S Y N T H E S E S IS T H E SUGAR GROUP.
B Y EMILFISCHER." Translated by L. H. FRIEDBURQ, Ph. D.
Until quite recently the sugars of the formula, C6Hl$ 0 6were , considered as the simplest members of the group. As long as the synthesis had not been applied products of animal and vegetable life were the only sources. for the small number of sugars. I n 1886 WB knew four sugars of the formula C,H, *OB, viz. : Grape sugar, or glucose. Fruit sugar, or laevulose. Galactose. Sorbinose. Closely connected with these is arabinose which Scheibler, its discoverer, held to be an isomere of glucose, while Kiliani' in 1887 characterized i t as a compound, C,H,,O,. A few other substances had in former times been erroneously incorporated into t h e sugar series. Of these inosite and dambose, which are identical, have been recognised by Maquennez as derivatives of hexamethylm e , while others, such as phlorose3, corcose3 nnd cerebrose4 are no longer considered as being chemical individuals. Of the four remaining sugars the rare sorbinose has been but sparingly examined. According to the latest communications of Kiliani and Scheibler6 it seems to have the same constitution as laevulose.
-
* Ber. d .
Chem. Ges., 28,2114 (Abstract.) Ber. d. Chem. Qes., 90,389. '1 Compt. rend., 104. * Ber. d. Chem: Qes., 21, 988. Thierfelder, Zeitschr. fiir physiol. Chem., 14, 209. Ber. (1. Chem. Qerr., 21,8276.
SYNTHESES IN THE SUGAR QROUP.
341
On t h e other hand the structure of the three other important sugars was essentially known before my own researches began. The f o r m u h now in use for glucose and galactose : CH, (OH). C I I (OH). C H (OH). C H (OH). C H (OH). COH ; a n d for laevulose : CH, (OH). C H (OH). CH (OH). C H (OH). CO. CH, (OH) are derived from the following facts : Sodium amalgam changes glucose and laevulose into mannite ; while galactose under the same conditions furnishes dulcite. But mannite and dulcite arc to be considered as the hexatomic alcohols of normal hexane, because they are able to take u p six acetyl groups and to furnish normal hexyl iodide with hydriodic acid. Furthermore glucose and galactose when subjected to moderate oxidation by means of chlorine or bromine water yield the monobasic gluconic and galactonic acids and, on continued oxidation, the bibasic saccharic and mucic acids. They consequently contain the aldehydic group. Zinckeg and V. Meyer' objected to this conclusion, upon t h e basis that ketones also with the. group CO. C H 2 (OH), as for instance acetylcarbinol, may be transformed into oxyacids. This objection is not justified, because the formation of gluconic and galsctonic acids takes place in acid solution, while the transition of acetylcarbinol into lactic acid has been effected only by alkaline oxidizers. I n this latter case the carbinol may a t first be transformed into the aldehyde, methylglyoxal, which then, under the influence of alkali must, a t once change to lactic acid. Unlike the two aldehydes, laevulose is but very slowly attacked by cold bromine water and under the influence of more Berere oxidizers it decomposes into products less rich in carbone. All three sugars combine like the ordinary aldehydes or ketones with hydrocyanic acid. By saponification of the cyanhydrines formed, .three different acids, C,H,,O,, are produced which are changed in to heptylic acids when boiled with hydriodic acid.
7
8
Ber. d . Chem. Ges., 23, 636 aud Ann. Chem.'(Liebig),216,518. Ber. d . Chem. Ges., %3,23&. Kiliani, Ann. Chem. (Liebig), 206 175.
34'2
SYBTHESES IN THIC SLG-iIL G R O C P .
Under these conditions glucose and galactose furnish normal heptylic acid, while laevulose is transformed into methylbutylacetic acid. This method devised by Kilianig, I consider to mark t h e greatest progress in the study of the sugar group during several decades. By its aid the old formula for glucose was coilfirmed and the ketonic formula given above for laevulose put beyond ambiguity. I n t h e same manner Kiliani found the st.ructure of arabinoseio to be CH,(OI-Z).CH(0H). CH(0H). CH(OH). COH. The addition of hydrocyanic acid implies the first successful step toward synthesis of compounds yicher in carbon out of natural sugars. Another support for the formula of glucose and galactose has been found recently in the observation that they form hydrazones11 and oximes 1 2 just as the simple aldehydes do. The only objection against the nldehgde formula which is maintained 111) t o date, conceriis the iudifference of sugars towards fuchsine-sulphurous acid'3. But this objection loses its importance if we consider that, heretofore 110 simple oxyaldehyde of the fatty series has b e m tested by this reagent. For the time being it scwm therefore not justifiable to ~ ~ p l a the c c aldehyde formula by any other, especially as it explains all simple metamorphoses of the two compounds. 'I'lins the forniulE for the three kinds of sugar are derived from observations secmingly ample c~~iougli to serve as n basis for s y i theses. Rut it was different in regard to the methods which werc in use for the rccognitioii and isolation of these compounds. Whosoever has tried to obtain glucose or laevulose in a pure state, from salt solutions only, by the methodsformerly in use, will agree that it is quite impossible in that way to isolate such an artificial product from a mixture with other organic compounds and to characterize it as a chemical individual. T h i ; want of suitable methods I experienced vividly myself Rer. d . Cliem. Ges., 18, 306C: 19,321, 767, l l ? S . Ber. d. Chenz. Ges., 20, 338. I ' E'ischer, Ber. t i . Cheiu. Ges., 20, 824. l a Rischbieth, Ber. 2. Chem. Ges., 20, 2673. V. Meyer, Ber.d. Chem. Ges., 13, 2343.
