Glucose with Acetone. by JAMESLESLIE AULD MACDOWALD (Carnegie Scholar)

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1896 MACDONALD: THE MECHANISM OF THE

CCIIL- The Mechanism of the Condensation of Glucose with Acetone. By JAMESLESLIE AULD MACDOWALD (Carnegie Scholar). DURINGthe past five years the preparation of glucose-monoacetone and -diacetone has been carried out in this laboratory on twenty occasions, the process being modified in various ways (Irvine and Scott, this vol., p. 563). The yields obtained have been very irregular, and, what is more surprising, the amount of monoacetone derivative fluctuated in the most remarkable manner. The conclusion drawn is tha,t the simplest possible explanation, namely, that the reaction consists of the simultaneous hydrolysis of glucosedimethylacetal and condensation with the solvent acetone, is untenable. Such a process should result, in the first instance, in the formation of a glucosidic monoacetone derivative, followed by a second condensation with the ketone, the final product being entirely glucosediacetone. The following research was undertaken in the hope of tracing the mechanism of the reaction, so as to improve the working methods of preparing these derivatives and to throw light on their constitution, as they may play an important part in the future development of synthetical work in the sugar group. As glucosemonoacetone possesses a glucosidic structure, the formation of the compound must of necessity involve a process of simultaneous hydrolysis and condensation, in which glucosedimethylacetal

Published on 01 January 1913. Downloaded by New York University 10/10/2014 11:36:57. parts with the acetal grouping and reacts with the solvent ketone. A reaction of this kind does not account for the persistence of glucosemonoacetone however long the t.reatment with the ketone may be extended. This type of reaction is, moreover, uncommon in the sugar group, and does not ta,ke place to any appreciable extent with acyl derivatives of glucose ; t.hus, a-penta-acetyl glucose, when dissolved in acetone containing the same percentage of hydrogen chloride as is necessary for the decomposition of glucosedimethylacetal, readily lost the acyl groups at the temperature of the room, but no condensation with the solvent took place, and the main product consisted of glucose. An attempt was therefore made, starting from glucosedimethylacetal, to arrest the condensation at the earliest possible stage, and thus isolate the first product of the reaction. This was carried out as explained in the experimental part, and a product obtained, which, although too unstable to permit of analysis, possessed the reactions which would be char- View Article Online

CONDENSATION OF GLUCOSE WlTII ACETONE. 1897

acteristic of a glucosedimethylacetalmonoacetone. The first stages of the rea.ction are therefore expressed in the following scheme : ~GH,,O, --3 (I.1 HO CH,*CH(OH)*C!H (OH)*CH( OH)*CH(OH)* CH (OMe), -+ (11.1 H, f! H C H (OH) CH (0H) C H (0H ) CH( OMe) 00 \/ c: (111.) /\ Me Me Since glucosedimethylacetalmonoacetone is the main product of the initial stages of the condensatian of acetone with glucosedimethylacetal, a knowledge of its propertles should furnish valuable evidence for establishing the mechanism of the formation of glucose-monoacetone and -diacetone. A most significant property of the compound is that on further treatment with acid acetone it yields glucosediacetone, and it is probable that this is the main route by which the latter compound is formed when prepared by the usual method. As might be expected, glucosedimethylacetalmonoacetone is extremely unstable, and when heated in a vacuum at as low a temperature as ZOO it is readily decomposed, a molecule of methyl alcohol being lost by ring-formation between the a- and &carbon atoms, and the 7-oxidic compound,* methylglucosidemonoacetone, is thus produced. In the light of the above explanation the product of this change should contain a stable glucosidic grouping and an unstable Published on 01 January 1913. Downloaded by New York University 10/10/2014 11:36:57. acetone residue. That such is the case was proved by carefully regulated hydrolysis. The crude glucosedimethylacetalmonoacetone was heated in a vacuum until constant in weight, and the syrup obtained hydrolysed with hydrochloric acid of a concentration insufficient to cause decomposition of methyl glucoside. In this way the acetone residue was removed without attacking the glucosidic position, and the final product, as indicated by the rotation value obtained, was an equilibrium mixture of a- and @-methylglucosides. This result cannot be explained on any assumption other than the elimination of methyl alcohol from the acetal and the formation of methylglucosidemonoacatone (V). * The nomenclature here adopted to express the position of substituent groups in the sugar molecule is the same as that used in this vol., p. 564. It is perhaps necessary to pvint out that if the expression " y-oxidic linking " is to be retained, the adoption of this system involves a certain amount of dubiety as the y-linking connects the a- and &carbon atoms of the sugar. View Article Online

1898 MACDONALD: THE MECHANISM OF THE

Glucosedimethylacetalmonoacetone, like other acetone compounds, is highly sensitive to dilute acids, which remove the acetone residue and simultaneously hydrolyse the acetal grouping, the final product of the reaction being the parent hexose. These reactions may be expressed as follows: .O 7 A,.~H*CH*CH(OH).FH*~H 00 00 \/ \/ c u

acid Glucosedimekhylacetalmonoacetone +CH 0 hydrolysis l2 ' \ Published on 01 January 1913. Downloaded by New York University 10/10/2014 11:36:57.

