[39] M. L. Wolfrom, M. Konigsberg, and S. Soltzberg, J. Am. Chem. Soc. 58, 490 (1936).

[40] A. Kunz, J. Am. Chem. Soc. 48, 1982 (1926).

[41] D. H. Brauns, J. Am. Chem. Soc. 47, 1294 (1925).

3. HALOGENO-ACETYL DERIVATIVES

General characteristics.-Since the chloro- and bromo-acetyl derivatives may be used for the synthesis of compound sugars and for the preparation of other substances, they rank among the most important sugar derivatives. The alpha derivatives may be prepared by treating the acetyl sugars with the corresponding hydrogen halides, preferably in acetic acid solution or by treating the acetyl sugars with phosphorus pentachloride, titanium tetrachloride, or other suitable halide. Under mild conditions the glycosidic acetyl group is replaced and the alpha halogen derivative is obtained. Prolonged treatment and higher temperatures result in the formation of dihalogen substitution products and in complex reactions which give new sugars of different configuration. The beta-chloro-acetyl derivatives are prepared by treating the alpha-bromo-acetyl derivatives with silver chloride.

The fluoro- and chloro-acetyl derivatives are usually stable and may be kept for long periods, but the bromo-, and particularly the iodo-acetyl derivatives tend to decompose at room temperature. The stability of the halogeno-acetyl derivatives decreases in the order of F, Cl, Br, and I, while the reactivity increases in the same order.

Although general methods of halogenation can be applied in many cases, modifications of these general methods are often necessary in order to obtain the desired derivatives in crystalline condition. This is especially the case for the halogeno-acetyl derivatives of fructose, mannose, maltose, and melibiose. Thus Fischer and Oetker [1] were not able to prepare crystalline bromo-tetraacetylmannose, while Micheel and Micheel [2], by a slight modification of their procedure, obtained the crystalline compound. The special procedure necessary to induce bromo-heptaacetylmaltose to crystallize is given by Brauns [3].

(a) PREPARATION OF FLUORO-DERIVATIVES

(1) 1-FLUORO-2,3,4,6-TETRAACETYL-a-d-GLUCOSE. Method [4].-The preparation is best carried out in a copper apparatus consisting of a retort, water-jacketed condenser, and receiver, which are connected by ground joints. The condenser is cooled with ice water and the receiver by an ice-salt bath. About 80 g of dry potassium hydrogen fluoride I is placed in the retort and 10 g of pentaacetyl-6-d-glucose in the receiver. The apparatus is connected, the retort is heated to a red heat, and the hydrogen fluoride distilled into the pentaacetylglucose over a period of about 30 minutes.2 The cold liquid in the receiver is then poured into a separatory funnel containing ice, water, and chloroform. The mixture is shaken and the chloroform separated. The aqueous layer is extracted several times with chloroform. The combined extract is washed several times with water and dried with anhydrous sodium sulfate. The chloroform solution is evaporated to a sirup which, after the addition of petroleum ether, yields crystalline 1-fluoro-2,3,4,6-tetraacetyl-a-d-glucose. The crystalline mass is dissolved in a small amount of hot ethyl alcohol and the solution is filtered and allowed to cool, whereupon crystallization

takes place. About 4 g of the crystalline substance is obtained, which may be purified by several recrystallizations from hot ethyl alcohol. 1-Fluoro-2,3,4,6-tetraacetyl-a-d-glucose melts at 108° C and gives [a]2+90.1° (chloroform, c=3).

NOTES

A supply of dry potassium hydrogen fluoride is prepared by dehydrating commercial potassium hydrogen fluoride. This is advantageously performed by heating the crushed salt gradually to 140° C in a vacuum oven. The dry salt is stored in copper beakers in a vacuum desiccator. Recently anhydrous hydrofluoric acid in iron containers has been put on the market and could advantageously be used. Precautions for handling anhydrous hydrofluoric acid are given by Ruff and Plato [5]. Adequate ventilation should be provided.

2 The amount of hydrogen fluoride produced may be determined by weighing the receiver before and after the distillation. About 20 g should be condensed in the receiver.

(b) PREPARATION OF CHLORO-DERIVATIVES

(1) 1-CHLORO-2,3,4,6-TETRAACETYL-a-d-GLUCOSE.

