GENERAL ARTICLE Research Work: Accidental, Repetitive or Fundamental?* In the Light of Benzoin Condensation: Part 1 Ahana Saha, Chandan Saha and Suchandra Chakraborty Eminent educators, as well as common people, often question why most of the research work is somewhat repetitive and there are very few options for fundamental research in dev oping science. So, the elementary question is, “what is funda- mental research?”. Scientific research is driven by an exten- sion of previous research. If we demask the word ‘research’, , further searching’, it obviously leads to repetitive work. But this repetitive work must be driven by some fundamental values of the researcher. In this article, the authors try to ad- dress this conflict between repetitive research and fundamen- tal research in light of the never-ending journey of benzoin condensation, which has continued for 150 years. With the help of this example, it can be established that the fundamen- tal outcome of the research can be achieved via a continuous i extension of the research process. 1. Introduction In developing science, research scholars often come across state- ments such as: In modem India, we have several excellent re- search institutions like the Universities, IITs, national laborato- ries, etc. with well-equipped provisions. Still, we are in dire need of much better infrastructural facilities, and we must carry out fundamental research with more difficult problems. Unfortu- nately, most of us are habituated to working on somewhat repet- itive problems that are not at all a part of fundamental research. Such research work is not at all applicable. It is simply for a *Vol.28, No.4, DOL: hitps://doi.org/10.1007/s12045-023-1587-3 Ahana Saha is an SRF at the Department of Chemistry, Pondicherry University She works on organic synthesis. ‘Chandan Saha retired as a professor of chemistry from CSTM, Kolkata. Interests: ‘Synthetic organic chemistry. ad Suchandra Chakraborty is an assistant professor of chemistry at BESC, Kolkata Interests: Synthesis of heterocyclic compounds. Keywords, Fundamental research, applied research, benzoin condensation, organic chemistry, amygdalin 633GENERAL ARTICLE Fundamental research, often addressed as pure research or basic research, refers to the scientific endeavour to advance scientific theories for improved understanding or forecasting of natural or other phenomena black-white representation in some scientific journals, and this is not accountable for improving our society. And undoubtedly, if we want to be at the cutting edge, we have to be innovators and originators with the concept of fundamental research work Such statements are not just made by common people but also by several uninformed scientists and educators. ‘Now the quite inevitable question is, what do we mean by the term ‘fundamental research’? The answer is: Fundamental re- search, often addressed as pure research or basic research, refers to the scientific endeavour to advance scientific theories for im- proved understanding or forecasting of natural or other phenom- ena. On the contrary, ‘applied research’ uses scientific theories to develop technology or techniques to mediate and modify nat- ural or other phenomena. One can easily say that fundamental research fuels applied science’s innovations, and both of them are interconnected with development. In this connection, it may be informed that selecting a topic can be the most challenging part of a research assignment, Usually, in most cases, our instructor will give us a rough guideline as to what can be the research question and what we can do to execute the research work. If we think appropriately, it will be appar- ent that the instructor's guidelines originate from his/her research guide. However, in some cases, a topic of personal interest is se- lected. However, such personal interests are not abrupt but orig- inate from some unexpected observations during studies on rou- tine work. Once we have identified the topic, a literature survey becomes necessary. After a proper and elaborate literature survey, we get the direction of our research work. Failure to work within these guidelines may also result, But this failure will again di- rect the proper pathway to carry out the research, Evidently, then research work is undoubtedly repetitive work. An appropriate analysis of the word ‘research’, which means ‘further searching’, also indicates so. In addition, we think it is better to