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The structures and conformations of some cyclic 0-benzylidene acetals of hexitols Conder, David W. 1961

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THE STRUCTURES AND CONFORMATIONS OF SOME CYCLIC O-BENZILIDENE ACETALS OF HEXITOLS  by David W. Conder  A THESIS SUBMITTED IN PARTIAL FUIFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE i n the Department of CHEMISTRY  We accept t h i s t h e s i s as conforming to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA November, 1961.  Ih presenting'this thesis i n p a r t i a l f u l f i l m e n t o f the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y available f o r reference and study.  I further agree that permission  for extensive copying of t h i s t h e s i s f o r scholarly purposes may be granted by the Head of my Department or by his  representatives.  It i s understood that copying or publication of t h i s thesis f o r f i n a n c i a l gain s h a l l not be alloived without my written permission.  Department of  CHEMISTRY  The University of B r i t i s h Columbia, Vancouver 8, Canada. Date  DEC.  5/1961  ABSTRACT  The structure of the previously reported  di-O-benzylidene  a c e t a l of a l l i t o l has been established as that of 2,4>3>5-diO-benzylidene a l l i t o l .  An i n f r a r e d spectroscopic  study i n  carbon t e t r a c h l o r i d e solution of the intramolecular  hydrogen  bonding e x i s t i n g i n t h i s compound and the r e l a t e d d i a c e t a l , l,3j4>6-di-0-benzylidene d u l c i t o l was made t o determine the preferred molecular conformations.  An i n t r a r i n g , bifurcated  hydrogen bonded conformation was assigned t o the d u l c i t o l derivative.  For the a l l i t o l derivative no f i n a l decision  could be made on the basis of e x i s t i n g evidence between the two possible intramolecularly hydrogen bonded conformations. A spectroscopic method f o r the determination of the number of c y c l i c O-benzylidene groups present per mole of parent alcohol has been developed.  ACKNOWLEDGMENT  I wish t o thank Dr. L. D. Hayward who has w i l l i n g l y assisted and provided encouragement t o make t h i s research possible.  TABLE OF CONTENTS. Page  GENERAL INTRODUCTION  1  HISTORICAL INTRODUCTION  2  I.  II.  Preparation and Properties of C y c l i c 0 Benzylidene Acetals of G l y c i t o l s  2  Stereochemistry  7  of C y c l i c Acetals  A.  Stereochemistry  of Sis-Membered  B.  Acetal Rings Stereochemistry  of Five-Membered  7 .16  Acetal Rings C. III.  IV. V.  Stereochemistry  Stereochemistry  of Fused Ring Acetals  IS  of Known O-Benzylidene  Acetals of Hexitols  19  A.  O-Benzylidene Acetals of S o r b i t o l  19  B.  O-Benzylidene Acetals o f Mannitol  22  C.  O-Benzylidene Acetals of T a l i t o l  22  D.  O-Benzylidene Acetals of I d i t o l  24  E.  O-Benzylidene Acetals of D u l c i t o l  25  F.  O-Benzylidene Acetals of A l l i t o l  27  Hydrolysis of C y c l i c O-Benzylidene Acetals  27  Spectra of O-Benzylidene Acetals  30  A.  Infrared Spectra  30  B.  NMR Spectra  31  Page  33  RESULTS AND DISCUSSION I. II. III. IV.  The Struct Tire of Di-O-Benzylidene A l l i t o l  33  Intramolecular Hydrogen Bonding  37  The Preferred Conformations of Di-OBenzylidene Acetals of the Hexitols  37  Synthesis of 2,5-Di-0-Benzoyl-l,4j3,6Dianhydro-L-Iditol  V.  '  Attempted Synthesis of 2,5-Di-O-Benzoyl-  l,3;4>o-Di-0-Benzylidene A l l i t o l VI.  42  Hydrolysis of O-Benzylidene Acetals  43 45  EXPERIMENTAL  51  I.  51  II. III.  IV. V.  VI. VII.  Materials and Reagents  2,4j3,5-Di-p-Benzylidene A l l i t o l 1,6-Di-0-Methyl-2,4j3 >5-Di-0-Benzylidene Allitol"  53  1,6-Di-O-Methyl A l l i t o l  54  Lead Tetraacetate Oxidation of l,6-Di-0Methyl A l l i t o l  56  Infrared Spectroscopy  56  2,5-Di-0-Benzoyl-1,4J 3,6-Dianhydro-LIditol  VIII.  52  57  Attempted Synthesis of 2,5-Di-O-Benzoyl-  l,3;4,6-Di-0-Benzylidene A l l i t o l  57  Tri-O-Benzylidene-D-Mannitol  59  X. Hydrolysis of O-Benzylidene Acetals SUGGESTIONS FOR FURTHER RESEARCH  62  IX.  60  TABLES. TABLE I Graded Acidic Hydrolysis of Acetals TABLE I I Absorption Bands Assigned to 1,3-Dioxane Ring TABLE I I I Infrared Absorptions of Alcohols (OH-Region) TABLE IV Hydrolysis of O-Benzylidene Acetals  FIGURES.  