IN MEMORIAM

DOI: 10.1002/ejoc.201100661

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Pietro Biginelli: The Man Behind the Reaction

Gian Cesare Tron,*[a] Alberto Minassi,*[a] and Giovanni Appendino[a]

Dedicated to Professor Gianfranco Scorrano on the occasion of his 72nd birthday

Keywords: Biginelli reaction / Multicomponent reactions / Nitrogen heterocycles / History of science

The Biginelli dihydropyrimidine synthesis is one of the mostimportant and oldest multicomponent reactions and has beenextensively investigated in terms of application and mecha-nism. Surprisingly, little information is available on its dis-coverer, the Piedmontese chemist Pietro Biginelli, who alsocarried out the first studies on the purification and characteri-zation of the (in)famous Gosio’s gas. The reasons for the lackof a current biography on Biginelli can be traced back to hisearly demise from the research community. This, combined

Introduction

Most named reactions, from Appel halogenation toYamaguchi esterification, celebrate synthetic chemists whodevoted their lives to the advancement of this disciplineand, in general, to research.[1] The Biginelli reaction is anexception, since its discoverer, the Piedmontese chemist Pie-tro Biginelli, dedicated only a few years of his professionallife to synthetic organic chemistry. Its longest part was, infact, focused on forensic analytical chemistry and commod-ity science and was plagued (or honored, depending on thepoint of view) with growing administrative commitments,culminating in his nomination to the Direction of theChemical Laboratories of the State Institute of Health (Isti-tuto Superiore di Sanità) in Rome. Unsurprisingly, his obit-uary in La Chimica e l’Industria,[2] the flagship professionaljournal of the Italian Chemical Society, did not even men-tion the discovery of what is now known as the Biginellipyrimidine synthesis. Biginelli collaborated with some pre-eminent scientists active in Italy at the turning of the 20thcentury (Icilio Guareschi in Torino, Wilhelm Körner in Mil-ano, Hugo Schiff in Florence, Bartolomeo Gosio in Rome),discovered what is still considered the most important pyr-imidine synthesis, and carried out the first chemical studies

[a] Dipartimento di Scienze Chimiche, Alimentari, Farmaceutichee Farmacologiche, Università del Piemonte Orientale,via Bovio 6, 28100 Novara, ItalyFax: +39-0321-375621E-mail: tron@pharm.unipmn.it

minassi@pharm.unipmn.itSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201100661.

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with the prematurity of bio-organometallic chemistry and thescarce popularity of pyrimidines before the discovery of theirbiological relevance, resulted in a paradoxical situation thatled Biginelli to be remembered mostly for his administrativemerits and career. By capitalizing on original documentationretrieved in archives or provided by his family, we presentan account of the life of this forgotten chemist in the contextof his contemporary chemical research.

on the structure of the (in)famous Gosio’s gas. However,the role of pyrimidines as a building block of biomoleculeswas still decades to come, as was the discovery that metalmetabolization had implications that went well beyond therealm of toxicology.

Furthermore, the strong scientific personality of HugoSchiff, in whose laboratory the Biginelli reaction was dis-covered, and that of Bartolomeo Gosio, who discoveredthat living organisms could metabolize, so as to say, metals,overshadowed the originality of Biginelli’s contributions tothe early history of multicomponent reactions and to bio-organic chemistry. Last but not least, Biginelli never starteda “school”, nor further pursued his germane achievementsin organic and organometallic chemistry, with his scientificoutput remaining substantially confined to a series ofstand-alone contributions published between 1890 and1900. These considerations underlie the oblivion in whichhe fell after his death.

Spurred by the growing relevance of the Biginelli reac-tion,[3] the lack of biographic information on its discoverer,and our interest in multicomponent reactions, we have capi-talized on the geographical proximity of his birthplace toour university to present a biographic sketch of this nowforgotten chemist, investigating the context in which hisseminal contributions to multicomponent reactions and tothe structure of naturally occurring organometals wasachieved. Owing to the paucity of published documentationon Biginelli’s life, a large part of the information we presentwas obtained through documents obtained from his threeliving grandsons, whose help was instrumental for ourwork. Only a selection of the documentation that the Bigi-

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nelli’s family made available to us is presented in this article,but a larger choice is provided in the Supporting Infor-mation that accompanies this article.

The Early Years: Palazzolo Vercellese, Torino,and Milano

Family and Youth

Pietro Giacomo Biginelli (Figure 1) was born on July 25,1860 in Palazzolo Vercellese, a small country town on theEastern continental border of the Kingdom of Sardinia,soon to become the Kingdom of Italy. Palazzolo Vercellese,today in the province of Vercelli, Piedmont, is located inthe rice belt of Europe, the wet area between Piedmont andLombardy where two thirds of the European production ofrice is still centered, and had 2084 inhabitants in 1861.[4] Itborders Fontaneto Po, where the celebrated violinist andcomposer Giovanbattista Viotti, one of the very few con-temporary composers estimated by W. A. Mozart, was born100 years earlier (May 12, 1755).

