1906 - An Auspicious Year for Organic Chemistry and for Jinan University

Martin G. Banwell

Director

Institute for Advanced and Applied Chemical Synthesis,

College of Pharmacy, Jinan University, Zhuhai 519070, China

ABSTRACT: 1906 saw the founding of Jinan University (JNU) and it was also the year in which at least four major reactions associated with organic chemistry were discovered. As such 1906 represents a key point-of-origin for the now emergent and ongoing research efforts in organic synthesis being undertaken on the Zhuhai and Shipai campuses of JNU. A good proportion of these activities occur within the Institute for Advanced and Applied Chemical Synthesis (or IAACS) that operates under the broad umbrella of the College of Pharmacy, a major faculty within the University. This short article describes both the four reactions discovered in 1906, their refinement and current applications as well as a description of the parallel development of JNU over the same 120 year period and that has allowed for the establishment of the IAACS and its focus on new research efforts in organic chemistry.

"合抱之木，生於毫末" 

(hé bǎo zhī mù, shēng yú háo mò),

"A tree as thick as a person can embrace grows from a tiny sprout"

from the ancient Daoist text Tao Te Ching (道德经) by Laozi.

"Mighty oaks from little acorns grow"

from the epic poem "Troilus and Criseyde" by Geoffrey Chaucer, 1374

Great things start from small beginnings, whether these be institutions, theories, disciplines or technologies. As was the case with so many of the other years of La Belle Époque, 1906 saw an extraordinary range of discoveries that blossomed dramatically from that point and that continue to have profound impacts on society in 2026. These include, to name just a few, the first certified heavier-than-air manned flight, the first voice and music radio broadcasts and the introduction of the BCG vaccine for treating tuberculosis. There were also major new chemical reactions reported in 1906 along with the foundation of the author's home institution that now hosts the Institute for Advanced and Applied Chemical Synthesis (IAACS). This article traces how these chemical discoveries and Jinan University (JNU) have developed in the intervening 120 years.   

1906 - A Bonanza Year for the Discovery of New Chemical Reactions

In 1906 the four key reactions in organic chemistry discussed below were reported, either for the first time or as refinements of earlier and less well understood processes. As such this year can be considered as something of a bellwether one in the then explosive era of discovery for the discipline. The four reactions in question, and that are considered in alphabetical order,  continue to be exploited in a multitude of settings today and not least because of their robustness and/or the refinements of them that have significantly enhanced their utility.

The Bargellini Reaction

This eponymous reaction was developed by the Italian chemist Guido Bargellini who recognized that an earlier report on this process had mis-identified the product. So, in its properly defined form,¹ this reaction (Scheme 1) involves treating a mixture of phenol (1), acetone (2) and chloroform (3) with sodium hydroxide and thereby affording an a-phenoxy carboxylic acid. This three-component coupling reaction (or 3MCR to use modern parlance) probably involves addition of the trichloromethyl anion (derived through deprotonation of chloroform by sodium hydroxide) to acetone and with the resulting oxyanion 4 cyclizing to give the dichlorodimethyl oxirane 5. Nucleophilic ring-opening of the last compound by the phenoxy anion leads to adduct 6 that collapses to the corresponding acid chloride that itself hydrolyses to afford the observed acid 7.

Scheme 1: An early example of a Bargellini reaction and the likely intermediates involved

When the phenol associated with the original process is replaced by either a b-amino alcohol (8) or a vicinal diamine (9) (Scheme 2) then morpholinones (10) or piperazinones (11), respectively, are formed. Such conversions have been particularly useful in pharmaceutical development.²

Scheme 2: The application of the Bargellini reaction to the synthesis of

morpholinones and piperazinones

Ketones other than acetone as well as analogues of the haloform 3 have been deployed in Bargellini-type reactions. A significant "variant" is the Jocic or Jocic-Reeve reaction in which trichloromethylated alcohols react with a range of nucleophiles in protic solvents and in the presence of a base to give a range of α-substituted carboxylic acids.³ These conversions probably proceed in a manner similar to that associated with the reaction sequence 4→5→6 (Scheme 1). Extensions of such chemistry to the synthesis of homochiral α-amino acids have been described by Corey and Link.⁴ 