FIGURE 1 Mechanism of C y c l i c Acetal Hydrolysis FIGURE 2 Structural Elucidation of Di-O-Benzylidene Allitol FIGURE 3 Lead Tetraacetate Oxidation of Di-O-Methyl Allitol FIGURE 4 Infrared Spectra of Solutions (OH Region) FIGURE 5 Concentration of Benzylidene Groups Versus Optical Density of C y c l i c O-Benzylidene Acetals  FIGURE 6 Hydrolysis Curves o f C y c l i c O-Benzylidene Acetals FIGURE 7 Hydrolysis Curves o f C y c l i c O-Benzylidene Acetals FIGURE 9 Infrared Spectra of S o l i d Samples  - 1 -  GENERAL  INTRODUCTION  The main objective of t h i s research was t o establish the structure and i f possible the preferred conformation of di-Obenzylidene a l l i t o l .  This compound was f i r s t synthesized i n  1932 and no previous attempt appears t o have been made t o elucidate i t s molecular structure.  From conformational analysis  two possible structures, l,3;4,6-di-0-benzylidene a l l i t o l and 2,4j3>5-di-0-benzylidene a l l i t o l , are favored f o r t h i s compound. Both are capable of e x i s t i n g i n two nearly equally probable conformations which would be s t a b i l i z e d by intramolecular hydrogen bonds. Of the ten isomeric hexitols only a l l i t o l and d u l c i t o l f a i l to form tri-O-benzylidene acetals when condensed d i r e c t l y with benzaldehyde.  An i n f r a r e d spectroscopic study of these two di-O-  benzylidene acetals i n carbon t e t r a c h l o r i d e solution was undertaken to  determine the nature of the intramolecular hydrogen bonding i n  these compounds and, i f possible, t o assign the molecular conformations. In the course of t h i s research a spectroscopic technique f o r the determination of the number of benzylidene groups i n c y c l i c O-benzylidene acetals was developed.  HISTORICAL I.  PREPARATION AND OF GLYCITOLS.  INTRODUCTION  PROPERTIES OF CYCLIC-O-BENZILIDENE ACETALS  Acetals are a general c l a s s of organic compounds formed by the condensation of alcohols with the carbonyl group of aldehydes i n the presence of a c i d i c c a t a l y s t s . C y c l i c O-benzylidene acetals w i l l be formed from the condensation reaction of benzaldehyde with polyhydroxy alcohols having s u i t a b l y oriented hydroxyl groups.  The reaction i s believed t o  f i r s t form the hemiacetal (II) which e x i s t s as an unstable i n t e r mediate before proceeding t o the a c e t a l ( I I I ) .  RHG-OH PhCHO +  RHG-OH  (OHOH)n ^ RHG-OH  i  (CHOH)  +  n  RHp—O  o ^  RHWM^-PII X)H  CTOH)n)CHPh+  H 0 2  RHC—O  m  n  The condensation reaction i s acid catalyzed, the  postulated  mechanism involving protonation of the hydroxyl oxygen, and, as the reaction i s r e v e r s i b l e , i t i s also f a c i l i t a t e d by dehydrating agents.  The standard c a t a l y s t s employed are concentrated s u l f u r i c ,  hydrochloric and hydrobromic acids, gaseous hydrogen c h l o r i d e , zinc chloride, cupric sulfate and phosphorus pentoxide.  In the absence  of an a c i d i c catalyst the reaction may proceed only as f a r as the hemiacetal formation; i t continues t o the complete a c e t a l only i f water i s removed from the reaction mixture. derived a c e t a l i s u s u a l l y independent  The nature of the  of the a c i d i c catalyst employed,  however, a few exceptions have been observed.  In one case i t was  reported that at room temperature hydrogen chloride catalyzed the formation  of a 2,3,4,5-di-O^benzylidene d e r i v a t i v e of 1 , 6 -  dibenzoyl d u l c i t o l whereas zinc chloride as c a t a l y s t yielded at room temperature an isomeric dibenzylidene  compound, which when  subjected t o zinc chloride and benzaldehyde at 60°C reverted i n t o the former isomer (1). C y c l i c O-benzylidene acetals generally form c r y s t a l l i n e , high-melting  derivatives of polyols and hence are u s e f u l f o r  characterization purposes.  These acetals are r e a d i l y hydrolysed  back t o the parent alcohol by aqueous acid as t h e i r a c i d catalyzed formation i s r e v e r s i b l e . Under mild conditions acetals are stable t o bases such as hydroxides, alkoxides, ammonia and pyridine.  