say that ‘re- search’ is simply for the sake of ‘research’ and whether it is the so-called fundamental or not does not matter. However, a scien tific researcher is prompted by a driving inquisitiveness about theGENERAL ARTICLE unknown, which is undoubtedly an extension of previous research work. Discovery of truth and understanding of nature are her/his objectives. A researcher's professional reputation depends upon the originality and soundness of the work. The individuality and creativity of the researcher are usually stamped on each of her/his efforts, just as an artist’s style is apparent in her/his work Let us look closer at the never-ending journey of ‘benzoin con- densation’, which began in 1824. The cyanide-catalysed benzoin condensation was first reported as early as 1824 by Carl Heinrich Strange [1], and since then, it has been the subject of many inves- tigations. Benzoin condensation was then described in 1832 [2] by Justus von Liebig and Friedrich Wohler during their research on bitter almond oil. The catalytic version of the reaction involv- ing cyanide was later developed by Nikolay Nikolaevich Zinin in the late 1830s [3]. Thus, the journey of benzoin condensation be- gan, and the research on this topic is still ongoing. Let us try to track this journey sequentially, in short, and authorise the scien- tists and educators to judge whether it is repetitive or fundamental research. 2. The Beginning: Is it an Accident? As we mentioned, Strange (in 1824) [1] first reported about the cyanide-catalysed benzoin condensation in Buch. Rep. Pharm. But such an early paper is not available in the archives, so it be- comes quite impossible to discuss his study. However, during their research on bitter almond oil in 1832, Justus von Liebig and Friedrich Wohler described benzoin condensation [2]. The two names, Justus von Liebig and Friedrich Wohler, have their own signature marks in the world of chemistry and are considered the principal founders of organic chemistry. Justus von Liebig estab- lished the first laboratory for experimental chemistry where qual- itative and quantitative analysis followed by organic preparations were taught systematically. Soon this experimental laboratory be- came well recognised, and students began to flock to his labora- tory from all parts of Europe, among whom some turned out to ‘The cyanide-catalysed benzoin condensation was first reported as early as 1824 by Carl Heinrich Strange, and since then, it has been the subject of many investigations During their research on bitter almond oil in 1832, Justus von Liebi; and Friedrich Wohler described benzoin condensation, igGENERAL ARTICLE Figure 1. Structures of cyanic acid and fulminic ac id, France, Pierre Robiquet, extracted a crystalline nitrogenous material called amygdalin from the almond nut, which © was also known to -ontain a poison called prussic acid. Cyanic acid: H N=Cc-O Fulminic acid: @ oO H-C=N-O be notable scientists of the next generation. Liebig’s own inves- tigations covered a wide range of interests, and one of his most famous collaborators was Friedrich Wohler. The friendship be- tween Liebig and Wohler grew stronger (in 1825) after they ami- cably resolved a dispute over two substances, i.e., cyanic acid and fulminic acid, that apparently had the same composition but very different characteristic features. The silver compound of fulminic acid, investigated by Liebig, was explosive in nature, whereas sil- ver cyanate, as Wohler found, was quite stable. In this context, let us have a look at the structures of cyanic acid and fulminie acid [4] (Figure 1). Let us have a look at the starting point of their research on bitter almond oil, where they described benzoin condensation. In June 1832, Liebig leamed that Wohler’s first wife passed away soon after giving birth to their child. He wrote a noble letter (15 June 1832) of consolation to his friend [5] (see Box 1) From this tragedy emerged one of the most important collabora- tive papers in the history of chemistry. Liebig and Wohler were not the first chemists or pharmacists to have investigated the com- position of bitter almonds. When they began their research, the status of knowledge on this topic was as follows: In 1823, the German pharmacist Carl Heinrich Strange identified the crystals formed from the aerial oxidation of oil of bitter almonds as ben- zoic acid [1]; he also extracted the same from the cherry laurel. In France, Pierre Robiquet [6] also extracted a crystalline nitroge- nous material called amygdalin from the almond nut, which was 636GENERAL ARTICLE also known to contain a poison called prussic acid, He found out that sweet almonds didn’t contain amygdalin; when oxidized with nitric acid, amygdalin gave benzoic acid. Amygdalin, with water, gave no smell of bitter almonds. (Here, a point to be noted is that prussic acid is hydrogen cyanide.) Box 1, Letter From Liebig to Wobler “My poor dear Wahler, who could have predicted such a dreadful misfortune after so happy a confinement; how empty are the words of consolation after such a loss. I cannot tell you; I cannot express the feelings I hhad on receiving the news; it was as if Thad actually experienced loss myself. When I think to myself how satisfied and lucky you were in your domestic arrangements and of the affection and love you had for one nother, and now this shocking dismemberment of all your hopes, this foundering of all your wishes! The 200d wife, so young, so full of life and goodness, and for her parents and yourself so irreparable. Come to us, dear Wobler if we can provide any consolation and help to heal your grief. To stay in Cassel at such a time will be injurious to your health. We can busy ourselves with something. Ihave bought some amygdalin from Paris (from Pelouze] and I shall have some 25 pounds of bitter almonds to work on, You must not travel, you must get occupied, but not in Cassel. I feel your distress will disappear in work and, it will also be better if your sorrow is shared with a friend...come to us; I expect you by the end of the week.” Liebig and Wohler obtained the almond oil in a much purified form through a rigorous distillation process, and they relied on consistent specific gravity readings as a criterion of purity as its boiling point (179°C) was beyond the reach of the graduated scale of the thermometer used in those times. The crude almond oil | Liebig and Wehler's was supplied to them by Gay-Lussac’s favourite student Jules studies established the idea that certain groups Theophile Pelouze [5]. This purified oil was later verified to be benzaldehyde, When they dissolved amygdalin in water and | ransmited unchanged treated it with crushed or emulsified sweet almonds, it yielded | through chemical the oil of bitter almonds. But when the mixture was allowed transformations and to boil, it coagulated and didn’t form the oil of bitter almonds. hese us, Ruch as the ‘They investigated the structure of benzaldehyde while treating it | sed to caplain a whole with a series of chemical reactions; and found out that the central | range of chemical ‘core’ of the molecule remained intact. Thus their studies on bit- | reactions and the ter almond oil further established the idea that certain groups of ‘molecules formed from atoms—what they called—‘radicals’ (what we might call ‘rea of atoms called might beGENERAL ARTICLE OH l Vs oKo ferment ~~ win 7" hyerolyals { _] + HON + Glucose Ho\ 0, oHC~ ~~ _prussic acid 0H bitter almonds oil amygdalin NC In 1832, FL. Winckler [8] found that crude oil of bitter almonds, containing hydrocyanic acid with hydrochloric acid, forms a new acid called mandeliec acid. Scheme 1. Fermentation of amygd: tive groups’ or “functional units’) might be transmitted unchanged through chemical transformations (in this case, the benzoyl group in benzaldehyde, benzoic acid, benzoyl halides, benzamide) and these units, such as the benzoyl unit could be used to explain a whole range of chemical reactions and the molecules formed from them. This opened the door for organic structure determina- tions. According to modem science [7], amygdalin is decomposed by a ferment (an enzyme) present both in sweet and bitter almonds (but not in the boiled emulsion of almonds!), and besides oil of bitter almonds and prussic acid, grape sugar is formed (Scheme 1, Amygdalin was the first example of a glycoside, Wohler and Liebig recognized that the action of the ferment, which they called emulsin, was similar to that of yeast on sugar (which Berzelius has attributed to a peculiar, catalytic force). In this context, it may be mentioned that amygdalin is classified as a cyanogenic glyco- side because each amygdalin molecule includes a nitrile group, which can be released as the toxic cyanide anion by the action of aB-glucosidase. Eating amygdalin will cause it to release cyanide in the human body and may lead to cyanide poisoning. In 1832, FL. Winckler [8] found that crude oil of bitter almonds, containing hydrocyanic acid with hydrochloric acid, forms a new acid called mandelic acid. In a note (1836), Liebig suggested that the hydrocyanic acid is hydrolysed into ammonia and formic 638GENERAL ARTICLE hydrolysis 2 HC + ONG 0-H formic acid Hee’ combination 9 O-H OH mandelic acid ‘OH Scheme 2. Generation of mandelic acid. OH Ho. HO. H + Ho. 0° HO. 0, Hs NC amygdalin further NC Hooc mandelic acid Scheme 3. Mandelic acid from amygdalin. acid, which combines with the benzaldehyde to yield mandelic acid (Scheme 2). Strictly speaking, mandelic acid is formed from amygdalin through the acid-catalysed hydrolysis of the glycoside to yield glucose and cyanohydrin of benzaldehyde followed by the acid catalysed hy- drolysis of the said cyanohydrin (Scheme 3). In this connection, it may be mentioned that mandelic acid is found in almonds, and its name is derived from the German word for almond—Mandel. The formation of benzyl alcohol by the action of alcoholic potash on the oil of bitter almond was noticed by Wobler and Liebig [2], but its true nature was first established by Cannizzaro. This is thus ‘The formation of benzyl alcohol by the action of alcoholic potash on the oil of bitter almond was noticed by Wahler and Liebig, but its true nature was first established by Cannizzaro, sali RESONANCE | Apri 2023 639GENERAL ARTICLE benzaldehyde ———_- ¢» + ¢ \-cu:04 Cannizzaro \=/ \—=/ Reaction potassium benzoate phenylmethanol Nikolay Nikolaevich Zinin, on the advice of Liebig {10}, was working on the synthesis of benzoin, and in the late 1830s, first showed that its formation depends on the presence of hydrocyanie acid in the oil of bitter almonds and that the catalyst for the reaction is potassium cyanide. Scheme 4. Cannizzaro reaction in 1853. a disproportionation reaction which was first reported by Can- nizzaro in 1853 [9] when he obtained benzyl alcohol and potas- sium benzoate from the treatment of benzaldehyde with potash (Scheme 4). As mentioned earlier, benzoin had been observed by Robiquet {6], but it was first correctly examined by Wohler and Liebig [2] They obtained it by the action of alkali on benzaldehyde (oil of bitter almond having molecular formula C;H¢0) and found by analysis that benzoin (having molecular formula C\4H1202) is isomeric with benzaldehyde. In this context, it may be informed that molecular formulae are given in accordance with modem sci- ence. Nikolay Nikolaevich Zinin, on the advice of Liebig [10], was working on the synthesis of benzoin, and in the late 1830s, first showed that its formation depends on the presence of hydro- cyanic acid [3] in the oil of bitter almonds and that the catalyst for the reaction is potassium cyanide. Let us discuss Nikolay Nikolaevich Zinin [11] and his study on benzoin condensation [3]. The rise to eminence of the chemistry school at Kazan can usually be traced back to Nikolay Nikolae- vich Zinin. Although his colleague at Kazan, Karl Karlovich Klaus, may have played an equally important part in its develop- ment, After graduating with a degree in physics and mathematics, Zinin was appointed as adjunct of those disciplines. However, the Ministry of Education had other plans for the young man. De- spite his lack of knowledge in chemistry, he was appointed to teach chemistry after the dismissal of the ‘undistinguished’ pro- fessor of chemistry, Dunaev. It was common practice at that time for professors to be appointed to lecture students in the requi-GENERAL ARTICLE " Oo [ € cH benzoin 0 aq ethanolic KC were" refi on benzaldehyde 2-hydroxy-1,2-ciphenylethanone Scheme 5. Benzoin condensation reported by Nikolay Zinin. site subjects without necessarily considering the qualifications of the instructor in the subject. As part of his training for the pro- fessoriate, Zinin was sent on a study leave abroad to attend lec- tures by eminent western chemists. This was not intended as a research trip, but Zinin nevertheless spent time in the Giessen laboratory of Justus von Liebig, where he established the ben- zoin condensation [3]. How this reaction was established is not known, but it was a well-known fact at that time that the conden- sation of benzaldehyde to benzoin was catalysed by cyanide an- ion, It is also known that Zinin was in Liebig’s laboratory when Liebig and Wéhler were carrying out their seminal research on benzoyl compounds. The synthesis of mandelonitrile (benzalde- hyde cyanohydrin) by