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The synthesis of allitol hexanitrate Bowering, William David Samuel 1956

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THE  SYNTHESIS  OF ALLITOL  HEXANITRATE  by  WILLIAM D.. S.  BOWERING  A THESIS SUBMITTED IN P A R T I A L F U L F I L M E N T O F T H E REQUIREMENTS FOR T H E D E G R E E O F M A S T E R O F SCIENCE  in the Department of Chemistry  We accept this thesis as conforming to the standard required for candidates for the degree of M A S T E R O F S C I E N C E .  Members of the Department of Chemistry  T H E UNIVERSITY O F BRITISH COLUMBIA April,  1956  ABSTRACT  Two methods for the synthesis of D - a l l o s e f r o m D - r i b o s e , the nitromethane condensation and the cyanohydrin synthesis, investigated.  were  The nitromethane condensation was f i r s t tested with  D - a r a b i n o s e and c r y s t a l l i n e derivatives of D - m a n n o s e and D - g l u c o s e were obtained.  In the nitromethane condensation with D - r i b o s e , it was,  found that a considerable portion of the D - r i b o s e d i d not r e a c t .  A partial  separation of the r e s u l t i n g n i t r o a l c o h o l s f r o m the unreacted D - r i b o s e was achieved on an adsorption chromatography c o l u m n . A p p l i c a t i o n of the cyanohydrin synthesis to D - r i b o s e y i e l d e d ^ - D - a l l o n o l a e t o n e which was r e d u c e d to D - a l l o s e and then to a l l i t o l by sodium a m a l g a m and Raney n i c k e l , r e s p e c t i v e l y .  The pure a l l i t o l which  was obtained i n c r y s t a l l i n e f o r m was c h a r a c t e r i z e d by the m e l t i n g point, a n a l y s i s , and acetylation to the known, c r y s t a l l i n e hexaacetate d e r i v a t i v e . C r y s t a l l i n e a l l i t o l hexanitrate was p r e p a r e d by the nitration of a l l i t o l with a mixture of fuming n i t r i c and sulfuric acids or with a mixture of fuming n i t r i c a c i d and acetic anhydride, and i s now r e p o r t e d for the f i r s t t i m e .  A qualitative experiment indicated that a l l i t o l h e x a -  nitrate r e a c t e d m o r e slowly with d r y p y r i d i n e at r o o m temperature than the c o r r e s p o n d i n g D-mannitoI derivative and produced no gaseous product.  A  C K N O W L E D G E M E N T S  I w i s h to express m y s i n c e r e thanks and a p p r e c i a t i o n to D r . L . D . H a y w a r d who has gladly given every possible assistance and encouragement i n the d i r e c t i o n of this investigation.  I w i s h to thank the National R e s e a r c h C o u n c i l of Canada for a B u r s a r y and a Studentship.  I a m indebted to the staff of the P a c i f i c F i s h e r i e s E x p e r i m e n t a l Station, V a n c o u v e r , B . C . , and M i s s W . Elia.s for assistance with m i c r o - a n a l y s e s .  T A B L E OF CONTENTS Page INTRODUCTION  1  HISTORICAL INTRODUCTION  3  DISCUSSION A. B. C. D. E. F. G. H.  The The The The The The The The  14 Nitromethane Condensation Cyanohydrin Synthesis Sodium Amalgam Reduction Raney Nickel Reduction Sodium B or ohydride Reduction Nitration of Allitol Reaction of Pyridine with Allitol Hexanitrate . . Preparation of Allitol Hexaacetate  EXPERIMENTAL A . Special Precautions B. Materials C . The Nitromethane Condensation 1. The Condensation of Nitromethane with D - A r abino s e 2. The Condensation of Nitromethane with D-Ribose D. The Cyanohydrin Synthesis of 9^-D-Allonolactone . E . The Reduction of "Y-D- A l l onolactone with Sodium Amalgam ; F . The Reduction of D-Allose with Raney Nickel . . . . . G. The Reduction of 'Y -D-Allonolactone with Sodium Borohydride . . . H . The Nitration of Allitol I. 1. Nitration with Fuming Nitric and Sulfuric Acids 2. Nitration with Fuming Nitric Acid and'.Acetic Anhydride I. The Reaction of Pyridine with Allitol Hexanitrate . . J. The Preparation of Allitol Hexaacetate K . The Preparation of D-Altritol L. The Reduction of 'K-D-Galaetonolactone with Raney Nickel M . The Reduction of D-Mannose with Raney Nickel . . . N. The Reduction of 'V-D-Galactonolactone with Sodium Borohydride O. The Reduction of D-Galactose with Sodium Borohydride P. The Preparation of D-Mannitol Hexanitrate  14 19 21 23 24 25 26 27 28 28 28 32 32 37 39 42 43 44 44 44 46 47 49 50 51 '52 52 53 53  TABLE  O F C O N T E N T S (continued) Page  C L A I M S T O ORIGINAL R E S E A R C H BIBLIOGRAPHY  54 •. . .,  55  T A B L E OF TABLES  Page TABLE  TABLE  I Yields of Nitroalcohols from the Nitromethane Condensation with Aldoses  ...  II Yields in. the Cyanohydrin Synthesis from D-Ribose  18  20  INTRODUCTION  The purpose of this r e s e a r c h was  to p r e p a r e allitol  hexanitrate, which has not p r e v i o u s l y been synthesized i n order that i t s r e a c t i o n with pyridine might be studied.  The denitrating action of p y r i -  dine on the s t e r e o i s o m e r i c hexanitrates of D-mannitol (14), (22) and dulcitol (39) has been p r o v e n to be selective for the nitrate group on C3 (or the equivalent C4) of the hexitol chain.  A s i m i l a r study of a l l i t o l  hexanitrate with pyridine would further test the s p e c i f i c i t y of this unusual selective reaction, and might a l s o give some i n f o r m a t i o n of the relationship between conformation  and configuration of these open-chain,  polyol d e r i v a t i v e s . The  synthesis of a l l i t o l hexanitrate r e q u i r e d the synthesis  of the c o r r e s p o n d i n g hexitol, a l l i t o l , which i s not found i n nature. a considerable portion of this r e s e a r c h was  Hence,  c o n c e r n e d with the p r e p a r a -  tion of D - a l l o s e and a l l i t o l . The hexitols have been r e v i e w e d by L o h m a r and Goepp (38), by L e s p i e a u (32), and by P i g m a n and Goepp (44). A l l i t o l (I), which i s also known as allodulcitol, i s one of the m e s o f o r m s of the hexitols. f o r m u l a I.  It has the p r o j e c t i o n - c o n f i g u r a t i o n a l  - 2-  CH OH 2  H-C-OH  I H-C-OH  I H-C-OH  I H-C-OH CH OH 2  (I)  - 3 HISTORICAL INTRODUCTION  The first synthesis of allitol {1} (33) was related to an earlier investigation made by Grlneri in 1892. Griner (20), in hydrogenating acrolein (II) by means of a zinc-copper couple and acetic acid, obtained a liquid corresponding in properties and analysis to the reduction product, divinylglycol (III).  The  yield was very low since no polymerization inhibitors were available, and the acrolein resinified very rapidly. Griner knew that divinylglycol could exist in optically active (d or 1), meso, or racemic (dl) forms.  If the d l -  mixture were present, and one of the isomers was preferentially attacked by a suitable mould, optical activity might appear.  L e B e l , at Griner s  request,, carried out such cultures which were successful, activity did not appear.  1  but optical  F r o m these results, Griner concluded that only  the meso form was present.  It has since been found, however, that  divinylglycol prepared according to Griner s method exists in both the meso 1  and racemic forms.  Thus, Griner's conclusion was erroneous (32).  A vinyl group may be oxidized to the corresponding diol by the action of dilute potassium permanganate solution, and Griner applied this reagent to the divinylglycol from which, theoretically, the hexitol should have been obtained.  However, in spite of all his attempts to mod-  erate the conditions, he was unable to arrest the reaction at the desired polyol stage.  >- 4 To another portion of the di vinyl glycol, Griner added two moles of hypochlorous acid, and obtained the two stereoisomeric forms of divinylglycoldichlorohydrin (IV).  F r o m one of these isomers,  Griner  obtained mannitol (V), but he reported that he was unable to obtain a hexitol from the other isomer.  C H = C H - CHO (ii) 2  Zn-Cu HOAc C H = C H - CHOH - CHOH - C H = C H 2  2  (ni> HOCi CH C1 - CHOH - CHOH - CHOH - CHOH - C H C 1 (IV) 2  2  In 1932 (33), (34) Lespieau and Wiemann synthesised allitol for the first time by adding four hydroxyl groups to divinylglycol {Ul} by using a solution of silver chlorate containing a small amount of osmic acid.  Their product also contained dl-mannitol (V). Lespieau and Wiemann also made use of another synthetic  method to obtain allitol.  They reacted chloroacetaldehyde (VII) with the  Grignard reagent (VI) derived from acetylene to give the meso-divinylacetylenedichlorohydrin (VIII) (31), from which the corresponding hexynetetrol (IX) was obtained.  This was then reduced to the hexenetetrol (X)  using Bourguel's catalyst (13), a dispersion of colloidal palladium on starch, and hydrogen.  The hexenetetrol was then hydroxylated with silver chlorate  - 5 and o s m i c a c i d yielding the two m e s o hexitols, a l l i t o l (1} and dulcitol (XI) (36), (35). •(II?  CH = CH  Zn-Cu HOAc  H I C  H I C  OH  OH  CH= C H  2  -4-  H i C  CH =CH2  OH  OH I - (p - C H = C H  2  H  (III)  AgC10 Os0  AgC10  3  Os0  4  4  CH OH  CH OH  CH OH  2  2  2  H-C-OH  H-C-OH  3  HO-C-H  I H-C-OH  H-C-OH  I  ._|_  HO-C-H  HO-C-H  H-C-OH  HO-C-H  H-C-OH  H-C-OH  I H-C-OH  CH OH  CH OH  CH OH  2  2  2  (V)  F o r the purposes of identification, W i e m a n n (67) p r e p a r e d two c r y s t a l l i n e derivatives of a l l i t o l ; the hexaacetate and the dibenzylidene acetal. Another method of synthesis which was available was the reduction of the c o r r e s p o n d i n g hexose,  D - a l l o s e , to a l l i t o l .  D-Allose  is a r a r e monosaccharide not found i n nature, which has, however, p r e p a r e d f r o m the pentose, synthesis (26).  D - r i b o s e , by a K i l i a n i cyanohydrin  been  - 6 -  BrMg - C = C - MgBr (VI) C1CH C1CH \  -  /  C  H -  C  =  C  -  C  \  C H O  CHC1 /  H -  O  -  2  O  (vni) Powdered K O H i n ether H O C H  -  C  H -  C  =  C  -  C  H -  o  C H O H  o H  2  Q  Warm C H  2  O H  -  C H O H  C = C  C H O H  -  C H  2  O H  (IX) H  2  Pd C H  2  O H  -  C H O H  -  C H ^ C H  -  C H O H  -  C H  2  O H  (X) AgC10  3  O S O A  C H  .  O  I  H  C H  j  2  H-C-OH H - C - O H  I  O  c*  H - C - O H  +  H O  - C - H  I  H - C - O H  I  H O - C - H  H - C - O H H - C - O H C H  2  O H  C H  (XI)  2  O H  H  - 7 In 1910, L e v e n e and Jacobs (37) r e a c t e d D - r i b o s e (XII) with hydrogen cyanide, and on h y d r o l y s i s of the r e s u l t i n g i s o m e r i c cyanohydrins, they obtained the i s o m e r i c D - a l l o n i c (XIII) and D - a l t r o n i c (XIV) acids, which they were able to separate.  Galcium-D-altronate  c r y s t a l l i z e d f r o m the solution f i r s t , and after r e m o v a l of the c a l c i u m f r o m the c a l c i u m - D - a l l o n a t e in the mother liquor, 'Y -D-allonolactone (XV) was obtained upon evaporation. to D - a l l o s e (XVIJ.  T h i s lactone was reduced by sodium a m a l g a m  In a s i m i l a r manner, D-altro.se (XVLty was obtained  f r o m calcium-D-altronate.  However, L e v e n e and Jacobs were unable to  obtain either of the two hexoses i n a c r y s t a l l i n e state. A u s t i n and H u m o l l e r , by application of the cyanohydrin synthesis to L-ribose., obtained c r y s t a l l i n e L - a l l o s e (3), (4) i n 1933.  