9
lo
SYNTHESES IN THE SUGAR GROUP.
343
when seven years ago I attemptedLfoi-thejirst time the syitthesis qf (I sugar from the bromine compound of acroleine. At that time I obtained by decomposition of the bromide with baryta water a syrup which showed the ordinary suger reactions. 13ut all endeavors to obtain a pure preparation from the raw product were without sucess. Only four years later this was obtained after a useful agent for this purpose had been found in phenylhydraxin'4. The reaction between this base and sugars is easily shown as follows : Adding to a warm aqueous ten per cent. solution of glncose, a solution of phenylhydrazin in dilute acetic acid, the mixture a t once assumes a yellow color. Heating on the water bath leads in ten or fifteen minutes to a deposit of fine yellow needles, which finally fill the entire liquid like a pulp. These needless have the composition C, 8 E i ? *N4O4, and are called glucosazone. They are formed by combiliation of one molecule of sugar and two of phenyl11ydrazin. But the formation of this substance takes place in two phases. At first, the sugar combines, like common aldehydes, with one molecule of the base to an hydrazone of the formula : C H , (OH). *CH (OH). CH : N. NH. C,H,. [CH (OH) This compound is easily soluble in water and consequently passes unnoticed in the experiment. On heating this hydrazone with an excess of liydrazin, it suffers a peculiar oxidation. The alcoholic group marked * in the above formula, is transitorily changed into a carbonyl group which latter then fixes in known manner a second molecule of phenylhydrazin. Thus the glucosazone results, the structure of which is given by the formula :
CH, (OH). [OH (OH) C,H,.
Is,
NH.
C
II
N
- CH I1
N. NH. C,H,
We are forced to look a t the reaction in this way by the behavior of laevulose, which permits the entrance of the hydrazin groups in an inverted sequence. I n this case also the first step
16
Ber.d. Cheni. Ges., 17,529. Ber.d. Chem. Ges., 20, 82.2.
Then agiiin the alcoholic group marked * becomes oxidized, a scrond nioleculc of ~)lieiiylli?draziiieenters and allows the formation of a glncosazone ideiitical with the one obtained from glucose. ‘J’he same reaction is showii by :ill natural sugars which reduce Fellling’s solution, including lactosc and maltose. It also obtains for the artificial sugars. or generally speaking, for all aldehydes and ketones which i n iieighboring position contain an oxidizable alcoliolic grocp, t h a t is, a primary o r seconditry alcoholic group. The liydrazones of natural sugars art! generally easily suluble in water ; this is truc for glucose, liwvulose, gitlitctose, sorltiiiose, lactose, maltose, ai~altinosu,xylose and rhamnose. h l i ~ n n o s e6 ~foimis it11 exception. I t s plienylhydrazone is very difficultly soluble i n water, conscquently it is precipitated from a cold solntioii of the sugar upon addition of phenglhydrazin acetate. Lysing :t IO per cent. mannose solution, a separation of almost colorless. fine crystais begins within one t o two minutes and soon tlie entire liquid is filled with them. Thc optical isomcres of mannose behave similarly, as d o also different artificiallx obtained sugars with seven, eight and ninci carbon atoms. Here the precipitation of the hydrazone is by far the best means for the recognition as well as for isolation and purification of the sugar, since this latter mtty easily be regenerated from its hydrazone by splitting this with hydrochloric acid in the following way. To finely pulverized mannose plieiiylhydraaorie add four times its quantity of fuming HC1 of Sp. Gr. 1.19 a t ordinary temperature. On vigorously shaking, a clear brown liquid is rapidly obtained, t h e hydrochloride forming. After 1 to 2 minutes the splitting of t h e hydrazone becomes noticeable, since the crystallization of phenylhydrazine hydrochloride begins. I n 10 to 15 minutes the reaction is completed and then the separation of the sugar from t h e filtered liquid offers no difficulty. 16
Ber. d. Chem. Ges., 20,832; 21, 1805.
