Learn Chemistry through the works of Great Chemists

[This article (8 pages), also has 18 chemical structures drawn on Chemdraw and Chemsketch, but I could not embed them into this article either in the Word or pdf form or even as a tiff image! Interested audience may please write to me and I shall send the full article by e-mail. Thanks and sorry for the inconvenience. If anyone can tell me how to embed the structures, I shall be happy to do it].

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Scientists’ published work, as it happens, is only a part of the story that the world gets to know though their papers, lectures and awards. A lot is lost in the limitations of space in the published work and they do not fully include either the scientist’s rationality of approach to the solution of the problem or the ramifications of the works to Science and humanity subsequently, and the inspiring guidance they could give to the students, who wish to learn more than the syllabus and make their own contribution. Science, being a very individualistic endeavor, the scientist’s life and experiences (and opportunities) and style, naturally, have a profound influence on the contributions published. Delinking a scientist’s personality from his scientific contribution will prevent the next generation from taking advantage of the ingenious ways in which they solved the problems at hand; it is like every scientist trying to reinvent the wheel! Chemistry is often looked upon as a very dry subject (mostly as a compilation of data or facts about the chemicals and their reactions) and, unless explained in a way that each reaction is logical for the structure of the given molecule and under the conditions of the reaction, the student is unlikely to get greatly interested. As a student of science myself, my attempt in these pages is to present in perspective the information (contributions, events, anecdotes, failures and, where possible, the reasons thereof) that I could gather about some of the great chemists I admire -- in the hope that it inspires the next generation. We are not arguing about who is the greatest. In my opinion, every scientist worth his/her name contributes as much as he/she could under the circumstances and opportunities permit in one’s life time. I begin this series with Prof. R. B. Woodward for reasons given below; also this year, 2017, happens to be his 100th birth anniversary! [See Chemical & Engineering News, April 19, 2017; Cover story -- “Happy 100th”].

R. B. Woodward

This is my humble tribute to the organic chemist whom I admired the most but with whom I could not, unfortunately, work. But I can humbly claim that his papers and lectures (in the mid-sixties, particularly) certainly inspired my formative years as an organic chemistry student of M.Sc. (1965-67) in Andhra University, in which library I could read most of his papers published in the JACS and his IUPAC plenary lectures published by Butterworths and in the Journal, “Pure and Applied Chemistry”. I can imagine him turning in his grave at this! But I was most fortunate to hear his talk on the total synthesis of Vitamin B12 at IUPAC symposium on the chemistry of natural products in 1972 at Delhi (where I was a Ph.D. student). It so happened that I was sitting next to the slide projector (just to get a good, uninterrupted view of the speaker and his slides); Powerpoint was unknown at that time. As I watched, Woodward walked to the projector operator and gave him the carousal loaded with the slides. He told the operator not to check the working of the projector with his slides; they are all arranged as they should be and if anything went wrong the operator would not be blamed for it; “but under no circumstance, he should project any slide on the screen till he was told”. Woodward started the talk saying there were two changes in the program; firstly, the program mentioned the starting time to be 9.00 AM which was fine but it would not end at 10.00 AM as mentioned in the program and it had to be open-ended – it actually ended at 1.00 PM with the usual standing ovation and huge applause; after all, it was about the synthesis of the largest and the most complex non-polymeric organic natural product ever synthesized by man (vitamin B12, that is). The second change he announced was, of course, that the title needed to be changed (from the usual “Recent Advances in the Chemistry of Natural Products”) to “the total synthesis of Vitamin B12” and there was the anticipatory standing ovation even before the lecture, which was again not unusual. The work presented was more like orchestration of a symphony conducted using 99 post-docs on both sides of the Atlantic, the work having taken 11 years to complete.