This  was immediately followed by the work of P h e l p s and Bates, i n 1934, i n which they p r e p a r e d c r y s t a l l i n e D - a l l o s e f r o m D - r i b o s e by the K i l i a n i cyanohydrin synthesis (42). A n i m p r o v e d application of the cyanohydrin synthesis to the p r e p a r a t i o n of D - a l l o s e f r o m D - r i b o s e was r e p o r t e d by P r a t t and R i c h t m e y e r (45) during the course of the present investigation. The reduction of D - a l l o s e to a l l i t o l was f i r s t  accomplished  by Steiger and R e i c h s t e i n , i n 1936 (61). A f t e r synthesising D - a l l o s e f r o m D - r i b o s e by the cyanohydrin synthesis, they reduced the D - a l l o s e with hydrogen under p r e s s u r e oyer a n i c k e l - s i l i c a gel catalyst.  The r e s u l t i n g  c r y s t a l l i n e product was shown to be identical with the one obtained e a r l i e r by L e s p i e a u and Wiemann.  8 -  COOH  GOOH  H-C=0  H-C-OH  H-C-OH  H-C-OH  H-C-OH  H-C-OH I ' H-C-OH  H-C-OH  H - C - O H + HCN + H 0 2  H-C-OH  I  CH OH  HO-C-H  I  H-C-OH  CH OH  CH OH  (xmy  (XIV)  2  2  2  •(xn>  (XIV) ,  (xrii)  H Q  - HO  2  2  o=c-  o=c-  HO-C-H  H-C-OH O  I  O  H-C-OH  H-C-OH  H-C-  H-C  H-C-OH  H-C-OH  I  CH OH 2  CH OH 2  (XV) Na/Hg  Na/Hg H-C = 0 H-C-OH  H-C=0  I  HO-C-H  I  I  H-C-OH  H-C-OH  H-C-OH  H-C-OH  I I  H-C-OH  I  I  H-C-OH  CH OH  CH OH  (XVI>  (XVH)  2  2  - 9 -' In 1946, W o l f r o m and c o - w o r k e r s p r e p a r e d allitol f r o m keto-D-psicose (71}.  T h e y reduced k e t o - D - p s i c o s e pentaacetate with  hydrogen under p r e s s u r e over a kieselguhr-rsupported n i c k e l catalyst at an elevated temperature.  The r e s u l t i n g product was  deacetylated with b a r i u m  hydroxide to y i e l d syrupy a l l i t o l which- was then converted to a c r y s t a l l i n e methylene derivative. The above investigation was  connected with a study of the  reduction of alkaline glucose solutions (69Js(70J under conditions known to cause sugar inter conversions.  W o l f r o m and co-workers also isolated a  v e r y s m a l l amount of allitol f r o m the e l e c t r o l y t i c reduction at amalgamated l e a d cathodes of glucose i n m i l d alkaline solution and at a temperature below 30" C.  {11}.  The appearance of a l l i t o l was  accounted for by the postu-  lation of s e v e r a l ene-diol type shifts. The same w o r k e r s also p r e p a r e d four new  crystalline  d e r i v a t i v e s of a l l i t o l ; monomethylene a l l i t o l , dimethylene allitol and the diacetate and dilaurate of the latter (71}. The foregoing methods of synthesis of allitol are the only ones which have been reported. However, a new  procedure for the addition  of one carbon atom to the carbon chain of an aldose was and F i s c h e r .  developed by Sowden  T h i s method c o n s i s t e d of a b a s e - c a t a l y s e d condensation  between an aldose and nitromethane.  The method has been reviewed by  Sowden (52). The only p r e v i o u s l y r e c o r d e d application (53) of the n i t r o paraffin-aldehyde condensation r e a c t i o n to the sugar s e r i e s was that  - 10 r e p o r t e d i n 1921 by P i c t e t and B a r b i e r (43).  These w o r k e r s treated  glycolaldehyde, glyceraldehyde, L - a r a b i n o s e , and D-glucose with nitromethane and potassium bicarbonate. to isolate the expected nitroalcohols.  T h e y made no attempt, however,  It was  i n 1944, that Sowden and  F i s c h e r on application of this procedure to an acetylated cyanohydrin were the f i r s t to isolate the nitroalcohols (53). In 1945, they treated 2, 4-benzylidene-L-xylopyranose one i s o m e r was  with nitromethane,  and isolated the nitroalcohol (only  obtained) f r o m which they obtained L - g u l o s e (54) by means  of the Nef r e a c t i o n (40). Nef (40), i n 1894, treated the sodium salt of simple p r i m a r y nitroparaffins with an excess of m i n e r a l acid causing oxidation of the n i t r o p a r a f f i n with the subsequent production of nitrous oxide (hyponitrous acid) and an aldehyde. Sowden and F i s c h e r r e p o r t e d nitromethane with other substituted sugars (55) (56). In 1947, ;  condensations  glucose and mannose were  p r e p a r e d by a condensation of nitromethane with arabinose (57).  From  D-arabinose (XVII), the i s o m e r i c nitroalcohols, 1-nitro-l-desoxy-D-mannitol (XIX) and 1-nitro-l-desoxy-D-glucitol (XX), were f o r m e d i n the condensation reaction, and then converted on treatment with s u l f u r i c a c i d to D-mannose (XXI), and D-glucose (XXII) r e s p e c t i v e l y .  In a s i m i l a r s e r i e s , the r a r e  L - f o r m s of these aldohexoses were p r e p a r e d f r o m L - a r a b i n o s e as starting material. Sowden and F i s c h e r r e p o r t e d a condensation between D - r i b o s e and nitromethane (56), however, they d i d not mention obtaining any c r y s t a l -  - 11 line condensation products or the preparation of D-allose.  The procedure  has since been used as a preparative method for other sugars (48), (51), (58), and has also been used in the preparation of D-glucose with a labelled glycosidic carbon atom (49), (50).  CH,NO,  I  I  2  I NaOCH, CH,NO,  I HO-C-H  I  I H-C-OH  H-C-OH  I  I  H-C-OH  H-C-OH  H-C-OH  I  CH OH  CH OH  CH OH  2  z  H-C-OH  HO-C-H  HO-C-H  I  CH NO  2  HO-C-H  H-C=0  H - C - O H +•  2  2  2  (XVIH)  (XX)  (XLX) H S0 2  H-C=0  H S0  4  2  H-C-O  I  I  H-C-OH  HO-C-H  I  HQ-C-H  HO-C-H  I  I  H-C-OH  H-C-OH I H-C-OH  1  H-C-OH  CH OH  CH OH  (XXI)  (xxn>  2  4  2  The use of either the cyanohydrin synthesis or the nitromethane condensation with D-ribose would lead to the production of D-allose which could then be reduced to allitol. been used for reductions of this type.  Several methods have  - 12 A s p r e v i o u s l y mentioned, Steiger and R e i c h s t e i n reduced D - a l l o s e to allitol with hydrogen under 120 atmospheres p r e s s u r e using a n i c k e l - s i l i c a gel catalyst and a temperature of 140° C. (61).  Catalytic  hydrogenation has also been applied to the reduction of other aldoses. P - A l t r o s e , the 2-epimer of D - a l l o s e , was  reduced to D - a l t r i t o l  (D-talitol) by Harm, Haskins, and Hudson (21) using a Raney n i c k e l catalyst and 127 atmospheres p r e s s u r e .  The c o r r e s p o n d i n g L - i s o m e r was  hydro-  genated using 135 atmospheres p r e s s u r e and a n i c k e l k i e s e l g u h r - s u p p o r t e d catalyst by H u m o l l e r , W o l f r o m , Lew,  and Goepp (27).  Glattfeld and  Schimpff (19) have p r e p a r e d v a r i o u s sugar alcohols f r o m the c o r r e s p o n d i n g aldose with hydrogen under p r e s s u r e and a platinum catalyst. The well-known sodium a m a l g a m reduction of E . F i s c h e r has been applied to the c o n v e r s i o n of an aldose to the sugar alcohol. A m o r e recent method f o r the reduction of an aldose has made use of sodium borohydride (1) which has also been used i n the d i r e c t reduction of a sugar lactone to the alcohol (72). K a r a b i n o s and B a l l u n have r e c e n t l y r e p o r t e d the reduction of aldoses and ketoses to the polyols by refluxing i n aqueous ethanol with R a n e y n i c k e l (29). The synthesis of the hexanitrate of allitol has not been reported, but the n i t r i c a c i d e s t e r s of s e v e r a l other hexitols have been obtained i n a c r y s t a l l i n e state.  In 1847,  Domonte and M e n a r d r e a c t e d  mannitol with fuming n i t r i c a c i d and s u l f u r i c a c i d (16) and obtained a c r y s t a l l i n e nitro compound which apparently was the analytical r e s u l t s were not too c l e a r .  the hexanitrate although  - 13 The hexanitrate of mannitol was definitely obtained by Sokoloff, in 1879, by using nitric and sulfuric acids (47), and this pre#• -  paration was repeated in 1929, by Patterson and Todd (41).  The  hexanitrate of dulcitol was prepared by the nitric and sulfuric acid method by Wigner, in 190 3 (68). In 1889, Vincent and Delachanal reported the nitration of sorbitol by a mixture of fuming nitric and sulfuric acids. however, obtain a crystalline product (64).  They did not,  Bergeim (9) reported haying  obtained crystalline sorbitol hexanitrate by nitration with nitric and sulfuric acids in 1930.  This was later confirmed by Tettamanzi and Arnaldi (62).  Urbanski and Kwiatkowska (63) investigated the possibility that the syrupy product obtained originally from sorbitol was a mixture of partially nitrated compounds.  They found that depending on the temperature at which.the  nitration was carried out, a mixture of penta- and hexanitrate or only the hexanitrate of sorbitol was produced.  The nitration was achieved by the  usual nitric-sulfuric acid mixture. An alternative method of nitration has been used by Honeyman and Morgan in the nitration of certain glucose derivatives  (25).  They applied a mixture of fuming nitric acid and acetic anhydride to a suspension of the sugar in acetic anhydride at 0° C . , and obtained nearly quantitative yields of the fully-nitrated derivatives.  - 14 DISCUSSION  A.  The Nitromethane  Condensation  The nitromethane condensation has been applied to the synthesis of s e v e r a l sugars by Sowden and co-workers.  Sowden and  F i s c h e r r e p o r t e d a condensation with D - r i b o s e (56). However, they did not obtain the n i t r o a l c o h o l in a c r y s t a l l i n e f o r m and d i d not separate the two i s o m e r s .  F u r t h e r m o r e , they did not convert the syrupy n i t r o a l c o h o l s  to the c o r r e s p o n d i n g hexoses.  It was  decided to attempt a synthesis of  a l l i t o l f r o m the pentose, D - r i b o s e , by application of this methdd, since L o h m a r and Goepp (38) had stated that this method would make the synthesis of some hexitols m u c h s i m p l e r than the older cyanohydrin synthesis. B e f o r e attempting the synthesis f r o m D - r i b o s e , the method was t r i e d on D-arabinose.  T h i s was done i n o r d e r to become f a m i l i a r with the tech-  nique (57), since D - r i b o s e was a r e l a t i v e l y expensive starting m a t e r i a l . D - A r a b i n o s e was expected to y i e l d D-glucose and D-mannose which have been the most thoroughly investigated of the hexoses. A sample of D-arabinose was condensed with nitromethane in the presence of sodium methoxide in a methanol solution, and the resulting mixture of sodium salts of the i s o m e r i c n i t r o a l c o h o l s isolated in a crude y i e l d of 122. 3%.  was  When this m i x t u r e was treated with  sulfuric a c i d to oxidize the nitro group, the two hexoses, D-mannose and D-glucose, were obtained in solution.  D-Mannose was  separated f r o m the  solution as the water-insoluble D-mannose phenylhydrazone, and the  -15phenylhydrazino residue was  r e m o v e d by treatment with benzaldehyde and  benzoic a c i d in aqueous ethanol solution. which could not be c r y s t a l l i z e d was  The crude, syrupy D-mannose  obtained in a y i e l d of 42. 6%,  and  was  reduced with sodium borohydride in aqueous solution. The solution containing the D-glucose was  phenylhydrazone  divided into two equal portions; one part was t r e a t e d with phenyl-  hydrazine again, and the insoluble D-glucose phenylosazone in a crude y i e l d of 24. 2%.  was  The other p o r t i o n of the D-glucose  isolated  phenyl-  hydrazone solution was t r e a t e d in the same manner as for D-mannose phenylhydrazone  in o r d e r to obtain D-glucose.  The resulting solution  gave a positive Fehling's test, but no c r y s t a l l i n e D-glucose could be i s o lated; a considerable amount of sodium acetate was present. product was line  The  syrupy  acetylated by the method of Gattermann (18), but no c r y s t a l -  ^3-pentaacetyl-D-glucose has been obtained. A sample of D - r i b o s e was  the same manner as for D-arabinose.  