Mauveine, alizarin, indigo: the serendipitous birth
of the fine chemical industry
Giovanni Appendino
Università del Piemonte Orientale
Novara
giovanni.appendino@uniupo.it
A chemical is defined as “fine” based on a multitude of elements
Outline
▪ The context
▪ Mauveine
▪ Alizarin
▪ Indigo
▪ Conclusions
The context
In the second half of the 19th century, the production of fine chemicals made coal economy circular
Animal fat was also use as carbonaceous material for gasification. The Faraday discovery of benzene (bicarburet of
hydrogen) in 1825 from the gasification of whale oil to produce “portable gas”
Royal Institution, Albemarie Street, London
Michael Faraday
(1791-1867)
“Portable Gas“ was created by dropping
whale or fish oil into a hot furnace, and
was use for lighting.
The gas was compressed and stored in
containers for use, but a liquid would
condense when the gas was pressurized.
Petroleum did not save the whale population, but brought it on the verge of extinction
Diesel-powered ships opened new hunting areas and
the blasting harpoon speeded up their killing
It has been estimated that between 1712 and 1899
300 000 whales were killed.
In the XX century, ca 3 000 0000 whaled were killed
Many “synthetic” compounds were first prepared from natural products
indigo
Distillation with
CaCO3
Heating with
HNO3
benzoin
distillation
Being a process chemist in mid 1800…..
Liebig's (1803-1873) government-supported laboratory in Giessen
..and at the turning of the 20th century
BASF research laboratory on Indigo
What you would obviously miss
Technique
Approximate year when it became routine*
UV spectroscopy
1940
IR spectroscopy
1958
1H
1963
NMR
13C
NMR
1980
MS
1950
Flash chromatography
1980
HPLC
Late 1970
TLC
Late 1950
* Taber, D. F. Wither Organic Synthesis? Isr. J. Chem. 2018, 58, 11-17
Your equipment
Eudiometer
Mechanical stirring was introduced in late 1800,
and was long carried out manually.
«I observed Dr. Villiger patiently rolling a large
bottle containing permanganate solution and a
little turpentine back and forth on the laboratory
table for days on end. The apparatus was then
perfected by placing a felt mat under the bottle»
Richard Wilstätter
Melting point apparatus
Safety glasses were not common
What you would miss most: lab coat (a good chemist could work in the lab even with a tuxedo)
Clemens Winkler
(1838-1907)
Justus von Liebig at the bench
Clemens Winkler who discovered germanium in 1886 strongly
believed that a good chemist could work in the lab even with a
tuxedo. When one of his students once dared to came to the
lab with a coat to protect his elegant clothes, he repriminded
him and sent him back to «dress up for the lab»
Physicians were not wearing lab coats, spreading infections just like chemists were spreading toxic compounds
Ignác Fülöp Semmelweis
(1818-1865)
The concept of «bacterial contamination»
was put forward by Pasteur in 1864
First operation with ether (October 16, 1856)
What you would miss most: hoods
The emission of vapors was controlled by working near a window.
Klaus suggested to work on OsO4 next to an oven to drain the toxic
vapours and wearing a humind sponge in the mouth
Justus von Liebig at the bench
What you could lose: health
Karl W. Scheele (1742-1786)
Intoxicated by HCN
If you want to become a true chemist, you will have to sacrifice
your health. Nowadays, those who study chemistry and do not
damage their health will never get anything our of this science
Liebig to Kekulé
Karl Klaus (1796-1864)
Intoxicated by OsO4
Adolf von Baeyer (1852-1919)
Emil Fischer (1852-1919)
Intoxicated by MeAsCl2
Intoxicated by phenylidrazine
Some appalling practices by famous chemists
pH Determination by tasting (Karl Klaus)
Finger stirring of strongly acidic and basic solutions (Karl Klaus, Bunsen)
Drinking from laboratory glassware (Thénard)
In 1825, while teaching, Louis
Jacques Thénard (1777-1857)
drank by mistake a solution of
mercuric chloride. When he
realized this, he asked his
student to bring him some raw
eggs (he survived)
Bunsen used to spread all new
compounds on his hands. As a result, they
became so rough that he was forced to
hide them under a table during social
events.
Bunsen used to show the invulnerability of
his fingers by putting his index finger in
the flame of a Bunser burner until the
odor of burned skin was around. He then
used to say: «Sirs, here the temperature is
over thousand degrees»
After preparing anhydrous
formic acid, Liebig discovered it
burns the skin. He shared the
experience with his students.