Method [6].-Ten grams of dry pentaacetyl-p-d-glucose dissolved in 70 g of purified chloroform is mixed with a solution of 4.9 g of titanium tetrachloride in 25 g of purified chloroform. The yellow precipitate which forms dissolves after shaking, with the simultaneous liberation of heat. The solution is refluxed on a water bath for 3 hours, during which time care is taken to exclude moisture. The yellow solution is cooled and mixed with ice water. The colorless chloroform layer is washed several times with water, dried with calcium chloride, and evaporated under reduced pressure. The colorless sirup is dissolved in absolute ether, and the solution is saturated with petroleum ether. After the introduction of seed crystals, crystallization takes place. About 7 g of crystalline material separates, and from the mother liquor another 1.5 g may be obtained. 1-Chloro-2, 3, 4, 6tetraacetyl-a-d-glucose melts at 75° to 76° C and gives [a]=+166.1° (chloroform, c=2).

NOTES

1 USP chloroform is washed several times with water, dried with calcium chloride, and distilled over phosphorus pentoxide. 2 Seed crystals are obtained by stirring a little of the sirup with absolute alcohol.

(2)

1-CHLORO-2,3,4,6-TETRAACETYL-a-d-MANNOSE.

Method [7].-Fifteen grams of crystalline pentaacetyl-6-d-mannose is dissolved in 30 ml of dry chloroform in a glass-stoppered Erlenmeyer flask, and 4 g of dry (sublimed) aluminum chloride and 9 g of phosphorus pentachloride are added. The mixture is slightly warmed on the steam bath in order to accelerate the reaction. In about 1 hour nearly all the aluminum chloride and phosphorus pentachloride go into solution and the mixture turns slightly green. The reaction product is then cooled, poured into ice water, and the product is extracted with chloroform. The chloroform extracts are washed several times with ice water, dried with anhydrous sodium sulfate, and evaporated in vacuo. The sirupy residue may be dried in a vacuum desiccator over paraffin wax in order to remove traces of chloroform. When the dry colorless residue is stirred with a small amount of petroleum ether, crystallization takes place. The product is recrystallized by reducing it to a powder which is extracted, first with a

100-ml portion of petroleum ether (which is kept separate as it contains most of the impurities), and then four times with 200-ml portions. By evaporating the petroleum ether in air, about 9 g of crystals is obtained. 1-Chloro-2, 3, 4, 6-tetraacetyl-a-d-mannose melts at 81° C and gives [a]=+89.9° (chloroform, c=2).

(c) PREPARATION OF BROMO-DERIVATIVES

(1) 1-BROMO-2,3,4,6-TETRA ACETYL-a-d-GLUCOSE.

3

Method [8, 9].-A mixture of 200 g of pentaacetyl-6-d-glucose2 and 130 ml of a glacial acetic acid solution of hydrogen bromide (saturated at 0° C) is prepared at room temperature, and the solution is allowed to stand for 2 hours. The solution is then diluted with 800 ml of chloroform, poured into 3 liters of ice and water, and stirred rapidly.* The chloroform layer is separated and the aqueous phase extracted once more with 200 ml of chloroform. The chloroform extracts are washed twice with ice water, dried with calcium chloride, and evaporated in vacuo to a thick sirup which is taken up with 500 ml of absolute ether. Petroleum ether is added until a second liquid phase begins to appear and crystallization is allowed to take place. The dried product weighs 150 to 160 g. The pure substance melts at 88° to 89° C. The material obtained at this point is sufficiently pure to be used for most purposes. However, recrystallization can be carried out by dissolving the product in the minimum amount of warm alcohol-free chloroform and then adding absolute ether. 1-Bromo2,3,4,6-tetraacetyl-a-d-glucose melts at 88° to 89° C and gives [a]=+197.8° (chloroform, c=2).

NOTES

The method as given has been worked out by B. Helferich and E. Günther, who have modified in some details the original method of E. Fischer and H. Fischer.

This material may be prepared by the sodium acetate method given on page 488. A 30 to 32 percent solution of hydrogen bromide in glacial acetic acid may be obtained from chemical-supply dealers.