Figure 1. A signed picture of 29-year old Pietro Biginelli.

On his birth certificate, Pietro’s father (Giuseppe Bigi-nelli) is identified as a “baker” (prestinaio, from the latinprestinum, mill), as is his mother (Dorotea Genovese). Atthat time, only one fifth of the Italian population was al-phabetized, and the first law granting universal public edu-cation (for two years only, Casati’s law of October 12, 1859)was being slowly implemented, mainly in large towns.[5] Itis therefore surprising that Pietro Biginelli, on account ofhis modest origin in a small village, had access to highereducation. We can only surmise that his uncle, the influen-tial priest Luigi Biginelli might have helped his bright ne-phew to complete his education in Torino, in a striking re-peat of the role that the prince Alfonso dal Pozzo della Cis-

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terna played for the musical education of Viotti, who sharedwith Biginelli a modest origin in a country village.[6] DonLuigi Biginelli (1843–1898) wrote a scholarly monographon the history of Benedictines in the Middle Age, still thereference book on the topic, and founded in 1869 the Jour-nal L’Ateneo religioso scientifico letterario artistico illus-trato, a multidisciplinary publication embedded with posi-tivistic culture, and eventually became the rector of theClerical University of Torino.[7]

University Studies

In 1881, Biginelli entered the University of Torino, twoyears after the departure of Hugo Schiff, who, after twounhappy years (see infra) as Professor of General Chemis-try and Director of the Pharmaceutical Laboratory, had fi-nally managed to return to Florence.[8] Unlike other Italiantowns, and despite the presence of Ascanio Sobrero (1812–1888), one of the most famous Italian chemist of the 19thcentury, Torino had not yet witnessed the birth of a“strong” regional school of chemistry. Sobrero had ac-quired European fame for his discovery of nitroglycerin andhis studies on terpenoids (immortalized by the name sob-rerol given to an α-pinene derivative still used in medicine),but these achievements were not enough to secure him anacademic position in his alma mater, probably because hisfervent Catholicism did not make him popular with thedominating anticlerical politic pursued in those years by thePiedmontese government. As a result, in 1855, the vacantchair of chemistry was not assigned to Sobrero but to Raf-faele Piria (1814–1865), a revolutionary anticlerical figurewho pursued politics rather than research in the decade hespent in Torino.[9] After his death, apart from a brief stayof Emanuele Paternò in 1871–1872, only minor figures tookthe chair until the arrival of Hugo Schiff in 1877, replacedtwo years later by Icilio Guareschi (1847–1918). This poly-math of Emilian birth and Tuscan formation, along withMichele Fileti (1851–1914), finally brought chemical pres-tige to the University of Torino.

Guareschi was an eclectic scientific personality, whosecurrent fame is due to the α-pyridone synthesis (Guareschi–Thorpe reaction), to a method for the preservation of his-torical manuscripts, and to a monumental history of theItalian chemistry.[10] Biginelli worked under the assistanceof Guareschi on the polyhalogenation of naphthalene bythe sequential agency of bromine and chlorine. At that time,Guareschi was one of the leaders in the study of naphtha-lene and its chemistry, a topic he had scholarly reviewed in1883 in a very long note published in Liebigs Annalen.[11]

Biginelli graduated in Chimica e Farmacia at the Universityof Torino in 1886, and the study on the polyhalogenationof naphthalene was eventually published a year later.[12] Al-though not particularly original, this research is technicallyhighly demanding because of the tedious fractionatedcrystallizations involved in the separation of the various iso-mers formed in the halogenations steps.

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First Studies on Heterocyclic Chemistry

At the end of 1886, the same year as his graduation inTorino, Biginelli was nominated Aiuto alla Cattedra di Chi-mica Organica of the Scuola Superiore di Agricoltura di Mil-ano, where, armed with considerable technical craftsman-ship, he worked with Wilhelm Körner (1839–1925) until1890. In modern academic lingo, he was nominated Assis-tant Professor at the School of Agricultural Sciences in Mil-ano. Körner was German by birth but Italian by adoptionand in 1870 had established a chemical laboratory in Mil-ano. He achieved European fame for his systematic studieson the concept of sito chimico (chemical site), namely, thetopological rationalization of the possible number of dif-ferent isomers resulting from the replacement of an aro-matic hydrogen atom with another group. In connectionwith the demonstration of the chemical equivalence of thesix hydrogen atoms of benzene, Körner introduced a seriesof locants (ortho/meta/para) that are still used today. Havingworked with both Kekulè in Gent and Cannizzaro in Pa-lermo, no one could have addressed this issue better thanhim.[13] The work of Biginelli and Guareschi on chlorobro-monaphthalenes had obvious connections to the studies ofKörner, who, since his move from Gent to Palermo, hadstarted to apply these concepts to the study of plant naturalproducts. He assigned Biginelli the study of fraxetin (1a,Scheme 1), the aglycon of the major constituent from thebark of Fraxinus ornus L. (fraxine, 1b). This compound hadbeen first isolated in 1857,[14] but its structure was still un-known. Biginelli and Körner demonstrated that fraxetinwas a trioxygenated coumarin derivatives substituted onring B with two hydroxy groups and one methoxy group.[15]