The biochmist K. Vogt (18171895) developed a white scar
on his hand that remained all
his life
Robert Bunsen (1811-1899)
Pets in the lab
The first casein plastic (galalite) was discovere because one day a cat knocked over some formaldehyde into her saucer of
milk at the Bavarian laboratory of Adolf Spitteler. This made it curdle into a hard substance resembling celluloid
Adolf Spitteler
(1846-1940)
Mauveine
Like William Perkin I personaly aspire
to metamorphose lower into higher
His transforming coal-tar into brillant dyes
has come for me of late to symbolise
Chemistry in its most profound and true
creating radiance out of basest residues
Sir William Crookes in the play Square
Rounds by T. Harrison
Arthur Hughes: April love
(1856)
Justus von Liebig and his five English tours (1837-1851):
Chemistry does have practical use!
Liebig’s laboratory in Giessen
England is not the land of science. There is only widespread dilettantism
J. von Liebig(England was the only country in Europe to lack a system of
technical education)
Justus von Liebig
(1803-1873)
Liebig’s lectures on the application of organic chemistry to agriculture,
medicine and industry exerted an impact on all levels of British society, from
the queen and her consort through the aristocracy and so-called improving
landlords, civic dignitaries, and government administrators, down to
academics, industrialists, and manufacturers, doctors, chemists, and working
men. Liebig:
a) Identified in coprolites of Glouchestershire a form of «fossil guano»
b) Planned to recyle London sewage into agriculture fertilizers
The creation of the Royal College of Chemistry in Oxford Street and the hiring of Hofmann in 1845-1864
Chemistry was looked down on as a
serious science in Britain. The Royal
College of Chemistry was founded by
private subscription from industrialists
and agriculturalists thanks to the support
of Faraday and of Prince Albert
Oxford Street 299,
Lonbdon
August Wilhelm von Hofmann
(1818-1892)
Prince Albert
(1819-1861)
Hofmann was a pioneer in the study of coal tar from which he had isolated aniline
coniine
(first alkaloid structurally elucidated, 1881)
William Henry Perkin and the serendipitous discovery of the first synthetic dye by a child prodigy
➢ Son of a relatively wealthy (parvenu middle class) carpenter, youngest of seven
siblings
➢ Shows a very early interest for chemistry spurred by seminars (alternative to lunch
time) of a Hoffmann student (Thomas Hall). In 1853, aged 15, enters the Royal
College of Chemistry(RCC) and establishes a home laboratory. Where he works in
the evening and during vactions.
➢ After two years,in 1855, he becomes assistant of Hoffmann and investigates the
structure of anthracene, publishing his first article in 1856, aged 18
➢ In 1856, three years after the entrance to the RCC, during an extended Easter
vacations because of Hofmann trip to Germany, Perkin attempted to synthesize
quinine from the oxidation of allyltoluidine
William H. Perkin
(1838-1907)
Aged 14 (selfie)
A molecular formulas-based retrosynthetic analysis
no quinine was formed, but only a dirty reddish brown precipitate
W. Perkin
The discovery of mauveine: serendipity hits twice: 1 the idea to use of a simpler model 2. the presence of an impurity
in the model
Undaunted, Perkin tested the chromate oxidation on a simpler compound (aniline),
obtaining a balck precipitate from which a purple ethanol solution was obtained.
Perkin had a strong interest in painting and in photograph, and realized immediately the
importance of his discovery
Without experiment, I am nothing. Still try for who
knows what is possible. M. Faraday
Aniline → mauveine
Mauve
(Malva officinalis)
Mauveine is a mixture of ca 13 phenazinium ions formed from aniline in the presence of o- and p-toluidines
1856, a magic year of 18-year old Perkin:
March:
discovery of
mauveine
May-June:
discovery that
mauveine can dye silk
August:
patent on
mauveine
October:
Perkin
drops out
from school
The establishing Perkin and Sons. Would you have done it?
1. No security that the capital to launch the company could be found (eventually
his father and his brother financed it)
2. No guarantee that the marked was interested in color mauve and that the
quantities required by dyers and printers would justify the building of a factory
to produce the dye
3. There was no supply chain for the starting material (aniline)
4. No site was available to build the factory
5. Methods had to be discovered to apply the color to cotton, the most
important textile fabric
6. Perkin had no experience in any of these activities
7. His patents had been rejected in France (the most important producer of dyes)
for being registered too late compared to the British filing. Time was lost to make
sure than a 18-year old person could file a patent
Luck strikes again twice: Empress Eugénie in France launches the mauve craze…
In 1855 Queen Victoria and Prince Albert visited Napoléon III and Eugénie
in Paris. The press judged unanimously Victoria’s clothes out of date.
Because of these critics, Victoria turned to Eugénie for guidance.
