[CONTRIBUTION PROM THE LABORa4TORI0 DE Q U f W C A O R G h I C . 4 ,
EXACTAS, FfSIChS
Y N A T U R 9 L E S AXD TEIE
BIOL6GICA,
FACULTAD DE CIENCIAS
LABORATORIO DE QU~XICA
FACULTAD DE CIENCIAS
kf$DICAS]
THE REACTION OF AMMONIA WITH SOME ACETYLATED AND BENZOYLATED MONOSACCHARIDES. PII. DERIVATIVES O F D-GALACTOSE JORGE 0. DEFERRARI
AND
VENANCIO DEULOFEU
Received January 16, 1962
In the first two papers of this series we have reported on the products obtained by the action of methanolic ammonia on acetylated and benzoylated derivatives of D-glucose (1) and D-mannose (2). Brigl, Muhlschlegel, and Schinle (3) ; Hockett and Chandler (4); and Niemann and Mays ( 5 ) have studied similar reactions. Our results and those of the forenamed authors show that aldose monoamides and aldose diamides are formed from the acylated monosaccharides by the action of ammonia. The type of amide compound obtained varies with the nature of the aldose and with the nature of the acyl group. Thus, pentaacetyl-P-D-glucopyranose (5) and pentaacetyl-aldehyde-D-glucose (4) produce N-acetyl-D-glucofuranosylamine, while pentaacetyl-/?-D-mannopyranose(2) gives D-mannosediacetamide. When the acetyl groups are replaced by benzoyl, a variation is found in the end products of the reaction. Both anomers of pentabenzoyl-D-glucopyranose (1) and pentabenzoyl-aldehydo-D-glucose(3) yield g glucose dibenzamide, while the anomeric forms of pentabenzoyl-D-mannopyranose produce mixtures of D-mannose monobenzamide and D-mannose dibenzarnide (2). It was also observed that the aldose amide compounds so obtained from the acylated aldoses were the same as those produced in the Wohl degradation of that acylated aldononitrile which yielded the same aldose in this degradation reaction. Thus, hexaacetyl-Dgluco-D-gulo-heptononitrile (4) and hexaacetyl-D-gluco-D-ido-heptononitrile(1) have the configuration D-glucose in their carbon atoms 3 to 6 and when treated with ammonia they yield the same N-acetyl-D-ghcofuranosyhmine that is obtained from pentaacetyl-D-glucopyranose ( 5 ) and from pentaacetyl-aldehydoD-glucose (4). Likewise, both hexaacetyl-D-manno-D-gala-heptononitrileand pentaacetyl-0-D-mannopyranose yield D-mannose diacetamide (2, 3) under these conditions. Similar results are obtained in the benzoylated series. Brigl and eo-workers (3) obtained D-mannose monobenzamide and D-mannose dibenzamide with ammonia ;these on treatment of hexabenzoyl-D-manno-D-galu-heptononitrile two products were likewise found by us (2) when the anomeric forms of pentabenzoyl-D-mannopyranose were subjected to the same conditions. A further example in the D-galactose acetate series will be noted below. The mechanism proposed by Isbell and Frush (6) for the formation of aldose diacetamides explains the like nature of the products obtained in the Wohl degradation and in the action of ammonia on the acylated aldoses. This has been discussed in our previous publications. A group of competitive reactions are involved among which the tendency to form acyclic structures and the differing rates of ammonolysis of the acyl groups play an important part. In some cases 1097
1098
J. 0. DEFERRARI AND V. DEULOFEU
aldose monoamides are formed and in others the aldose diamides constitute the principal OF sole products. We report herein the extension of our studies to the galactose series. This sugar is significant because it is known to react readily in the aldehydo form and because seven isomeric pentaacetates of it have been described. Five of these were treated with methanolic ammonia and each yielded D-galactose diacetamide (IV) in a yield of: 24-2601, from the anomeric forms of pentaacetyl-D-galactopyranose; 42--44% from the anomers of pentaacetyl-D-galactofuranose; 397, from pentaacetyl-aldehydo-D-galactose.As with the derivatives of D-glucose and Dmannose, @-I epimerization does not influence t'hc reaction. On the other hand, the effect of the ring structures or of a true aldehyde group can be readily noted. D-Galactose &acetamide (IV) was obt,ainedin 34% yield in the Wohl degradation (I) in which compound the conof hexaacetyl-~-gala-~-nzanno-heptononitrile figuration of carbons 3-6 is that of D-galactose. C.=N I
HdO( C=O )GI%,
HdOH
I cwa (C=O)OCH
HOCH
CHs(C=O)O CH
HOCH
I
I HCO(C=O)CB I
I I
I
HCOH
I
"I ow HC=O
I HCOCCH3 I I1
a
I
HCNH2
I
RCOCCHI
I/
l o
I1 111 If praduct yields are any indication of the facile formation of a true aldehyde group (11),or of its ammonia adduct (111),while the acetyl groups that rearrange t o produce D-galactose diacetamide are still attached to oxygen, then the high yield of IV obtained from pentaacetyl-aldehydo-D-galactoseis easily explained. In this derivative the aldehyde group and all of the 0-acetyls are initially present when it is submitted to ammonolysis. When the aldehyde group is not preformed, the yields of IV are lower. See Ref. 1 for details of these reactions.