condensed with nitromethane i n  The resulting, insoluble sodium  salts (76. 4% of theory) were d i s s o l v e d i n water, and the sodium ion r e m o v e d with an ion.exchange column.  A crude, syrupy m a t e r i a l , p r e -  sumed to be the mixture of the two i s o m e r i c nitroalcohols, was  obtained  in a y i e l d of 53. 1%. E x t r a c t i o n of this syrupy mixture with absolute ethanol at 50° C. gave a syrupy f r a c t i o n A and extraction with absolute ethanol at r e f l u x temperature crystallized.  gave a s i m i l a r f r a c t i o n B which also could not be  The ethanol insoluble r e s i d u e (C) amounted to 20. 7% of the  - 16 -  total m a t e r i a l before extraction and was soluble in water.  Paper  c h r o m a t o g r a m s were r u n on fractions A and B and c o m p a r e d to D - r i b o s e as a standard. D-ribose.  It was found that both fractions contained unreaeted  A l s o i n each case a second spot appeared which was a s s u m e d  to be the two nitroalcohols.  F r o m the density of the spots it appeared  that the concentration of the n i t r o a l c o h o l s was greater than that of D - r i b o s e in f r a c t i o n A, but that i n f r a c t i o n B, the opposite was true. On the b a s i s of both fractions A and B together, D - r i b o s e and the n i t r o alcohols appeared to be present in approximately equal amounts. the approximate y i e l d of both n i t r o a l c o h o l s was 20%.  Hence,  Residue C gave no  spot at a l l when c o m p a r e d to D - r i b o s e as standard on a paper chromatogram. Attempts were then made to separate the D - r i b o s e  from  the nitroalcohols in f r a c t i o n A on an adsorption chromatography column using a mixture of celite and s i l i c i c acid.  A f t e r many t r i a l s ,  in which  the composition of the developer was v a r i e d , a p a r t i a l separation was achieved.  A paper c h r o m a t o g r a m was r u n on the ethanol extracts of  the column and c o m p a r e d to a standard solution of D - r i b o s e .  The f i r s t  two sections contained only D - r i b o s e , but the last two contained D - r i b o s e as well as some other m a t e r i a l which gave a spot v e r y near to the s o l vent front.  T h i s spot was i n a c o n s i d e r a b l y different position to the one  that was a s s u m e d to be the n i t r o a l c o h o l s on the paper c h r o m a t o g r a m s of the fractions A and B.  -. 17 The work, at this point, was  discontinued since the y i e l d s  f r o m this method appeared to be rather low and also since the  separation  of the two i s o m e r i c nitroalcohols appeared to be difficult. The nitromethane condensation may  be e x p r e s s e d by the  following e q u i l i b r i u m : RCHO +  The r e a c t i o n was  CH NQ 3  2  '  R-CHOH - C H N 0 2  2  catalysed by a base which when applied e s p e c i a l l y to  reducing sugars, had to be m i l d since strong a l k a l i i n the p r e s e n c e of oxygen r e s u l t e d in fragmentation of the carbon chain and complex i s o m e r ization reactions.  F u r t h e r m o r e , it has been found that strong a l k a l i  shifts the e q u i l i b r i u m to the left.  Hence in these condensations sodium  methoxide andean excess of nitromethane were used in o r d e r to displace the e q u i l i b r i u m to the right. However, the most important factor was  the solubility  relationships between the r e a c t i o n medium, the aldose, and the sodium nitroalcohols.  The  optimum conditions for m a x i m u m y i e l d were those  in which the aldose was  quite soluble and the sodium n i t r o a l c o h o l s  r e l a t i v e l y insoluble in the r e a c t i o n medium.  The r e s u l t s of v a r i o u s con-  densations have been s u m m a r i z e d i n Table I. The benzylidene group which was  stable to base was  used  effectively i n the case of. D-glucose to improve the solubility r e l a t i o n ships.  In a paper by Sowden and T h o m p s o n (59) which appeared during  the. course of the present investigation, they stated that an alcoholic m e d i u m had not been v e r y s a t i s f a c t o r y for the nitromethane condensation with some  - 18 sugars and. that the use of an aqueous solution of sodium hydroxide was being investigated.  T h e y found that with D-arabinose in aqueous solution,  the r e a c t i o n p r o c e e d e d r a p i d l y with comparable y i e l d s .  TABLE I YIELDS OF NITROALCOHOLS F R O M THE NITROMETHANE CONDENSATION WITH ALDOSES % Y i e l d s of Nitroalcohols  Reacting Aldose  2,4- benzylidene - L - xylopy r ano s e 4, 6-benzylidene-D-glucose L-xylose D-xylose D-ribose D-glucose D-erythrose 2, 4-benzylidene-D-erythrose D-mannose D-arabinose  a 50.4 21. 0 21.0 35. 0  a  c  C  5.°d 40. 0 64. 0 55. 0 69. 0  d  e  e  e  Reference  54 55 56 56 56 56 51 51 58 57  a b c d  - Isolated only one i s o m e r - Isolated as acetylated n i t r o o l e f i n , - N i t r o a l c o h o l s are syrupy - i s o l a t e d as acetylated n i t r o o l e f i n - N i t r o a l c o h o l s a r e p a r t i a l l y c r y s t a l l i n e - i s o l a t e d as acetylated nitroolefin e - C r y s t a l l i n e nitroalcohols separated by f r a c t i o n a l c r y s t a l l i z a t i o n  Sowden and F i s c h e r r e p o r t e d a condensation with D - r i b o s e (56)' which gave syrupy n i t r o a l c o h o l s which Were converted to the c r y s t a l line acetylated n i t r o o l e f i n (21%). r e a d i l y in the reaction medium.  T h e y stated that D - r i b o s e d i s s o l v e d F r o m the r e s u l t s of the present i n v e s t i -  gation, it did not appear that D - r i b o s e did dissolve r e a d i l y as the r e s u l t ing nitroalcohols contained a l a r g e portion of unreaeted D - r i b o s e .  This  - 19 was probably the main r e a s o n for the poor yields of n i t r o a l c o h o l s . The separation of the two i s o m e r i c n i t r o a l c o h o l s was second difficult feature of the method.  the  In most of the cases where the  nitromethane condensation has been s u c c e s s f u l l y applied to the synthesis of higher sugars, the n i t r o a l c o h o l s have been c r y s t a l l i n e and were separated f r o m each other by f r a c t i o n a l c r y s t a l l i z a t i o n but in the present case the n i t r o a l c o h o l s were obtained only as a crude syrup.  The  paper  c h r o m a t o g r a m s gave no evidence that two i s o m e r i c nitroalcohols were present. was  However, as the s t r u c t u r a l difference between the two  isomers  rather small, it would be anticipated that such a separation would be  difficult.  The work on the adsorption chromatography columns tended to  support this assumption.  B.  The Cyanohydrin Synthesis The cyanohydrin synthesis has been the conventional method 1  for the p r e p a r a t i o n of higher sugars since the work of E .  Fischer.  R e c o u r s e was taken to this method when the nitromethane  condensation  p r o v e d to be unsatisfactory.  A m o d i f i e d p r o c e d u r e (45) of the synthesis  was followed. A n aqueous solution of D - r i b o s e was solution of sodium cyanide for 24 hours at 5° C.  treated with an aqueous  T h i s solution, after b o i l -  ing to hydrolyze the n i t r i l e s and expell the ammonia, was p a s s e d while s t i l l hot through an ion exchange column containing A m b e r l i t e I R 120 r e s i n in the c a l c i u m cycle.  P a s s a g e through the column converted the two  - 20 i s o m e r i c acids, D - a l l o n i c and D - a l t r o n i c , to the c a l c i u m salt f o r m .  On  concentration of the solution, the c a l c i u m salt of D - a l t r o n i c a c i d c r y s t a l l i z e d out f i r s t and in this manner, the i s o m e r s were separated. mother liquor containing c a l c i u m - D - a l l o n a t e was  The  then p a s s e d through the  ion exchange column i n the hydrogen cycle in o r d e r to r e m o v e the c a l c i u m and leave the free acid. lactone (m.p.  On subsequent evaporation s o l i d  98-123" C.). was  m a t e r i a l under the m i c r o s c o p e  obtained.  'V-D-allono-  However, examination of this  indicated that it was not c r y s t a l l i n e .  In  the l i t e r a t u r e this compound has been r e p o r t e d as being c r y s t a l l i n e with a melting point of 97-120° C. (7). The yields f r o m three runs have been s u m m a r i z e d in Table II and c o m p a r e d with those obtained by other w o r k e r s .  T A B L E II Y I E L D S IN T H E  Run  1 2 3  C Y A N O H Y D R I N SYNTHESIS F R O M D-RIBOSE  % Y i e l d of C al c ium - D - A lt r on at e 34. 2 41. 6 10. 9 40.0 ' 31. 0 52. 3 a  a  % Y i e l d of 'V-D-Allonolactone 37.8 34. 6 31. 7 34. 0 46. 9 not available b  C  a  a  C  Reference  T h i s work T h i s work T h i s work 45 42 37  a - Isolated as the hemiheptahydrate , b - A p p e a r e d to contain some D-altronolactone c - A v e r a g e of seven runs  The yields s u m m a r i z e d in Table II indicate that the two i s o m e r s were p r o duced i n approximately equal amounts.  "With other sugars a p r e f e r e n c e for  - 21 one i s o m e r has been reported; for example, D-manno-D-gala-heptose obtained f r o m D-mannose in almost t h e o r e t i c a l y i e l d and the e p i m e r not detected (26). In two runs the ion exchange c o l u m n used was  was  was  contam-  inated with a s m a l l amount of i r o n which complexed with the cyanide ion f o r m i n g a c o l l o i d a l solution of P r u s s i a n blue, F e  4  (Fe ( C N J ^ ^ .  On con-  centration of the eluate, the blue m a t e r i a l coagulated and was r e m o v e d by filtration.  On the t h i r d run, apparently most of the i r o n on the r e s i n had  been r e m o v e d and no P r u s s i a n blue was  encountered.  D u r i n g the r e c r y s t a l l i z a t i o n of the c a l c i u m - D - a l t r o n a t e hemiheptahydrate p r e p a r e d i n one run, some m o u l d began to grow i n the solution which might account for the c o m p a r a t i v e l y low y i e l d obtained in this case.  C.  The Sodium A m a l g a m Reduction The sodium a m a l g a m reduction of sugar 1-actones to aldoses  has been used in the synthesis of sugars since it was f i r s t d i s c o v e r e d by F i s c h e r in 1889, even though it was not investigated in a quantitative manner until 1947 (60). The p r o c e d u r e followed here was that outlined in P o l a r i m e t r y , Sac char imetry, and the Sugars (7). The s o l i d  /  Y-D-  allonolactone was reduced to syrupy D - a l l o s e as indicated by the positive Fehling's test,- and has r e s i s t e d a l l attempts at c r y s t a l l i z a t i o n .  A yield  of 44. 0% was obtained. The specific rotation of the syrupy D - a l l o s e  was  s e v e r a l degrees lower than the r e p o r t e d value indicating the p r e s e n c e of  - 22 impur itie s. * A c c o r d i n g to Sperber, Zaugg, and S a n d s t r o m (60), the of the reaction m e d i u m was  pH  the most important single factor for m a x i m u m  yields in the lactone reduction.  T h e y found that a pH  range of 3. 0-3. 5  a temperature not greater than 15° C. were the optimum conditions. of 2-3  A  pH  gave approximately the same y i e l d s but the reaction p r o c e e d e d at a  much faster rate and hence the pH was of 4-5,  and  m o r e difficult to control.  however, the yields were 10-15% lower.  The  At a  pH  yields varied f r o m  82-84% for V D-galactonolactone to 50-57% for D-arabonolactone. <  -  Iii this investigation the pH using Congo r e d indicator paper.  