Heinrich Kiliani’s discoveries on the chemistry of sugars.
This first article on sugars in this blog is dedicated to the work done by Heinrich Kiliani (1855 –1945), a German chemist. He began studying chemistry in 1873 by enrolling at the Technische Hochschule in Munich. He had Emil Erlenmeye as a chemistry teacher, who appreciated him so much that he made him his assistant within three years in 1877. In 1883 he became a full professor at the Technische Hochschule. In these years he obtained the extraordinary results on the chemistry of sugars that were collected and continued by E. Fischer. In 1888 he began his collaboration with the Boehringer Sohn Factory. Thanks to his studies on Digitalis and Antiaris toxicaria in 1897 he was called to the University of Freiburg as director of the chemical laboratory of the School of Medicine. He remained at this university until the end of his career
Hermann Emil Fischer (1852 –1919) was a German chemist who was awarded the Nobel Prize in Chemistry in 1902 for his outstanding achievements in the field of sugar chemistry. It was the second Nobel Prize awarded after the one obtained by Jacobus Henricus van ‘t Hoff in 1901 which inaugurated the series of Nobel Prizes. We are used to seeing the family tree of D-aldose sugar depicted (see below). And as is often the case with things that are familiar to us, we do not understand their complexity. In this blog we will try to reconstruct the path that led to the construction of this tree, going back to the essential contributions of those who preceded Fischer’s work such as Heinrich Kiliani
The work of Heinrich Kiliani
Prof. McBride in his beautiful lecture Proving the Configuration of Glucose by Open Yale Courses called Heinrich Kiliani the “hydrogen cyanide man”. This joking appellation actually refers to one of the most important means used by Heinrich Kiliani in elucidating the structure of sugars. In his important article Ueber das Cyanhydrin der Lavuloee which appeared in the journal Berichte der Deutschen Chemischen Gesellschaft in 1885 he presents the problem he will solve:
While in the oxidation of dextrose by dilute nitric acid or halogens, compounds are formed very easily and in large quantities, the molecule of which still contains 6 carbon atoms chained together, levulose produces under the same conditions bodies with a lower carbon content (glycolic acid and inactive tartaric acid). Oxidation, therefore, causes a splitting of the molecule in this case, a fact that indicates that levulose is a ketone. Furthermore, if we take into account the fact that levulose is converted to mannitol by nascent hydrogen, i.e. it contains a normal carbon chain, [unbranched] we come to the conclusion that the following two constitutional formulas must be attributed to levulose:
It was now to be hoped that the correctness of one or the other formula could be demonstrated with certainty if it were possible to bind the hydrogen cyanide to the ketone radical of levulose and convert the formed cyanohydrin into the corresponding carboxylic acid. This is due to the fact that the carboxylic acid resulting from compound I, with the reduction carried out completely by concentrated iodidric acid, should produce methylbutylacetic acid, while the carboxylic acid formed by compound II should form ethylpropylacetic acid under the same conditions. Of the two heptyl acids, the extraction and identification of which is therefore the ultimate aim of this investigation, the first, methylbutylacetic acid, has been extensively examined and described by Hecht, while the second, hitherto unknown ethylpropylacetic acid, can be produced without difficulty by means of the synthesis of the acetacetic ester
From these points of view, I studied the effect of hydrogen cyanide on levulose. In the following sheets I report the results obtained so far, I note at the same time that I have already begun to study the relationship between dextrose and galactose and hydrogen cyanide, and that at least for the first type of sugar the formation of a cyanohydrin has been established with certainty.
In his fundamental article Synthesis in the sugar group of 1890, Emil Fischer wrote about the work done by Heinrich Kiliani:
This method, devised by Kiliani, I consider the greatest advance in the study of the sugar group over the course of several decades. With his help, the old formula for glucose was confirmed, and the ketone formula indicated above for levulose was put beyond any ambiguity. Similarly, Kiliani found that the structure of arabinose was
The addition of hydrogen cyanide allows you to take the first successful step towards the synthesis of more carbon-rich compounds from natural sugars.
One of the main problems encountered in working on sugars was the difficulty of obtaining them in the crystalline state, i.e. pure. Heinrich Kiliani, in his autobiography of 1923, when he lists the results achieved in his experimental activity carried out during the development of his doctoral thesis, mentions in the first point the preparation and purification of inulin1 by the freezing process. From inulin he then obtained levulose or fructose.
1 Inulin is the polymer of β-D-fructose. Inulin is mainly present in Jerusalem artichoke tubers, chicory and salsify roots. It is not digestible by humans
Preparation of levulose cyanihydrin
The article follows with a detailed description of the process for the preparation of pure cyhydrin of levulose, by reacting hydrogen cyanide and levulose, obtained from inulin. Determine the melting point of the product that was the most important measure to characterize a substance. It reports the data of the analysis carried out on levulous cyanidrin, comparing them with the theoretical values referred to a known hypothetical formula of levulous cyanidrine.
Conversion of cyanihydrin into the corresponding carboxylic acid and reduction of the latter.
Kiliani, once the levulose cyanide has been produced, proceeds to transform it into the corresponding acid. The procedure he describes is very complex. The final result is a product that corresponds to the analysis to a heptolactone and which, he specifies, does not solidify in a cold mixture.
This is followed by an equally complex analytical procedure to obtain heptylic acid through reduction with iodidric acid and red phosphorus. Determine the boiling temperature and note that it does not solidify into a cold mixture. The conclusion is that the product obtained cannot be normal heptyl acid, and that it is still confirmed that levulose cannot be an aldehyde. Recall that the hypothesis from which he started was precisely that of not obtaining normal heptylic acid but methylbutylacetic acid or ethylpropylacetic acid, depending on the position of the carbonyl group.
After a long and problematic work that is contained in two other articles (in the first of which, the continuation of what we have briefly reported, describes the synthesis and characterization of methyl-n-butylacetic acid, while in the second he describes the synthesis and characterization of ethyl-n-propylacetic acid) Kiliani resolves the position of the carbonyl group.
To obtain the two isomers of heptyl acid, Kiliani uses acetoacetic synthesis. Acetoacetic synthesis generates a carbonyl compound, but the conditions under which Kiliani operated were highly basic and an acid is formed in this environment. This is how he prepares the two heptyl acids. To characterize them, he obtains their calcium and strontium salts and compares them with those obtained from the acid obtained from levulosium cyanidrine and one of the two provides the solution:
The calcium and strontium salts of this acid behave exactly like the corresponding salts of the heptylic acid of levulocarboxylic acid2…. Therefore the heptylic acid obtained by reducing levulocarboxylic acid is undoubtedly identical to methyl-n-butylacetic acid prepared from the acetoacetic ester… But the levulous must ultimately have the constitutional formula:
2 It should be remembered that levulocarboxylic acid is the acid that, as we have seen, was obtained by first forming the hydrogen cyanosis of levulose and then transforming it into carboxylic levulous acid by acid hydrolysis.
La ricerca continua
In conclusion, the witness to the solution of the great enigma of the structure of sugars will start from Kiliani’s hand to that of Fischer. But Kiliani has provided Fischer with formidable tools that he will be able to exploit in a brilliant way.
