Several New Aspects of Indigo Chemistry

 

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 and delocalization 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 indigo and indigotin are generally considered to refer to the same chemical substance , 2,2'-bis(2,3-dihydro-3-oxoindolyliden) [underlined blue hyperlinks can 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 [the references are presented at the end of the text , below] , as illustrated in the following sketch :

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 compound copper(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 :

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 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 excreted in their urine . King George III (1738-1820) of Great Britain apparently was affected by 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 by Khan and co-workers .

The chromophore is the atomic grouping within a dye molecule responsible for its light absorption properties . Indigo's chromophore has 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 .

 

Historical Syntheses of Indigo

 

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 it for the first time (in 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 :

Adolph von Baeyer was awarded the Nobel Prize for chemistry in 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 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 :

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

 

Several Proposed New Routes to Indigo from Anthranilic Acid

 

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 200–300 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 thirty different 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 is considerably 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 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 the entire 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 –NH2 group 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 modification of the Wittig reaction , in which the phosphite group extracts the aldehyde or ketone oxygen atom :

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 indigo product might energetically assist the reaction to completion . I may be optimistically daydreaming here , but just “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 perfumery ingredient (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 ?

The same sort of reactions might be applied to the syntheses of thioindigo , a well-known indigo 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 . Thioindigo is actually a red dye (its industrial name is Vat Red 41) , so oxyindigo could conceivably be colorless !

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 extraordinarily powerful , non-nucleophilic base potassium hydride , KH , would probably be the optimum reagent for these cyclizations . Brown has 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 .

 

An “Acetylene Route” to Indigo and Indigo Analogues

 

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 , this approach could be used to synthesize many other indigo analogues as well :

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 be used 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 AlCl3 to 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 acid could be used as the starting material , with the –COOH groups acylating the aniline rings . Hartough has 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 of an aromatic ring system , as with indigo .

The hypothetical compound “pseudo-indigo” (for lack of a better term) has the indigo chromophore and it 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 condensation of 3-hexyne-2,5-dione with two equivalents of formaldehyde and ammonium cation (in effect , the transient methylol intermediate HO–CH2–NH3+) , followed by the a,b-addition of the neutral amino groups to the reactive triple 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 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 Purple dye , 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 , with dozens of substituted anilines commercially available , the acetylene route would make many other interesting indigo analogues readily available for study .

Wurster Blue compounds also have a deep , sapphire blue color , caused by the molecule-wide resonance 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 :

A powerful one-electron oxidizer , the nitrosonium cation NO+ (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 compounds with either electron acceptor or electron donor molecules . Examples of both types of compounds are illustrated as follows :

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 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 with various acceptors :

TTF forms a mixed-valent charge transfer compound with TCNQ (above sketch) in which there are both TTF0 molecules (41%) and TTF1+ cations (59%) . TTF-TCNQ is a molecular metal , with an ambient electrical conductivity of ~ 9000 ohm-1-cm-1 at 58 K ; below that temperature 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 very polar solvent propylene carbonate , which has been used to dissolve various inorganic salts in electrochemical studies , might also be tried as an indigo solvent .

 

Transition Metal Complexes of Indigo

 

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-workers around 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 metal cations . These so-called “nindigos”, which are bi-funcionalized ketimines , were prepared by the rather forceful condensation of indigo with anilines : 2 R–NH2 + 2 (indigo)C=O --------> 2 R–N=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 be formed 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) :

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) :

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 the dye molecules onto the fiber surfaces . Such copper(II) indigo complexes might deposit a deeper , more intense shade of blue on 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 green color . These examples will give the reader a glimpse into the new research area of indigo–metal cation complexes .

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

 

References and Notes

 

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 to Dr. Cooksey .

Farris : R.E. Farris , Dyes , Natural”, pp. 351-373 in the Kirk-Othmer Encyclopedia of Chemical Technology , 3rd edition , 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] .

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”, Vogel’s Textbook of Practical Organic Chemistry , 4th edition , 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 , 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. Leonard and 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 Organic Reactions [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 (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 .

antimony pentachloride : SbCl5 has 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 SbCl5 in 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 Donor–Acceptor 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 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 of Victoria , British Columbia , Canada (2008) [PDF , 1828 KB] ; “Research Project – Dr. Skye Fortier” [web page] .

 

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