of the solution was  T h i s was  a rather crude method and  pH meter would give a m o r e accurate control. t r o l of the pH was  controlled a  T h i s r e l a t i v e l y poor con-  probably the m a i n cause of the poor y i e l d since  L-allonolactone has been r e d u c e d to L - a l l o s e with sodium a m a l g a m in a y i e l d of 7 7 %  (4). The  control of the pH has been s i m p l i f i e d by a  to the standard procedure (28).  In place of the addition of the s u l f u r i c  acid, a r e l a t i v e l y insoluble s o l i d a c i d such as oxalic a c i d was the mixture.  modification  added to  A s the sodium a m a l g a m reacted, the a c i d d i s s o l v e d  maintained an approximately constant pH.  and  Y i e l d s of the o r d e r of 70-90%  * Seed c r y s t a l s of authentic D - a l l o s e have r e c e n t l y been r e c e i v e d f r o m Dr. H. S.Isbell to whom we are grateful. The use of this m a t e r i a l in the c r y s t a l l i z a t i o n of our syrupy sample i s s t i l l under investigation.  have been obtained.  ' " Y - D - A l l o n o l a c t o n e has been reduced in this manner  to D - a l l o s e i n a y i e l d of 7 1 % (45).  D.  The Raney N i c k e l Reduction Refluxing with Raney n i c k e l in aqueous ethanol solution has  been applied to the reduction of s e v e r a l aldoses to the corresponding alcohols and yields of 74-90% have been obtained (29).  sugar  Attempts were  made to apply this simple method to the reduction of a sugar lactone d i r e c t l y to the sugar alcohol.  With T-D-galactonolactone  o r d e r of 5% of c r y s t a l l i n e dulcitol were obtained. low,  sodium a m a l g a m reduction was  yields of the  Since the y i e l d  p r e f e r r e d for converting the  allonolactone to D - a l l o s e and the Raney n i c k e l method was reduction of the D - a l l o s e to a l l i t o l . and r e c r y s t a l l i z e d D-mannitol was  The method was  was 'Y-D-  used for the  tested on D-mannose  obtained in a y i e l d of 47. 2%.  One p o r t i o n of syrupy D - a l l o s e was hydrogenation with a platinum dioxide catalyst.  subjected to low p r e s s u r e The product which  not hydrogenated as indicated by the reducing power was  was  then completely  reduced to a l l i t o l by refluxing i n aqueous ethanol with Raney nickel. A sample of a l l i t o l obtained f r o m the reduction of crude, syrupy  ^ Y - D-allonolactone p a r t i a l l y c r y s t a l l i z e d on standing in vacuo  over phosphorus pentoxide but when it was  allowed to stand in the open  air it became syrupy within s e v e r a l minutes.  D - A l t r i t o l has been  r e p o r t e d as being h y g r o s c o p i c (10), (11) and therefore the sample of * Y - D - a l l o n o l a c t o n e was acid.  probably contaminated with a lactone of D - a l t r o n i c  - 24 A l l i t o l has been obtained in a y i e l d of 69. 1% (crude) f r o m D - a l l o s e with reduction by the Raney n i c k e l procedure.  On concentration  of the r e a c t i o n mixture after the reduction, a green colour was which was  obtained  shown to be due to nickelous n i c k e l . P u r e a l l i t o l was  obtained as long, slender needles after  repeated r e c r y s t a l l i z a t i o n f r o m aqueous ethanol, was and showed the c o r r e c t analysis.  optically inactive,  The melting point of 151. 0 - 151. 5° C.  a g r e e d with the r e p o r t e d value and acetylation to the known allitol hexaacetate completed the c h a r a c t e r i z a t i o n .  E.  The S o d i u m B o r o h y d r i d e Reduction Sodium borohydride has been used for the reduction of sugar  lactones (72) and aldoses (1) to the sugar alcohols.  P r e v i o u s l y , the  reduction of the lactone to the aldose was p e r f o r m e d using sodium amalgam.  T h i s method of reduction was  difficult to control and unless the  technique had been w e l l studied, the yields were low.  The reduction of  the aldose to the sugar alcohol has been done by sodium a m a l g a m or by high p r e s s u r e hydrogenation with Raney n i c k e l catalyst. borohydride was  The use of sodium  a m o r e convenient method than the latter, although the  yields were somewhat lower. In the borohydride reduction, the sugar alcohol complexed with the b o r i c acid, and f o r m e r l y the sugar alcohol was  isolated as the  polyacetate which was then converted back to the sugar alcohol or the reduction mixture was  refluxed with dilute h y d r o c h l o r i c a c i d in order to  - 25 destroy the complex.  A newer method in which the borate was r e m o v e d  as the volatile methyl ester has been r e p o r t e d (6). The borohydride reduction was f i r s t tested on 'Y-D-galactonolactone and c r y s t a l l i n e dulcitol was isolated i n a y i e l d of 48. 0%.  T h e mother  liquor gave a positive test for reducing sugar which indicated that a longer reduction p e r i o d might have i n c r e a s e d the yield.  In a s i m i l a r manner,  D-galactose was converted i n a y i e l d of 33. 9% to c r y s t a l l i n e dulcitol; i n this case also, reduction was incomplete. In an attempt to simplify the synthesis of allitol, VrD-allonop  lactone was treated with sodium borohydride, and a syrupy, product was obtained.  non-reducing  T h i s m a t e r i a l has not yet been thoroughly worked  up but probably contains a l l i t o l .  F.  The N i t r a t i o n of A l l i t o l D-Mannitol has been nitrated with a mixture of fuming n i t r i c  and s u l f u r i c acids by P a t t e r s o n and T o d d (41) in a y i e l d of 75%.  McKeown  and H a y w a r d (39) nitrated dulcitol by the same method in a y i e l d of 92%. Sorbitol hexanitrate was p r e p a r e d i n a y i e l d of 6 0 % by U r b a n s k i and Kwiatkowska (63) and in 9 7 % y i e l d by T e t t a m a n z i and A r n a l d i (62). A l l i t o l was nitrated with the n i t r i c - s u l f u r i c a c i d mixture and the c r y s t a l l i n e hexanitrate was obtained in a y i e l d of 36. 3%. A syrupy by-product was obtained which may p o s s i b l y be p a r t i a l l y nitrated allitol. U r b a n s k i and Kwiatkowska (63) found that the temperature at which the nitration was c a r r i e d out influenced the degree of nitration of sorbitol.  - 26 In the f i r s t n i t r a t i o n of a l l i t o l , the temperature was not r i g i d l y c o n t r o l l e d . The  second method of n i t r a t i o n which was used was that of  M o r g a n and Honeyman who treated methyl-4, 6-O-ethylidene-  (9 -D-  glucoside with a mixture of fuming n i t r i c acid, and acetic anhydride and obtained the 2, 3- dinitrate of the above compound i n a y i e l d of 8 9 % (25). C r y s t a l l i n e a l l i t o l hexanitrate was p r e p a r e d by this method i n a y i e l d of 59. 1%.  The crude product was obtained in approximately  90% y i e l d .  In  this case, also, some syrupy m a t e r i a l was obtained f r o m the nitration mixture which did not c r y s t a l l i z e and may p o s s i b l y be p a r t i a l l y nitrated allitol.  The pure allitol hexanitrate which had the c o r r e c t nitrogen content  m e l t e d at 59. 0 - 59. 5° C.  A sample of the p r i s m a t i c c r y s t a l s slowly decom-  posed with the evolution of nitrogen dioxide after standing i n a glass v i a l at r o o m temperature, for about s i x weeks.  G.  The R e a c t i o n of P y r i d i n e with A l l i t o l  Hexanitrate  The r e a c t i o n of pyridine with D-mannitol hexanitrate has been investigated and the r e s u l t i n g pentanitrate shown to be D-mannitol1, 2, 3, 5, 6-pentanitrate by H a y w a r d (22).  Some features of the m e c h a n i s m  of this denitration r e a c t i o n and some of the by-products by B r o w n and H a y w a r d (14).  were investigated  D u l c i t o l hexanitrate was known to r e a c t i n a  s i m i l a r manner with p y r i d i n e and the resulting pentanitrate was shown to be D, L-galactitol-1, 2, 4, 5, 6-pentanitrate by M c K e o w n and H a y w a r d (39). The r e a c t i o n of pyridine with allitol hexanitrate was i n v e s t i gated only i n a qualitative manner.  That some r e a c t i o n o c c u r r e d was  - 27 indicated since the solution changed f r o m c o l o u r l e s s to amber and c r y s t a l s which were apparently p y r i d i n i u m nitrate appeared on the walls of the testtube above the surface of the solution. No gas evolution was o b s e r v e d during the r e a c t i o n and in this r e s p e c t the behavior of allitol hexanitrate differed f r o m that of:D-mannitol hexanitrate which was treated with p y r i d i n e at the same time for comparison.  A c o l o u r l e s s syrup was r e c o v e r e d f r o m  the allitol r e a c t i o n mixture by dilution with water.  T h i s syrup did not  c r y s t a l l i z e when seeded with allitol hexanitrate, or on long standing i n a v a c u u m desiccator^ and slowly turned yellow after s e v e r a l days.  The  c r y s t a l l i n e mannitol pentanitrate was r e c o v e r e d in good y i e l d f r o m the cont r o l when worked up i n a s i m i l a r manner.  H.  The P r e p a r a t i o n of A l l i t o l Hexaacetate The p r e p a r a t i o n of acetates with acetic anhydride i n the p r e -  sence of a b a s i c catalyst such as pyridine i s quite general i n the carbohydrate field.  D-Manriitol hexaacetate was p r e p a r e d by this method i n a  y i e l d of 86. 7 % (5). A l l i t o l hexaacetate was obtained by this p r o c e d u r e i n the f o r m of long, thin, needle-like c r y s t a l s in a y i e l d of 58.0% and m e l t e d at 62. 0 - 62. 5° C. (reported values were 61° C. (44) and 61 - 62° G. (71) ). The a n a l y s i s and m o l e c u l a r weight determination c o n f i r m e d the identity of this compound. The d r a s t i c acetylation method of W i e m a n n (67) using acetic anhydride under r e f l u x for 12 hours gave no c r y s t a l l i n e a l l i t o l  hexaacetate.  D a r k e n i n g of the r e a c t i o n mixture indicated that some degradation had taken place.  - 28 EXPERIMENTAL  A.  Special Precautions In view of the sensitivity of carbohydrates, e s p e c i a l l y r e d u c -  ing sugars, to heat, a l l concentrations were c a r r i e d out under reduced p r e s s u r e at a temperature not exceeding 50° C.  Bumping of the solutions  was prevented by introducing a fine s t r e a m of bubbles of nitrogen gas f r o m a "bleeder", or by the use of a r o t a r y C r a i g - t y p e evaporator (15).  B.  Materials D-Arabinose D - A r a b i n o s e as supplied by the P f a n s t i e h l C h e m i c a l Company  was d r i e d over phosphorus pentoxide i n vacuo; m.p.  ~  L^JQ  1 0 4  were m.p.  «  6  0  ( » - »" M i 2 ° ^ ( c  0  53  160° C. ;  H  c o n s t a n t  J-  T  h  e  160 - 161° C. ;  r e p o r t e d constants  -104.5° (H O) (equilibrium) (44). z  D-Ribose D-Ribose purchased f r o m the P f a n s t i e h l C h e m i c a l Company was d r i e d i n vacuo i°0 D  *  over phosphorus pentoxide; m. p. 85 - 87° C. ;  -22.6° (c, 1.06; 1,1; HoO) (constant).  A sample of D - r i b o s e pur-  J  chased f r o m the Nutritional B i o c h e m i c a l s C o r p o r a t i o n when s i m i l a r l y d r i e d did not differ significantly i n melting point and specific rotation.  Pigman  and Goepp r e p o r t e d a m. p. of 87° C. and specific rotation to -23.7° (c, 4; HoO) for pure D - r i b o s e (44) which showed complex mutarotation.  The L - r i b o s e had  'Y"-D-Galactonolactone A sample of 'Y-D-galactonolactone (Pfanstiehl C h e m i c a l Company) after d r y i n g i n vacuo over phosphorus pentoxide had m. p .. 134.0 - 135. 5° C. and specific rotation (constant).  {°C\^'  The r e p o r t e d v a l u e s were m.p.  5  -80.0° (c, 0.54; 1, 1;:H 0) 2  133 - 135° C., M  D  -77. 