The 1-bromo-acetyl derivatives generally decompose readily. Therefore it is necessary that the extraction be carried out rapidly and that a low temperature be maintained by adding ice. A large volume of water is desirable in order that the hydrobromic acid be as dilute as possible.

The bath temperature should be kept below 45° C.

The product decomposes fairly readily at room temperature. If it is to be used for further preparatory work, it should not be separated from the mother liquor until the day it is needed. Until that time the unfiltered crystals and mother liquor should be kept at 0° C. The dry crystalline substance may be kept for a considerable time at 0° C if placed over sodium hydroxide in a desiccator and spread in a thin layer.

(2)

1-BROMO-2,3,4,6-TETRAACETYL-a-d-TALOSE.

Method [10].-Ten grams of pentaacetyl-6-d-talose is dissolved in 50 ml of glacial acetic acid containing 38 percent of hydrobromic acid and 2 ml of acetic anhydride at 0°C. After the acetate has dissolved, the solution is allowed to stand for several hours at room temperature. Chloroform (60 ml.) is then added, and the solution is poured into a mixture of ice and water and extracted several times with chloroform. The extracts, washed several times with ice water and cold sodium bicarbonate solution, and dried with anhydrous sodium sulfate, are evaporated in vacuo to a thin sirup which is taken up with toluene and again evaporated to a sirup. The sirup is mixed with a small

quantity of dry ether, whereupon crystallization takes place. After several hours about 7 g of crystalline 1-bromo-2,3,4,6-tetraacetyla-d-talose separates and from the mother liquors about 0.5 g more may be obtained. The substance is recrystallized from warm dry ether. 1-Bromo-2,3,4,6-tetraacetyl-a-d-talose melts at 84°C and gives [a]20=+165.6° (chloroform, c=4).

(d) PREPARATION OF IODO-DERIVATIVES

(1) 1-IODO-HEPTAACETYL-4-(B-d-GLUCOSIDO)-a-d-MANNOSE. Method [11].-Eight grams of octaacetyl-4-6-glucosido-6-d-mannose is dissolved in 16 ml of dichloromethane in a large Pyrex test tube and cooled in an ice-and-salt bath. A slow stream of dry hydrogen iodide is passed through the solution for one-half hour. The solution is poured into a cold crystallizing dish and evaporated under a glass jar by means of a rapid current of dry air. The sirup left after evaporation is extracted with petroleum ether by stirring and pouring off the solution. This procedure is repeated several times. Anhydrous ether is added to the residue, and by rubbing with a glass rod the sirup may be brought to crystallization. The crystals are washed with ether. They are recrystallized by dissolving in a small amount of alcohol-free ethyl acetate and adding ether and finally petroleum ether until turbidity appears. The substance crystallizes in small clusters of needles. It melts with decomposition at 140°C and gives [a]2+111.50° (chloroform, c=2).

NOTE

1 The iodo-acetyl sugars are not very stable, but if kept in a thin layer in a desiccator over sodium hydroxide at 0°C they may be stored for several weeks.

(e) TRANSFORMATION OF THE ACETATE OF ONE SUGAR TO THE
HALOGENO-ACETATE OF ANOTHER SUGAR

(1) CONVERSION OF OCTAACETYLCELLOBIOSE TO FLUORO-HEXAACETYLGLUCOSIDOMANNOSE, (1-FLUORO-HEXAACETYL-4-(8-d-GLUCOSIDO)

a-d-MANNOSE).

Method [11, 12].-Octaacetylcellobiose is fluorinated according to the method described for the preparation of fluoro-tetraacetylglucose. In this case, however, 200 g of the cellobiose derivative and 2 kg of potassium hydrogen fluoride are used. The distillation requires about 2 hours and about 400 g of hydrogen fluoride is obtained. The receiving vessel containing the octaacetylcellobiose and the hydrogen fluoride, after standing at room temperature for 5 hours, is cooled in an ice-and-salt bath and the contents poured into a large separatory funnel containing water, cracked ice, and chloroform. The chloroform extract is dried, concentrated in vacuo, and the chloroform-free sirup dissolved in methyl alcohol. The mixture solidifies gradually to a thick mass of white crystals which are separated after standing overnight. A second crop is obtained from the mother liquors. The total yield is more than 30 g. The recrystallization of 1-fluorohexaacetyl-4-(6-d-glucosido)-a-d-mannose is easily accomplished from hot methyl alcohol, from which it separates in small needles on cooling. The pure compound melts at 145°C (not sharply) and gives [a]2+20.8° (chloroform, c=3).