Eugénie loved the colour lilac (mauve), obtained by combining murexide
with lichen-derived dyes, and started wearing it in 1857, soon after the
establishment of Perkin and Sons
In early 1858 Queen Victoria wore mauve at her daughter’s wedding,
starting the «mauve craze» that swept England until 1861
Empress Eugénie, the most influential
woman in the world of fashion in mid 1800
Murexide (ammonium purpurate), the first synthetic organic dye (1776) was in short supply
alloxanthin
HNO3 and then NH3
Gallstones
(1776)
Boa constrictor excrements
(1818)
Karl W. Scheele
(1742-1786)
William Prout
(1785-1840)
The synthesis of murexide was industrialized when guano from Chile became available, and commercialization started
in 1851
… and crinoline becomes fashionable. Fashion makes Perkin a rich man
The crinoline is the best ad for a dye. A crinoline required a great amount of both fabric and dyes, and Perkin’s mauveine was
cheaper and resisted fading.
In 1859, Sheffield was producing steel wire for over 500 000 crinolines per week.
By 1860, Perkin and Sons was exporting to Europe and as far as Hong Kong a concentrated mauve solution at 6 pounds/L,
with a 80% net profit. On weight basis, mauveine had the price of platinum
Wearing a crinoline could be dangerous
because of its inflammability. 2000 women
wearing a crinoline died in a single fire in
Santiago
Perkin not only discovered mauveine, but he also industrialized its synthesis at the Greenford Green plant
Perkin was lucky because:
a) Discovered mauveine by chance
b) The colour of mauveine became fashionable soon after he had
estblished the Perkin and Sons with his father
c) The crinoline fashion required huge amounts of dye that the
competition from murexide could not supply
On the other hand, Perkin:
a) developed a cheap preparation of aniline from coal tar
b) developed ways to let mauveine bind to cotton and silk
c) staved off competition
d) survived the primitive conditions of the preparation of aniline
(nitration of benzene with fuming nitric acid, reduction with hydrogen
sulfide)
1881: post stamp
colored with mauveine
Important “sensory-based” discoveries in chemistry
Saccharin (sweet taste)
Nitromusks (fragrance)
Aspartame (sweet taste)
Cyclamate (sweet taste)
The industrialization of benzene nitration. William Perkin as the first process chemist
The kind of apparatus required and the character of the operations to be performed were so entirely different from any
in use that there was little to copy from
(W. Perkin)
The reaction was carried out in iron vessels, generating HJNO3 in situ from KNO3 (ex guano) and H2SO4.. The reaction is
highly exothermic and explosion-prone
Albright, Carr, Schmitt, Nitration, ACS Symposium 1996
The carbon footpring was appaling:
100 pounds (45 Kg) coal -→ 10 pounds(4.5 Kg) coal tar →2.25 ouces (65 g) aniline → 0.25 ouces (7 g) of mauveine
ca 6.5 Kg of coal were necessary to obtain 1 g mauvenine (0.016%)
Other processes developed by Perkin:
1. Reduction of nitrobenzene to aniline
2. N-methylation of aromatic amines
3. Production acetyl chloride and phosphorous trichloride
4. Purification of anthracene from coal tar and industrial conversion into alizarine
Competition develops. Perkin follows the fuchsine fashion, but academic honour goes to Hofmann
In 1858 Hofmann synthesized rosaniline (fuchsine) by treatment of aniline (obtained rom Perkin) and CCl4.
Rosaniline had previously be obtained and patented by a French chemist (Verguin), and commercialized by the French
company Renard (Fuchs in German) which obtained the patent in 1859, only three years after the discovery of mauveine.
Verguin discovered fuchsine while attempting to produce mauveine replacing chromate with tin (IV) chloride to oxidize
«aniline».
Perkin had a factory to run and products to sell, and had no time to engage in public relationships and meeting presentations.
Hoffmann was an engaging orator and liked to talk in public, and became the leading character in colouring issues
After three year, the» mauve madness» ceased, and Perkin developed novel aniline dyes based on fuchsine (and next
developing an original synthesis of alizarine)
Fuchsia hybrida
Demethylfuchsine = pararosaniline
Just like mauveine, also fuchsine was a mixture of homologues
due to the contamination of aniline with toluidines. By alkylation
and arylation, all the rainbow of colours could be obtained (green,
blue…) (methyl violet, chrystal violet..)
Fuchsine, rosaniline, magenta
England was a strong supporter of Italian independence, and fuchsine was also named magenta from the battle in the Italian
II Independence war. Garibaldi’ «thousand» shirt was dyed with fuchsine
The battle of Magenta (June 4, 1859)
The production of fuchsine was highly pollutant
Fuchsine could be obtained by
a) treating «aniline» with various halogenated
compounds [CCl4 (Hofmann), 1,2-dichloroethane
(Natanson), 1,2-dibromoethane (Cloesz)]
b) treating «aniline» with oxidants (SnCl4, HgCl, FeCl3,
and, with better yields with As2O5.
With As(V) oxidants, the yield was up to 40%, better than
the 10% yield of mauveine, but the product retained up to
6% As. The method was replaced by the nitrobenzene-iron
powder
Mauveine is not of relevance any more, but fuchsine is used , as Schiff test, in histochemical dyeing
The Schiff test can distinguish between aldehydes and
ketones.