A lot about Woodward has been written in a number of accounts by his colleagues and students. A volume entitled “Robert Burns Woodward: Architect and Artist in the World of Molecules” covering his biographical sketches (including one by his own daughter, Crystal Woodward (!) and selected works, edited by O. T. Benley and P. J. T. Morris, has been published by Chemical Heritage Foundation, available from Google Books]. Almost everything about him, including his horoscope, he being the only child of his parents, he having lost his father in his second year, brought up with a lot of hardship by his Scottish-origin mother in a Boston suburb, is in print. Chemists are awed by his meticulous planning of elaborate synthetic schemes; his structures on the black board (which all have identical bond lengths, like in a printed textbook), the multistep structural schemes (however complicated, they invariably started on the left hand top corner of the wide black board and ended at the right hand bottom), his Thursday late evening discussion meetings with students and colleagues that usually went up to the early hours of the next day, his meticulous preparation for the 3-4h long lectures and his chain smoking (Benson & Hedges) habit, fondness for whiskey, are all legendary and much written about. People even wondered if so much of smoking and drinking probably was needed for the extraordinary intellectual output he constantly demonstrated throughout his life as an organic chemist. Massachusetts Institute of Technology, Boston, even bent the rules to give him a Ph.D. one year after his B.S. at the age of 19! Harvard University, where he was a Professor all through his career, also exempted him from teaching duties for undergraduate and graduate programs (what a loss to the students!) and he mostly had only post-docs. Also well known was his fondness for blue color; everything from his suits to the parking lot in Harvard campus had to be blue. He was also known for his glad eye towards women but never had a female post-doc – may be to avoid distraction!

           Woodward’s major achievements probably could give him 4 Nobel prizes or more if he only he lived longer, but for his untimely death at a relatively young and most productive age of 62, most probably because of the killing combination of alcohol and his chain smoking habit noted above and which he could not, unfortunately, kick.

           (1) Organic syntheses of the most complex of organic compounds, from quinine, cortisone, cholesterol, strychnine, reserpine, etc. to Chlorophyll, for which he actually got the Nobel prize in 1965 at the age of 48. For the record, he had 111 nominations for the prize, the first at the age of 35 and 75, between 1960, when he completed the Chlorophyll synthesis and till he got the Prize (1965).

           (2) Woodward-Hoffmann rules, for which the holocaust survivor Roald Hoffmann got the Nobel in 1981, 2 years after Woodward’s death; it is on record that Woodward was not included in the prize as the prize is not given posthumously; they are still called the Woodward-Hoffmann rules.

           (3) Vitamin B12 – almost every organic chemist expected that this unparalleled and monumental work in organic synthesis would be rewarded with a Nobel.

           (4) Ferrocene chemistry and structure, which had the novel sandwich structure proposed by Woodward and Wilkinson and acknowledged as such by the Nobel committee itself, while awarding the Prize to the inorganic chemists, Ernst Otto Fischer and Geoffrey Wilkinson in 1973; Woodward was apparently disappointed that he did not share the Nobel with the awardees and he actually wrote to the Nobel committee about the unfairness.

From Woodward’s papers and lectures, an interested student learns not only a lot of chemistry but also the way of its presentation with total perspective of history as well as the brevity and at the same time the comprehensiveness of the treatment of the subject at hand. He always presented the rationality for his choice of the problem, the historical background, how he approached the solution, how it was carried out in the laboratory, the problems faced during the experimentation and how each problem was solved and, more importantly, recorded. Interestingly, his 1960 synthesis of chlorophyll [published as a short note in the Journal of American Chemical Society 82 (1960) 3800], was revisited by his old co-authors and colleagues [published 30 years later, in Tetrahedron, 46 (1990) 7599]. Prof. Raymond Bonnett, a co-author of the paper, diligently reviewed the lab notes of the 17 post-docs to compile the experimental details for the full paper. The authors were, of course, the same as the original 1960 paper, R. B. Woodward, followed by the 17 post-docs in the alphabetical order! One is amazed at the meticulousness with which the lab notes were maintained, all the crystalline intermediates and derivatives were labeled and preserved along with the recorded physical and chemical properties and spectral and elemental analysis data. It must be noted that when the synthesis was performed (before 1960), there were no HPLC or mass spectrometry or high-resolution NMR. But when they re-recorded all the spectrometric data of the preserved intermediates using the newer and more sophisticated instruments, they were gratified that there was no discrepancy whatsoever!!!

While a brilliant presentation (which Woodward was well known for) by itself may not lead to recognition of a great scientist, inability to get across to the audience effectively can certainly delay recognition (if at all it happens), as it happened with Alexander Fleming’s 1928 discovery of penicillin (ahead of its time?). He was so famously a poor communicator that his epoch-making discovery remained unnoticed till Howard Florey and Ernst Chain revived it in 1939 at the beginning of the World War II (out of sheer necessity and urgency because of the War?) at Oxford. He, however, shared the Nobel Prize for medicine in 1945 with Florey and Chain. But the fact remains that proper recording of experimental details, the data and their presentation are all important in science; after all, one is as great a scientist as he (or she) is recognized to be. As an example of Woodward’s brilliance of not only the work but also the presentation, I give below an annotated or paraphrased version of his Nobel Lecture of 1965 on the total synthesis of Cephalosporin C, a simple molecule compared to most of his other syntheses. I must admit that several times in this note, I could do no better than reproducing some of passages from his Nobel lecture, particularly where I thought any alteration would kill the idea or the presentation. I hope to follow this up with accounts of his and other great chemists’ works, depending on the reception this account gets.