dRiMONIA O N ACYLATED MONOSACCHARIDES. 111
1099
That the yields of IV from the furanose derivatives are higher than from those in the pyranose series is susceptible of two explanations. The most probable is that once the acetyl group on C-1 is ammonolyzed, the furanose ring opens more rapidly than the pyranose ring and the aldehyde group thus forms more readily. Once the aldehyde group is formed, the production of D-galactose diacetamide is initiated. This proposition is supported by the measurements of Compton and Wolfram (7) on the relative rates of opening of these rings inacetylated derivatives of D-galactose. A second but less probable explanation consists in the assumption that' the true aldehyde group is produced with equal velocity in both ring structures and that the yield variation is due to the differing reactivities of the as yet unhydrolyzed 0-acetyl groups. While the varying reactivities of the latter undoubtedly play a role it is probably not a decisive one. Hexaacetyl-D-gala-L-manno-heptononitrile(I) occupies ax1 intermediate position between the pentaacetyl-D-galactofuranoses and the pentaacetyl-D-gala!actopyranoses. In I the cyanide group and one acetyl must be eliminated t o give the aldehydo form I1 and only then can the remaining acetyls rearrange to give D-galactose diacetamide (IV). We have also submitted the pentabenzoyl-a-D-galactopyranoseof Wolfram and Christman (8) to the action of methanolic ammonia. It gave n-galactose dibenzamide. It is of interest to note that the ammonolysis of these acetylated and benzoylated derivatives of n-galactose yielded a diamide compound whereas in the corresponding derivatives of D-glucose and D-mannose a variation in the acyl group produced a change in the nature of the final reaction products.
EXPERIMENTAL^ Pentaacetyl-a-D-galactopyranose. This was prepared according to Hudson and Parker (9) except that 2 g. of zinc chloride in 14 ml. of glacial acetic acid and 26 ml. of acetic anhydride was employed for each 10 g. of pentaacetyl-8-D-galactopyranoseisomerized; map. 95-96", [cy]: +105.5" (chloroform). Hudson and Parker cite: m.p. 95.5", [a]: +106.7". Pentaacetgl-a-D-galactofuranose. Pentaacetyl-p-D-galactofuranosewas prepared according t o Schlubach and Prochownick (10) and this was isomerized by the procedure of Hudson and Johnson (11) with the modifications noted above in the preparation of pentaacetyl-an-galactopyranose; m.p. 87", [a]: +61.O0 (chloroform). Hudson and Johnson cite: m.p. 87", [a]: $61.2". D-Galactose diacetamide f r o m pentaacetyl-p-n-galactopyranose.A solution of 4 g. of pentaacetyl-p-D-galactopyranose in 120 ml. of methanolic ammonia was maintained a t room temperature for 24 hours. The residue obtained on solvent removal under reduced pressure was extracted with four 20-ml. portions of warm ethyl acetate to remove acetamide. The residual galactose diacetamide showed a strong tendency t o separate as a gel from water, methanol, or ethanol; yield 700 mg. (24.4%) from ethanol, m.p. 192-195", producing 720 mg. of the crystalline pentaacetate (m.p. 200-201", [CY]: -38.6" in chloroform) described below. A mass of microscopic irregular plates was obtained on the fourth separation effected b y cooling its warm ethanolic solution; m.p. 195-197", [a]: +6.8" (c, 1.67, water). The above
contents compare well with those obtained on purification through its crystalline pentaacetate described below. The pure pentaacetyl-D-galactose diacetamide (2 g.) was treated with methanolic ammonia as described above for pentaacetyl-p-n-galactopyranose and the 2 Ammonia content of all methanolic ammonia employed was 16%. Ethanol was 96% unless otherwise noted. Mixture melting points were performed in all identifications.