Fuchsine is decolored by the addition of bisulfite and
the colour is regenerated in the presence of
aldehydes.
The mechanism is unclear (why should SO2 leave and
generate a less conjugated chromophore? Aromatic
sulfonamides reacts slowly with aldehydes).
The Schiff test is used to reveal:
Glycogen (after HIO4 oxidation)
DNA (after depurination with dil. HCl)
The structure of fuchsine was established by Emil
Fischer and his cousin Otto Fischer in 1878, twenty
years after the report by Hofmann.
1870ties: the dyeing industry moves to Germany
1861: Prince Albert dies
1865: Hoffmann leaves London because of lack of «financial support and encouragement for teaching»
1873: Perkin, aged 36, sells his company, after 18 years in business
Caro,Martius, Griess, Liebermann trained in the industrial production of dyes in England, and then went back to Germany
Reasons to sell:
1. Scarce academic relevance of chemistry in the British educational system. British Universities were reluctant to train
chemists
2. Impossibility to expand Perkin and Sons and compete with larger German companies due to the shortage of chemists
and difficulty to find investors
3. Inadequate patent protection from the British legislation
4. Growing number of casualties in the company due to explosions
The dismal state of chemical manufacture in Britain was finally realized during WWI, and Perkin’s early retirement was
suggested as the major cause for this state. His son (William Perkin Jr, professor at Oxford), corageously defended his
father from these allegations
From dyes to perfumes: the discovery of Perkin reaction and the synthesis of coumarin (1868)
William Perkin: the coal tar hero as a person
Deeply religious, eventually becoming evangelican churchman
Vegetarian, teetotaler, and preached abstinence from alcohol
Music-lover: played violin at professional level, and also piano
and woodwind instruments. He owned a Stradivarious violin.
All his sons played musical instruments, and the family used to
play 9-instrument compositions. His son William Jr. was a skilfull
pianist
Meek and humble, hating patent litigations and lecturing
After his retirment at 36, he carried out basic research in organic
chemistry and the optical rotation of organic compounds. He
developed a synthesis of paratartaric acid (rac-tartaric acid) and
provided it to Pasteur.
Curious titbits on William Perkin
In 1907 he received the degree of Doctor of Science from the
Oxford University in the same ceremony where Mark Twain
was made a Doctor of Literature
Perkin was adverse to medicine, and when the symptoms of
pneumonia appeared, he dismissed his doctor and called for
his dietician.
He died of pneumonia in 1907, aged 69. After citing the last
line of the hymn When I survey the Wondrous Cross (and pour
contempt on all my pride) he said «proud? Who could be
proud?» , fell asleep and died.
Given his activity, the death was not considered premature
He left all his properties to his wife and his servants 10 shilling
for every month they had been employed. The value of his
properties (including china and musical instruments) was
estimated > 10 million Euro
Perkin’s gravestone in Christchurch, Harrows,
Alizarin
A dirty lab-coat is worth more than a
computer program
(anonymous)
Raphael: Portrait of Pope Leo X with
cardinals Giulio d’Medici and Luigi
de’Rossi (around 1518)
Alizarin from the roots of madder was, along with indigo, the leading dyestuff since antiquity
The color of alizarin is modulated by
metal mordants from pink to
crimson
Rubia tinctorum L.
(azara in Arabic)
Johannes Vermeer,
Christ in the House of Martha and Mary,
1654-56
Madder was extensively grown in Provence and Alsace, and France dominated the market of dyes in the first
half of the 19th century
The roots of madder were dried,
powdered and traded in barrels.
The annual export from France
was in the range of 2 500 ton/year
ruberythric acid,
the native form of alizarin
French soldiers brought breeches dyed
with alizarin, a practice abandoned only
in 1914
The dyeing principles of madder were isolated by Robiquet in 1826
Asparagine
(1806)
Codeine
(1832)
Cantharidin
(1806)
R
Alizarin
Purpurin
Pierre Jean Robiquet (1780 –1840)
R
H
OH
The synthesis of alizarin was a key moment in the history of chemistry, and possibly the most serendipitous of
all natural products syntheses
The only substance which could possibly dethrone madder would be its
artificially prepared active principle
Paul Schutzenberger in Traité des matières colorantes (1867)
Few scientific discoveries appeal spo strikingly to the imagination as the first
laboratory preparation of one of the oldest and most beautiful of natural
dyestuffs. The problem was difficult, the manner in which its solution was
accomplished was altogether remarkable, and the importance of the discovery
to the development of organic chemistry and to agricultural and chemical
industries is to great to be estimated at all adequatedly.