The Chichibabin Pyridine Synthesis^5-8 

The Russian organic chemist Aleksei Chichibabin reported⁵ that the reaction of certain aldehydes and/or ketones in the presence of ammonia or an equivalent thereof provides access to variously substituted pyridines. The complexities of the process and the various side reactions that can occur has resulted in extensive attempts to optimize this synthesis. Studies directed toward such ends carried out in the late 1940's⁶ and early 1950's⁷ have also established a possible mechanism for the process. So, as shown in Scheme 3, when benzaldehyde (12) and acetophenone (13) are reacted with one another in the presence of ammonium acetate in refluxing acetic acid then pyridine 14 is obtained in 68% yield.⁷ This conversion is believed to involve a Claisen-Schmidt condensation of substrates 12 and 13 that leads to chalcone 15 while another molecule of the latter substrate reacts with ammonium acetate to give enamine 16. Michael addition and Schiff-base condensation reactions (no specific order implied) involving products 15 and 16 would then lead to a dihydropyridine such as 17 and this then undergoes aerial oxidation to deliver the observed product 14. Variations on such pathways may be operative⁸ depending on the specific substrates and reaction conditions involved.

Scheme 3: An early example of a Chichibabin pyridine synthesis and a likely mechanism for the formation of product 14.   

Extensive investigations of catalysts and reaction conditions continue to be pursued in efforts to tune the selectivities of such processes^8,9 while a recent study has demonstrated how biomimetic and intramolecular Chichibabin reactions can be used to great effect in natural product synthesis.¹⁰ 

The Goldberg Reaction

In its simplest form this reaction, which was reported^11,12 by the Jewish/Russian and female chemist Irma Goldberg, involves the copper(I)-mediated cross-coupling of aryl halides with aromatic amines or amides and so affording N-arylated products. An original and compelling example is shown in Scheme 4 with the coupling of bromobenzene (15) and anthranilic acid (16) leading, after just 3 hours in refluxing nitrobenzene, to product 17 in near quantitative yield.    

Scheme 4: An original example of a Goldberg reaction

A more contemporary example¹³ involving a β-lactam as substrate is shown in Scheme 5. So, cross-coupling of aryl iodide 18 with compound 19 in the presence copper(I) iodide, potassium carbonate and the ligand N,N-dimethylethylenediamine (DMEDA) affords the N-arylated β-lactam 20 in 96% yield.

Scheme 5: A contemporary example of a Goldberg reaction

A modern and extensively deployed variant of the Goldberg reaction is its Buchwald-Hartwig counterpart that only requires catalytic quantities of palladium to effect analogous conversions.¹⁴ Additionally, the Buchwald-Hartwig reaction generally proceeds under relatively mild conditions and refinements of it have allowed for remarkably low catalysts loadings to be employed at low temperatures and with impressive functional group tolerances being observed.

Another widely exploited variant leading to N-arylated amines is the Chan-Evans-Lam reaction¹⁵ in which aryl boronic acids replace the corresponding aryl halide and Cu(II) species replace metallic copper. Such reactions can often be carried at ambient temperatures and also work in air meaning that catalytic quantities of the Cu(II) species can be used.

Interestingly, combinations of copper and palladium species can be used in related Ullmann cross-coupling reactions for the formation of unsymmetrical biaryls and related species.¹⁶

The Tishchenko Reaction

This disproportionation reaction between two aldehydes (both enolizable and non-enolizable forms can participate) leads, via complexation and then intramolecular 1,3-hydride transfer steps, to the formation of esters and can be promoted by a range of agents such as alkoxides especially the mildly Lewis acidic aluminum or magnesium forms. In one of its original incarnations, as reported by the Russian chemist Vyacheslav Tishchenko^17-20 and shown in Scheme 6, benzaldehyde (12) reacts, in the presence of the sodium salt of benzyl alcohol, to give ester 21. Intramolecular variants lead to lactones.²¹ The reaction is related to the Cannizzaro, Merwein-Ponndorf-Verley and Oppenauer processes and these can compete with it.   

Scheme 6: An early example of a Tishchenko reaction

The utility of the Tishchenko reaction has been greatly enhanced in recent times²² including, inter alia,  through the selective cross-coupling of two different substrates^23,24 as shown, for example, in Scheme 7. In this case two distinct benzaldehydes 22 and 23 couple in the presence of di-n-butylmagnesium and the thiol catalyst/ligand L to afford ester 24 in an impressive 93% yield.

Scheme 7: A crossed Tishchenko reaction

The Evans variant of the Tishchenko reaction^25,26 has come to the fore in recent times and provided a valuable means of selectively forming anti-configured 1,3-diol mono-esters.  The remarkably efficient conversion 25 → 26 shown in Scheme 8²⁵ and mediated by samarium(II) iodide highlights the value of the so-called Evans-Tishchenko process.  

