The Story of the Discovery of Configuration Reversal by Paul Walden.
The article addresses the origin of Walden’s discovery of the phenomenon of configuration reversal. The origin of this discovery is very interesting because it was born while Walden is busy confirming the asymmetric carbon hypothesis proposed by Van’t Hoff and Le Bell. Walden’s experimental work covers a period of several years, from 1891 to 1896 where he carries out a copious experimental activity in which, moreover, he verifies the experiments conducted by other chemists. The problem to be solved is whether all the substituent groups are effective in the constitution of asymmetric carbon or whether some groups, in particular halogens, are not relevant. The question is so important that a large representation of authoritative European chemists takes part in its solution. The solution of this problem has as an indirect and unexpected result Walden’s discovery of the phenomenon of the inversion of the optical configuration.
When producing compounds with molecules having an asymmetric carbon atom, where one of the substituents was a halogen, it happened that the substance produced was not optically active. This result led to the conclusion that not only was the difference between the four substituent groups a necessary condition for optical activity, but that the type of substituent groups was important. The reason why the substituted halogen compounds were not optically active was due to the frequent formation of racemic mixtures, i.e. the formation of both enatiomers. In addition, the attempt to separate any enatiomers was made difficult by the fact that carbon compounds containing one halogen among the four substituents hydrolyzed easily even at room temperature.
Paul Walden’s verification work
Walden experimentally verifies the conclusions reached by many chemists of calibre, presented above, who maintained that not all groups, particularly halogens, were capable of producing optical activity. Walden’s experimental genius consisted in seeking the synthesis of compounds using different conditions and different reagents to obtain substituted halogen compounds, and in the deep critical sense in evaluating the results.
In an article in the Berichte der Deutschen chemischen Gesellschaft of 1895,9 Walden resumes the investigation begun three years earlier:
Some time ago I made in these reports, Diese Berichte 1892, a small contribution to the question whether any group difference on carbon is sufficient to determine optical activity, or whether in an intrinsically active body the substitution of a group (e.g., hydroxyl) by a halogen necessarily eliminates the activity. The discussion of this question, so important for the general validity of van’t Hoff’s theory of the asymmetric carbon atom, seemed necessary, since new data have recently been added to the previous facts, all of which have led to the conclusion that in particular the substitution of the hydroxyl group by a halogen involves racemization.
Walden riconosce il ruolo del fenomeno della racemizzazione dei prodotti alogeno sostituiti . Si mpegna allora in una vasta attività sperimentale che consiste nella clorurazione e bromurazione di acido malico, acido tartarico, acido lattico e acido mandelico usando come alogenanti pentacloruro e pentabromuro di fosforo. Ottiene la sintesi di una vasta gamma di derivati alogeno sostituiti che presentano attività ottica. Può affermare alla fine che:
Con ciò è anche dimostrato che, per la produzione del potere rotatorio, la condizione essenziale è in realtà solo la diversità dei quattro gruppi legati al carbonio, mentre la natura specifica di questi gruppi determina solo l’entità e la direzione della rotazione.
Paul Walden recognizes the role of the racemization phenomenon of substituted halogen products. He then engaged in a vast experimental activity consisting in the chlorination and bromination of malic acid, tartaric acid, lactic acid and mandelic acid using pentachloride and phosphorus pentabromide as halogenants. It achieves the synthesis of a wide range of substituted halogen derivatives that exhibit optical activity. Can he state at the end that:
This also shows that, for the production of rotational power, the essential condition is really only the diversity of the four carbon-related groups, while the specific nature of these groups determines only the magnitude and direction of rotation.
Paul Walden’s First Configuration Reversal Test
The experimental work we have seen before, which leaves no doubt to the conclusions drawn by Walden, nevertheless leaves a result uncertain. Walden is a skilled experimenter, attentive but also very scrupulous. No experimental data should possibly remain unanswered.
In reporting the results of the experiments concerning the substitution of bromine in place of the hydroxyl group in free and active malic acid, I had obtained the negative result, because, instead of the active bromosuccinic acid sought, only the inactive acid was isolated.
Paul Walden refers to the results obtained by the reaction of malic acid with PBr5. It obtains inactive bromine succinic acid, while esters are active. Hence the idea of starting not from malic acid but from asparagine because normal malic acid is obtained from asparagine. He reports the experiments of Piria, Pasteur and Piutti through which asparagine and aspartic acid, under the action of nitrous acid, give malic acid.
Since I was now interested not only in obtaining the esters of active bromo-succinic acid, but also in free acid, I tried to transform not malic acid, but another related body, namely asparagine, into the bromine-active derivative. The attempt was successful, but with a different result than expected. Now that I had shown for this common malic acid that it, under the action of phosphorus pentachloride, produces d-chlorosuccinic acid and its esters, and under the action of phosphorus pentabromide, produces esters of d-bromosuccinic acid, I could expect with certainty that asparagine, which produces this common malic acid, would also give only d-bromosuccinic acid. Instead I got an l-bromosuccinic acid.
At the same time he has news of the results obtained by Tilden and Marshall:
While I was still busy elucidating this unexpected phenomenon, a communication appeared from Tilden and Marshall, who, under the action of nitrosyl chloride on asparagine and aspartic acid, also obtained a l-chlorosuccinic acid levorotary, the optical antipode of my dextrorotatory acid.
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At this point Walden is bewildered, to say the least. The results are not as expected.
The contradiction inherent in these two facts led me to modify my experiments many times, to repeat the retroconversion of asparagine to malic acid and also to treat the isolated malic acid with phosphorus pentachloride.
It details the transformation of asparagine into bromine succinic acid first by replacing the amino group with bromine, then the amide group with the hydroxyl group. It obtains l-bromine succinic acid and esters of l-bromine succinic acid. On the other hand, as we have seen, starting from malic acid, he had obtained the antipodes d.
After all this, here we find ourselves with the optical antipode of d-bromine succinic acid (or its esters), the latter obtained from ordinary malic acid via phosphorus pentabromide. Since asparagine, according to the works cited above, also produces ordinary malic acid, the fact that from the same active body (asparagine), depending on the method of processing, one can obtain now one, now the other optically opposite modification, seemed to me incredible; consequently I undertook a revision or a repetition of the experiments of Piria and Pasteur.
Starting from asparagine and aspartic acid with the method used by Piria and Pasteur he obtains common malic acid.
Both common asparagine and asparaginic acid (aspartic acid) give l-malic acid. optically identical to common malic acid.
He closes the circle by using this malic acid to produce, as he had already done, chlorosuccinic acid and bromosuccinic acid, both right-handed.
The conclusion is precise.
… Starting from a single body, optically active and with a single asymmetric carbon atom, we are therefore able, by applying optically inactive agents, chemically different agents, at relatively low temperatures, to obtain two types of active substitution products, i.e. the two optical antipodes. Experiments continue and more details will be provided soon.
The results of the experimental path made by Walden can be illustrated by these diagrams:
A summary of the steps that led to the discovery of the configuration reversal of halogensuccinics compounds