…pure admiration for the way in which these great men availed themselves of
every opportunity which chanced their way
Louis Fieser, J. Chem. Ed. 1930, 2609-2633
Louis Fieser
(1899 –1977)
Graebe and Liebermann obtained alizarin despite:
a) referring to a wrong formula of the natural product
b) playing with dice, assuming that only one of the eight possibile isomers was formed
c) using mechanistically wrong reasoning
The synthesis of alizarin: the landscape
In the late sixties, ten years after the discovery of mauve, the industry of synthetic dyes was not progressing because of
a) competition favored by unclear patent protection
b) lack of knowledge on the theory of colour and the structure of the dyes: discoveries based on chance can not
continue indefinitely
The 1860ties saw the birth of the structural theory of organic chemistry: Kekule theory of tetrahedral carbon (1865) and
of benzene
England was still the capital of dye industry, but Hofmann return to Berlin, followed by a group of young German chemists
that had trained in England (Caro, Martius, Griess), set the stage for the ascent of German dye industry
Carl Gräbe, and industrial chemist turned academic because of a laboratory accident
1862: PhD with Bunsen in Heidelberg
1864: Works in a dye company producing fuchsin (Meister Lucius und
Brüning in Höchst (now Aventis) and develops severe eye damage
caused by methyl iodide. Abandons industrial chemistry
1865: Join Bayer group at the Gewerbe Akademie in Berlin
Main research interest: The structure of quinone
Carl Gräbe
(1841-1927)
Kekulé
Gräbe
From quinone to naphthoquinone and to an interest in alizarin, an alleged naphthalene derivative
Gräbe was working on chloranil (from the chlorination of phenol) because cheaper than quinone
Chloranilic acid was highly colored, reminiscent of alizarine, believed to be a naphthalene derivative
Gräbe showed that naphthalene contains two benzene rings
Carl Liebermann: a colorist turned researcher
Liebermann had a technical background having worked as a colorist in an
Alsacian company producing madder-derived dyestuff, and where he
became frustrated by the variability of madder and the primitive quality
control, based on chewing (to detect adulteration with sand) and sputum
to evaluate the tintorial qualities of the plant material)
In 1865 Liebermann leaves industry and enter Baeyer laboratory in Berlin,
becoming assistant of Gräbe
Liebermann discovered that cholesterol (and sterols in general) give a
color reaction with a mixture of sulfuric and acetic acid (or acetic
anhydride)
Carl Liebermann
(1842-1914)
The Liebermann-Grabe study on the structure of alizarin: how to become famous in four days
Friday, February 21, 1868:
Liebermann and Gräbe decide to apply the deoxygenation used by Baeyer to turn oxindole to indole also to alizarin
(heating with zinc dust)*
Saturday, Sunday:
Liebermann and Gräbe work in the lab and discover that alizarin is deoxygenated by zinc to anthracene and not to
naphthalene as expected
Monday February 24, 1868:
7 am: Liebermann and Gräbe register for an important communication at the Chemische Gesellshaft meeting due
to start at 7.30 and present their discovery
Evening: Liebermann and Gräbe are invited at a dinner at Baeyer’s intended for close friends. A wreath of madder
blossoms to celebrate Grabe 27th birthday is placed at his place, and Bayer makes a toast to Liebermann’s 26th
birthday, that had been the day before.
* Bayer had suggested Gräbe to do the reaction, but Gräbe exitated, since he believed the reaction belonged to
Bayer. So Bayer said: Gräbe, you are my assistant, and I am ordering you to distill alizarin with zinc dust» Bayer
never claimed merits for the work on alizarin.
Why the discovery that alizarin is a derivative of anthracene made such an impression all over Europe
• Alizarin was, along with indigo, the most important dye of the times
• The cultivation of madder was of great economic relevance for France, and it was feared that clarification of its
structure could lead to a synthesis and to the eventual collapse of the madder-based economy
• Numerous attempts to prepare alizarin had been done, and had all failed, since starting from naphthalene
• Anthracene was available from coal tar, and, in principle, a supply chain for a total synthesis of alizarin existed
However:
✓ The isolation of anthracene from coal tar had not bee yet industrialized and anthracene was expensive
✓ The structure of alizarin was not know, not was that of anthracene
In this scenario is remarkable that in only a few months Liebermann and Gräbe achieved the synthesis of alizarin
How to synthesize a compound with unknown structure from a starting material with a wrong structure (and devoid
of a supply chain)….
Liebermann and Gräbe received a 500 g sample of anthracene from Martius who had purchased it in England
The (wrong) structure of anthracene:
Based on the formation of phthalic acid by oxidative degradation, Liebermann and Gräbe assign a tricyclic structure
to anthracene, favoring, however, the wrong angular geometry because of Berthelot’s synthesis from benzene and
styrene and because it seemed more stable than the linear one (true)
The (wrong) structure of alizarin:
Based on his studies on chloranil, Gräbe proposed a dihydroxyanthraquinone structure for alizarin. The problem was
where to put the two carbonyl, that, according to Gräbe, were adjacent, and were to locate the two hydroxyls
… but with a correct logic
Grabe and Liebermann had to locate two carbonyls and two hydroxyls on the framework of anthracene.