In later work, submitted after his move to Florence, Bigi-nelli provided some hints regarding the location of the threeoxygen functions of fraxetin.[16] Using the von Pechmansynthesis, he prepared 5,6,7-trimethoxycoumarin (2) anddemonstrated that this compound was different from di-methylfraxetin (1c). Therefore, the aglycon of the naturalproduct was differently oxygenated, with functionalizationon ring B being located at any of the three alternative pos-sibilities (5-,6-,8-/6-,7-,8-/5-,6-,8-). The structure of fraxetinwas eventually established by Wesseley in 1928, almost threedecades after the studies of Biginelli,[17] and there is cur-rently a resurrection of interest in this compound due to itspresence in various plant extracts used in the health food

Scheme 1. Fraxinus coumarins 1a,b and model compound 2 synthe-sized by Biginelli, which was found to be different from the di-methyl derivative of natural product 1c.

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and cosmetic market and to its dietary relevance related toits occurrence in maple syrup,[18] a popular sweetener. Whilein Milano, Biginelli published, as the only author, two pre-liminary notes on the Hantzsch-type reaction of ethyl ace-toacetate, ammonia (or diamines), and aldehydes (cinnam-aldehyde, glucose), which testify to his early interest inmulticomponent reactions.[19] In one of them,[19a] he ac-knowledges Körner for having spurred his interest in theHantzsch reaction, which had been published a few yearsearlier, in 1882.

Florence and the Discovery of the PyrimidineSynthesis

Biginelli moved from Milan to Florence in October 1890,where he remained for the following seven years with a titleequivalent to that he had in Milano (Aiuto a Cattedra, chairassistant). We can surmise that, as a young researcher (hewas 31 at that time), he was lured to Florence by the mag-netic personality of Hugo Schiff (1834–1915) and the pros-pect of working in one of the major schools of chemistryin Italy (Figure 2).[8]

Figure 2. Pietro Biginelli in the Sala delle Lezioni (Lecturing Room)of the Palazzina dei Servi in Florence, where Schiff ’s laboratorieswere located. The Sala delle Lezioni, currently Aula Schiff, was thefirst chemistry lecturing room established in Italy.[20a]

Apart from his seminal contribution to many aspects ofchemistry, Schiff (Figure 3) was also a talented innovator inlaboratory equipments, a real follower of Bunsen, and lifein his laboratories, while plagued by the extraordinarily fru-gality of this temperamental chemist, was undoubtedly aunique opportunity for a young investigator. Guareschi, Bi-ginelli’s mentor in Torino, was on friendly terms with Schiff,a surprising observation on account of the vitriolic temper-ament of the German expatriate, whose bitterness mighthave been mellowed by a common interest in the history ofchemistry.[8] Therefore, it does not seem unrealistic to as-sume that Guareschi took part in Biginelli’s move to Flor-

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ence, who in turn was probably also familiar with the com-plex personality of Schiff, who, incidentally, during his briefperiod in Torino (1876–1879) had been assaulted andbeaten by some students, exasperated by his harshness.[20b]

Figure 3. Pietro Biginelli and Hugo Schiff (Florence, 1890–1897).

Biginelli worked at the Regio Istituto degli Studi Superioridi Firenze with a salary of 1700 Italian Liras, ca. one thirdof that of a Full Professor, an overall fair salary.[21] Thecontract is still preserved in Florence,[22] maybe as a testi-mony to the generosity of Schiff, who was otherwise knownfor his avarice.

In the early 1890s, activity in Schiff laboratories was stillvibrant, and Biginelli witnessed, for instance, the discoveryof the Pellizzari synthesis of 1,2,4-triazoles by reaction ofacyl hydrazines and amides.[8] In 1891, the very first yearafter his arrival in Florence, Biginelli reported in two pre-liminary notes to the Gazzetta Chimica Italiana[23,24] and toBerichte[25,26] what is nowadays known as his eponymousreaction. Full accounts of the reaction were eventually pub-lished in the Gazzetta Chimica Italiana in 1895[27] and inBerichte[28] in the following year. Biginelli was the only au-thor of all these accounts. His previous experience with theHantzsch synthesis,[19] and the vibrant Florentine environ-ment, had undoubtedly combined to foster his interest incarbonyl condensation chemistry. The striking novelty ofthe reaction was first overlooked, as open-chain crotonylur-amate structure 3 was originally assigned to the ternary ad-duct (Scheme 2), whose next structural revision is a fittingtestimonial to Biginelli’s chemical insight.

Scheme 2. The multicomponent reaction of aldehydes, urea, andethyl acetoacetate as originally reported by Biginelli in 1891. Com-pounds like 3 are actually dihydropyrimidines.