Structure and Coiistitutioit of Intennediate Compounds. As Irvine and his collaborators have already pointed out, the position taken up by an acetone residue when entering a sugar molecule, where the number of hydroxyl groups renders the formation of isomeric forms possible, depends largely on the relative stability of the rings thus produced. This stability is influenced by two factors, namely, (a) ths number of atoms forming the ring, and (b) the position of the hydroxyl groups relative to the plane of the y-oxidic: ring of the sugar. Since glucosedimethylacetalmonoacetonereadily forms a glucoside it follows that the acetone residue cannot be linked to the &carbon atom. Methylglucosidemonoacetone must therefore have two free View Article Online

CONDENSATION OF GLUCOSE WITH ACETONE. 1899

hydroxyl groups, and the position of these may be established by rnethylation and hydrolysis of the resulting compound. This was carried out, and a dimethyl methylglucoside and finally a dimethylglucose were obtained. The general reactions, solubilities, and rotation values of the dimethylglucose thus isolated corresponded with those quoted by Irvine and Scott (this vol., p. 575) for By-dimethyl glucose. The optical values are compared below : [u]~O"for dirnethyl- glucose obtained [ajEoofor fir-di me thy1 - from dirnethyl methyl- glucose Solrent. gI ucosidemonoacetoii e. (Irviiie aiid Scott). Water...... + 65.3" + 64'4" Methyl alcohol ... 157'2 +58*1 * Ethyl alcohol .. . + 50.0 +49'4 * New determination. Although the methylated sugar could not on this occasion be obtained crystalline, the resemblance is sufficiently striking to warrant the conclusion that the compound is By-dimethylglucose. From this it follows that the acetone residue in methyl glucoside- monoacetone and glucosedimethylacetalmonoacetone is linked to carbon atoms E and 5. Now, since glucosediacetone is obtained by further condensation of acetone with glucosedimethylacetalmonoacetone, it follows that the acetone residue not atkached to the reduciag group in this compound is in the €3-position. This is not in agreement with the constitution assigned to glucosediacetone by Irvine and Scott (this vol., p. 564), although it was there pointed out that the evidence on which the suggested constitution is based was capable of a different interpretation. Glucosediacetone formed in the manner now described must have the following structure (VI), provided that the glucosidic acetone residue forms a five- Published on 01 January 1913. Downloaded by New York University 10/10/2014 11:36:57. membered ring. Formula (VII) represents the alternative constitution advanced by Irvine and Scott:

1 -~ 0 0-7 FH,*FH.CH.CH(OH)*FH*CH HO.CH,*qH*bH*~H*FH*FH 00 0 0 0-CMe,-0 0 0 \/ \/ \/ c: c C /\ /'\ /\ Me Me Me Ale Ale Me (VI. 1 (\'II*) 0 -___ HO*CH;CH(OH)*GH*CH(OH)*~H* 0H 00 (VIII.) \/ C A Me Me View Article Online

1900 MACDONALD: THE MECHANISM OF THE

If the above reasoning be accepted the ruonornethyl glucose described by Irvine and Scott must have the alkyl group ill the y-position, and this conclusion harmonises with all the available evidence regarding the structure of this compound. It may be mentioned here that an extended investigat.ion of the sugar has now been commenced in this laboratory. It is evident, however, that glucosediacetone may also be formed by a different route. When acid acetone is brought into contact with glucosedimethylacetal the first reaction may be t.he hydrolysis of the acetal grouping and the entry of a molecule of acetone in the c&positioii producing the glucosemonoacetone isolated by Fischer (Bey., 1595, 28, 2496), formula (VIII), which in turn condenses with a second molecule of acetone to form the di-derivative. The second molecule of acetone may be attached in three alternative ways; the linking may be y and 5, y and E, or E and 3. The first possibility may be rejected on stereochemical grounds, since a seven-membered ring is involved. Comparing the two remaining alternatives, it will be seen that formula (11) requires the formation of a six-membered ring having a trans-configuration in respect of the y-oxidic ring, a condition involving severe molecular strain. Formula (I) is therefore the more probable, and the fact that only one glucosediacetone has been isolated, although not conclusive, tends to strengthen this view. The series of probable changes which take place in the formation of acetone derivatives of glucose are thus expressed in the following scheme: Glucose I .J.