Location of the carbonyls on the terminals or central rings (the two carbonyls were wrongly assumed to be adjacent
and the framework was wrongly assumed to be angular):
Naphthalene is oxidized to a quinone more rapidly than benzene, and anthracene more rapidly than naphtyalene:
«Carbon accumulation»* increases reactivity, and therefore the oxidation site should be the central ring of
anthracene
*presence of substituents on the adjacent carbon (modern lingo)
Location of the two hydroxyls:
Alizarin yields phthalic acid on oxidative degradation, and therefore the two hydroxyls should be on the same ring
ALIZARIN SHOULD BE ONE OF THESE 5 FORMULAS
The two-step synthesis of alizarin by Liebermann and Gräbe was based on a wrong structure of alizarin and on wrong
reasoning
What Liebermann and Gräbe assumed:
1. Bromination of anthraquinone would afford a dibromoderivative with the bromine atoms located at the hydroxylbearing carbons of alizarine (wrong)
2. If aqueous bases can turn chloranil (tetrachlorobenzoquinone) into chloranilic acid
(dichlorodihydroxybenzoquinone), so dibromo-anthraquinone will be converted into alizarin (wrong since only a
single halogen in vic-halogenated quinones is displaced by alkalies)
How could they succeed?
Br2
NaOH fusion
(Br)2
(OH)2
Bromination of anthraquione affords 2,3-dibromoanthraquinone and not 1,2-dibromoanthraquinone, and a
rearrangement via benzine must take place during NaOH fusion
Liebermann and Gräbe patented their alizarin synthesis in 1868, licencing it to BASF and reporting it at the January 11,
1869 meeting of the Chemische Gesellschaft .
The contract with BASF: rights of technical exploitation in exchange of 3% royalties over 15 years, but process
development turned impossible because:
a) bromine was too expensive
b) the NaOH fusion required reaction vessel unavailable
BASF plant in Ludwigshafen, 1865 (the company was actually based in Mannheim, but the town council, afraid of air
pollution from the chemical plant force the company to build its plant the other side of Rhine)
Enters Caro…
Caro’industrial formation was in England, where he was employed in Manchester by
the company Roberts & Dale where he had improved to production of mauveine and
other aniline dyes.
In 1861 he went back to Germany and joined a company next becoming BASF
Caro was the most gifted process chemist of the 19° century, industrializing the
synthesis of alizarin and indigo, with enormous economic damage to France and
England and enormous benefits for the German industry
Caro’s acid
Heinrich Caro
(1834-1910)
Plaque at the place where Caro lived in Mannheim
…and serendipity
Caro’s strategy was to introduce the hydroxyls via the alkali fusion of sulfonates, a reaction discovere in 1867 by Kekulé
However, anthraquinone was not reacting with concentrated sulfuric acid.
Since both phenol and antraquinone contain oxygen, one day, Caro reacted anthraquinone with oxalic acid and sulfuric
acid to to obtain the analogues of triphenylmethane dyes obtained from phenols in the reaction. After starting heating,
he was colled to another room and forgot to adjust the flame of the Bunsen burner. When he came back, he found that its
reaction mixture had almost bolied down to dryness, producing the sulfonated derivative!
Fusion of the sulfonic acid with
NaOH in aerobic conditions, directly
led to alizarin
A Pyrrhic victory in Germany..
The Prussian patent office
rejected the BASF application
on the ground of «insufficeint
novelty» (simple replacement
of the bromine atoms with two
sulfonate groups).
The original patent was not
preventing competitors from
using the sulfonation method,
and BASF found itself in the
strange position of
a) Having patent protection
for an unworkable process
b) Lacking patent protection
for the workable process
c) Having to pay royalties to
use his own process
Berichte der Deutschen Chemischen Gesellschaft 1870, 3 (1): 359–360
Gräbe and Liebermann received little monetary conpensation for their synthesis.
Gräbe died in poverty in 1920, having lost all his savings because of the inflaction of
post-war Germany
..but a fortuitous victory in England, where Perkin had developed an independent synthesis
Perkin was familiar with the anthracene purification from coal tar and its chemistry, having worked on its (unsuccessful)
amination with Hofmann at the Royal College of Chemistry in London
Perkin solved the problem of the sulfonation by using 9,10-dichloroanthraced as substrate
Early June 1879: BASF sends the alizarin patent application to London
June 25: the application is received by the British Patent Officed, registered with that date, and put aside
June 26: Perkin application is received and Perkin is granted a patent
Mid-July: The BASF application is discovered at the British Patent Office
The perfect stage for litigation!