The discovery of the Biginelli multicomponent reactiondraws from earlier work from Behrend[29] and Schiff[30] onthe possibility of using urea as an amine replacement in

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carbonyl chemistry. Behrend discovered that urea givesstable adducts with ethyl acetoacetate, dubbed uramides(i.e., 4) in the chemical lingo of those times (Scheme 3),[29]

while Schiff had reported, in his classic studies on the reac-tion of aldehydes with nitrogen functionalities, that ureacan react with aromatic and aliphatic aldehydes to affordsymmetrical aryl or alkylidene-bisureas 5 (Scheme 4).[30]

Scheme 3. The Behrend reaction between urea and ethyl acetoacet-ate.

Scheme 4. The Schiff reactions between urea and salicylaldehyde.

Building on these observations, Biginelli investigated thereaction of ethyl acetoacetate and urea in the presence ofaldehydes. In the event, by heating urea, salicylaldehyde,and ethyl acetoacetate at reflux in absolute ethanol for twohours, he obtained a precipitate, which was filtered off,washed with cold ethanol, and recrystallized with the samesolvent. Elemental analysis of the precipitate (C14H16N2O3)evidenced the dehydrative incorporation of all atomsfrom the reactants into the adduct (Scheme 5), to whichuramidocrotonate structure 6 was assigned by combiningprevious knowledge on the reactivity of the single electro-philic species involved (aldehydes and ethyl acetoacetate)with urea.

Scheme 5. The first Biginelli multicomponent reaction as originallyreported by the author in 1891.

Doubts on the actual structure of the ternary adductspurred the publication of the notes from 1895 and 1896that represent a remarkable exercise in chemical logic.[27,28]

Formulated into the current synthetic thinking, Biginelli’splan was to combinatorially dissect the multicomponent re-action into a series of distinct binary process. Since all threereagents could be independently combined, either in a 1:1(ethyl acetoacetate/urea or ethyl acetate/aldehydes) or in a2:1 (urea/aldehydes) fashion, the alkylideneuramate ternary

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Scheme 6. The logic behind the dissection of the multicomponent reaction of benzaldehyde, ethyl acetoacetate, and urea planned byBiginelli to confirm the benzylideneuramate structure of the ternary adduct.

adduct could be directly obtained by incorporating an alde-hyde into a uramide, while compounds of this type couldbe generated in a dimeric form from the arylidene adductsof urea and aldehydes, with the benzylidene derivative ofethyl acetoacetate having no possibility to generate the al-leged alkylideneuramate from the multicomponent reac-tion. This logic is summarized in Scheme 6.

In the event, while the uramic adduct of ethyl acetate andurea could easily incorporate an additional alkylidene motiffrom an aldehyde and afford the same product (i.e., 7) ob-tained in the three-component condensation (Scheme 7),the latter was, unexpectedly, also obtained when ethyl ace-toacetate was treated with the dimeric adduct of urea andaldehydes, as well as from the treatment of benzylideneethyl acetoacetate and urea. Thus, by heating the Schiffarylidene-bisurea with ethyl acetoacetate at reflux inethanol for six hours, Biginelli obtained the ternary adductfrom the multicomponent reaction (i.e., 7) rather than theexpected bisuramide (i.e., 8, Scheme 8). The same ternaryadduct from the multicomponent condensation of benz-aldehyde, ethyl acetoacetate, and urea was also obtainedwhen ethyl acetoacetate and benzaldehyde were combinedand the resulting benzylidene derivative was treated withurea (Scheme 9). Of interest was also the obtainment of asmall amount of the uramide of ethyl acetoacetate from thereaction of benzylidene-bisurea and ethyl acetoacetate. Thisobservation suggested that the formation of both theBehrend and the Schiff primary adducts was reversible, pro-viding a rationale for the observation that the three reac-tants were eventually affording the same ternary adduct in-dependently from the order in which they were combined.

Taken together, these observations also suggest that,as expressed in the current lingo of organic chemistry,uramates behave toward aldehydes as dinucleophilic speciesrather than as simple nitrogen mononucleophiles. The logi-cal conclusion of this reasoning was that the ternary adduct

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Scheme 7. Reaction between Behrend’s product 3 and benzaldehyde(5).

Scheme 8. Reaction between Schiff ’s compound and ethyl aceto-acetate.

Scheme 9. Reaction between urea and the product derived from thecondensation between benzaldehyde and ethyl acetoacetate.

had a heterocyclic, not a linear, structure and that a pyrim-idine derivative was obtained.