Published on 01 January 1913. Downloaded by New York University 10/10/2014 11:36:57. glucosedimethylacet a1 -+ met hy lglucoside / \\ Ir x glucosemonoscetone glucosedirnethylacetalmonoacetone

glucmediacetone .i nie t hylglucosidemonoacet one. A review of the whole sequence of changes indicates in a striking manner the complexities introduced into the reactions of the sugars when the latter are converted, even temporarily, into straight- chain derivatives of an acetal nature. View Article Online

COXDENSATION OF GLUCOSE WlTH ACETONE 1901

EXPERIMENTAL.

GI ti c.osuclinietI~ylu6etn7. The conditions laid down by Fischer (Zoc. cat.) were, in essentials, followed in the preparation of this compound. Inasmuch as the preparation was carried out on a much larger scale than that employe1 by Fischer, it was found convenient, in the first place, to make a solution of dry powdered glucose (90 grams) by boiling the sugar with pure dry methyl alcohol, and, after cooling, to add the requisite arr.ouizt, of hydrogen chloride dissolved in methyl alcohol so as to make the final volume 1600 C.C.and the acid content 1.5 per cent. After remaining at the temperature of the room for sixty hours the acid was removed by shaking first with dry powdered barium carbonate and finally with silver carbonate. After shaking with freshly ignited animal charcoal the solvent alcohol was removed at 35O/15 mm., a Winchester bottle being used as a distil- ling flask. The syrupy residue was well shaken with 300 C.C. of dry acetone, which was subsequently removed in a vacuum. In this way a clear, colourless syrup was obtained lining the sides and bottom of the bottle, these conditions being extremely well adapted for the subsequent treatment with acetone.

Glucosccli w e t h ylace falmonoacetone.

Five hundred C.C. of dry acetone containing 0.5 per cent. of hydrogen chloride were added to the crude glucosedimethylacetal, and the contents of the bottle were subjected to alternate shaking and heating on the water-bath at 35O for three and a-quarter hours. Published on 01 January 1913. Downloaded by New York University 10/10/2014 11:36:57. To aid the incorporation of the syrup with the acetone some chips of porous porcelain were added. The acetone liquor was poured off, and immediately neutralised with barium carbonate, followed by treatment with silver carbonate and charcoal. The undissolved syrup remaining in the bottle was given a further treatment with acid acetona for the same period. A third treatment yielded a negligible amount of product. Extracts 1 and 2 were mixed and dried over anhydrous sodium carbonate. The solution was then coircentrated to about one-third of the volume over fresh carbonate on the water-bath, filtered, and concentrated further in a vacuum at a low temperature, When the liquor had become slightly syrupy the concentration was stopped, and a large volume of dry light petroleum added. This precipitated a transparent, colourless, mobile syrup, from which the mother liquor wm poured away, and fresh quantities of light petroleum were added from time to time. The deposition of the syrupy product extended over several weeks. VOL. CIII. 6K View Article Online

1902 MACDONALD: THE blECHANlSh1 OF THE

The product, which amounted to 25 per cent. of the glucose used, was extremely soluble in water, cold acetone, or warm ethyl acetate. The reactions of the compound were essentially the same as those of glucosedimethylacetal, but the increased solubility indicated that condensation with acetone had proceeded. All attempts to confirm the idea that the syrup consisted of glucosedimethylacetalmonoacetone by means of analyses were fruitless. When dried in a high vacuum at the minimum possible temperature the combustion results obtained corresponded with those required for methyl- g~ucosidemonoace~one,indicating that a molecule of methyl alcohol had been removed during the drying process. Hydrolysis of Glucosedirn ethylacetalmonoacetone . Hydrolysis of glucosediniethylacetalrnonoacetone syrup, which had been heated in a vacuum at 30° until constant in weight, was carried out under conditions which do not affect methylglucoside. A 2.5 per cent. solution of the syrup was prepared in 50 per cent. ethyl alcohol coataining 0.5 per cent. of hydrogen chloride, and the solution examined polarimetrically in a jacketed tube, which was maintained at 3G0. Under these conditions hydrolysis was complete in eighty hours. Some of the readings obtained are appended :

q3J"* Time in hours. [a];;j. 0 -0 74" - 15.10" 1 - 0.79 - 16-12! 3 - 0'62 - 12.65 ti -- 0.29 - 5 -29 9 - 0'04 - 0.82 19 + 0'60 + 12'24 Published on 01 January 1913. Downloaded by New York University 10/10/2014 11:36:57. 26 +1'00 + 20'40 YO + 1 -20 -t24 '49 4d +1'49 + 30.40 63 i-1 '87 + 38'16 SO +1'89 i-38 -57 1=2. Methylglucoside-E(-monoacetone. The crude glucosedimethylacetalmonoacetone described above was dried at 2Z0/12 mm. until constant in weight. A colourless syrup then remained, which could not be obtained crystalline. Found: q=51.19; H= 7-71; OM0= 11.2. C$H,,O,*OMe requires C=51-25 ; H= 7.69 ; OMe = 13.2 per cent. The following rotation values were observed :