The BASF-Perkin agreement and the mechanism of the sulfonation
Caro, Grabe and Engelhorn (business director of BASF) meet with Perkin and agree that Perkin and Son commercializes
synthetic alizarin in England and its colonies, and BASF in the rest of the world. Perkin next developed a second process for
alizarin based on the direct sulfonation of anthraquinone
In the conditions used for the synthesis of alizarin, anthraquinone is MONOSULFONATED. If it were disulfonated, the
second group would go on the other ring, not leading to alizarin. The second hydroxyl is introduced by an
autooxidation process from 2-hydroxyanthraquinone.
The bottom line
If Liebermann, Grabe, Caro and Perkin had known the structure of alizarin and the mechanisms of aromatic chemistry,
the synthesis of alizarin had never been discovered.
1. The structure of anthracene and of anthraquinone were wrong, and location of the two hydroxyl groups unknown
2. The structure of the intermediates was wrong: 2,3-dibromoanthraquinone and not 1,2-dibromoanthraquinone and
antrhaquinone-2 sulfonate and not anthraquinoe 1,2-disulfonate
3. The logic of halogen-to-hydroxyl replacement was based on a wrong model and was mechanistically wrong
The aftermath of the industrial synthesis of alizarin: the structure elucidation of alizarin
The linear (and less stable) structure of anthracene was established by Liebermann in the 1970ties
The location of the hydroxyls in alizarin was established by Caro and Baeyer by a series of reaction
The aftermath of the industrial synthesis of alizarin: chemical industry
Competition established between German companies for the synthesis of alizarin, with improvements in
a) the isolation of anthracene from coal tar
b) the discovery of the lead chamber and then the contact process (Knietsch process) to produce sulfuric acid (1888),
the first catalytic process to be industrialized
c) the discovery that, depending on the conditions of sulfonation and alkali fusion side-products modulating the colour
of alizarin could be obtained (disulfonated products gave isomeric alizarins, overoxidation during the alkali fusion
gave purpurin)
Commercialization of synthetic alizarin started in 1871, two years after the development of the industrial synthesis
The overall yield from anthracene was consistently in the range of 80%.
In 1900, the production of alizarin was in the range of 2 000 tons/year, but then declined due to competition from
cheaper dyes.
The aftermath of the industrial synthesis of alizarin: society
Alizarin was the first natural product to be replaced by a synthetic version, and is the first natrual product whose
synthesis was industrialized. The cultivation of madder collapsed completely, and its value was transferred from France
to Germany
The obtaining of a precious product (alizarine) from a waste (coal tar) cought people’s imagination. In 1896, this inspired
Theodore Herzl to write a short story (The Aniline Inn) where the processing of a waste into «beautiful radiant colours» is
a metaphor for the condition of Jewish people from «refuse of human society» to a radiant future in an Jewish state.
Herzl Day is a national feast in Israel
Avignon. Monument to Jean Althen, who
introduced the cultivation of madder in Provence
Theodor Herzl
(1860-1904)
Indigo
So what is England invented crickte? Even a proud nation would
come to accept that another country would one day learn to
beat them at it every time
iSmon Garfield
Yves Klein: blue monochrome
(1961)
Indigo and the quest for its industrial synthesis: Which company will nowadays invest 20 years on a risky development
project ?
Only natural dye produced industrially by large scale synthesis (ca 17 000 tons/year, 10% of the dye market)
The production of natural indigo is labour-intensive and difficult to standardize in terms of tinctorial quality. First
synthesized (1878, 1882) before its structure was clarified (1883). The laboratory syntheses were based on the same logic
of the alizarine synthesis, reversing a reductive degradation sequency using an oxidation step
The industrialization of the synthesis of indigo required two decades of investment by BASF and had dramatic
consequences on the Indian society, leading to the complete collapse of the natural indigo supply chain
The industrialization of the synthesis of indigo was unusual, since the very first step was the last one to be optimized and
the whole project was mit en sehr grossen Risiko verbunden
The industrial synthesis of indigo consolidated German chemical industry as the world’s most powerful and influential
Adolf von Baeyer was the most influential organic chemist at the turning of the 19th century
Bayer did PhD work with Bunsen and in his doctorate thesis came to the wrong conclusion that «methylchloride
from the chlorination of methane is different from methyl chloride derived from methyl alcohol and hydrogen
chloride or from cacodylic acid and hydrochloric acid»
Bayer was a born empiricist, the king of «test tube chemistry». Before his seventieth birthday he confessed
Willstätter that «chemistry has changed. I would not study organic chemistry again»
Memorabilia from Baeyer:
« I never undertook an experiment to see if I was right, but to see how compounds behave. This explains my
indifference to theories»
Bamberger on showing Baeyer a vial full of coloress crystals: This is the most beautiful substance I have ever found
in my life. Bayer replied «The most beautiful substance you have discovered is your wife» (Bamberger wife was an
attractive woman
«The only reason I am so well known is that people don’t know how to spell my name» Commenting on people
believing that the Bayer company belonged to him.
