Synthetic Dyes and the Development of Organic Chemistry

1856 – Perkin's Easter vacationFormula, but not structure of quinine knownPerkin attempted oxidation:2C 10 H 13 N + 3[O]KCr 2 O 4H 2 SO 4C 20 H 24 N 2 O 2 + H 2 OquinineWilliam Henry Perkin, age 14HHN[O]HOHNMeONExperiment resulted in v. impure brown powder, but Perkin tried to assess whether the oxidationwas general:NNH 2+KCr 2 O 4H 2SO 4black sludgeEtOH, refluxH 2 NNNHNH 2Meimpuritiespurple crystals = "aniline purple," later mauveine--------------------------------------------------------------------------------------------------------1857 – An industry beganCurrent synthetic dyes were unsuitable, but demand was highO 2 NOHNO 2 yellowmade from phenolnot lightfastHNNO 2picric acidOHNOOONmurexideHNNHOO - NH 4+reddish-purplereasonably light-resistantapplication complex and expensivesynthesize from urea and nitric acidPerkin left school, father risked fortuneSuccess required establishment of large scale organic chemicals industryRaw materials to make aniline needed on large scale: benzene, nitric acid, anilinePerkin's sketch of Perkin and Sons dye factory2

1800-1845 – Coal tar and Justus Liebig set the stageIn late 1700s coal distilled for tar; after 1812, illuminating gas became desirable, excess coal taraccumulatedLiebig one of the premier educators of all timeFresenius, Erlenmeyer, Kekulé, Wurtz...Small links between industry and chemistry establishedAugust Wilhelm Hofmann began to analyze coal tar extractsHofmann establishes Royal College of Chemistry in England *Liebig's lab in Giessen-----------------------------------------------------------------------------------------------------------H 2 NNH1856-1867 – Post-mauveine developments2Concious search for new dyes – fuchsin found by Emanuel VerguinTriphenylmethine dyes enable systematic synthesis of new compounds – HofmannProduction of mauveine stopped after ten yearsNH 2+rosaniline or fuchsin1867 – value of dyes had tripled since 1862 despite price dropsN N NH 2Price per kilo of raw materials and dyesaniline yellow1862 1867+ HNbenzene 5 fr 70 crosaniline 300 fr 30 fr- O 3 SNHNHaniline blueNOHNNNN[O]H + SO 3 NH 4SO 3 NH 4NOHNNmalachite green3

1858 – Peter Griess and the azo dyesMore Germans in EnglandYNONH 2- ONONH 22 diazotization azo couplingOtto Witt, Heinrich Caro and Carl Alexander MartiusVersatile chemistry exploitedHNO 2+-Y - H 2N ONHONOONONO-H + N + N+ H 2 ONOYNONH 2HNNOClN ONNOH+ N O H +N N NH 2NNOH 2+aniline yellowAzo dyes today account for 60-70% of dyes used in textile applicationsnitrite anionnitrious acidnitrosoacidium ionnitrosonium cation-H 2 OPeter GriessN N H 2 NNH 2chrysoidineN + NpH important in diazotization aswell as azo couplingdinitrogen trioxidenitrosyl chlorideincreasing acidity----------------------------------------------------------------------------------------------------------1869 – Alizarin, then decline for England and FranceO OHOalizarinOH1868 – Graebe and Liebermann deduce structurePerkin and Sons first commercial producers:Class of carbonyl dyes – anthraquinones1869 - 1 ton1870 - 40 tons1871 - 220 tonsMadderGraebe and Liebermann:Caro, Perkin:OBr 2OBrBrOH2SO4OSO 3 HOOOONaOH, ![O]OBrOOHOHOSO3HSO3HOOHOHBrOOOOBut England was on the decline:Hofmann departs in 1865Not enough trained chemistsMinimal state fundingBusiness complacencyLittle cultivation of scientific inquiryFrance too:Not enough raw materialsLoss of Alsace-Lorraine in 1871Patents for products, not processesPrivate labs did not supply enough trained chemists4