Solvent. C. 1. a200* [U];O". Methyl alcohol ...... 4'451 1 - 0 '82" - 11'68" Ethyl alcohol .. , . . , .. . 4 '1 10 1 - 0.47 - 11-43 View Article Online

CONDENSATION OF GLUCOSE WITH ACETONE. 1903

The compound, which was practically devoid of action on Fehling's solution, was readily soluble in water, methyl and ethyl alcohol, acetone, ethyl acetate, or ether, but only moderately 60 in methyl iodide. When heated in a vacuum at 60° for some time it was partly hydrolysed, and gave an insoluble residue when extracted with dry ether. The reactions and solubilities of this residual product agreed with those of methyl glucoside, thus indicating that the acetone residue had been removed.

p y-Ulnietii yl Metiqlglucoside-e~-monoacetone. The alkylation of the methylglucosidemonoacetone was carried out by the silver oxide method in the usual way. Three times the theoretical quantity of alkylating mixture was used, and, owing to the sparing solubility of the unalkylated compound in methyl iodide, a few C.C. of acetone had also to be added in the first methylation. To ensure complete alkylation two further treat- ments were given. On working up the final product in the usual manner a syrup (b. p. 142--143O/12 mm.) was obtained, having no action on Fehling's solution. The yield was slightly less than the weight of unalkylated material used. Pound : C = 54.53 ; H = 8-45; ONe = 32.2. C,H,,O,(OMe), requires C = 54.96 ; H =8.40 ; OMe = 35.5 per cent.

Solvent. c. 1. p [a]Eoa. Methyl alcohol ,...... 6 *11 1 -- 1.16" - 19.00" 80 per cent. ethyl alcohol 10.0 2 - 2-98 - 15.00

By-Dimethyl M ethylglucoside. Published on 01 January 1913. Downloaded by New York University 10/10/2014 11:36:57. A 10 per cent. solution of dimethyl methylglucosidemonoacetone in SO per cmt. alcohol containing 0.5 per cent. of hydrogen chloride was heated in boiling water for twelve hours, during which time the rotation altered from laevo to dextro and became constant. After neutralisation with silver carbonate the solvent was removed in a vacuum, and the resulting syrup dissolved in dry acetone. This solution was dried over magnesium sulphate, the solvent evaporated, and the residue extracted repeatedly with dry ether. After removal of the solvent in a vacuum an attempt wits made to distil the product; a fraction almost without action on Fehling's solution and showing [a]: -+15*28O in methyl alcohol was thus obtained. Fractions of higher boiling point were more strongly dextro-rotatory, the maximum optical value recorded being + 51-1O. Fouiid : C = 48.05 ; I€= 7.87 ; OMe = 40-3. C,H,O,(OMe), requires C = 48.65 ; H = 8.11 ; OMe = 41.9 per cent. 6K2 View Article Online

1904 TURNER AND RISSETT: THE SOLUBILITIES OF

/3 y-llinw t hyl Clucosp. Complete hydrolysis of the glucoside described above was readily effected by heating an 8 per cent. solution'of the compound in 80 per cent. alcohol containing 8 per cent. of hydrogen chloride at 90° for forty-five minutes. After neutralisation and removal of the solvent in a vacuum a syrup remained, which failed to crystal- lise, although attempts to affect this were continued throughout several months. (Found, C = 45.99 ; H = 7.59 ; OMe= 30.2. G~H~o04(OMe)2requires C! = 46.15 ; H = 7.69 ; OMe = 29.8 per cent.)

Solvent. C. 1. $0". [Uj?. Water ...... 1 *056 2 + 1 '38" + 65.3" Methyl alcohol ... 1'2ti 1 0 '72 57 *2 Ethyl alcohol ... 1.617 2 1%7 50.0

I take this opportunity of expreesing my thanks to Professor J. C. Irvint: for his valuable help and advice, which was at all times at my disposal during the course of this work, and also to the Carnegie Trust for a grant which partly defrayed the expenses of the research. CHEMKCALRESEARCH LABORATORY, UNITEDCOLLEGE OF ST. SALVATORAND Sr. LEONARD, UNIVERSITYOF ST. ANDREW. Published on 01 January 1913. Downloaded by New York University 10/10/2014 11:36:57.