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Biginelli improved the yield of the multicomponent reac-tion by discovering the beneficial effect of the addition ofBrønsted acids (hydrochloric acid) and by demonstrating itsgenerality with a vast array of aldehydes (aliphatic alde-hydes, α,β-unsaturated aldehydes, and furfural). Neverthe-less, the reaction went into oblivion until the second partof the following century. At the turning of the 19th century,the condensation reactions of ureas were probably consid-ered an “old-fashioned” topic (the synthesis of barbituricacid by von Baeyer dated from 1864), and pyrimidine wasnothing but an esoteric heterocycle. In those years, the at-tention of Schiff was focused on amino acids and their reac-tions with formaldehyde, and it is significant that the pyrim-idine synthesis was not even mentioned in the brief obituaryof Biginelli that appeared in 1937 in La Chimica e l’Indus-tria.[1]

Over the past decades, the Biginelli reaction has becomea hot topic, and several modifications have been intro-duced.[3] Catalysts different from Brønsted acids have beendiscovered, making it possible to run the reaction undermilder conditions and with higher yields than those out-lined by Biginelli in the original protocol,[3] and microwaveirradiation has also proved beneficial.[31] Of special rele-vance is the Atwal modification,[32] where a preformed un-saturated keto esters reacts with a protected urea to afford2-substituted dihydropyrimidines (9), which may be con-verted into classic dihydropyrimidines (10) by deprotection,or alternatively into aminopyrimidines (11) by treatmentwith ammonia or amines (Scheme 10).

Scheme 10. The Atwal modification of the Biginelli reaction.

The mechanism of the Biginelli reaction was long de-bated and was eventually clarified by Kappe in 1997.[33]

Scheme 11 summarizes the currently accepted mechanismof the reaction.

The growing biological relevance of dihydropyrimidinesand their validation as privileged structures in medicinalchemistry underlie the current interest in this heterocyclicsystem.[34–36] In this context, a critical event was the discov-ery of monastrol (12), an antimitotic agent that, unlike clas-sic antimitotic agents (colchicine, paclitaxel, Vinca alka-loids) does not target tubulin, but rather inhibits the mitotickinesin Eg5, a promoter protein required for spindle bi-polarity.[37] A pyrimidine scaffold is also present in somebioactive marine natural products (batzelladines, crambes-cidin, and ptilolomycalin alkaloids), for whose synthesis an

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Scheme 11. Mechanism of the Biginelli reaction according toKappe.[33]

intramolecular Biginelli reaction was developed by Over-man.[38] Last but not least, the Biginelli reaction is one offew multicomponent reactions that have been developed ina robust asymmetric version.[39]

Rome and Studies on Gosio’s Gas

In February 1894, while still in Florence, Biginelli ap-plied for a Privatdozent habilitation (Libera Docenza) inChimica Farmaceutica (Medicinal Chemistry) at the Uni-versity of Rome. The evaluation of the titles he had pre-sented (Concorso) took place on October 24 of the sameyear (what a striking difference with the current situationin Italy, where years passes before applications are exam-ined and Concorsi carried out!), and the Commissione(Committee) was made up by Stanislao Cannizzaro, Eman-uele Paternò, and Luigi Balbiano. The eight publicationspresented by Biginelli, six as a stand-alone author, werepositively evaluated,[40] especially those of fraxetin and onthe reaction now referred to as the Biginelli reaction. Afterpassing the Concorso and obtaining the title of Privatdozenteight years after his graduation, Biginelli did not move toRome until 1897, when, at the age of 38, he become Assis-tente to the Chair of Chimica Farmaceutica of Balbiano.Those years also brought changes in Biginelli’s private life.Still a bachelor, while travelling by train, he met Luigia Riz-zini. She and her husband had separated the year after thebirth of their son Luigi in 1888, and Biginelli lived withLuigia for the rest of his life, taking care of the educationof Luigia’s son. The couple had their own son in 1908 (UgoBiginelli, Figure 4), when Pietro was 48 and Luigia 43, but

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they could not get married until 1923, after the death ofLuigia’s first husband. Biginelli at that time was 63, and hisspouse 57.

Figure 4. Pietro Biginelli, Luigia Rizzini, and their son, Ugo (ca.1918).

Four year after becoming Privatdozent at the Universityof Rome, in 1901 Biginelli moved to the newly establishedLaboratorio di Chimica of the State Medicinal Institute (Is-tituto di Sanità Pubblica, ISS; Figure 5) in Rome, directedby Emanuele Paternò (1847–1935), one of the leading Ital-ian chemists of that time.[41] Biginelli was one of the twoattendee (coadiutori) of Paternò, each of them having twocollaborators and two technicians.

Figure 5. Pietro Biginelli in the chemistry laboratory of the StateMedicinal Institute (Istituto di Sanità Pubblica).

A germane collaboration developed with the Microbiol-ogy Department (Laboratorio di Micrografia e Batteriolo-gia), directed by Bartolomeo Gosio, another Piedmontesescientist,[42] and Biginelli gave a second important contri-bution to chemistry in his study of Gosio’s gas. The rele-vance of this (in)famous chemical, the only one dedicatedto a person,[42] can hardly be underestimated, and it hasrecently surfaced in connection to events as various as thedeath of Napoleon, sudden infant death syndrome, and thepoisoning of wells in Bangladesh.[42]