SYXTHESES
IN THE SUGAR GROUP.
345
The osa;ones, which are almost insoluble in water, have proved to be still more valuable for t h e developemeiit of work in the sugar group. They crystallize with comparative ease and precipitate even from most dilute solutions. I n addition, they differ in solubility, melting point and in optical behavior, and they are now consequently used for recognizing natural sugars. The derivatives of these latter, as well as the important marks of difference arc put down in the following table : GI~~comzoize, C, H,, N, 0,. Is formed from glucose, laevulose, mannose, glucosamine and isoglucosarnine. Almost insoluble in water, difficultly soluble in hot alcohol. llclting point near 205" C. T h e solution in glacial acetic acid turns the plane of polarization to the left. Gnlnctosnzotze, C , ,H, ,N,O,. From galactose. Almost insoluble in water, a little more soluble in alcoliol than the preceding. Melting point near 1 9 3 O C. No noticeable action on polarized light when dissolved in glacial acetic acid. Sovbiiiosazoiie, C, H, I N, 0,. From sorbinosc. Almost insoluble in water, easily soluble in hot alcohol. Melting point 164" C. Lactosazone, C,, H,, N, 0,. From lactose. Soluble in SO to 90 parts of hot water. Melting point near 200" C. Dilute sulphuric acid changes it into its anhydride C,, H,, N, 0,, which is almost insoluble in water. Maltosazone, C,,H,,N,O,. From maltose. Soluble in about 75 parts of hot water. Melting point near 206' C. Does not furnish an anhydride. Ambinosazone, C , 7 H 2,N,O,. From arabinose. Sparely soluble in hot water, easily soluble in hot alcohol. Melting points near 160" C. Its alcoholic solution shows no action upon the polarized light. Xytosazone, C, ,R,,N,O,. From xylose. Deceptively similar to arabinosazone, but, in alcoholic solution strongly turns polarized light to the left. Rha.mnosazone, C, ,H, ,N,O,. From rhamnose (isodulcite). Almost insoluble in water, easily soluble in hot alcohol. Melting point near 180" 0.
34 6
SYNTHESES IS T H E SCGAR QROUI'.
As before stated, the osazones are formed by a process of oxidation. The reconversion into sugars is coiisequen tly much more difficult than with the hydrazones. But for the investigatioii of synthetical sugars which could onl~/-be isolated in the form of osazon(:s, a way t o effect t h i s conversion had inevitably to be obtained. After many vain experiments I have found a way i n the following two reactions : Zinc dust and acetic acid reduce the osazones to nitrogenized, basic products. 'l'he glucosazorie thus forms a compound, C,H, ,NO,, which is isomeric with the glucosamine discovered by Ledderhose arid which consequently was called isoglucosamine. 1 7 It forms a beautifully crystallizing acetate and has the structural formula : CI-I,(OH). CH(OH). c"(oH). CH(OH). co. CH,. m,.
I t s formation from the osazone is a very remarkable process. One hydrazine group is split off entirely; in the other one the nitrogen cliaiii is broken by the nascent hydrogen, aniline being formed. The other nitrogen atom remains united with carbon of the sugar molecule, in form of an amido group. If the base is treated with nitrous acid in the cold, it loses its amido group and is easily transformed int.0 fruit sugar.' 5 But this treatment which furnishes such good results for the glucosazone, is not applicable in othcr cases, simply because t h e corresponding bases d o not crystallize and cannot therefore be isolated from the mixture of the reaction. Far more serviceable is the second method. Fuming hydrochloric acid splits the osazones of the sugar group into phenylhydrazine and the so called osones. 1 9 Considering the glucosazone the process takes place according t o the following equation : c 11 " 0 , ( N ,H. c 6 11,) 213,o C,H,,O,+SC,H,. - N , H 3 . Cflucosazone. Glucosone. But t h e practical performance of this reaction requires very close attention. The following experiment shows the condi-
+
Ber. d. Cheni. Ges., 19, 1920. Ber. d . C'hem. Ges., 20, 2569. 1 0 Brr. d. Chena. Ges., 22, 87. 17 18
SYNTHESES IN TIIE SCGAH. GROUP.