40° (7).  N i t r ome thane Nitromethane  supplied by E a s t m a n O r g a n i c C h e m i c a l s (white  label) was d i s t i l l e d i n an a l l - g l a s s apparatus under r e d u c e d p r e s s u r e i n an atmosphere of nitrogen.  The distillate was  colourless.  O r g a n i c Solvents Methanol, ethanol, benzene, pyridine, toluene, ether, and n-pentane were p u r i f i e d as r e c o m m e n d e d by F i e s e r (17), and d i s t i l l e d in aii a l l - g l a s s apparatus. A c e t i c Anhydride Reagent grade acetic anhydride p u r c h a s e d f r o m May B a k e r L t d . was  and  d i s t i l l e d i n an a l l - g l a s s apparatus, and the f r a c t i o n d i s -  t i l l i n g at 136.5° -C. collected. Raney N i c k e l Catalyst The n i c k e l - a l u m i n u m alloy (technical grade) was obtained f r o m the Raney C a t a l y s t Company.  The catalyst was p r e p a r e d a c c o r d i n g  to the procedure outlined by V o g e l (65). A solution of 190 gm. was  of sodium hydroxide i n 750 m l . of water  m a g n e t i c a l l y s t i r r e d i n a two l i t r e beaker, and cooled i n an ice-bath  while 150 gm.  of n i c k e l - a l u m i n u m alloy was  added i n s m a l l portions.  - 30 Hydrogen gas was evolved i n copious quantities, and the solution t e m p e r a ture was kept below 25° C. during the additon which r e q u i r e d about two hours.  The solution was  allowed to come to r o o m temperature overnight,  and was then heated on the steam-bath until the evolution of hydrogen again became slow (12 hours).  The supernatant l i q u i d was decanted, and the  black, f i n e l y - d i v i d e d Raney n i c k e l was washed with d i s t i l l e d water,  50%  sodium hydroxide solution, and again with d i s t i l l e d water until the wash l i q u i d showed no b a s i c i t y to litmus paper.  The catalyst was then washed  an additional ten times with water, three times with 100 ml. portions of 95% ethanol and three times with 100 m l . portions of absolute ethanol. The n i c k e l catalyst was bottle.  stored under absolute ethanol i n a g l a s s - s t o p p e r e d  A p p r o x i m a t e l y one ml. of catalyst weighed 0. 6  gm.  Sodium A m a l g a m (2. 5%) (65) Sodium (19. 0 gm. ) was p l a c e d i n a 500 m l . flask, and 20 ml. of d r y toluene was a free flame, and 350 gm.  added.  Erlenmeyer  The sodium was  melted with  of m e r c u r y was then added dropwise.  At first  s e v e r a l flashes of flame o c c u r r e d , but this was followed by the evolution of dense white fumes. of the flame.  The toluene continued to b o i l even after the r e m o v a l  The toluene r e m a i n i n g after the additon of the m e r c u r y  was  decanted, and the a m a l g a m was poured into a m o r t a r and p u l v e r i z e d . Permanganate-Periodate  Spray Reagent for C h r o m a t o g r a m s (30)  A 2% aqueous solution of sodium metaperiodate and a 1% p o t a s s i u m permanganate i n a 2% aqueous sodium carbonate soution were prepared.  T h e s e two solutions were m i x e d i m m e d i a t e l y before use i n the  o  -31ratio of four parts of the periodate solution to one part of the permanganate solution, and sprayed on the chromatogram.  A f t e r the brown spots indicat-  ing the location of the sugar had appeared, the purple colour of the p e r manganate was r e m o v e d by washing the c h r o m a t o g r a m with water. A l k a l i n e Permanganate Reagent (12) .A 1% solution of potassium permanganate i n 2. 5 N sodium hydroxide was prepared,  and used as a reagent f o r detection of sugars on  adsorption column c h r o m a t o g r a m s . Red Tetrazolium R e d T e t r a z o l i u m (2, 3, 5 - t r i p h e n y l t e t r a z o l i u m chloride) was p u r c h a s e d f r o m the Nutritional B i o c h e m i c a l s C o r p o r a t i o n .  One ml. of a  0. 5% aqueous solution of the dye was t r e a t e d with one drop of sugar s o l u tion.  The mixture was heated on a water-bath, and a r e d precipitate, or  colour, indicated the presence of reducing sugar (17). P r e p a r a t i o n of the Ion Exchange C o l u m n The ion exchange c o l u m n containing about 400 gm. of A m b e r lite IR 120 r e s i n was converted to the c a l c i u m c y c l e by p a s s i n g through a 10% c a l c i u m c h l o r i d e solution until the eluate gave a test f o r calcium.  The column was then washed with water until evaporation of  an aliquot (10 ml.) of the eluate gave a negligible amount of residue. The r e s i n was converted to the hydrogen c y c l e by washing' with 3 N h y d r o c h l o r i c acid until the eluate gave no test for c a l c i u m .  The  column was then washed with water until an aliquot of the eluate gave a negligible amount of residue on evaporation.  - 32 C.  The Nitromethane 1.  Condensation  The Condensation of Nitromethane with D - A r a b i n o s e D - A r a b i n o s e (10. 00 gm. ) was suspended i n a m i x t u r e of  40 m l . of nitromethane and 50 m l . of methanol, and a solution of 2. 3 gm. of sodium in 70 m l . of methanol was added. came noticeably cooler immediately.  The resulting mixture be-  The container was wrapped in  aluminum f o i l to avoid photochemical decompositon, hours at r o o m temperature.  and shaken for 18  The precipitated sodium salts were r e m o v e d  by suction filtration, and washed with c o l d methanol, ether, and p e t r o l e u m ether.  The light brown, amorphous salts were d r i e d  phosphorus pentoxide for s e v e r a l days.  i n vacuo  Y i e l d 19. 0 gm.  oyer  (122.3%).  The salts were d i s s o l v e d i n 70 m l . of water, and the dark r e d solution was added dropwise with constant s t i r r i n g and external c o o l ing to a solution of 13 m l . of concentrated s u l f u r i c a c i d i n 19 m l . of water. A gas was evolved during the additon, and the final, pale yellow solution was n e u t r a l i z e d to Congo r e d (pH 5) with solid^sodium carbonate, then treated with c h a r c o a l , and f i l t e r e d by suction through a bed of celite.  The  filtrate was then treated with s o l i d sodium bicarbonate until just alkaline to litmus paper, and then made just a c i d with acetic acid.  Fehling's solu-  tion gave a positive test f o r reducing sugars. Phenylhydrazine (7, ml. ) i n 1 3 m i . of 2 5 % acetic a c i d was added to the sugar solution.  A precipitate of D-mannose phenylhydrazone  appeared within s e v e r a l minutes.  .After standing overnight, the orange-  brown precipitate was r e m o v e d by suction filtration, and the filtrate which  - 33 contained the soluble D-glucose phenylhydrazone worked up as d e s c r i b e d below.  was  set aside to be  The crude D-mannose  phenylhydrazone  was washed s u c c e s s i v e l y with water,- 6 0 % ethanol, absolute ethanol, and acetone, which r e m o v e d m u c h of the o r i g i n a l colour leaving a f i n a l p r o - " duct which was  only slightly yellow.  phosphorus pentoxide, 7. 3 gm.  (40. 6%) of D-mannose  with a melting point of 176° G. was was  A f t e r drying i n vacuo  obtained.  over  phenylhydrazone  The r e p o r t e d m e l t i n g point  199 - 200° C. (7). The D-mannose phenylhydrazone  2.5 hours with 100 ml. of water, 20 mL hyde, and 1 gm.  of benzoic a c i d .  r e f l u x e d for  of ethanol, 10 ml. of benzalde-  A dark brown oil separated  the solution, and the supernatant liquor was times with c h l o r o f o r m .  (7. 3 gm. ) was  outfrom  decanted and'extracted three  The aqueous solution was  d e c o l o u r i z e d with  charcoal, and concentrated to a syrup which after d r y i n g in vacuo phosphorus pentoxide weighed 5. 11 gm.  over  (42.6% y i e l d calculated as  D-mannose), and could not be induced to c r y s t a l l i z e although numerous attempts were made over a p e r i o d of 18 months. The syrupy D-mannose was  d i s s o l v e d i n 90 m l . of water and  a solution of sodium borohydride (1. 0 gm.) dropwise with s t i r r i n g . kept at r o o m temperature  i n 10 mL  of water was  The r e s u l t i n g solution had a p H of 8, and for 2 hours.  added was  A t the end of that time, the evolu-  tion of hydrogen had almost completely stopped, and two or three drops -  of the solution gave a negative Fehling's test after a c i d i f i c a t i o n with acetic a c i d to destroy the excess borohydride.  The-bulk of the solution  was then a c i d i f i e d with acetic acid, and concentrated to a syrup.  The  - 34 syrup was s u c c e s s i v e l y diluted, and concentrated s i x t i m e s with methanol to destroy the borate complex, and remove the borate as the volatile methyl ester (6). The white, amorphous residue was d i s s o l v e d i n water, and the f i l t e r e d , aqueous solution gave a negative test for reducing sugar with r e d t e t r a z o l i u m reagent.  The solution was made just t u r b i d by the  addition of ethanol, and allowed to stand.  A syrupy product was obtained.  One half of the filtrate containing D-glucose  phenylosazone  (150 ml. ) was treated in the same manner as for the D-mannose phenylhydrazone i n o r d e r to remove the phenylhydrazino r e s i d u e .  The aqueous  solution after extraction with c h l o r o f o r m , and treatment with c h a r c o a l was pale yellow in colour, and was concentrated to approximately 50 ml. whereupon solid, inorganic m a t e r i a l began to precipitate.  Sufficient water was  added to r e d i s s o l v e the precipitate, and the solution was n e u t r a l i z e d to Congo r e d with warm, saturated b a r i u m hydroxide solution. tated b a r i u m sulfate was r e m o v e d by centrifugation.  The p r e c i p i -  The centrifugate was  treated with b a r i u m acetate solution to r e m o v e any r e m a i n i n g sulfate ion (pH 5 - 6), and passed through the ion exchange column i n the hydrogen cycle (eluate p H 5 - 6).  The c o l u m n was washed with about 500 ml. of  water, and the total eluate concentrated until s o l i d m a t e r i a l began to p r e cipitate.  F u r t h e r d r y i n g i n a v a c u u m d e s i c c a t o r over phosphorus pentoxide  for s e v e r a l days gave 9. 20 gm. of brown, s o l i d m a t e r i a l . The s o l i d residue was rgfluxed with 35 ml. of ethanol for one hour giving a dark brown extract.  The extraction was repeated with  - 35 a further 35 m l . of ethanol, and the two extracts were combined, allowed to stand. tion. drying  The extract gave a positive test with Fehling's solu-  Some c r y s t a l l i n e m a t e r i a l was i n vacuo  obtained f r o m the extract which after  over phosphorus pentoxide melted at 323- 327° C.  Anhydrous sodium acetate was The  r e p o r t e d to melt at 324° C. (24).  s o l i d r e s i d u e r e m a i n i n g f r o m the extractions, was  solved i n water giving a brown c o l o u r e d solution which was charcoal.  The  dis-  treated with  solution gave a positive test with Fehling's solution.  standing some c r y s t a l l i n e m a t e r i a l was had a melting point of 57° C. acetate was  and  58 ° C . (24).  On  r e m o v e d which after a i r - d r y i n g  The r e p o r t e d m e l t i n g point of hydrated sodium  The aqueous mother liquor was  added to the  ethanol extract, and after standing, m o r e c r y s t a l l i n e , hydrated sodium acetate was  obtained.  The presence of reducing sugar was  the Fehling's test, but none was  isolated i n a c r y s t a l l i n e state.  The above crude m a t e r i a l was i z e d i n a m o r t a r with 3 gm. was  indicated by  dried  i n vacuo, and p u l v e r -  of anhydrous sodium acetate.  