. Pegg , and P. Wirz , The Preparation of Protio and Deuterio

Derivatives of the Tetracyanoquinodimethane Tetrathiofulvalene Complex, Can. J. Chem. 52

(24) , pp. 4078-4082 (1974) [PDF, 215 KB .Note : this file can be opened only with Acrobat

Reader v. 6 or later] ; E. Engler , Organic Metals, Chemtech 6 (4) , pp. 274-279 (April , 1976)

; see Figure 1 , p. 275 ; A.J. Epstein and J.S. Miller , Linear Chain Conductors, Scientific

American 241 (4) , pp. 52-61 (October , 1979) ; see esp. pp. 57 and 59 ; M.R. Bryce ,

Tetrathiafulvalenes (TTF) and Their Selenium and Tellurium Analogs (TSF and TTeF) :

Electron Donors for Organic Metals, Aldrichimica Acta 18 (3) , pp. 73-77 (1985) [PDF, 4186


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KB .Note : the entire Issue 3 must be downloaded to obtain the article] .

propylene carbonate: W.J. Peppel , Preparation and Properties of the Alkylene Carbonates,

Ind. Eng. Chem. 50 (5) , pp. 767-770 (1958) . Several physical properties of PC tabulated in this

review : m.p. 49.2 C ; b.p. 241.7 C (note : PC begins to decompose at ~ 150 C); s.g. 1.2057

; dielectric constant , 69.0 ; R. Jasinski , Electrochemistry and Application of Propylene

Carbonate, Adv. Electrochemistry Electrochem. Eng. 8 , pp. 253-335 , P. Delahay and C.W.

Tobias (eds.) , Wiley Interscience , New York , 1971 .

Beck and co-workers: W. Beck et al. , Indigo-Metal Complexes : Synthesis and Structure of

PdII and PtII Compounds Containing the Anions of Indigo and Octahydroindigo as Mono- and

Bis-Chelate Ligands, Angew. Chem. Internat. Ed. Engl. 28 (11) , pp. 1529-1531 (1989) .

nindigos: S.R. Oakley et al. , Nindigo : Synthesis , Coordination Chemistry , and Properties

of Indigo Diimines as a New Class of Functional Bridging Ligands, Chem. Commun. 2010 (46)

, pp. 6753-6755 ; G. Nawn et al. , Redox-Active Bridging Ligands Based on Indigo Diimine

(Nindigo) Derivatives, Inorg. Chem. 50 (20) , pp. 9826-9837 (2011) ; S. Oakley , Synthesis ,

Characterization and Coordination Chemistry of Indigo Diimines, M.Sc. Thesis , University ofVictoria , British Columbia , Canada (2008) [PDF, 1828 KB] ;Research Project Dr. Skye

Fortier [web page] .

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