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Environmental metal poisoning was a major health issuein the 19th century. Wallpapering had been very fashionablesince the late 1700s, and inorganic arsenic dyes (Scheele’sGreen, Emerald Green) were extensively used for green col-oring. To give an idea of the extent of the use of wallpaper,it was estimated that in 1858, 100 million square meters ofarsenic-colored wallpaper were present in Englandonly![42,43] Indoor arsenic poisoning from wallpaper wasrecognized early in the 19th century and was first attributedto the presence of powdered elemental arsenic released intothe air from the wallpaper. In 1839, Leopold Gmelin sug-gested the involvement of a volatile arsenic derivative, sincepoisoning was always associated with a garlic smell.[43] In1874, Francesco Selmi suggested that indoor arsenic poi-soning could be due to the action of molds on wallpaperpaste and the release of a volatile arsenic species.[43] Amyl-aceous materials were, indeed, used as a glue for wallpaperand humidity could easily promote the growth of variousmicro-organisms. While Selmi’s theories were widely ac-cepted in Europe, the nature of the volatile arsenic deriva-tives associated with the so-called arsenio-molds (arsenio-muffe) was hotly debated. Arsine (AsH3) seemed a plausiblecandidate, but Gosio surprisingly suggested that this gascontained carbon.[43] Gosio demonstrated that severalmicro-organisms could happily grow on arsenic and releasea poisonous gaseous mixture containing arsenic bound tocarbon.[44]

By capitalizing on the ad hoc fermentation systems builtby Gosio, Biginelli managed to purify a volatile organo-arsenic derivative from the obnoxious arsenic fermentationeffluvia.[45] After considerable efforts to get analytical datafrom the crude gas, Biginelli went back to the original pro-posal by Gosio of trapping the gas by the formation of aninsoluble precipitate. Gosio suggested the use of silver salts,but Biginelli found that a solution of 10% mercury chloridein 20 % hydrochloric acid was much better, affording a nicecrystalline precipitate when the fermentation gas wasbubbled into it. This solution became known as Biginelli’ssolution, and it is difficult to imagine the difficulty and thedanger associated with these studies. Noteworthy is thatBunsen had been almost fatally poisoned, lying for daysbetween life and death and eventually losing one eye, bycacodyl cyanide (Me2AsCN). Anyhow, after bubbling thefermentation gas for a few weeks through this solution,Biginelli obtained sufficient amounts of a nice crystallineprecipitate with a strong garlic odor that, after desalifi-cation, was identified as diethylarsine based on its elementalanalysis. A flask containing these crystals is still preservedin Rome and has generated some misunderstanding in thefield of antibiotic research. Thus, Gosio reported in 1929the first purification of an antibiotic, mycophenolic acid,which is nowadays a blockbuster immunosuppressiveagent.[46] The flask preserved in Rome with Biginelli’s mer-cury adduct of Gosio’s gas is marked as “penicillina arsen-icale”, with the name penicillin making obvious referenceto the nature of the mold from which the gas had beenobtained and not to the drug penicillin.[47] To prove thestructure of Gosio’s gas, Biginelli tried to synthesize it by

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reacting arsine and ethanol with a metal catalyst (palladiumor platinum), observing, however, only the formation of ele-mental arsenic and acetic acid. The structure of Gosio’s gaswas questioned in the 1930s and was eventually establishedas trimethylarsine.[48] The error by Biginelli was presumablydue to the analytical data he had at his disposal. Indeed,the elemental analysis of Biginelli’s salt showed a largedominance of heteroatoms over carbon (ca. 60% mercury,21% chlorine, 11.3 % arsenic), with carbon and hydrogenmaking up only 6.15 and 1.56% of the solid, respectively.Under these conditions, it was difficult to differentiate thecontribution of three methyl groups (C3H9) from that oftwo ethyl groups (C4H10).

After studying the composition of Gosio’s gas, Biginelliwas not involved anymore in cutting-edge research. WhileGosio’s fame increased steadily, Biginelli was increasinglyinvolved in analytical work as well as in representative andadministrative tasks, with his research activity being refo-cused on commodities like technical oils[49] and quinine-based medications[50] rather than on organic chemistry. ThisWarenkunde-based research was to fill his professional lifeuntil retirement and is documented in nine publications.The most important achievement was the development of amethod for the detection of picric acid in biological li-quids.[51] This assay is based on reduction of the acid withmetals (zinc, tin) to triaminophenol, which gives a blue oxi-dation product in air; because of its sensitivity, this test en-joyed ample diffusion in forensic chemistry, where it wasknown as the “Biginelli test”. Capitalizing on his knowl-edge of arsenic chemistry, Biginelli investigated the struc-ture of the artificial tannin discovered by Schiff, who hadobserved that heating of gallic acid at reflux in the presenceof arsenic acid afforded a material with tannin-like proper-ties. Biginelli proposed an arsenic-containing formula forthis compound.[52] The growing administrative commit-ments of Biginelli were rewarded by the awarding of theCavaliere title in 1914 and the Commendatore title in 1919,two important recognitions. In 1925, he eventually suc-ceeded Paternò and became Director of the Chemical labo-ratory of the Istituto di Sanità Pubblica (later renamed Isti-tuto Superiore di Sanità), a charge that he maintained untilhis retirement in 1928. He was succeeded by Camillo Manu-elli and in 1934 by Domenico Marotta, who, after WorldWar II, brought fame to this Institute, by brain-draining toRome the Nobelist Ernst Boris Chain from London andthe future Nobelist Daniel Bovet from Switzerland. Mar-otta directed the Institute until 1961. In 1963, Marotta wasaccused of administrative malpractices and imprisoned,with immense damage to his Institution, a tragic example ofthe interference of politics with science[53] and the bloodlessequivalent of Lavoisier’s beheading for Italian biomedicalresearch.