1100
J. 0. DEBERRARI AND V. DEULOFEU
product vas isolated and purified in the same manner. It showed similar properties; poorly formed plates t h a t were found t o be crystalline by x-ray powder diffraction,a m.p. 195-197", [a]: f7.1" (c, 1.40, water). Anal. Calc'd for CloHaoNaO~; C, 42.85; H, 7.14; N, 10.00. Found: C, 42.36; K,6.77; N, 9.38. Pentaacetyl-B-galactose diacetamide. D-Galactose diacetamide (1.17 g.) was dissolved in 34 nil. of a boiling i:l mixture of pyridine and acetic anhydride and the resultant solution was maintained at room temperature for 24 hours. A residue of fine needles was obtained on evaporating the solution in a desiccator over sulfuric acid and potassium hydroxide; yield 1.98 g., m.p. 192-196'. The product was recrystallized from ethanol; m.p. 200", [a]: -38.3" (c, 0.848, chloroform). Anal. Calc'd for C P O H ~ V ~C, O ~48.31, Z : H, 6.10; N, 5.71. Found: @, 48.97; H, 6.12; N, 5.71. D-Galactose diacetamide from pentaacetyl-cr-D-galactopyranose.Pentaacetyl-a-D-galacto. pyranose (4 g.) mas treated with methanolic ammonia as described above for thep-D-isomer and the product was isolated in the same manner; yield 750 mg. (26.5%) of D-galactose diacetamide, m.p. 189-190" producing 800 mg. of pentaacetyl-D-galactose diacetamide (m.p. 200°, [a]: -37.8" in chloroform) on acetylation as described above. D-Galactose diacelwmide from the anomeric forms of pentaacetyl-D-galactofuranose.From the pentaacetyl-P-D-galactofuranose(4 9.) a yield of 1.20 g. (41.9%) of D-galactose diacetamide (m.p. 192-193") was obtained that on acetylation produced 1.17 g. of the pentaacetyl derivative (m.p. 200-202°, [CY]: -38.0" in chloroform). From pentaacetyl-a-D-galactofuranose(2 g.) a yield of 640 mg. (44.5%) of D-galactose diacetamide (m.p. 190-193") was found. This gave 550 mg. of pentaacetyl-D-galactose diacetamide of m . ~200-202" . and [a],"-38.4" (chloroform). D-Galactose diacetamide from pentaacetyl-aldehydo-D-gazactose. Pentaacetyl-aldehyde-Dgalactose (12) (3 g.) was dissolved in 90 ml. of methanolic ammonia and treated as above t o yield D-galactose diacetamide; yield 1.12 g. (49%), m.p. 196-197", producing 1.01 g. of pentaacetyl-D-galactose diacetamide of m.p. 200" and [a]," -37.9' (chloroform). Preparation of hexaacetyl-D-gala-L-manno-heptonamide. Finely ground D-gala-L-mannoheptonamide (10 8.) was suspended in 120 ml. of a 1 : l mixture of pyridine and acetic anhydride. Solution was effected by heating on a boiling water-bath, with vigorous stirring, for 90 minutes. Heating was prolonged for 20 additional minutes whereupon the dark solution was poured with stirring into 1000 ml. of ice and water. The mixture containing the separated crystalline product was kept at 5" overnight and the filtered solid was dried and recrystallized from ethanol (decolorizing charcoal); yield 16.4 g., plates, m.p. 187-188", [a]: $3.2" (chloroform). Robbins and Upson (13) cite for hexaacetyl-n-gala-L-mannoheptonamide: map. 185-187', [a]: $2.1" (chloroform). Hexaacetyl-D-gala-~-manno-heptononitriZe. Hexaacetyl-D-gala-L-manno-heptonamide (10 g.) was boiled for 25 minutes with 50 m l . of phosphorus oxychloride. The residue obtained on solvent removal under reduced pressure was dissolved in a mixture of water (100 ml.) and chloroform (250 m1.). The chloroform layer was washed successively mvith sodium bicarbonate solution and water. The residue obtained on solvent removal from the dried chloroform extract was crystallized from ethanol; yield 6.1 g. (53.4%)' plates, m.p. 188-189". One further crystallization from ethanol yielded material of m.p. 190.5-191.5" and [a]: +31.4" (chloroform). Hann and Hudson (14) cite for hexaacetyl-D-gala-Lmanno-heptononitrile: m.p. 194" (corr.), [a]: $31.7" (chloroform). D-Galactose diacetamide from hexaacstyl-D-gala-L-nzanno-heptononitrile. The hexaacetyl~-gala-~-manno-heptononitrile (6.5 9.) was dissolved a t room temperature in 165 ml. of methanolic ammonia and processed as above to produce D-galactose diacetamide; yield 1.19 g. (34.6%), m.p. 186-187". The pentaacetyl derivative showed m.p. 200" and [a],"-38.3' Pentabenzo$-a-D-galactose. ilnhydrous a-D-galactose was added slowly with shaking, 3
We are indebtod t o Ing. Galloai for this determination.