slow addition of hydrogen cyanide to ben- zaldehyde failed to give the desired product. So, under certain conditions, when the cyanide salt was added to the aldehyde too slowly or when insufficient amounts of cyanide (catalyst) were used, the product isolated from the reaction tumed out to be ben- zoin. Thus, the optimised reaction condition was when benzalde- hyde was refluxed with aqueous ethanolic KCN; benzoin was formed (Scheme 5). Zinin presented his research results at the University of Saint Pe- tersburg, a Russian federal state-owned higher education insti- tution from where he received his PhD. Another piece of infor- mation worth mentioning is that in St. Petersburg, Zinin was a private chemistry teacher to the young Alfred Nobel and left for the University of Saint Petersburg in 1841. However, is it possi- 6aGENERAL ARTICLE In 1823, from where did Carl Heinrich Strange get the idea to study the oil of bitter almonds? ble that Zinin’s experimental technique was expected to remain in the embryonic stage due to lack of experience and that it later led to the discovery of a new reaction? Our experience in organic synthesis leads us to believe so, but this cannot be proven beyond doubt, On his return to Kazan in 1841, Zinin became increasingly interested in organic compounds. His work on benzaldehyde and benzoin could not continue as the import of the poisonous oil of bitter almonds was prohibited by Russian customs regulations. Asa result, he began studies with nitro-aromatic compounds [12] that led to the monumental discovery of the reduction of nitroaro- matic compounds to anilines and the synthesis of azobenzene, azoxybenzene, and benzidine, Now there are two questions ‘© Firstly, in 1823, from where did Carl Heinrich Strange get the idea to study the oil of bitter almonds? ‘* Secondly, from where did Justus von Liebig (in 1832) get the idea to conduct research on bitter almonds? ‘There isn’t very vivid information or answers to these queries. Hence, can it be concluded that both of these ideas found their way back to continued research from the laboratory of Joseph- Louis Gay-Lussac in Paris? This appears to be, to some extent, logical, as we had pointed out that almond oil was supplied by Gay-Lussac’s favourite student Jules Theophile Pelouze [5]. If this is so, then it appears that Justus von Liebig and Friedrich ‘Wohler might have started their research on bitter almonds by taking the lead from their research guide. However, undoubt- edly, it is known [11] that Nikolay Nikolaevich Zinin was ad- vised to study bitter almonds,or rather benzoin condensation by Justus von Liebig. Again, with Liebig’s recommendation, Zinin [11] went to Paris, where he attended the lectures of luminar- ies of chemistry such as Jean-Baptiste-André Dumas and Joseph- Louis Gay-Lussac. Note that Zinin had a close association with Joseph-Louis Gay-Lussac in Paris while working in the labora- tory of Jules Theophile Pelouze (who was also a close associate of Liebig). Thus, although it is unclear from where the studies on bitter almonds originated, it is fair enough to conclude that 642GENERAL ARTICLE benzoin condensation was an accidental observation during the studies on bitter almonds! And this versatile reaction was devel- oped due to continuous research efforts. 3. Establishment of the Mechanism of Benzoin Condensa- tion: Arthur Lapworth’s Breakthrough! The observation that readily converted benzaldehyde into benzoin | ‘The observation that, using potassium cyanide was first made by Zinin in 1840 [3] readily converted However, the details of the method as practised were described | benzaldehyde into . benzoin using potassium by Emst Carl Theodor Zincke only in 1879 [13]. Notably, since] oy oniue was frst made the first result, 40 years had elapsed before developing the ex- | by Zinin in 1840 [3] act experimental method to obtain benzoin from benzaldehyde. } However, the details of In 1882, Hermann Emil Louis Fischer [14], German chemist and the method as practised 7 were described by Ernst 1902 recipient of the Nobel Prize in Chemistry, along with Hans | O.1y Theodor Zincke V. Neyman extended it to the condensation of furfural to furoin | only in 1879 (Scheme 6). i \ aq ethanolic KCN Om reflux 0 furfural Scheme 6. Benzoin condensation of furfural in 1882. Of the various theories which have been put forward pertaining to the mechanism of the reaction, the theory proposed by Ernst Carl Theodor Zincke in 