Cephalosporin C (I)

The antibiotic (I) is a metabolite of Cephalosporium acremonium, which was isolated in 1955 by G. G. F. Newton and E. P. Abraham [Nature, 175 (1955) 548; Biochem. J., 62 (1956) 651; 79 (1961) 377], whose strenuous work, noted for its perspicacity and attention to detail (in the words of Woodward, to whose work we normally associate these words), resulted in the elucidation of its structure by chemical methods and confirmed by X-ray crystallographic techniques [by Dorothy Hodgkin, with E. N. Maslen, Biochem. J., 79 (1961) 393]. It belongs to the class of beta-lactam antibiotics, the best known example of which is Penicillin G (IIa), earlier isolated by A. Fleming, and developed further by E. B. Chain and H. Florey [who all shared the well deserved 1945 Nobel Prize, as noted above]. The benzylacetamido group of Penicillin G is easily hydrolyzed yielding 6-aminopenicillanic acid (6-APA, IIb), recognizable as a bicyclic peptide of valine and cysteine. By linking a variety of acyl groups to the amino group thus released, a large number of newer, semi-synthetic penicillins could be made, some of which proved to be more useful therapeutically than the originally discovered Penicillin G. Cephalosporins, several of which have also been identified to occur along with Cephalosporin C, could also be hydrolyzed to 7-amino-3-desacetoxy-cephalosporanic acid (7-ADCA, IIIa) or 7-aminocephalosporanic acid (7-ACA, IIIb) and, by linking a variety of acyl groups to thus generated amino group, again, could produce a variety of beta-lactams of varying bioactivity and utility as antibiotics against a variety of disease-causing bacteria.

A serious student of chemistry is at once led to the important and very useful area of fungal metabolites, to the large variety of antibiotics, the methods of their structure determination by chemical and X-ray crystallographic methods as well as the production of newer antibiotics by synthetic and semisynthetic methods to yield more usable antibiotics in medicine. He or she would learn to appreciate the strenuous works of Newton, Abraham and Hodgkin, not to mention the earlier work of Fleming, Chain and Florey on penicillins; association of the works with the authors would inspire the student immeasurably. On the other hand, it pains to find that most organic chemistry students now in India have not even heard of any of them. Blame the question-answer system of our exams, where the student gains nothing by knowing more than the expected answer and the job market where only the degree and marks count.

For his Nobel lecture of 1965, Woodward chose to speak on the total synthesis of Cephalosporin C (I), a relatively simple molecule for someone who had synthesized the likes of reserpine, strychnine and chlorophyll; even so, it is astonishing how much chemistry he packed into the lecture, obviously for the benefit of the audience, students and posterity! He started with a homage to the chemists noted above in connection with the isolation and structure elucidation of Penicillin G and Cephalosporin C and also the painstaking work of John C. Sheehan [with K. R. Henry-Logan, J. Am. Chem. Soc., 81 (1959) 5838; 84 (1962) 2983] on the synthesis of penicillin (though not practical from commercial point of view). He also spoke of the British-American collaboration on penicillin chemistry during the World War II. While I lament (see foregoing paragraph) about the ignorance of Indian chemistry students about the lack of historical perspective of chemistry, Woodward felt that “there can be few organic chemists who do not know the fascinating history of penicillins” [H. T. Clarke, J. R. Johnson and R. Robinson, eds., The Chemistry of Penicillin, Princeton Univ. Press, 1949; see also E. H. Flynn, Cephalosporins and Penicillins: Chemistry and Biology; Academic Press, 1974]. Sadly, we count among the “few organic chemists” who do not know the subject.

For the total synthesis of Cephalosporin C, Woodward selected, as starting point, the amino acid, L-cysteine (IV), which is a veritable example of the utility of alpha-amino acids for the synthesis of chiral molecules. With 19 of the 20 common, widely occurring proteogenic amino acids possessing at least one asymmetric carbon atom and a variety of chemical functionalities in the side chains, they form versatile chiral pool for asymmetric synthesis of a wide variety of complex organic compounds. Availability of the amino acids in large quantities and at low cost is, of course, an advantage for commercialization of processes involving them. L-Cysteine to Cephalosporin C is but one such example and there are several instances where abundant natural products have lent themselves as starting materials for exciting and useful organic syntheses. Chemists have long learnt to exploit the various structural features of natural organic compounds, particularly the amino acids and carbohydrates. Of course, utilization of abundant natural products to make value-added products should be the goal of any organic chemist who wants his/her work to be immediately useful.