Scheme 8: An example of an Evans-Tishchenko reaction

Contemporary Considerations and Assessments

It is interesting to consider the atom economics and "greeness" of the above-mentioned reactions using contemporary metrics/concepts. The Tishchenko reaction is particularly notable in this regard because it displays 100% atom economy and there is no waste. Such features have attracted considerable attention especially when considered alongside the capacity to engage, under low catalyst loadings, biomass-derived aromatic aldehydes in this process and so generating biodegradable polyesters.²⁷ Similarly, the contemporary use of more environmentally appropriate solvents, of ligands and of microwave irradiation techniques have all served to make the Goldberg reaction ever more effective/broadly applicable¹⁵ and so, inter alia, less-energy demanding. The use of abundant copper rather than the palladium required in the Buchwald-Hartwig variant also offers some advantages by virtue of the reduced environmental and toxicological of impacts of the former metal.

Whilst in its original and early forms the Chichibabin pyridine synthesis suffered from a lack of selectivity and, therefore, attendant inefficiencies, modern refinements of the process have enhanced its sustainability profile considerably. Given the potential to employ biomass-derived substrates in the synthesis of at least certain substituted pyridines as well as the atom economics of the process there would seem to be good prospects for further enhancing the "green credentials" of the Chichibabin pyridine synthesis.   

The traditional Bargellini reaction is perhaps the least green of the four reactions considered here because, inter alia, of the large amounts of chloroform and concentrated aqueous sodium hydroxide used. However, offsetting this are its multi-component features that allow for the one-pot formation of products that might otherwise require a multi-step reaction sequence to assemble.  

Other Chemical Discoveries and Events in 1906

1906 also saw the development of chromatography by the Russian botanist Mikhail Tsvet, the award of the Nobel  Prize in chemistry to Henri Moissan for his discovery of fluorine and the identification of magnesium in chlorophyll, this representing the first detection of a metallic element occurring within biological tissue.   

1906 - The Genesis of Jinan University and the Emergence of Organic Chemistry Within

The Jinan Academy, the progenitor to JNU, was proposed in 1906 by Duanfang, the Viceroy of Liangjiang, and thereafter received the approval of the Guangxu Emperor. The intention of the Academy was to disseminate learning as extensively as possible as well reaching out to the Chinese diaspora ("Jinan" literally means "reaching southward"). In the following year the academy was established in Nanjing and in 1927 it was rebadged as the National Jinan University and by that time was located in Shanghai. In 1949, and following the foundation of the People's Republic of China, the university was closed and its schools transferred or merged with other institutions including Fudan University. In 1958 the University (now JNU) was re-established as a national public university in the Southern Chinese metropolis of Guangzhou and was the first university in China to recruit foreign students. As a consequence it now has one of the largest contingents of international students in the country. In its current (2026) form, and distributed over five campuses, JNU a offers courses in a wide range subject areas and now hosts more than 200 research stations, institutes and laboratories. Not only is JNU one of the oldest universities in China it is also a so-called "Double First Class" one.

The beginnings of research activities in organic chemistry at JNU probably emerged in 1929 in Shanghai with the establishment of the College of Science. After the university's re-establishment in Guangzhou in 1958 specialized chemical research programs began to emerge and with the creation of the College of Science and Engineering in 1985 the focus of organic chemistry activities was on polymer chemistry and biomaterials. From the 1990s to the 2010s JNU's rapidly expanding efforts in the life sciences, in pharmacology and in natural products and medicinal chemistries resulted in the development of even greater interests in organic chemistry. As a result and as part of an effort to further enhance efforts in the discipline, JNU and the College of Pharmacy (itself formed in 2001) established the IAACS in late 2018. From its embryonic beginnings at that time, and through the generous support of the Central Chinese Government and various counterparts within the Guangdong province, a dedicated and chemistry-themed research building (Figure 1) has now been established on the Zhuhai campus of JNU. The major proportion of the experimental work currently being undertaken within the IAACS now occurs on this site.                       

Figure 1: The JNU and IAACS logos (left) and the dedicated new chemistry building (right) on the Zhuhai Campus of JNU 

The State-of-Play in 2026

Like JNU itself, in 2026 the IAACS has a distinctly international flavor as exemplified by the recent  appointment to its staff of the eminent organic chemist Samir Zard (Professor Emeritus of the Ecole Polytechnique in Paris, France). Professor Zard is engaged in an extensive collaboration with the Australian/Italian organic chemist A/Professor Lorenzo White (Figure 2) (also a member of the JNU faculty) and that is concerned with the exploitation of free-radical chemistry techniques for the assembly of complex organic compounds including biologically active natural products. Both Zard and White have recently received significant major provincial and central Chinese government awards to support their research.

