IN MEMORIAM DOI: 10.1002/ejoc.201100661 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 most with the prematurity of bio-organometallic chemistry and the important and oldest multicomponent reactions and has been scarce popularity of pyrimidines before the discovery of their extensively investigated in terms of application and mecha- biological relevance, resulted in a paradoxical situation that nism. Surprisingly, little information is available on its dis- led Biginelli to be remembered mostly for his administrative coverer, the Piedmontese chemist Pietro Biginelli, who also merits and career. By capitalizing on original documentation carried out the first studies on the purification and characteri- retrieved in archives or provided by his family, we present zation of the (in)famous Gosio’s gas. The reasons for the lack an account of the life of this forgotten chemist in the context of a current biography on Biginelli can be traced back to his of his contemporary chemical research. early demise from the research community. This, combined Introduction on the structure of the (in)famous Gosio’s gas. However, the role of pyrimidines as a building block of biomolecules Most named reactions, from Appel halogenation to was still decades to come, as was the discovery that metal Yamaguchi esterification, celebrate synthetic chemists who metabolization had implications that went well beyond the devoted their lives to the advancement of this discipline realm of toxicology. [1] and, in general, to research. The Biginelli reaction is an Furthermore, the strong scientific personality of Hugo exception, since its discoverer, the Piedmontese chemist Pie- Schiff, in whose laboratory the Biginelli reaction was dis- Special Section tro Biginelli, dedicated only a few years of his professional covered, and that of Bartolomeo Gosio, who discovered life to synthetic organic chemistry. Its longest part was, in that living organisms could metabolize, so as to say, metals, fact, focused on forensic analytical chemistry and commod- overshadowed the originality of Biginelli’s contributions to ity science and was plagued (or honored, depending on the the early history of multicomponent reactions and to bio- point of view) with growing administrative commitments, organic chemistry. Last but not least, Biginelli never started culminating in his nomination to the Direction of the a “school”, nor further pursued his germane achievements Chemical Laboratories of the State Institute of Health (Isti- in organic and organometallic chemistry, with his scientific tuto Superiore di Sanità) in Rome. Unsurprisingly, his obit- output remaining substantially confined to a series of [2] uary in La Chimica e l’Industria, the flagship professional stand-alone contributions published between 1890 and journal of the Italian Chemical Society, did not even men- 1900. These considerations underlie the oblivion in which tion the discovery of what is now known as the Biginelli he fell after his death. pyrimidine synthesis. Biginelli collaborated with some pre- Spurred by the growing relevance of the Biginelli reac- eminent scientists active in Italy at the turning of the 20th tion,[3] the lack of biographic information on its discoverer, century (Icilio Guareschi in Torino, Wilhelm Körner in Mil- and our interest in multicomponent reactions, we have capi- ano, Hugo Schiff in Florence, Bartolomeo Gosio in Rome), talized on the geographical proximity of his birthplace to discovered what is still considered the most important pyr- our university to present a biographic sketch of this now imidine synthesis, and carried out the first chemical studies forgotten chemist, investigating the context in which his seminal contributions to multicomponent reactions and to [a] Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche the structure of naturally occurring organometals was e Farmacologiche, Università del Piemonte Orientale, via Bovio 6, 28100 Novara, Italy achieved. Owing to the paucity of published documentation Fax: +39-0321-375621 on Biginelli’s life, a large part of the information we present E-mail: [email protected] was obtained through documents obtained from his three [email protected] Supporting information for this article is available on the living grandsons, whose help was instrumental for our WWW under http://dx.doi.org/10.1002/ejoc.201100661. work. Only a selection of the documentation that the Bigi- Eur. J. Org. Chem. 2011, 5541–5550 © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5541 IN MEMORIAM G. C. Tron, A. Minassi, G. Appendino nelli’s family made available to us is presented in this article, terna played for the musical education of Viotti, who shared but a larger choice is provided in the Supporting Infor- with Biginelli a modest origin in a country village.