1879 [13] and Chalanay and Knoeve- nagel [15] were the first ones to come up with a plausible mech- anistic pathway, Zincke assumed that mandelonitrile was formed as an intermediate product and that this, reacting with unchanged benzaldehyde, with the elimination of hydrogen cyanide, yielded benzoin (Scheme 7) HESNANGE hos Niv~ weGENERAL ARTICLE \ OH pH 4 tN mandelonitrile Desiion gut onc \) iadéon A Heiminavonornen” (J én + HON benzaldehyde sense Scheme 7. First proposed plausible mechanism of Benzoin condensation in 1879. hod) ty OH benzoin Scheme 8. Proposed plausible mechanism in 1892. Arthur Lapworth was one of the first, if not the first, organic chemists to present his findings from a contemporary mechanistic perspective. Evidently, it is a simple representation and not in accordance with modern science’s mechanistic details. At the same time, it was found that benzaldehyde and hydrocyanic acid did not react to give benzoin; the aqueous solution of KCN is alkaline in nature. In this context, it may be noted that the theory of Chalanay and Knoevenagel proposed in 1892 [15] is well-known. They sug- gested that a potassium derivative of benzaldehyde and mande- lonitrile was formed in the first instance, and this subsequently reacted (Scheme 8). But the existence of this potassium compound was purely hypo- thetical, as neither a compound of this kind had been isolated, nor was there any indirect evidence that the hydrogen atom assumed to be replaced by potassium was reactive in the presence of alkali. Then appeared Arthur Lapworth’s work on divulging the mech- anistic course of benzoin condensation [16]. Arthur Lapworth was one of the first, if not the first, organic chemists to present his findings from a contemporary mechanistic perspective. In at-GENERAL ARTICLE Box 2. Sir Robert Robinson on Arthur Lapworth (in 1974) “He contributed in particular, a series of fundamental observations which workers in various parts of the world have expanded into whole fields of investigation, and amongst the mass of information, which was organic chemistry, he picked out certain laws, at first of quite limited application, which he and others have been able to fuse into more general principles of great scientific significance.” Me Me KUMe, r aq. alcoholic KCN eee 3 camphorquinone a cyanohydrin (yellow in color} (colorless) Scheme 9. Loss of colour of yellow camphor quinone with time. tempting to evaluate the beginnings of the mechanistic view not only of benzoin condensation but also of organic reactions, the contribution of Arthur Lapworth deserves a considerable degree of appreciation. Sir Robert Robinson, British organic chemist and Nobel laureate recognized in 1947, has written about Arthur Lap- worth [17] (see Box 2). Lapworth’s most fantastic achievement in elucidating reaction mech- anisms dealt with transformations associated with carbonyl com- pounds. In his mechanistic studies, Lapworth constantly applied novel approaches using kinetic methods wherever possible. Thus, in the pioneering study of the rate of cyanohydrins formation from carbonyl compounds in 1903 [17], he studied the loss of colour of yellow camphor quinone with time as shown in Scheme 9. 645GENERAL ARTICLE Scheme 10. Lapworth’s proposal for the formation of ionic complex. OH Pon Scheme 11. Protonation of ionic intermediate to generate cyanohydrin. Assuming that the reaction was ionic in nature and reversible, Lapworth proposed that the carbonyl group was polarized because of the “residual affinity’ of ‘oxygen and thus reacted with cyanide ion to form an ionic complex which may also follow the reverse course. Assuming that the reaction was ionic in nature and reversible, Lapworth proposed that the carbonyl group was polarized be- cause of the ‘residual affinity’ of oxygen and thus reacted with cyanide ion to form an ionic complex which may also follow the reverse course (Scheme 10) According to the kinetic evidence, the second step of the reaction must be a rapid reaction of the ion with a proton source such as water, alcohol, or an acid (Scheme 11) In order to prove that the initial complex of carbonyl compound and cyanide was a stable entity, Lapworth, in 1904, studied vari- ous carbonyl compounds with an excess of KCN [16] and isolated compounds that had the composition representing the composi- tion of ‘a hydrated potassium salt of the corresponding cyanohy- drins’. Now, it was only a small jump to extend this elegant explanation