Structure of L-cysteine has a carboxylic acid group, an alpha-amino group a beta-sulfhydryl group and, of course, a chiral centre, whose configuration, incidentally, is the same as in the target Cephalosporin C. The small molecule with so many features packed in such proximity is at once a boon and a problem (due to the interfering chemistry of the various groups in proximity). One would expect the least active portion of the molecule to be the lone methylene group but that is from where one needs to depart to build the rest of the molecule, preferably by introducing a nitrogenous group in a stereospecific manner because this carbon becomes the other nitrogen-bearing chiral centre in the target molecule! But then, an organic chemist does not relish the prospect of dealing two electronegative groups on the same carbon atom, given the unstable nature of such molecules. Anyway, as any organic chemist dealing with amino acids knows, it is best to keep the active groups protected till the end or till the need arises to free them. A variety of protective groups have been designed to orthogonally protect the amino, carboxy and the side chain functionalities which occur in different amino acids, namely, again, amino, carboxy, hydroxyl, thiol, guanidino, imidazole and so on; the easily removable protective groups proved to be of immense utility in peptide synthesis, both solution-phase and solid-phase. L-Cysteine is known to yield the thiazolidine (V) on reaction with acetone which could be further reacted with tert-butoxycarbonyl chloride and pyridine to yield (VI). Treatment of the carboxylic acid (V) with the acid chloride is expected to first yield the mixed anhydride (VIa) which smoothly transfers the acyl group to the nitrogen in basic medium (pyridine). The free carboxylic acid in (V) was again protected by esterification to the methyl ester (VII). The stage was now set for further elaboration but it must be mentioned here that the structure of the molecule (VII) has in it the key feature of the methylene group frozen into a cyclic structure that may be expected to facilitate stereospecific reactions at the centre, with the carboxylic ester group and the bulky tert-butoxycarbonyl group exerting the steric control. These reactions may appear very simple, but, as it happens with most (even simple) reactions in chemistry, the choice of the solvent, temperature, reaction time and method of work up are all very important to get satisfactory results; not any less important are the chemist’s skill, temperament, commitment and application. After all, not everyone who knows the rules of cricket or plays cricket can become a Tendulkar!

Indeed, the next step of introducing a N-function at the methylene group next to the sulfur in the thiazoldine ring was a tough task and required a lot of experimentation, the details of which, I am afraid, are lost to the chemical world, unless, of course, some of his collaborators review and publish the experimental details in full as it happened with chlorophyll, 30 years after a short note on the total synthesis of chlorophyll was published. It is thus anybody’s guess how Woodwards’s group found that (VII) could be reacted with dimethyl azodicarboxylate at 105 degrees C during 45 h to yield the hydrazo ester (VIII) quantitatively! At lower temperatures, the reaction was too slow to be useful and, at even a slightly higher temperature, the reaction was “less clean”, yielding unexpected side-products like (IX). But the Group “assembled” evidence to show the reaction proceeded through initial attack of the sulfur on the azo grouping and, simultaneously (in a concerted manner!), the hydrogen on the methylene group migrated to the second N atom of the azo group. Needless to say that there was no parallel to the particular scheme of reactions. Thus, both the reaction scheme and the experimental conditions for the quantitative conversion were new. Such developments and discoveries are indeed exhilarating to the chemist at the bench; and Woodward had so many of them! Actually, the famous, Nobel Prize winning work on Woodward-Hoffmann rules were developed to explain some of the unexpected reactions during the course of vitamin B12 synthesis, while Hoffmann was on sabbatical at Harvard.