347
tions for a successful operation. T o finely powdered glucosazone the tenfold quantity of fuming H C I is added. It turns dark red, a n d a portion goes into solution with the same tint. It is thus transformed into its hydrochloride, which, however, is decomposed by water. If the mixture is rapidly heated t o 40" C. a n d vigorously shaken a clear solution is obtained. This is kept for b u t one minute a t 40° C. and then cooled down to 35" C. Now a n ample crystallization of phenylhydrazine hydrochloride sets in which indicates the splitting of the osazone. A t the same time the dark red tint of the liquid turns to a dark brown. I n ten minutes the reaction is finished. The filtered liquid is freed from HC1 and the glucosone is precipitated ns an iiisoluble lead compound. I t has not, so far, been made to crystallize, and, consequently, could not be malyzed, but its reactions, which correspond absolutely to those of glyoxal and with 1, 5-diketones, do not leave any doubt, t h a t the compound is the aldehyde of fruit sugar a n d possesses the formula :
CH,(OH). CH(0H). CII(0II). CH(OH). CO. COH. The behavior towards phenylhydrazine is particularly characteristic. The cold aqueous solution upon addition of phenylhydrazine acetate becomes rapidly turbid, and in fiye to ten minutes a dense precipitate of glucosazone iR formed. The glucosone combines also with aromatic orthodiamines and forms well-crystallizing chinoxaline derivatives. Finally its transformation by means of nascent hydrogen is particularly interesting, since heating with zinc dust and acetic acid changes it entirely into fruit sugar. This' method thus leads from grape sugar by way of the osazone a n d osone to fruit sugar and it is to be expected that in this manner most of the still unknown ketone sugars will be prepared from all aldehyde sugars. If we want tQreturii from the ketone sugars to t h e aldehyde sugars we have to go by way of the alcohol. Considering the last example, the transformation would be as follows : Fruit sugar is easily reduced to mannite by means of sodium amalgam. Careful oxidation with nitric acid forms out of this its aldehyde, the mannose, and further, from this, as I shall show, grape sugar. I n studying t h e sugars t h e osazones are capable of application to other purposes.
348
SYNTHESES IN T H E S U G A R GROVP.
T h e formula: C?,H,,O, ; (.'511,(,05 : C , H 1 4 0 , , etc., showing the same percentage composition, the analysis alone of these sugars will never allow to decide in regard to the number of carbon atoms; we are therefore forcwl to analyze a derivative. I'or this purpose t h e osazones are best fitted since, as ;L rule? they may bc obtained it1 a very pure state. 'I'hey have been utilized so f'ar for the determination of tlie empirical forniulx of arabinose 2 " . sorbine" and xylose 2 2 . In still other cases the osazoiies offer a new means of determining the constitution of a sugar. In former times rhamnose (isoclulcite) was considered to be a Iiexatomic alcohol and an analogue of inmiiitc, altliough its reducing a'ction up011 alkdine copper sol. wits known. But the use of the hyclrazin test showed, in furnishi r i g 2 3 ;In osazone, C 6 i € , ,Os (X211, C6H5)2, t h a t the anhydrous rhamnose isasugar of the formula c', 11, O j , for whicli later on tlie stlucturul formula was f o a r i c i 2 * to be C",. CII(0II). CH ( 011).C' I-€(0IT). c 1%(( ) 11). c'( ) 1€. Another example is offered by milk sugar, wliicli, as we know, is a i i anhydride of equal molecules of glucose and galactose. I t s fitculty of forming a11 osazone proves t h a t it still contains one group--c'I€(OII). (2011. Sitice, furthermore, the osone wliich is formed from the osazone decomposes into gnlactost: and glucosone when boiled with dilute acids, it follows that wc find in sugar of milk the unchanged aldehydic group of the glucose molecule. 9 5 This conclusion, which has been corroborated by the preparation of lactobionic acid20 and by the hydrolysis of this latter, has led to a new conception of the constitution of milk sugar and of the closely related maltose. Finally the hydrazones and osazones proved to be particularly valuablu for the discovery of iiew sugars and of subst:tnces similar to sugars. These latt,er are obtained in a comparatively easy manner by moderate oxidation by polyatomic alcohols. As far as I know, it was (larlet27 w h o made the first observation of this kind. .~
Kiliuni, Ber. d . Cheni. Ges.. 20, 346. E . Ei'scher, Ber. d . Chem. Ges., 20, 827. 2 2 Tdlens und Wheeler, Alzn. Client. (Liebig),064, $1,;. 9 3 E'ischrr iinrl Tafel, Ber. d. Chem. Ges., 20, 1091. 2 4 E'ischer und Tafel, Ber. d . CheitL. Ges., 21, 217.;'; seertlso Jlaquenne, Compt. Rend., 109, ~ 2 . 2 6 J'iseher, Ber. d . C'heiii. Ges., 21, %%!. 2 8 >.'ischcr und ilfeyer, Rer. d . Chem Ges., ??, , j G l . 2 ' J c t l , tY?sber.ichffiir Cllvlnie ( / s ' q " 0 . 20 21
(To !)e c o t i t i n u e t l . )