After retiring, Biginelli lived between his nice Romanhouse in Corso Trieste 45 and his wife’s family house inCoenzo di Sorbolo (Figure 6) near Parma. He suffered astroke and was assisted in his last year by his faithful ser-vant Cesarina. Pietro Biginelli eventually died on January15, 1937, at the age of 78 in Rome. He is buried at Coenzo

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di Sorbolo, not far away from Secondo Parmense, whereIcilio Guareschi, Beginelli’s mentor, had been born 90 yearsearlier. The tomb still exists (Figure 7).

Figure 6. Pietro Biginelli, Luigia Rizzini, and their son, Ugo, in thegarden of their house in Coenzo di Sorbolo (Parma).

Figure 7. Pietro Biginelli’s and Luigia Rizzini’s grave in Coenzo diSorbolo.

Conclusions

Pietro Biginelli is a curious figure in the history of chem-istry. In a mere decade, he managed to leave an impact ontwo of the hottest areas of current organic chemistry,namely, the application of a multicomponent reaction tothe synthesis of biomolecules and the study of organomet-als. Next, at the age of 41, he turned to a nonacademiccareer, devoting his talents to the study of commodities andeventually ascending to a prestigious professional position.It is surprising that, after his early collaboration on natu-rally occurring arsenicals, Biginelli played only a marginalrole in the many brilliant investigations on organometalsthat led Gosio close to winning the Nobel Prize for Medi-cine in 1923.[42] We can surmise that the irregular familial

Pietro Biginelli: The Man Behind the Reaction

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situation of Biginelli did not help his relationship withGosio, a pious and religious person. However, within thegeneral oblivion to which the work of this great scientisthas fallen, the reasons are nowadays impossible to assess.In this context, Biginelli suffered even more from the rav-ages of time, and in lack of the documentation made avail-able by his living grandsons, it would have been impossibleto provide “Biginellicists” a biographic and scientific sketchof their “hero”. Finally, the eclecticism of Biginelli’s“golden decade”, when, as a stand-alone author, he pub-lished remarkable papers in the realm of natural productchemistry, organic synthesis, and bio-organic research, isalso amazing from the point of view of our current multi-disciplinary standards of research.

It is common place in science nowadays to complain that“there are too many people around smelling flowers andtoo few taking the time to plant some new ones”. Biginelliwas just the opposite and seems to have taken much morecare to plant new flowers than to enjoy their smell and pub-lish rehashed-type literature (how many variations of hismulticomponent reaction could he have easily produced?).The lack of a critical mass of articles in the different areasin which he worked, while qualifying him as a good “gar-dener”, paradoxically also contributed to the oblivion inwhich he fell after his death.

Supporting Information (see footnote on the first page of this arti-cle): Birth and wedding certificates of Pietro Biginelli, minutes fromthe Privatdozent Concorso of 1894, selection of pictures of PietroBiginelli obtained with courtesy of his descendants.

Acknowledgments

We are grateful to the many people and institutions that made itpossible for us retrieve the information underlying this article. Firstand foremost, Pietro, Iacobella, and Alberto Biginelli, the threeliving grandsons of Pietro Biginelli, and Mario Gontier, the grand-son of his nephew Alessandro Stavorengo. Next, the Comune ofPalazzolo Vercellese and that of Sorbolo for providing us with Pie-tro Biginelli’s birth and wedding certificates, respectively, and Dr.Mariapina Di Simone (Archivio di Stato di Roma) for her helpin finding the original documentation on Biginellis’ PrivatdozentConcorso. We apologize to our students for moonlighting with thehistory of chemistry and stealing time from the various ongoingprojects in our laboratories. We also thank Prof. Luigi Cerruti andAlessandro Bargoni (University of Torino), Prof. Antonio Guarna(University of Florence), and Dr. Walter Cabri (Sigma Tau, Pome-zia) for useful discussions. Finally, we are grateful to Dr. AlbertoMassarotti for his help with all the graphical parts of the article.

[1] For leading references, see: a) L. Kürti, B. Czakó, StrategicApplications of Named Reactions in Organic Synthesis, Elsevier,2005; b) J. J. Li, Name Reactions, Springer, Berlin, 2003. J. J.Li also edits a multivolume comprehensive treatise of namedreactions published by Wiley. The Biginelli reaction is discussedin J. J. Li, Name Reactions in Heterocyclic Chemistry (Ed.: J. J.Li), Wiley, Weinheim, Germany. 2005, vol. 1, pp. 509–520.