[6] Don mation that accompanies this article. Luigi Biginelli (1843–1898) wrote a scholarly monograph on the history of Benedictines in the Middle Age, still the reference book on the topic, and founded in 1869 the Jour- The Early Years: Palazzolo Vercellese, Torino, nal L’Ateneo religioso scientifico letterario artistico illus- and Milano trato, a multidisciplinary publication embedded with posi- tivistic culture, and eventually became the rector of the [7] Family and Youth Clerical University of Torino. Pietro Giacomo Biginelli (Figure 1) was born on July 25, 1860 in Palazzolo Vercellese, a small country town on the Eastern continental border of the Kingdom of Sardinia, University Studies soon to become the Kingdom of Italy. Palazzolo Vercellese, today in the province of Vercelli, Piedmont, is located in In 1881, Biginelli entered the University of Torino, two the rice belt of Europe, the wet area between Piedmont and years after the departure of Hugo Schiff, who, after two Lombardy where two thirds of the European production of unhappy years (see infra) as Professor of General Chemis- rice is still centered, and had 2084 inhabitants in 1861.[4] It try and Director of the Pharmaceutical Laboratory, had fi- borders Fontaneto Po, where the celebrated violinist and nally managed to return to Florence.[8] Unlike other Italian composer Giovanbattista Viotti, one of the very few con- towns, and despite the presence of Ascanio Sobrero (1812– temporary composers estimated by W. A. Mozart, was born 1888), one of the most famous Italian chemist of the 19th 100 years earlier (May 12, 1755). century, 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 and his studies on terpenoids (immortalized by the name sob- rerolgiventoanα-pinene derivative still used in medicine), but these achievements were not enough to secure him an academic position in his alma mater, probably because his fervent Catholicism did not make him popular with the dominating anticlerical politic pursued in those years by the Piedmontese government. As a result, in 1855, the vacant chair of chemistry was not assigned to Sobrero but to Raf- faele Piria (1814–1865), a revolutionary anticlerical figure Special Section who pursued politics rather than research in the decade he spent in Torino.[9] After his death, apart from a brief stay of Emanuele Paternò in 1871–1872, only minor figures took the chair until the arrival of Hugo Schiff in 1877, replaced two years later by Icilio Guareschi (1847–1918). This poly- math of Emilian birth and Tuscan formation, along with Michele Fileti (1851–1914), finally brought chemical pres- tige to the University of Torino. Guareschi was an eclectic scientific personality, whose current fame is due to the α-pyridone synthesis (Guareschi– Figure 1. A signed picture of 29-year old Pietro Biginelli. Thorpe reaction), to a method for the preservation of his- torical manuscripts, and to a monumental history of the On his birth certificate, Pietro’s father (Giuseppe Bigi- Italian chemistry.[10] Biginelli worked under the assistance nelli) is identified as a “baker” (prestinaio, from the latin of Guareschi on the polyhalogenation of naphthalene by prestinum, mill), as is his mother (Dorotea Genovese). At the sequential agency of bromine and chlorine. At that time, that time, only one fifth of the Italian population was al- Guareschi was one of the leaders in the study of naphtha- phabetized, and the first law granting universal public edu- lene and its chemistry, a topic he had scholarly reviewed in cation (for two years only, Casati’s law of October 12, 1859) 1883 in a very long note published in Liebigs Annalen.[11] was being slowly implemented, mainly in large towns.[5] It Biginelli graduated in Chimica e Farmacia at the University is therefore surprising that Pietro Biginelli, on account of of Torino in 1886, and the study on the polyhalogenation his modest origin in a small village, had access to higher of naphthalene was eventually published a year later.[12] Al- education. We can only surmise that his uncle, the influen- though not particularly original, this research is technically tial priest Luigi Biginelli might have helped his bright ne- highly demanding because of the tedious fractionated phew to complete his education in Torino, in a striking re- crystallizations involved in the separation