Figure 2: Professor Samir Zard (left) and A/Professor Lorenzo White (right), key international members of the IAACS at Jinan University

Dr Róbert Reiberger, a graduate of Charles University, located in Prague in the Czech Republic, has also recently joined the IAACS and is collaborating with Professor Martin Banwell (formerly of the Australian National University) on the valorization of biomass (particularly chitin^28,29) through the generation of new platform molecules (Figure 3).

Figure 3: The structure of the abundant, nitrogen-containing biopolymer chitin and the platform molecules that can be derived from it through the pyrolysis of the acid-treated material

Another focus of the Reiberger/Banwell collaboration is on the development of semi-quantitative scales for ranking different types of non-covalent interactions.

Members of the senior staff of the IAACS are also involved in external collaborations with colleagues both within China and overseas. In the latter category, for example, A/Professor White is working with Professor Margaret Brimble FRS (University of Auckland, New Zealand) on the development of new methods for the highly selective modification of complex and biologically active poly-peptides. This project is being funded from both Guangdong Provincial Government and New Zealand Government sources.

Within the IAACS there is also a vibrant group of Chinese students studying, through the applications of experimental chemistry, for either their Masters or PhD degrees. In this connection it is interesting to note that in 1906 Edmund James, the then President of the University of Illinois and commenting on educating the young people of China, stated that their education in America would give it (viz. the USA) "moral, intellectual and commercial influence". In 2026 and on his visit to Washington, Chinese President Xi Jinping stated that he hoped 100,000 young Americans would visit or study in China over the coming five years and with the result that this would create "a new generation of ambassadors".³⁰ There is no doubt about the wisdom of both of these statements given the prescience of the first and likely outcomes of the second. This is all to say that co-operation in science is pivotal to its development and its translation into societal benefits. The IAACS aspires to continue to play its part in furthering the JNU tradition of reaching out "from China to the rest of the world"³¹ through the on-the-ground application of this most important principle and the execution of ongoing and high-level studies in organic chemistry.

Conclusion

The quotes by Laozi and by Chaucer presented at the start of this article not only neatly capture how the four organic chemistry reactions discovered in 1906 have developed from single-lab efforts of 120 years ago into indispensable and widely-deployed techniques, modern variants of which have proven pivotal, for example, in pharmaceutical development.¹⁴ Similarly, the emergence, in 1906, of the idea of creating an educational system to assist China in reaching out to the world has blossomed, over the same time-frame, into the dynamic institution we now know as Jinan University. Given such extraordinary trajectories it would seem almost impossible to imagine how this educational and research landscape might look in twenty years time let alone in another eighty. Of course, that will never stop organic chemists from trying to do so.³²  

Acknowledgements

The author is most grateful to Jinan University, the Chinese Central Government and the Guangdong Provincial Government for the outstanding support they have provided in helping to establish the IAACS. A/Professor Ping Lan, a MSc graduate of JNU, a PhD graduate of the Australian National University and now a staff member of Jinan University, has provided exceptional assistance in establishing the IAACS not just through his astute logistical and administrative efforts but also through his most impressive scientific ones.

References

1.G. Bargellini, "Azione del cloroformio e idarto sodico sui fenoli in soluzione nell'acetone", Gazz. Chim. Ital. 1906, 36, 329–338.

2.M. Serafini, I. Murgia, M. Giustiniano, T. Pirali and G. C.Tron, "The 115 Years Old Multicomponent Bargellini Reaction: Perspectives and New Applications",  

Molecules, 2021, 26, 558.

3.W. Reeve, J. R. McKee, R. Brown, S. Lakshmanan and G. A. McKee, "Studies on the rearrangement of (trichloromethyl)carbinols to α-chloroacetic acids", Can. J. Chem. 1980, 58, 485–493 and references cited therein.

4.E. J. Corey and J. O. Link, "A General, Catalytic, and Enantioselective Synthesis of α-Amino Acids", J. Am. Chem. Soc. 1992, 114, 1906–1908.

5.A. E. Chichibabin, "Hantzsch (dihydro) pyridine synthesis: Kröhnke pyridine synthesis", J. Russ. Phys. Chem. Soc. 1906, 37, 1229.

6.R. L. Frank and R. P. Seven, "Pyridines. IV. A Study of the Chichibabin Synthesis", J. Am. Chem. Soc. 1949, 71, 2629–2635.

7.M. Weiss, "Acetic Acid-Ammonium Acetate Reactions. An Improved Chichibabin Pyridine Synthesis", J. Am. Chem. Soc. 1952, 74, 200-202.

8.R. S. Sagitullin, G. P. Shkil', I. I. Nosonova and A. A. Ferber, "Synthesis of pyridine bases by the Chichibabin method (review)", Chem. Heterocycl. Compd, 1996, 32, 127-140.