[2] D. Marotta, Chim. Ind. 1937, 19, 217.[3] O. C. Kappe, A. Stadler, Org. React. 2004, 64, 1–116.[4] http://it.wikipedia.org/wiki/Palazzolo_Vercellese.[5] A. L. Fadiga Zanatta, Il Sistema Scolastico Italiano, il Mulino,

Bologna, 1976, ISBN 7710939.

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Torino, 1895.[8] I. Guareschi, Atti Acc. Sci. Torino 1917, 52, 333–352.[9] a) G. Garbarino, Alla Scoperta di Ascanio Sobrero. Centro

Stampa Cavallermaggiore, Cavallermaggiore, 1995, pp. 190–191. See also: http://www.minerva.unito.it/Storia/ChimicaClas-sica/ChimiciItaliani/Chimici1.htm#I chimici italiani e il Risor-gimento.

[10] G. C. Tron, G. Sorba, A. Minassi, G. Appendino, manuscriptin preparation.

[11] I. Guareschi, Justus Liebigs Ann. Chem. 1883, 222, 262–300.[12] P. Biginelli, I. Guareschi, Chem. Zentralbl. 1887, 518–519.[13] A. Menozzi in La Chimica Italiana (Ed.: G. Scorrano). Avail-

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[14] A. Salm-Horstmar, Pogg. Ann. 1857, 100, 607.[15] G. Körner, P. Biginelli, Gazz. Chim. Ital. 1891, 21, 1891–000.[16] P. Biginelli, Gazz. Chim. Ital. 1895, 25, 365–373.[17] F. Wessely, E. Demmer, Ber. Dtsch. Chem. Ges. 1928, 61, 1279–

1284.[18] L. Li, N. P. Seeram, J. Agric. Food Chem. 2010, 58, 11673–

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nelli, Gazz. Chim. Ital. 1889, 19, 215–217. In ref.[19a] Biginellistates that “Dietro proposta del prof. Körner, tentai la stessareazione (Hantzsch synthesis of pyridine) sull’aldeide cin-namica, impiegando invece dell’ammoniaca alcolica, etilendiam-mina” [Following a suggestion by Prof. Körner, I tried the samereaction (Hantzsch pyridine synthesis) with cinnamaldehyde,replacing alcoholic ammonia with ethylendiamine].

[20] a) A. Guarna, L. Colli, Chim. Ind. 2011, 4, 104–108; b) M.Fontani, M. Costa, Il Tedesco Ugo Schiff Padre della Chimicaa Firenze, available at: http://www.unifi.it/dpcorg/upload/sub/ugo_schiff.pdf.

[21] G. Scorrano, Chim. Ind. 2011, 3, 104–108.[22] Personal communication between Prof. A. Guarna and G.A..[23] P. Biginelli, Gazz. Chim. Ital. 1891, 21, 337–340.[24] P. Biginelli, Gazz. Chim. Ital. 1891, 21, 455–461.[25] P. Biginelli, Ber. Dtsch. Chem. Ges. 1891, 24, 1317–1319.[26] P. Biginelli, Ber. Dtsch. Chem. Ges. 1891, 24, 2962–2967.[27] P. Biginelli, Gazz. Chim. Ital. 1893, 23, 360–416.[28] P. Biginelli, Ber. Dtsch. Chem. Ges. 1893, 26, 447.[29] R. Behrend, Ann. Chem. Pharm. 1879, 209, 5.[30] U. Schiff, Ber. Dtsch. Chem. Ges. 1882, 15, 1393–1397.[31] A. Stadler, O. C. Kappe, J. Comb. Chem. 2001, 3, 624–630.[32] K. S. Atwak, G. C. Rovnyak, B. C. O’Really, J. Schwartz, J.

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[40] The minutes of the Concorso are available in the SupportingInformation.

G. C. Tron, A. Minassi, G. AppendinoIN MEMORIAM

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was preceded by two preliminary notes (P. Biginelli, Atti. Real.Accad. Lincei 1900, 9, 210–214; P. Biginelli, Atti. Real. Accad.Lincei 1900, 9, 242–249).

[46] R. Bentley, Chem. Rev. 2000, 100, 3801–3826.[47] R. Bentley, T. G. Chasteen, Microbiol. Mol. Biol. Rev. 2002,

250–251.

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[48] F. Challenger, C. Higginbottom, L. Ellis, J. Chem. Soc. 1933,95–101.

[49] P. Biginelli, Atti del Convegno Nazionale di Chimica Industri-ale, 1925 [Chem. Abstr. 1925, 19 10302].

[50] P. Biginelli, Ann. Chim. Appl. 1914, 1, 397–400.[51] P. Biginelli, Ann. Chim. Appl. 1924, 14, 209–222.[52] a) P. Biginelli, Gazz. Chim. Ital. 1908, 38, 559–582; b) P. Bigi-

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[53] M. Pivato, Il Miracolo Scippato, Donzelli, Roma, 2011, pp.143–155.

Received: May 11, 2011Published Online: August 12, 2011