T h i s mixture  heated in a water-bath for 2 hours with 30 ml. of acetic anhydride,  and the r e s u l t i n g brown solution was  poured into about 150 ml. of ice-water,  and allowed to stand i n the r e f r i g e r a t o r for two days. separated which was f o r m was  A brown syrup  extracted three times with c h l o r o f o r m .  The c h l o r o -  removed, and the resulting brown syrup d i s s o l v e d iii ethanol  and allowed to stand.  Many attempts to obtain c r y s t a l l i n e  D-gluCose f r o m ethanol and aqueous ethanol have a l l failed. had the same odour as c h a r r e d sugar.  ^5-pentaacetylThe  syrup  -•36 -  .  The brown oils obtained i n the r e m o v a l of the phenylhydrazino r e s i d u e f r o m D-mannose and D-glucose phenylhydrazones were c r y s t a l l i z e d f r o m aqueous ethanol. The c r y s t a l l i n e m a t e r i a l had a melting point of 154 - 158° C.  The two i s o m e r i c f o r m s of benzaldehyde  phenylhydrazone were r e p o r t e d to melt at 154  r  155° C. and 15,7 - 158° C.  (23). The r e m a i n i n g portion (150 ml.) of the solution containing D-glucose phenylhydrazone was heated i n a boiling water-bath with 90 ml. of f r e s h l y prepared, phenylhydrazine raagent f o r 20 minutes after which it was  allowed to stand overnight. The phenylhydrazine reagent was  pre-  p a r e d i n the following manner (2): phenylhydrazine h y d r o c h l o r i d e (10 was  d i s s o l v e d i n 90 ml. of water; 15 gm.  gm.)  of sodium acetate and three or  four drops of glacial acetic a c i d were added, and the r e s u l t i n g solution was treated with c h a r c o a l and f i l t e r e d . The orange-brown precipitate of D-glucose was  phenylosazone  r e m o v e d by suction filtration, and d i s s o l v e d i n 5 0 % aqueous ethanol.  T h i s solution on treatment with c h a r c o a l gave a dark r e d c o l o u r e d solution. was  C r u d e m a t e r i a l (1. 86 gm.)  with a melting point of 180 - 1 85° C.  obtained on standing. T h i s was  r e c r y s t a l l i z e d f r o m anisole, and  gave a m e l t i n g point of 186 - 189° C... A further I. 04 gm. D-glucose phenylosazone was a total y i e l d of 2. 9 gm.  of crude  obtained f r o m the o r i g i n a l solution giving  (24. 2%).  aqueous ethanol, and after d r y i n g  T h i s m a t e r i a l was in vacuo  r e c r y s t a l l i z e d from-  over phosphorus pentoxide  had a melting point (decomposition point) of 199 - 203° C.  The r e p o r t e d  - 37 melting point of D-glucose phenylosazone was 2.  208  C. (7).  The Condensation of Nitromethane with D-Ribose D-Ribose  (23. 68 gm ) ;  was treated with 50 ml. of methanol,  90 ml. of nitromethane, and a solution of 5; 3 gm.  of sodium i n 175 m l .  of methanol, by the procedure d e s c r i b e d for D-arabinose.  The y i e l d of  dried, amorphous, sodium salts of the m i x e d nitroalcohols was (76.4%).  28.09  gm.  The salts were d i s s o l v e d in 700 ml. of water, and the solution  (pH 10) was p a s s e d through the ion exchange column in the hydrogen cycle-. The r e d eluate (pH 5-6) was d a r k e r after p a s s i n g t h r o u g h the column, and treatment with c h a r c o a l r e m o v e d a c o n s i d e r a b l e amount-of the colour. The column was washed with water until a 10 ml. aliquot of the eluate on evaporation y i e l d e d a negligible amount of residue. The total eluate was which was d r i e d  i n vacuo  concentrated to a dark brown syrup  over phosphorus pentoxide f o r s e v e r a l days.  Y i e l d of the supposed mixture of crude nitroalcohols was  17. 68 gm.  (5 3.1%).  The d r i e d syrup was extracted with 50 m l . of absolute ethanol f o r 2 hours at 50° C. with protection against m o i s t a i r , and the orange-yellow absolute ethanol extract was f i l t e r e d through a f r i t t e d glass funnel, and allowed to stand at r o o m temperature.  Three more similar  absolute ethanol extractions were c a r r i e d out on the syrup. A descending paper c h r o m a t o g r a m was run i n a n-butanol, g l a c i a l acetic acid, and water s y s t e m (5:1:2) on Whatman No. the f i r s t absolute ethanol extract.  The c h r o m a t o g r a m was  1 paper on  s p r a y e d with  L e m i e u x ' s periodate solution (30) and two spots were obtained with R:f  - 38 values of 0. 33 and 0. 43; the latter spot being l a r g e r and d a r k e r .  Slow  evaporation of the combined ethanol extracts left a dark brown syrup (A) which reduced Fehling's solution, but could not be c r y s t a l l i z e d .  A paper  c h r o m a t o g r a m of.A c o m p a r e d to a D - r i b o s e standard gave two spots; one c o r r e s p o n d e d to the D - r i b o s e standard, and the other which was d a r k e r had a l a r g e r R f value. The s o l i d r e s i d u e r e m a i n i n g f r o m the w a r m ethanol e x t r a c tions was further extracted with 50 m l . of absolute ethanol at r e f l u x temperature  for 2 hours, and the o r a n g e - c o l o u r e d solution was r e m o v e d  by f i l t r a t i o n through a f r i t t e d glass funnel.  The extraction was repeated  twice, and the three extracts combined, and allowed to evaporate to a brown syrup (B) which reduced Fehling's solution.  A paper c h r o m a t o g r a m  of syrup B c o m p a r e d to D - r i b o s e as standard gave two spots; the l a r g e r and d a r k e r of the two c o r r e s p o n d e d to the spot obtained f r o m the D - r i b o s e standard. The ethanol insoluble, dark residue (C) r e m a i n i n g f r o m these extractions weighed 3.56 gm. , and was completely water soluble. It failed to give a spot on a paper c h r o m a t o g r a m when c o m p a r e d with D-ribose. In an adsorption chromatography column, 0. 8 5 x 1 3 c m . , was p l a c e d 2 gm. of a mixture, of s i l i c i c a c i d and celite (2:1), and this column was washed with a solution of ethanol-benzene mgm.  ( l : 4 / v ) , and 2.1 V  of A in dilute ethanol (0. 2 ml.) was placed on the column, and the  c h r o m a t o g r a m was developed with 2. 5 m l . of the ethanol-benzene  mixture.  - 39 The column, on extr.usion, was streaked with Lemieux's periodate reagent (30),  and the f i r s t brown band extended for.2. 9 cm. f r o m the top of the  column. wide.  The second band began 3. 6 cm. f r o m the top, and was 1. 1 cm.  The total .column length was 5. 9 cm. A s i m i l a r c o l u m n was s l i c e d into sections c o r r e s p o n d i n g to  these bands, and each of these sections was extracted with w a r m ethanol. The extracts were r u n on a paper chromatogram, and c o m p a r e d to a D - r i b o s e standard.  F r o m these c h r o m a t o g r a m s , the f i r s t section (first  brown band) and the second section both contained D - r i b o s e .  The t h i r d  section (second brown band) and the fourth section both contained D - r i b o s e as w e l l as some other m a t e r i a l which appeared v e r y close to the solvent front.  D.  T h e C y a n o h y d r i n Synthesis of T-D-AUonolactone D-Ribose (45.00 gm.) was d i s s o l v e d i n 325 m l . of water  and the solution cooled to 3° C. i n an i c e - s a l t - b a t h .  T o this was added  a solution containing 19.6 gm. of sodium cyanide i n 135 m l . of water, also cooled to 3 ° C . The r e s u l t i n g solution was allowed to stand at 5° C. for 24 hours.  T h e c l e a r , pale yellow solution (pH 11) then gave a nega-  i tive test with Fehling's solution, and was heated on the steam-bath for 2 hours, and then b o i l e d gently under, r e f l u x for 6 hours during which ammonia was evolved.  While s t i l l hot, the solution was p a s s e d through the  ion exchange column i n the c a l c i u m c y c l e .  The p H of the eluate was  about 5. T h e c o l u m n was thoroughly washed with water, and the total  - 40 eluate was  concentrated until c a l c i u m - D - a l t r o n a t e hemiheptahydrate began  to c r y s t a l l i z e .  The r e c o v e r e d c a l c i u m - D - a l t r o n a t e hemiheptahydrate  r e c r y s t a l l i z e d , and a i r - d r i e d ; y i e l d 25. 30 gm.  was  (34. 2%).  The amber filtrate containing the c a l c i u m - D - a l l o n a t e (pH 5) was p a s s e d through the ion exchange c o l u m n i n the hydrogen c y c l e to r e m o v e the c a l c i u m .  The eluate and washings were concentrated to a  brown syrup which s o l i d i f i e d on d r y i n g i n vacuo oxide.  over phosphorus pent-  T h i s solid m a t e r i a l was then d i s s o l v e d i n water, t r e a t e d with  charcoal, f i l t e r e d , and allowed to stand.  S o l i d 'V-D-allonolactone with  a melting range of 98 - 123° C. separated i n a y i e l d of 20. 19 gm.  (37. 8%).  E x a m i n a t i o n of this m a t e r i a l under the m i c r o s c o p e indicated that it was not c r y s t a l l i n e . 29.79 gm. r  F r o m a second r u n starting with 50. 00 gm.  (41.6%) of c a l c i u m - D - a l t r o n a t e , and 20.51  S~~ D-allonolactone were obtained.  gm.  above.  The  (34.6%) of  The lactone melted at 68 - 91°  In a t h i r d experiment, D - r i b o s e (8.20 gm.) with 3. 68 gm.  of D - r i b o s e ,  C.  was treated,  of sodium cyanide i n a s i m i l a r manner to that d e s c r i b e d  solution on passage through the ion exchange c o l u m n became  blue-green i n colour, and on subsequent concentration, a f l o c c u l e n ^ blue precipitate was  obtained which was  of the filtrate gave 7. 23 gm. hemiheptahydrate.  r e m o v e d by f i l t r a t i o n .  of crude, wet  Evaporation  calcium-D-altronate  R e c r y s t a l l i z a t i o n f r o m water, and d r y i n g over  phosphorus pentoxide, of c a l c i u m - D - a l t r o n a t e . grow i n the solution.  i n vacuo,  converted this to 1. 28 gm.  (10.9%)  D u r i n g this r e c r y s t a l l i z a t i o n a m o u l d began to  - 41 When the mother liquor containing the c a l c i u m - D - a l l o n a t e came into contact with the ion exchange r e s i n , the blue colour was obtained again.  Concentration of the eluate r e s u l t e d i n the p r e c i p i t a t i o n  of this m a t e r i a l which was r e m o v e d by f i l t r a t i o n .  Crude,  syrupy  'V-D-all onolactone was obtained i n a y i e l d of 3.08 gm. (31.7%) which s o l i d i f i e d on drying.  M a n y attempts to c r y s t a l l i z e this crude m a t e r i a l  f r o m aqueous and aqueous ethanol solutions failed.  The m a t e r i a l was  twice precipitated f r o m ethanol solution by the addition of l i g r o i n to give 0. 37 gm. of s o l i d 'V-D-allonolactone with a melting point of 95 - 129° C. (7).  E x a m i n a t i o n under the m i c r o s c o p e indicated that this m a t e r i a l was  not c r y s t a l l i n e . in vacuo  The mother l i q u o r s when concentrated, and d r i e d  over phosphorus pentoxide y i e l d e d 1.42 gm. of crude  syrupy  Y~ D-allonolactone.  t  The blue s o l i d m a t e r i a l was soluble i n oxalic a c i d solution, and, i n sodium hydroxide gave a brown precipitate which on the addition of h y d r o c h l o r i c a c i d to the solution r e v e r t e d to the blue colour.  The  addition of concentrated a c i d to the blue c o l o u r e d solution gave a faint odour of hydrogen cyanide.  A s m a l l sample of the r e s i n was t r e a t e d  with a solution of sodium cyanide, but no blue colour was obtained.  On  the addition of either c a l c i u m c h l o r i d e or h y d r o c h l o r i c a c i d to this mixture, the blue colour developed.  A second sample of r e s i n was ignited  in a c r u c i b l e , and the r e s i d u e d i s s o l v e d i n concentrated h y d r o c h l o r i c acid. T h i s solution, when treated with potassium thiocyanate gave a r e d c o l o u r ation t y p i c a l of i r o n (66).  - 42 E.  The Reduction of Y-D-Allonolactone with Sodium A m a l g a m r  Solid X " D  d i s s o l v e d in 200 ml.  a l l  o  n o l a c t o n e  ' ( 2 0 . 51 gm.)  of water in a 600 ml.  s t i r r e d magnetically.  The  solution was  68-91° C.)  cooled in an ice-salt-bath,  D u r i n g one hour, four 100 gm.  of 10%  portions of 2. 5%  kept just a c i d to Congo r e d by the addition of 10%  burette.  sodium The  solution  sulfuric acid f r o m a  A greenish-yellow s o l i d substance which appeared to be sulfur  floated to the surface of the solution during the reduction. Was  and  sulfuric acid  a m a l g a m were added to the solution with continuous s t i r r i n g . was  was  beaker, and the solution  after ice had begun to f o r m i n the solution 1. 6 ml. were added.  (m.p.  kept in the i c e - s a l t - b a t h throughout the entire reduction The  solution was  The  solution  period.  decanted f r o m the m e r c u r y and treated with  sufficient s o l i d sodium carbonate such that the solution after standing for one-half hour in the cold, was  just alkaline to l i t m u s .  then made just a c i d to litmus by the additon of 10% fine precipitate was The  solution  sulfuric acid, and  was the  r e m o v e d by suction f i l t r a t i o n through a bed of celite.  almost c o l o u r l e s s filtrate was  Ethanol was  The  concentrated to a volume of about 75  ml.  added until no further p r e c i p i t a t i o n o c c u r r e d , and the white  precipitate was  r e m o v e d by filtration.  pale-yellow syrup which was one-half hour.  The  filtrate was  refluxed with 25 ml.  A l l of the syrup dissolved,  slowly evaporated in the  T h e r e was  (25. 8%) of crude, s e m i - c r y s t a l l i n e D - a l l o s e . this m a t e r i a l were f r u i t l e s s .  of absolute ethanol for  and the r e s u l t i n g solution which  gave a positive test with Fehling's solution was p r e s e n c e of anhydrous c a l c i u m chloride.  concentrated to a  thus obtained 13. 94  Attempts to r e e r y s t a l l i z e  gm.  -43A n aqueous solution of the crude D - a l l o s e was  clarified  with charcoal, and made up to 50 ml. , and an aliquot of this solution contained 0. 1941  gm.  of dry, syrupy D - a l l o s e .  y i e l d of syrupy D - a l l o s e was r  +9. 79°(c, 3. 88; I; 1; H 0 )  The  (constant).  2  specific rotation of  F.  (16.9%).  specific rotation  n21  L^Jj)  was  9. 12 gm.  On this b a s i s , the total  ^ - D - a l l o s e was  The  reported  +14. 4° (c, 5; H O J (constant) (7). 2  The Reduction of D - A l l o s e with Raney N i c k e l Crude, syrupy D - a l l o s e (8. 7 3 gm.)  was  r e f l u x e d for 1. 5  hours i n 450 ml. of 7 0 % aqueous ethanol with approximately Raney n i c k e l catalyst.  The  catalyst: was  The green solution was for n i c k e l was  6. 1 gm.  of  r e m o v e d by filtration, and the  filtrate concentrated to a green syrup. over phosphorus pentoxide,  100 gm.  On d r y i n g overnight  i n vacuo  of crude syrupy a l l i t o l was  tested with dimethylglyoxime,  obtained.  and a positive test  obtained (66). The crude a l l i t o l was  give 0. 38 gm.  c r y s t a l l i z e d f r o m aqueous ethanol to  of c l e a r , needle-shaped c r y s t a l s which after a i r - d r y i n g  m e l t e d at 147 - 148° C.  T h i s product was  r e c r y s t a l l i z e d to a constant  melting point f r o m aqueous ethanol, and after d r y i n g over phosphorus pentoxide point was a l l i t o l was  i n vacuo  melted at 151. 0 - 151. 5° C.  150 - 151° C. (44).  A total of 1. 41 gm.  isolated i n four c r o p s . mm.  to be  (c, 1.92;1, 0. 5; H 0 ) .  5  0°  (.2. 6%) of c r y s t a l l i n e  The c r y s t a l s were long, slender  needles, about 2 - 3 [*]^*  The r e p o r t e d melting  i n length.  The 2  specific rotation was  observed  The r e p o r t e d specific  - 44 rotation was  t°Q  C  C, 39.55%; H,  6  G.  H  0 :  1 4  6  D  0° (44).  The Reduction of Solid  Found: C, 39.46%; H, 7.62%.  C a l c . for  7.76%.  ^ D - A l l o n o l a c t o n e with Sodium B o r o h y d r i d e  ^f-D-allonolactone (20.19 gm.)  (m.p.  98-123° C.)  was  d i s s o l v e d i n 40 m l . of water, and added dropwise to a solution containing 5.0 gm.  of sodium borohydride in 65 m l . of water which was  ice-bath, and m a g n e t i c a l l y s t i r r e d . 145 minutes, the temperature  cooled i n an  Throughout the r e a c t i o n p e r i o d of  was kept below 20° C.  The rate of evolution  of hydrogen was quite r a p i d at f i r s t , but gradually diminished. i n i t i a l pH of the solution was  7, and the final 8.  The  The excess borohydride  was then destroyed by the dropwise addition of 6 N  s u l f u r i c a c i d after  which the solution gave a positive r e d u c i n g sugar test with r e d t e t r a z o l i u m . The treatment with sodium borohydride was  repeated.  T e s t s with r e d  t e t r a z o l i u m and Fehling's solution after the second r e d u c t i o n were negative.  The solution was then concentrated to a heavy syrup which contained  some c r y s t a l l i n e m a t e r i a l . T h i s syrup was  concentrated to dryness eight  t i m e s with methanol to remove the b o r i c acid, and then d i s s o l v e d i n w a r m water, and allowed to stand over phosphorus pentoxide i n a v a c u u m desiccator.  H.  The N i t r a t i o n of A l l i t o l 1.  N i t r a t i o n with F u m i n g N i t r i c and S u l f u r i c A c i d s A l l i t o l (0. 097 gm.)  was  p u l v e r i z e d to a white powder with a  s t i r r i n g rod, and added i n s m a l l portions to 0. 33 m l . of fuming n i t r i c  -.45 a c i d (d. 1.49 was  -  - 1. 50) p r e v i o u s l y cooled i n an i c e - s a l t - b a t h .  s t i r r e d after each addition until a l l of the a l l i t o l was  The  mixture  i n solution.  The  r e a c t i o n test-tube was kept i n the i c e - s a l t - b a t h throughout the procedure. Concentrated sulfuric a c i d (0. 55 ml.) was then added dropwise with s t i r r i n g to the mixture, and at this point, the solution became opaque. was  The  mixture  allowed to stand i n the i c e - s a l t - b a t h for 15 minutes after which an  additional 0.05 m l . of concentrated s u l f u r i c a c i d were added. that the nitrate had separated as a syrup.  The mixture was  It appeared  poured with  s t i r r i n g into 30 m l . of ice-water, and a heavy, viscous, c o l o u r l e s s syrup separated, which did not c r y s t a l l i z e after s c r a t c h i n g with a glass r o d for s e v e r a l minutes. The aqueous mixture was then extracted with three 12 m l . portions of c h l o r o f o r m .  The c h l o r o f o r m extract was  washed with water,  10% sodium bicarbonate solution, and again with water, and d r i e d over anhydrous m a g n e s i u m sulfate. r a t e d to give 0. 156 gm.  The d r i e d c h l o r o f o r m solution was  of dry, crude, syrupy m a t e r i a l .  evapo-.  A f t e r standing  for s e v e r a l days, the syrup became v e r y slightly yellow i n colour; no odour of oxides of nitrogen could, be detected.  The syrup was  ether, and allowed to stand i n an ice-salt-bath. been cooled i n the i c e - s a l t - b a t h was until a cloudiness just p e r s i s t e d . at r o o m temperature, occurred.  d i s s o l v e d i n cold  n-Pentane which had  added to the ether solution dropwise  The solution was then allowed to stand  and, after s e v e r a l days, no c r y s t a l l i z a t i o n had  The syrup was  r e d i s s o l v e d i n ether, and n-pentane added until  turbid, but this time at r o o m temperature.  The  solution on standing i n the  - 46 r e f r i g e r a t o r for s e v e r a l hours deposited p r i s m a t i c c r y s t a l s . r e m o v e d by suction filtration, and a i r - d r i e d . and were obtained i n a y i e l d of 0. 087 gm.  T h e s e were  T h e y m e l t e d at 57. 5-58. 0° C. ,  (36. 3%).  After several r e c r y s -  tallizations f r o m aqueous ethanol, a constant m e l t i n g point of 59. 0-59. 5° C. was  obtained.  F r o m the mother liquor of the o r i g i n a l c r y s t a l l i z a t i o n ,  some syrupy m a t e r i a l was crystallization.  obtained which has r e s i s t e d a l l attempts at  A nitrogen analysis of the pure allitol hexanitrate by the  Dumas method (8) gave the following r e s u l t : Found: N, 18.8%. C a l c . f o r hexitol hexanitrate, hexitol pentanitrate,  2.  C5 Hg  C^ Hq N5 O j ^ : N,  0  : 1 8  N  18.5, >  17.8,  19.7,  1-8.6-%. C a l c . for  17.2%.  N i t r a t i o n with F u m i n g N i t r i c A c i d and A c e t i c Anhydride P o w d e r e d allitol (0. 199 gm.)  was p l a c e d i n a 15 m l . test-  tube with 1. 82 m l . of acetic anhydride, and cooled to a temperature below 0° C. i n an ice-salt-bath.  A mixture of 1. 82 m l . of acetic anhydride and  0. 73 m l . of fuming n i t r i c a c i d (d. 1. 49 - 1. 50) was prepared, and cooled to a temperature below  0° C.,  and  then added to the above suspension of  a l l i t o l , and the r e s u l t i n g mixture kept at about 0° C. i n the i c e - s a l t - b a t h for one hour with o c c a s i o n a l agitation.  The test-tube was then removed,  and allowed to come to r o o m temperature over a p e r i o d of 15 minutes. At the bottom of the test-tube, there was a s m a l l amount of white c r y s talline m a t e r i a l .  The mixture was then poured into approximately 75 m l .  of ice-water with s t i r r i n g .  A syrup i m m e d i a t e l y separated, and the m i x -  ture was allowed to stand overnight i n the r e f r i g e r a t o r .  - 47 The aqueous mixture was of ether; the ether extract was  extracted three times with 25  ml.  washed with 50 ml. of water, 50 m l . of  1,0% sodium bicarbonate solution, a final 50 m l . of water, and was d r i e d for  3.5 hours over anhydrous m a g n e s i u m sulfate which was  r e m o v e d by f i l t r a t i o n .  The ether solution was  concentrated to 0.448  of syrup which p a r t i a l l y c r y s t a l l i z e d on d r y i n g i n vacuo pentoxide.  The p a r t i a l l y c r y s t a l l i n e product was  alcohol, and pure a l l i t o l hexanitrate was (59. 1%), m e l t i n g at 59. 0 - 59. 5° C.  subsequently gm.  over phosphorus  recrystallized from  obtained i n a y i e l d of 0. 292  gm.  The mother l i q u o r s , on evaporation,  left a syrupy r e s i d u e which has not been obtained i n c r y s t a l l i n e f o r m . The  sample of a l l i t o l hexanitrate was  with a polyethylene cap at r o o m temperature. for  stored i n a glass v i a l  A f t e r it had been standing  six weeks, it slowly decomposed with the evolution of dense, red-brown  fumes of nitrogen dioxide.  A sample of D-mannitol hexanitrate standing  beside the a l l i t o l hexanitrate sample showed no signs of  I.  decomposition.  The R e a c t i o n of P y r i d i n e with A l l i t o l Hexanitrate A sample of c r y s t a l l i n e a l l i t o l hexanitrate (0.047 gm.)  was  powdered with a s t i r r i n g r o d i n a test-tube, and 0. 34 m l . of d r y p y r i d i n e was  added.  Within two minutes a l l of the a l l i t o l hexanitrate had d i s s o l v e d  f o r m i n g a c l e a r , c o l o u r l e s s solution at r o o m temperature (27° C.).  Within  five minutes the solution began to take on a yellow colour, and after standing for twenty minutes, long, fine, needle-like c r y s t a l s of p y r i d i n i u m nitrate had f o r m e d on the inner walls of the test-tube above the surface of  \ -  48  -  the solution. Throughout the reaction, no temperature increase could be detected, and no bubbles of gas were observed. After standing overnight, the colour of the solution had darkened considerably, and was now  amber.  