of cyanohydrin formation to benzoin condensation. Arthur Lap- worth and Reginald W. L. Clarke [18] proclaimed in 1907 that al RESONANCE | Apri 2023GENERAL ARTICLE ° pron * “ Soon Phen Ho N — fo _H° Hoon oe, SE oC HLOn i) Pho pre Pare Bh HO._CN prO-e-© + HON - ww Scheme 12. The mechanistic course of benzoin condensation proposed by Arthur Lapworth. benzoin condensation is of special interest, firstly, because potas- sium cyanide plays the part of a true catalytic agent, being prac- tically unaltered in the amount at the end of the operation and re- quired to be used only in relatively small quantities, and secondly, because it is not applicable to the aldehydes of the fatty series. Lapworth argued that adding the elements of hydrogen cyanide to benzaldehyde would produce mandelonitrile. The mechanistic course of benzoin condensation as proposed by Arthur Lapworth [18] with slight modification in accordance with modern science is as shown in Scheme 12. ‘The enhancement of acidity and labiality! of the methine hydro- gen between cyanide and an aromatic nucleus was recognized as the key to the reaction and thus explained why the condensation could not proceed without this anion. To prove this hypothesis, Arthur Lapworth put forward several pieces of information along with some experimental observations [18], as follows: # In 1903 he pointed out that (and it is now generally accepted) the condensation of ketones and aldehydes with compounds such as ethyl malonate, acetoacetate, benzyl cyanide, and in general, easily broken bonds, ‘The enhancement of idity and labiality of the methine hydrogen between cyanide and an aromatic nucleus was recognized as the key to the reaction and thus explained why the condensation could not proceed without this anion, sal RESONANCE | Apri 2023 647GENERAL ARTICLE condensation Ph pH $$ vnc NC Ph Scheme 13. Formation of hydroxy compound in an additive process. OH C PhoHOCN it condensation Ph OH opp’ ”:SCO#HO-C—-CH NC Ph Scheme 14. Additive product of mandelonitrile and benzaldehyde. ‘The kinetics of the benzoin reaction, as, determined by Bredig and Stern, confirmed Lapworth’s predictions. such substances is the result of an additive process in which a hydroxy-compound is produced, as in Scheme 13. Now it has been shown that the first product of the action of potas- sium cyanide on benzaldehyde is mandelonitrile. The former, like benzyl cyanide itself, has a labile a-hydrogen atom and, in the al- Kaline solution, would condense with benzaldehyde as in Scheme 14, which is simply the unstable cyanohydrin of benzoin. This would break up reversibly into benzoin and hydrogen cyanide, which would then be available for further conversion of the ben- zaldehyde. To test this view, Lapworth placed mandelonitile, benzaldehyde, and tripropylamine in contact for 20 days and iso- lated a quantity of benzoin. # The kinetics of the benzoin reaction, as determined by Bredig and Stem [19], confirmed Lapworth’s predictions. Lapworth put forward this information in 1907 [18] as mentioned in Box 3. # Arthur Lapworth was well aware of the fact that , B-unsaturated carbonyl compounds are susceptible to conjugate addition. Thus Lapworth proposed that mandelonitrile might be expected to reactGENERAL ARTICLE Box 3. Kinetic Confirmation of Lapworth’s Prediction “Sometime after these suggestions were published, a communication fom Bredig and Stern appeared in 1904, They described experiments on the velocity of the benzoin condensation and were able fully to establish thatthe reaction is brought about catalytically by the potassium cyanide, the velocity being directly proportional to the concentration of the cyanogen ion in all cases.” Scheme 15. Proposed reaction of mandelonitrile with @,6- unsaturated ketones. with a, B-unsaturated ketones (Scheme 15), This is the same cyanohydrin of a 6-diketone, in which the prod- uct is obtained by eliminating hydrogen cyanide, as in the benzoin condensation itself. According to Lapworth, the product from mandelonitrile and @,f-unsaturated ketones were too unstable, and decomposition took place. It was therefore decided to employ anitrile derivative, less easily affected by alkalis but of analogous structure, Thus, Lapworth used the aniline derivative, namely, the compound obtained by combining hydrogen cyanide with ben- zylideneaniline (Figure 2) and carried out the reaction with car- vone as the unsaturated ketone and desired the phenylimino-derivative of