German industry on the riseBayerAGFAKalle,HöchstBASFCIBA, SandozDecentralization – lack of investment necessitated imitation, competition among small statesPatent situation – laws difficult to enact, foreign technology not protected, competition increasedGeography – raw materials, transportation in Rhein river valleyEducation – the Liebig tradition supplied fresh ideas, trained chemistsUnification in 1871 – Patent Act of 1876 arrived at the right timeBusiness – ties between industry and universities established quickly--------------------------------------------------------------------------------------------------------Education – Universities and the Technische Hochschule1809 Univeristy of Berlin – model for a modern university:SeminarsSemestersVernacularProfessional training, productive citizensLiebig's pedagogical model:Close relationship with professor, whose enthusiasm evoked admiration and loyaltyFull enthusiasm for studies – 6 days/wk, 12-15 hrs/dayCompetitive atmosphere among students"ample opportunities of witnessing, in a comparatively short time, a vast variety ofprocesses which are being constantly carried on in an institution consisting of a greatnumber of experimentalists" (Hofmann, 1849)1860s – glut of doctoral students led to technische hochschule: *Proximity to state centersTies with state and industryIncluded education in other fieldsStimulated improvements at universities (v. similiar by 1900)Ties with professors highly sought after by companies5

1870s – Heinrich Caro exemplifies industrial and academic cooperationAs director of research at BASF, Caro tirelessly fostered ties with academics1868 – Graebe and Liebermann consult Caro regarding alizarin1873 – Adolf von Baeyer and Caro collaborate on research programThey discover eosinMartius at Agfa discovers secret formula with the help of HofmannHeinrich Caro1876 – Caro stymied again with chrysoidine by Martius and Hofmann *1876 – Griess supplied Caro with samples from azo coupling reactions1878 – Emil and Otto Fischer (under von Baeyer) solve structure of triphenylmethine dyes, butonly with help from CaroHOBrOBrOBrCO 2 HBrEosinA. W. HofmannAdolf von BaeyerEmil Fischer------------------------------------------------------------------------------------------1870-1890 – Rise of the industrial research laboratory and the Bayer exampleResearch labs enabled acceleration of research by consolidating resourcesTeamsFacilitiesAcademically trained scientists in management positionsBayer was slower to innovate than other major german firmsBy 1882, a full research staff was still not established1884 –Duisberg enables Bayer to compete with AgfaCarl DuisbergDuisberg spontaneously evolves into a research directorPrimitive labs replaced with Duisberg design of new building, layout adopted almost universally*Also quality control, library, conferences, product testingIn 1896, 1 in 70 dyes approved for productionBy 1900, 1 in 200 dyes marketedca. 1905, 1 in 300 dyes marketedNH 2SO 3 NaNNN N NH 2benzopurpurin 4BSO 3NaBayer laboratories after Duisberg6

Back to the mosquitoH1918 – Paul Rabe takes quinotoxine to quinineMeOONHMeOHOHNNN1944 Woodward and Doering's planquinotoxineHONRabeONHHNHMeOMeOHOHNNquinotoxineOhomeroquineneHON7-hydroxyisoquinoline----------------------------------------------------------------------------------------Woodward's Quinotoxine synthesisNHHONCH2OpiperidineMeOHHONNMeOH/NaOMe220 °C, 10h64%HONMeOON7-hydroxyisoquinoline1. H 2, PtOAcOH2. Ac 2O, MeOH95% (for 2 steps)HONOH 2 Raney NiquantHOONOHONEtOH/NaOEtEtONO68%mixture of isomersH36% cis recrystallizedHONHNOMeI, K 2 CO 3EtOHNHNO1. 60% NaOH40 °C2. KOCNHCrO 3N NH2O1. 0.1 N HCl!2. AgO, H 2 SHNHEtOOH90%EtOOH42%HOOHquantHO HOhomeroquineneOOEt1. EtOH, HCl2.BzCl, K 2CO 396%EtOHHNOPhMeONNaOEt, !MeOEtOOOHHNOPh6 N HCl, !50% (2 steps)quinotoxineON9

ConclusionsONHHOHNMeOMeONNquinotoxineWhile dye chemistry is a limited field, it facilitated the development of organicchemistry, chemical industry, chemical education as we know them today.10