9.Z. Wang, Comprehensive Organic Name Reactions and Reagents, 2010, 140, pp. 635-638 (John Wiley and Sons).

10.B. B. Snider and B. J. Neubert, "Syntheses of Ficuseptine, Juliprosine, and Juliprosopine by Biomimetic Intramolecular Chichibabin Pyridine Syntheses", Org. Lett. 2005, 7, 2715-2718.

11.I. Goldberg, "Ueber Phenylirungen bei Genegnwart von Kupfer als Katalysator", Ber. Dtsch. Chem. Ges. 1906, 39, 1691-1692.

12. Interestingly, Irma Goldberg is one of the earliest female chemists to have a reaction named after her (see J. A. Olson and K. M. Shea, "Critical Perspective: Named Reactions Discovered and Developed by Women", Acc. Chem. Res. 2011, 44, 311-321).

13.J. Lange, A. C. Bissember, M. G. Banwell and I. A. Cade, "Synthesis of 2,3-Dihydro-4(H)-quinolines and the Corresponding 4(1H)-Quinolones via Low-Temperature Fries Rearrangement of N-Arylazetidin-2-ones", Aust. J. Chem. 2011, 64, 454-470. 

14. P. A. Forero-Cortés and A. M. Haydl, "The 25th Anniversary of the Buchwald-Hartwig Amination: Development, Applications and Outlook", Org. Process Res. Dev. 2019, 23, 1478-1483 and references cited therein.

15.S. Bhunia, G. G. Pawar, S. V. Kumar, Y. Jiang and D. Ma, "Selected Copper-Based Reactions for C-N, C-O, C-S, and C-C Bond Formation", Angew. Chem. Int. Ed. 2017, 56, 16136-16179 and references cited therein. 

16.F. Khan, M. Dlugosch, X. Liu and M. G. Banwell, "The Palladium-Catalyzed Ullmann Cross-Coupling Reaction: A Modern Variant on a Time-Honored Process", Acc. Chem. Res. 2018, 51, 1784-1795.

17. V. E. Tishchenko, J. Russ. Phys. Chem. Soc. 1906, 38, 355.

18. V. E. Tishchenko, J. Russ. Phys. Chem. Soc. 1906, 38, 482.

19. V. E. Tishchenko, Chem. Zentralbl. 1906, 77, 1309.

20. V. E. Tishchenko, Chem. Zentralbl. 1906, 77, 1552.

21.For an extensive review of the Tishchenko reaction, see: A. M. P. Koskinen and  A. O. Katana, "The Tishchenko Reaction", Org. React. 2015, 86, 107-409.

22.R. Dhanya, T. Shilpa, S. Saranya and G. Anilkumar, "Recent Advances and Propsects in the Tishchenko Reaction, Chem. Select. 2020, 5, 754-763.

23.Y. Hoshimoto, M. Ohashi and S. Ogoshi, "Nickel-Catalyzed Selective Conversion of Two Different Aldehydes to Cross-Coupled Esters",  J. Am. Chem. Soc. 2011, 133, 4668-4671.

24.S. P. Curran and S. J. Connon, " The Thiolate-Catalyzed Intermolecular Crossed Tishchenko Reaction: Highly Chemoselective Coupling of Two Different Aromatic Aldehydes", Angew. Chem. Int. Ed. 2012, 51,10866-10870.

25.D. A. Evans and A. H. Hoveyda, Samarium-Catalyzed Intramolecular Tishchenko Reduction of b-Hydroxy Ketones. A Stereoselective Approach to the Synthesis of Differentiated Anti 1,3-diol Monoesters", J. Am. Chem. Soc. 1990, 112, 6447-6449.

26.K. J. Ralson and A. N. Hulme, "The Evans-Tishchenko Reaction: Scope and Applications",  Synthesis, 2012, 44, 2310-2324 and references cited therein.

27. See, for example, H. Qiang, X. Liang, W. Wang, J. Jiang, J. Li, J. Du, Y. Zhu, "Exploiting Catalytic Steric Hindrance for Enhanced Tishchenko Polymerization: Toward Biorenewable Aromatic Polyesters",  Macromolecules, 2024, 57, 10576-10585 and references cited therein

28.M. Nikahd, J. Mikusek, L.-J. Liu, M. L. Coote, M. G. Banwell, C. Ma and M. G. Gardiner, "Exploiting Chitin as a Source of Biologically Fixed Nitrogen: Formation and Full Characterization of Small Molecule Hetero- and Carbo-cyclic Pyrolysis Products", J. Org. Chem. 2020, 85, 4583-4593.