Water (5. 0 ml.) was added with stirring to the solution, and a syrup separated which could not be induced to crystallize by scratching with a glass rod.  After standing several hours, a seed of allitol hexanitrate  was added, and the aqueous mixture was allowed to stand overnight, but crystallization did not occur. three 10 ml. portions of ether.  The aqueous mixture was extracted with The ether extract was washed with 10 ml.  of 10% hydrochloric acid, 10 ml. of water, and evaporated, and the resulting syrup dried in vacuo over phosphorus pentoxide. 0. 032 gm.  (76. 2%) of yellow syrup which may  There resulted  possibly be allitol pentanitrate.  In a parallel reaction a powdered sample of D-mannitol... hexanitrate (0.052 gm.)  was treated with 0. 37 ml. of pyridine, and a clear,  colourless solution was obtained immediately. Within two minutes, the solution took on a yellow colour, and the evolution of gas bubbles was observed. Within fourteen minutes crystals of pyridinium nitrate had appeared on the inner walls of the test-tube above the surface of the solution. After standing overnight, the colour of the solution had darkened considerably, and was  slightly darker than that of the allitol hexanitrate.  Water (5. 0 ml.) was added with stirring to the solution, and a white precipitate was immediately obtained which was removed by suction filtration, and dried in vacuo over phosphorus; pentoxide. obtained 0.029 gm.  There was  (61.7%) of crude, crystalline D-mannitol pentanitrate  - 49 with a m e l t i n g point of 77. 5 - 80. 5° C.  The r e p o r t e d m e l t i n g point was  81 - 82° C. (22).  J.  The P r e p a r a t i o n of A l l i t o l  Hexaacetate  P y r i d i n e (0.6 ml.) and 0. 6 m l . of acetic anhydride were added to 0. 060 gm. of pure c r y s t a l l i n e a l l i t o l , and the mixture was heated i n a water-bath at, 65° C. for ten minutes.  Since the a l l i t o l had not com-  pletely dissolved, p y r i d i n e and acetic anhydride were added i n equal volumes, and the temperature a l l i t o l had d i s s o l v e d .  of the water-bath i n c r e a s e d to 70° C. until a l l of the T h i s r e q u i r e d a total heating p e r i o d of forty minutes  and a total volume of 1.0 m l . of p y r i d i n e and 1. 0 m l . of acetic anhydride. The flask was fitted with a c a l c i u m c h l o r i d e drying-tube, and allowed to stand for 24 hours at r o o m  temperature.  The solution was, then poured into 125 m l . of ice-water with constant s t i r r i n g , and the r e s u l t i n g mixture allowed to stand i n the r e f r i g e r a t o r for two days.  A t the end of this period, s o l i d m a t e r i a l had  deposited on the inner w a l l s of the beaker.  T h e aqueous m i x t u r e was  extracted three t i m e s with c h l o r o f o r m , and the extract after d r y i n g over anhydrous m a g n e s i u m sulfate was concentrated to a syrup which on d r y i n g over phosphorus pentoxide  i n vacuo  partially crystallized, yielding  0. 144 gm. of crude a l l i t o l hexaacetate.  A f t e r s e v e r a l attempts this  m a t e r i a l was r e c r y s t a l l i z e d f r o m aqueous ethanol.  Long, thin needles of  a l l i t o l hexaacetate with a m e l t i n g point of 62. 0 - 62. 5° C. were obtained in a y i e l d of 0. 083 gm. (58. 0%). (44) and 61 - 62*C. (71).  The m e l t i n g point was r e p o r t e d as 61° C.  Found: C, 50.77%; H, 6. 23%. C a l c . for q  8  H  2 6  q : 2  - 50 C, 49. 76%; H, 6. 04%.  The molecular weight was determined by the Rast  method (8) using the lactam of p - aminohexahydrobenzoic acid as the solvent.  Found: 437,446. Calc. for C  1 8  H& 2  C> : 12  434.  F r o m a sample of crude allitol, 0.20 gm.  of crude allitol  hexaacetate was obtained in the same manner as described above.  This  material was recrystallized from aqueous ethanol and melted at 60 - 61° C. A second sample of crude allitol (0.49 gm.) was reluxed with 3. 5 ml. of acetic anhydride for 12 hours. Within a few minutes, the solution became orange-brown in colour, and at the end of the reflux period some dark brown, solid material was present.  The reaction mixture was poured into  50 ml. of ice-water, and allowed to stand in the refrigerator for two days. A dark brown syrup separated, and the aqueous mixture was extracted three times with chloroform.  The dried chloroform solution was  con-  centrated to a brown syrup which after repeated attempts has not crystallized from aqueous ethanol.  K.  The Preparation of P - A l t r i t o l The specific rotation of the pure calcium-D-altronate was r  observed to be  -jl 9  L^J  D  -2.02  (c, 1. 79; 1, 1; H-0)'. The reported 2  specific rotation for calcium-D-altronate hemiheptahydrate was r .-|20 i^Jjy  -2.4°  (c, 1. 8; H 0 ) 2  (46).  Calcium-D-Altronate (29. 79 gm.) was dissolved in 400 ml. of hot water, and passed through the ion exchange column in the hydrogen cycle.  The column was washed with 500 ml. of hot water to remove any  - .51 -  m a t e r i a l which might have c r y s t a l l i z e d i n the column, and then with c o l d water.  The total eluate was  in vacuo  concentrated to a syrup which was  over phosphorus pentoxide.  T h e r e was  dried  obtained 22. 33  gm.  (164. 5%) of crude, yellow, syrupy D - a l t r o n i c a c i d which probably contained some of the c o r r e s p o n d i n g lactone (37). A sample of the above product (1.01 gm.) 20 minutes with 0. 2 gm. for  'V'D-allonolactone.  was treated.for  of sodium borohydride as p r e v i o u s l y d e s c r i b e d A white amorphous m a t e r i a l was  obtained after  concentration and treatment with methanol, which d i d not become syrupy on standing i n the open a i r . D - A l t r i t o l has been r e p o r t e d to be h y g r o s c o p i c (10), (11).  T h i s m a t e r i a l was then d i s s o l v e d i n aqueous ethanol, and this  solution gave a positive r e d u c i n g test with Fehling's solution and with r e d t e t r a z o l i u m reagent.  The treatment with sodium borohydride was  and this time the solution exhibited no reducing power, and was stand  i n vacuo  over anhydrous c a l c i u m c h l o r i d e .  repeated,  allowed to  Some c r y s t a l l i n e  inorganic m a t e r i a l has been removed, but the syrupy m a t e r i a l has not crystallized.  L.  The Reduction of '>f-D-Galactonolactone  with Raney N i c k e l  'Y-D-Galactonolactone (1.0 gm. J i n aqueous ethanol solution was treated as d e s c r i b e d for D - a l l o s e with 10 gm. was  obtained 0. 028 gm.  There  (2. 7%) of dulcitol with a melting point of 184 - 185° C.  after two r e c r y s t a l l i z a t i o n s f r o m aqueous ethanol. point of dulcitol was  of R a n e y n i c k e l .  188. 5 - 189. 0° C. (44).  The r e p o r t e d melting  The product was  chromato-  - 52 graphed on paper as d e s c r i b e d previously, and gave a single spot identical to that displayed by dulcitol. In a second run with 2.0 gm. dulcitol was  of 0(-D-galactonoiactone,  obtained in a y i e l d of 0. 110 gm.  (5.4%).  After recrystalliza-  tion f r o m aqueous ethanol, the m a t e r i a l m e l t e d at 179 - 181° C. melting point with  ^ - D - g a l a c t o n o l a c t o n e was  about 135° C. whereas with  an authentic sample of dulcitol, the mixted m e l t i n g point was In a t h i r d run with a 1,5 gm. the reflux p e r i o d was y i e l d of 0. 068 gm.  M.  A mixed  181 - 1.85° C.  sample of /^-D-galactonolactone,  6 hours, and c r y s t a l l i n e m a t e r i a l was  obtained in a  (4. 4%) with a m e l t i n g point of 187. 5 - 188. 0° C.  The Reduction of D-Mannose with Raney N i c k e l D-Mannose (0.65 gm.)  was t r e a t e d with approximately 5  of Raney n i c k e l as d e s c r i b e d f o r D - a l l o s e . A crude y i e l d of 0. 96 gm. D-mannitol was and 0. 31 gm.  obtained.  T h i s was  of  r e c r y s t a l l i z e d f r o m aqueous ethanol  (47. 2%) of m a t e r i a l m e l t i n g at 163 - 164° C. was  obtained.  second r e c r y s t a l l i z a t i o n i n c r e a s e d the melting point to 166 - 167° C. r e p o r t e d m e l t i n g point of D-mannitol was  N.  The Reduction of  gm.  The  165 - 166° C. (44).  ^ D - G a l a c t o n o l a c t o n e with Sodium B o r o h y d r i d e  fN^-D-Galactonolactone (1.00 gm.)  was  t r e a t e d with sodium  borohydride. i n the manner p r e v i o u s l y d e s c r i b e d . R e c r y s t a l l i z e d dulcitol with a m e l t i n g point of 183 - 187° C. was (48.0%).,  obtained i n a y i e l d of 0.49  gm.  The mother l i q u o r s gave a positive test for r e d u c i n g sugar with  red tetrazolium.  A  - 53 O.  The Reduction of D - G a l a c t o s e with S o d i u m D-Galactose (1.0 gm.)  Borohydride  was t r e a t e d with sodium borohydride  in the manner d e s c r i b e d by A b d e l - A k h e r , H a m i l t o n and Smith (1). talline dulcitol was  obtained i n a y i e l d of 0. 34 gm.  (33. 9%).  tallization f r o m ethanol, this m a t e r i a l m e l t e d at 187.5  On  Crys-  recrys-  - 188. 5° C.  The  mother l i q u o r s gave a positive reducing sugar test with r e d t e t r a z o l i u m .  P.  The P r e p a r a t i o n of D - M a n n i t o l Hexanitrate D - M a n n i t o l (0. 100 gm.)  was nitrated a c c o r d i n g to the p r o -  cedure of P a t t e r s o n and T o d d (41"). R e c r y s t a l l i z a t i o n f r o m aqueous ethanol y i e l d e d 0. 174 gm.  (70.4%) of c r y s t a l l i n e D-mannitol hexanitrate with a o  melting point of 109 - 110 (22).  O  C.  The r e p o r t e d melting point was  111 - 112  C.  -  54. -  CLAIMS T O ORIGINAL  1.  RESEARCH  Two routes for the synthesis of a l l i t o l f r o m D - r i b o s e have been i n v e s t igated and pure c r y s t a l l i n e allitol was obtained and c h a r a c t e r i z e d .  2. C r y s t a l l i n e a l l i t o l hexanitrate was synthesized for the f i r s t time by the nitration of a l l i t o l with fuming n i t r i c and s u l f u r i c acids, or with fuming n i t r i c a c i d and acetic anhydrides  3.  P r e l i m i n a r y experiments indicated that a l l i t o l hexanitrate r e a c t e d slowly at r o o m temperature with dry.pyridine, p o s s i b l y suffering p a r t i a l denitration.  4.  The Raney n i c k e l method of reduction of aldoses to alditols was extended to the reduction of D - a l l o s e to a l l i t o l .  5.  The nitromethane condensation with D - r i b o s e was r e i n v e s t i g a t e d and it was found that a considerable portion of the D - r i b o s e d i d not r e a c t . A p a r t i a l separation of the components of the r e a c t i o n m i x t u r e was obtained on adsorption chromatography columns.  6.  Some studies were made of the reduction of aldoses and aldonolactones with sodium borohydride  i n aqueous solution.  - 55 BIBLIOGRAPHY  1.  Abdel-Akher, M., Hamilton, J..K. and Smith, F . J . Am. Soc. 73: 4691. 1951.  2.  Adams;, R. and Johnson, J.R. In E l e m e n t a r y l a b o r a t o r y e x p e r i m e n t s i n o r g a n i c c h e m i s t r y . 3 r d ed. The M a c m i l l a n Co., New Y o r k . 1940.  3.  Austin, W.C. and HumoIIer, F . L . 1933.  4. Austin, W. C. and H u m o l l e r , F. L .  J . Am.  Chem.  Chem. Soc. 55: 2167.  J . Am. Chem. Soc. 56: 1153.  1934. 5.  B a e r , E . and F i s c h e r , H. O. L .  J . Am.  Chem. Soc. 61: 761. 1939.  6. Ballou, G.E., F i s c h e r , H. O. L . and MacDonald, D . L . Chem. Soc. 77: 5967. 1955. 7.  J . Am.  Bates, F . J . and A s s o c i a t e s . 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