The mother liquor is evaporated in vacuo to a thick sirup from which 4-glucosidomannose is obtained by acetylating the sirup and

crystallizing octaacetyl-4-glucosidomannose from the mixture. The acetylation is conducted by the zinc chloride method given on page About 35 g of pure octaacetyl-4-(6-d-glucosido)-a-d-mannose is obtained.

NOTE

1 Occasionally an acetylated sugar may be converted to the halogeno-acetate of another sugar by treatment with a very active halogenating reagent. However, this type of reaction does not appear to be generally applicable.

(2) CONVERSION OF OCTAACETYLLACTOSE TO CHLORO-HEPTAACETYLNEOLACTOSE, (1-CHLORO-HEPTAACETYL-4-(B-d-GALACTOSIDO)-dALTROSE).

Method [13, 14].-One hundred grams of powdered anhydrous aluminum chloride and 50 g of phosphorus pentachloride are added to 50 g of octaacetyllactose dissolved in 350 ml of alcohol-free anhydrous chloroform in a 2-liter flask. The mixture is shaken for a minute or two, the flask is connected with a reflux condenser, and the contents are heated to gentle boiling for 20 minutes. The mixture is cooled and the chloroform layer is poured into 5 liters of ice and water. The residue is also carefully decomposed with ice water and the aqueous solution is extracted with chloroform. The combined chloroform extracts are washed with ice water, dried with calcium chloride, and concentrated in vacuo to a thick sirup. This is taken up in 400 ml. of dry ether and allowed to stand for several days in the refrigerator for crystallization to take place. The crystals, which consist of 1-chloro-heptaacetyllactose and 1-chloro-heptaacetylneolactose, are collected on a filter and washed with dry ether. The crystals are then trituated with 100 ml of cold ethyl acetate. The chloro-heptaacetyllactose goes into solution and leaves a residue of crude chloro-heptaacetylneolactose. This is recrystallized by dissolving it in a small quantity of chloroform and adding several volumes of ether. The yield is about 16 to 22 g. 1-Chloro-heptaacetylneolactose melts at 182°C and gives [a]=+71.2° (chloroform, c=1). 1-Chloroheptaacetyllactose (melting point, 120°C) is recovered from the ethyl acetate extract.

(f) REFERENCES

[1] E. Fischer and R. Oetker, Ber. deut. chem. Ges. 46, 4035 (1913). [2] F. Micheel and H. Micheel, Ber. deut. chem. Ges. 63, 386 (1930).

[3] D. H. Brauns, J. Am. Chem. Soc. 51, 1820 (1929).

[4] D. H. Brauns, J. Am. Chem. Soc. 45, 833 (1923).

[5] O. Ruff and W. Plato, Ber. deut. chem. Ges. 37, 673 (1904).

[6] E. Pacsu, Ber. deut. chem. Ges. 61, 1508 (1928).

[7] D. H. Brauns, J. Am. Chem. Soc. 44, 404 (1922).

[8] E. Fischer and H. Fischer, Ber. deut. chem. Ges. 43, 2534 (1910).

[9] H. Ohle, W. Marecek, and W. Bourjau, Ber. deut. chem. Ges. 62, 849 (1929).

[10] W. W. Pigman and H. S. Isbell, J. Research NBS 19, 210 (1937) RP1021.

[11] D. H. Brauns, J. Am. Chem. Soc. 48, 2776 (1926).

[12] H. S. Isbell, BS J Research 5, 1185 (1930) RP253.

[13] A. Kunz and C. S. Hudson, J. Am. Chem. Soc. 48, 1978 (1926).

[14] N. K. Richtmyer and C. S. Hudson, J. Am. Chem. Soc. 57, 1718 (1935).

4. BENZOYL DERIVATIVES

General characteristics.-The benzoyl derivatives of the sugars were first prepared by application of the Schotten-Baumann reaction, using sodium hydroxide and benzoyl chloride, but it is difficult to