The rationale of von Baeyer indigo synthesis
If reduction of indigo by distillation on zinc dust produces indole, treatment of indole with oxidants should afford
indigo
D, Zn
Oxidation
Baeyer first indigo synthesis (Baeyer-Emmerling synthesis, 1878)
If indigo is turned
into isatin by
oxidation, there
should be a way to
reductively turn
isatin into indigo
Baeyer second indigo synthesis (1882, Baeyer-Drewsen synthesis): a simple reaction from an expensive starting material...
The preparation of o-nitrobenzaldeyde from
toluene was problematic due to
a) limited availability of toluene
b) Poor yield of the nitration and
chlorination
Berichte 1882, 15, 2856–2864
…and with a complex mechanism involving nitro-to amine formal reduction (not unlike the Bartoli indole synthesis)
Both Bayer syntheses left unsolved the regiochemistry of dimerization. An unexpexted solution came in 1883
indoxyl
The double bond configuration of indigo was
established as E by X-ray only in 1928
Letter of Bayer to Caro dated August 3,
1883, disclosing the structure of indigo
The quest for an industrial synthesis of indigo
Indigo production from BASF
BASF and Farbwerke Meister, Lucius & Brüning (next Hoechst) joined forces to industrialize the synthesis of indigo.
They purchased Baeyer’s patents and worked on the issue for 17 years, with an investment of 18 million gold marks
Heumann and a change of disconnection (1890)
Baeyer
1st synth
Structure of indigo
(1878)
(1883)
Baeyer
2nd synth
(1882)
Commercialization
(1897)
Heumann
2nd synth
(1890)
Karl Heumann
(1850-1894)
Heumann licenced his syntheses to BASF but died young
and could not benfit from his discoveries
The 1st and 2nd generation of Heumann phenylglycine-based indigo syntheses (1890)
From the yield of the indigo synthesis, the issue moved to the supply of anthranilic acid
The anthranilic acid issue and its fortuitous solution
[H2SO4, HgSO4]
Cr(III) was difficult to reoxidize, and the oxidation of naphthalene with sulfuric acid under aerobic condition gave poor
results
One day, a thermometer dropped into a flask where the oxidation with sulfuric acid was investigated, and the reaction
gave outsdanding yield. Hg2+ catalysis was necessary for the reaction!
The Degussa NaNH2 modification of first generation Heumann synthesis (Pfleger synthesis)
*
sodium salt of N-phenylglycine is dissolved in a NaOH-KOH eutectic
* The
and molten NaNH is added
2
The Pfleger indigo process” was patented in 1901 was exploited jointly by the Farbwerke
Meister, Lucius & Brüning (later Hoechst AG) and by Degussa until 1940.
Sodium amide was an intermediate from the Castner synthesis of sodium cyanide*
*At 400 °C, sodium absorbs ammonia forming NaNH2, next fused with NaCN to produce
sodium cianamide, that reacts with carbon to produce two “molecules” of NaCN
Johannes Pfleger
(1867-1957)
The aftermath of the industrial synthesis of indigo
Germany alone was importing 2 000 tons of indigo from India, where over 1 250 000 acres (> 5 000 Km2) of land were
dedicated to the cultivation of the indigo plant. The whole supply chain collapsed.
During WWI, the German syntetic dye was not available any more, and farmers were forced to grow indigo, a plant that
was rendering the soil infertile.
In 1917, Mahatma Gandhi led the first satyagraha movement to support the protests of farmers.
Conclusions
Circular economy is not a modern fad. It used to be called «waste recycling»
The production of fine chemicals (dyes, drugs, perfumes) was developed industrially from coal tar, one of the worst
industrial by-products
In the second half of the 19the century, profits from the production of dyes provided the financial capitals necessary
for the birth of drug industry
The chemical logic underlying the three landscape-changing syntheses of dyes (mauveine, alizarin, indigo) is basically
different from the current logic of chemical synthesis, and based on the reversal of degradation reactions or on
considerations of molecular formulas
The establishment of Germany as a chemical giant had an educational basis and was the result of long-term industrial
investments
The introduction of synthetic dyes changed foreved our society:
The suggestion that the use of the dyes should be abandoned in favor of cochineal, indigo, maddr and other animal or
vegetal substances is unpractical because the supply of these substances is limite, and has outgrown the demand for
coloured goods. It would be now impossible to return to what we may call the pre-aniline stage of manufacture and
we must be content with the enforcement or such precautions as may banish or minimize the risk of injury
The Times, 1884, on the health danger of synthetic dyes