As noted above, the 5-membered cyclic structure of (VII) and the two bulky groups were expected to exert steric control on the reaction leading to (VIII) and indeed, it was so and the reaction was stereo-specific in the sense only one product (VIII) was formed with no other isomer! But the configuration of the incoming hydrazo group was exactly the opposite to that needed; that is, the trans to the adjacent carboxy function and formation of a small, beta-lactam ring requires them to be cis related. One could think of substituting the hydrazo group with inversion of configuration at the carbon in question except for the fact that there was this sulfur atom next to the chiral centre which would render the “invertible intermediates non-existent or malefactory”. To cut a long story (or explanation) short, the hydrazo ester, on treatment with lead tetraacetate yielded the trans-hydroxy acid (X) whose structure and stereochemistry was confirmed by X-ray crystallography. Normally, especially in those days (when there were no computer programs of the kind we have today), X-ray crystallographic approach to structure determination used to be considered very cumbersome and tedious and rarely used (mainly for only structure determination of complex organic natural products) but Woodward used the technique for the confirmation of the structures several of the intermediates in Cephalosporin C synthesis, obviously due to the importance he attached to ensuring that he was always on the right track, particularly with the stereochemistry of all the intermediates, which was critical to the success of the scheme. For interesting explanation of the factors involved in these transformations, see Woodward’s Nobel lecture, which is easily accessible. (X) was converted into its methanesulfonate and treated with sodium azide (configuration at the reaction center inverted in this step, as expected) to give the desired cis-azido ester (XI) that could be readily converted to the cis-beta-amino acid in preparation for the conversion to the desired beta-lactam. Again, by X-ray crystallography, it was shown that the beta-amino group and the carboxylic ester group were in such close proximity (2.82 A) that they had but to cyclize to form the beta-lactam (XII), the strain of the 4-membered ring system and the difficulty in its formation notwithstanding! A favorite saying of Woodward was that “enforced propinquity often leads to greater intimacy!” He obviously used this idea to the hilt in forcing chemicals to behave the way he wanted in many of his syntheses. Another of his sayings that I would always remember is that “any problem in chemistry can be solved just by thinking about it!”

Having obtained the beta-lactam of the right stereochemistry, but with its known and expected susceptibility to a variety of transformations under very mild conditions, further elaboration to Cephalosporins could still be daunting. The subsequent steps and reactions were therefore planned to avoid the use of any acids or bases or even catalysts; “apprehension was that such substances may well mobilize one or more of the capacities for self-destruction inherent in the intricate construction of the key intermediate (XII)”. To react with the free amino group (only) in the deprotected derivative of the molecule (XII), without an acid, base or a catalyst, a powerful electrophile had to be designed. The required electrophiles (XIII and thence XIV) were achiral but the chiral d-tartaric acid di-2,2,2-trichlorethyl ester was chosen to make it! Treatment of this molecule with sodium metaperiodate in methanol gave (XIII) which, with malondialdehyde, produced the powerful electrophile (XIV) that could be reacted with (XII), which with trifluroacetic acid gave the amino aldehyde (XV). The sequence of events leading to (XV) was explained as a consequence of the attack strongly electrophilic carbon atom of a protonated carbonyl group upon the nucleophilic sulfur atom as shown in (XVI).

To obtain Cephalosporin C the amino aldehyde was condensed with N-(2,2,2-trichloroethyl)adipic acid in presence of dicyclohexylcarbodiimide (DCC), the well known condensing agent popularized by H. G. Khorana in his synthesis of DNA. The product was again esterified with 2,2,2-trichloroethanol in preparation to converting the unsaturated aldehyde to the enol acetate using diborane, followed by acetic anhydride and pyridine. In the process the unconjugated enol acetate smoothly isomerized to the conjugated enolate as present in Cephalosporin C (I). To remove the 2,2,2-trichloroethyl groups Woodward used zinc dust under near-neutral conditions which removed the chlorines sequentially.

It was most gratifying to note that the two protective groups, namely, the tert-butoxycarbonyl group of the amino group and the isopropylidene group holding the sulfur and nitrogen together were no longer required and, lo and behold, they were gone in the last step as shown in the structure (XVII), leading eventually to the desired 7-aminocephalsporanic acid (III) and thence to the desired Cephaloporing C (I) by the usual steps.  

After reading the above account, I will be surprised if any serious student of organic chemistry does not run and try to read further about:

a)   The other works and syntheses of Woodward.

b)   The historical aspects of pencillins and cephalosporins and synthesis of their analogs.

c)   Distribution, structures, synthesis/semisynthesis and bioactivities of other important antibiotics.

d)   Orthogonal protection of amino acids and their use in peptide synthesis.

e)   Mechanism of organic reactions with special reference to stereo control.

f)    Designing of reagents and reactions to make molecules behave the way needed.

As already mentioned, the reason for most students not doing the above is our examination system for degrees to earn a livelihood. But, by personal experience, I can say that one could learn and understand enough chemistry (by this approach) to make at least a modest contribution to chemistry and, at the same time earn enough money for a comfortable working life and retirement!