B-benzoyldihydrocarvone being produced (Scheme 16). The new substance is easily hydrolysed by acids to yield aniline and two stereoisomeric (diastereoisomeric) benzoyldihydrocar- vones. Thus, it absorbs only one molecular proportion of bromine, showing that it now contains only the carbon-carbon double link- ing in the isopropenyl group. It shows the phenomenon of mu- tarotation in the presence of traces of alkalis, indicating that it HESNANGE hos Ww woGENERAL ARTICLE Figure 2. The compound obtained by combining hydrogen cyanide with benzylideneaniline; the reaction carried out with carvone as the —unsatu- rated ketone, The desired phenylimino-derivative of B-benzoyldihydrocarvone is produced (Scheme 16). NHPh | CH Pr cn Pn Me. ateohote KOH Me wasnea_ en-fivcn Me Ph Me “wth waterto Ph | n {tee trom aka g no wien Ey wal NPh CHa phenylimino-derivatve of B-benzoyldinydrocarvone Scheme 16. Reaction of carvone as unsaturated ketone. contains the carbonyl group attached to an asymmetric centre, not present in the original carvone, Further, only one molecular proportion of hydroxylamine combined to give an oxime deriva- tive, and its dioxime was finally isolated by the indirect process of treating the original phenylimino-compound with hydroxylamine acetate, Undoubtedly, it is a nice piece of research work, even by modem standards. At the same time, it may be informed that this work is the origin of the Stetter reaction, which will be discussed in the next part of the article. 4, In Closing... Summing up our discussions so far, we may have the impres- sion that there is enough on benzoin condensation as the proper method for preparation of benzoins and its mechanistic course is firmly established. Hence, anyone is unlikely to conduct further 650GENERAL ARTICLE research in this field! However, the findings from any study car- ried out in a proper direction are simply that of the researcher and are always prone to (and need) additional interpretation. We will continue to study this area further in the second part of the article. It will be revealed that improved results are the consequence of a continuous research process Acknowledgement ‘The authors want to dedicate this article to the hard-working young researchers and acknowledge them for their tireless effort to carry out the research work for the sake of research. Suchandra Chakraborty acknowledges WBDST for their funding (0093/RND/CHS/C-12009/ Jan-2021/1/1 dt. 25/10/2019) to carry out the research work in her institution. Suggested Reading {1] C Stange, Buch. Rep. Pharm.,93, p16, 1824. [2] (a) F Wohler, J Untersuchungen ber das Radikal der Ben- aocsiure, Annalen Der Pharmacie, Vol, No, pp-249-282,1832, doi org/10. 1002/jlac. 18326036302. () F Wobler, J Licbig, Ucber die Bildung des Bittermandelils, Annalen Der Pharmacie, Vol22, No.l, p-1-24, 1837, oi .org/18, 1602/lac. 18376226102. [3] (@) N Zinin, Beitrige zur Kenntniss ciniger Verbindungen aus der Benzoylreihe, Annalen Der Pharmacie, VolS1, No, pp.329-382, 1839, doi .org/10,1602/jLac. 18390310312, (b) N Zinin, Ueber einige Zerset- ungsprodukte des Bittermandeléls, Annalen Der Pharmacie, Vol34, No.2, p.186-192, 1840, doi .org/16. 1902/jlac, 18409346205, {4] S Esteban, Liebig-Wobler, Controversy and the concept of isomerism, Journal of Chemical Education, Vol88, No, pp-1201-1203, 2008, doi .org/10. 1621/ed085p1201. [8] (a) WH Brock, Justus Von Liebig: The Chemical Gatekeeper, Cambridge Sei- ence Biographies, Cambridge University Press; Reprint edition pp.77, 2002. (b) WA Hofmann, Liebig's and Waker’ Briefwechsel, VoL, pp.S3. {6] P Robiquet, B Chatlard; Nouvelles Expériences sur les Amandes Améres et sur P'Hulle Volatile qu’elles Fournissent, Annalen Chimie, Vol, pp.382-385, 1830, IT] G Nagendrappa, Benzoin condensation: The cyanide Connection with tapioca and vitamin Bl, Resonance, Vol13, No, pp.385-868, 2008, von. ias.ac.in/article/fulltext/res0/013/04/0355-0368GENERAL ARTICLE Address for Correspondence ‘Anana Saha Senior Research Fellow Department of Chemistry Venkat Raman Nagar Kalapet Pondicherry 605 014, India, Email ahal6munni@gnail.com Chandan Saha Rid, Assistant Prof, of Chemistry Dept. of Clinical and Experimental Pharmacology ‘Schoo! of Tropical Medicine Kolkata 700 073, India E-Mail cskatichandanégnail.com ‘Suchandra Chakraborty Assistant Prot. of Chemistry Dept. of Chemistry ‘The Bhawanipur Education Society College Kolkata, India. 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