A4MM0KIA ON ACYLATED MONOBACCKARIDE8. 111
1101
while maintaining the temperature below 35', t o a solution of 39 ml. of pyridine, 33 ml. of benzoyl chloride, and 66 ml. of chloroform. After solution of the sugar, the mixture was maintained a t room temperature for one hour and then for 20 hours a t 5'. Dilution was then effected with 150 ml. of chloroform and pyridine was removed by washing with 3 N sulfuric acid. After washing with 5% sodium bicarbonate solution and with water, the solvent was removed under reduced pressure from the dried solution and the residue was crystallized from ethanol and recrystallized from the same solvent; yield 23.1 g. (89%) of pentabenzoyla-D-galactose, m.p. 158-159', [a]: f187.1" (chloroform). Wolfrom and Cbristman (8) record m.p. 128-129' and [a]: +187.1" (chloroform). It is possible that the difference in melting points between these two preparations is due t o dimorphism. The stored sample of the original preparation of Wolfrom and Christman now melts a t the higher temperarure.* D-Galaclose dibenzamide from pentabenzoyl-a-D-gafactose.Pentabeazoyl-a-D-galactose (10 g.) was dissolved, by shaking a t room temperature, in 260 ml. of methanolic ammonia and the solution was kept a t room temperature for 20 hours. The residue obtained on solvent removal was crystallized from 15 ml. of boiling ethanol; yield 2.2 g., m.p. 195'. Pure material was obtained on one further crystallization from ethanol; yield 2.02 g. (35%) of D-galactose dibenzamide, fine needles, m.p. 207', [CY]: -6.2' (c, 1.348, pyridine). Anal. Calc'd for C~,,H~&-POI: C, 59.37; H , 5.98; N, 6.93. Found: C, 59.02; I€, 6.06; N, 7.11. SUMM.4RY
1. D-Galactose diacetamide has been obtained in the following yields by treatment, with methanolic ammonia, of: the a- and p-forms of pentaacetyl-D-galactopyranose (24-26%) ; the CY- and p-forms of pentaacetyl-D-galactofuranose (42-44%) ; pentaacetyl-aldehydro-n-galactone (49%) ; and hexaacetyl-D-gala-Lmanno-heptononitrile (34%). 2 . An explanation is given correlating the difference in yields with the structure and the possible reaction course for each type of compound. 3. Treatment of pentabenzoyl-a-D-galactose with methanolic ammonia produces D-galactose dibeazamide. BUENOS AIRES, ARGENTINA REFERENCES
DEULOFEU AND DEFERRARI, J. Org. Chem., 17, Paper I, this issue (1952), DEFERRARI AND DEULOFEU, J . Org. Chem., 17, Paper 11, this issue (1952). BRIGL,~~UHLSCHLEGEL,AND SCHINLE, Ber., 84, 2921 (1931). HOCKETT AND CHANDLER, J . Am. Chem. Soc., 66,957 (1944). N x E h i A " AND HAYS,J. Am. Chem. soc., 67, 1302 (1945). ISBELL A N D FRUSH, J. Am. Chem. SOC.,71, 1579 (1949). COHPTON &VD WOLFROM, J . Am. Chem. Soc., 68,1157 (1934). (8) WOLFROM AND ~ R I s T & r A NJ. , Am. Chem. soc., 68, 39 (1936). AND PARKER, J. Am. Chem. SOC.,57,1589 (1915). (9) HUDSON (10) SCHLUBACH AXD PROCHOWNICK, Ber., 63, 2298 (1930). AND JOHNSON, J. Am. Chem. SOC.,58, 1223 (1916). (11) HUDSON (12) WOLFROJI,J. Am. Chem. SOC.,62,2464 (1930). AND UPSON,J . Am. Chem. SOC., 82,1074 (1940). (13) ROBBINS (14) HANNAND HUDSON, J. Am. Chem. SOC.,69,1898 (1937). (1) (2) (3) (4) (6) (6) (7)
4
Private communication from Dr. M. L. Wolfrom.