This c h a r a c t e r i s t i c of acid l a b i l i t y and base s t a b i -  l i t y makes c y c l i c acetals extremely u s e f u l as intermediates i n the synthesis of p a r t i a l l y substituted polyhydric alcohols. As protective substituents c y c l i c a c e t a l linkages may be employed t o block p a i r s of hydroxyl groups with a high degree of s p e c i f i c i t y .  Furthermore, they possess the nature that they  can be placed and removed under mild conditions without  causing  inversion of configuration at asymmetric centers. Acetals are generally stable toward the common o x i d i s i n g agents employed i n carbohydrate chemistry such as lead tetraacetate and the periodates. reducing agents.  S i m i l a r l y acetals appear t o be stable toward  An example i s the preparation of 2,4-O-benzylidene-  D - x y l i t o l by reduction of 2,4-0-benzylidene-D-xylose with hydrogen and Raney n i c k e l under neutral conditions (2).  Most acetals of  polyhydric alcohols w i l l remain stable i n basic solution during  - 4 acylation, sulfonation, methylation, benzylation, and t r i t y l a t i o n providing the customary mild conditions are employed.  However,  an exception to basic s t a b i l i t y has been noted by Harm, Maclay and Hudson (3) who observed that ketal migration occurred when 2,3»5»6diisopropylidene-D,L-galactitol was  subjected to benzoylation i n  quinoline at elevated temperatures and yielded l,6-dibenzoyl-2,3»4»5diisopropylidene d u l c i t o l .  Barker and Bourne (4) accordingly  state that although treatment of an acetal or k e t a l with a basic reagent i s u n l i k e l y to cause s t r u c t u r a l rearrangements, t h i s p o s s i b i l i t y should not be ignored. Interest i n c y c l i c a c e t a l formation has up to the present been concerned mainly with either stereochemical studies i n the determination of the most stable structures of these compounds or with t h e i r use as intermediates i n the synthesis of p a r t i a l l y substituted polyhydric alcohols. Very l i t t l e i n d u s t r i a l use has so f a r been found f o r these compounds.  Since t h i s research has  been mainly concerned with the stereochemistry of the c y c l i c acetals t h i s aspect -will be considered i n d e t a i l . The formation of c y c l i c acetals from polyhydric alcohols -will t h e o r e t i c a l l y produce many isomeric products that w i l l d i f f e r i n structures, configuration, and conformation.  The effect of configura-  t i o n of the reactants on the course of the reaction depends considerably on whether the reaction i s reversible or i r r e v e r s i b l e .  Cyclic  a c e t a l formations are examples of reversible reactions where, prov i d i n g a true equilibrium i s attained, the composition of the products i s independent of mechanism and determined by the r e l a t i v e thermodynamic s t a b i l i t i e s of the constituents. The conversion of benzylidene (5)  and  ethylidene acetals (6)  i n t o the corresponding methylene analogues  gives evidence f o r the r e v e r s i b l e nature of the r e a c t i o n .  However,  i t i s not always possible t o assess whether a true equilibrium has been reached f o r as Harm and Hudson (7)  point out, the condensation  of an aldehyde with a polyhydric alcohol w i l l constitute a series of competitive  reactions and a state of r e v e r s i b l e equilibrium  involving several acetals w i l l be reached.  Should one of these  acetals c r y s t a l l i z e during the reaction then the equilibrium cond i t i o n s may  cause t h i s s o l i d phase t o be the p r i n c i p a l product.  In predicting the most probable structures and conformations of c y c l i c acetals several important factors should be The major considerations w i l l  considered.  be:  (1)  The configuration of the hydroxyl groups i n the alcohol.  (2)  The structure of the carbonyl component.  polyhydric  (3) The conditions under which the acetalation occurs. Although i t appears that many variable f a c t o r s d i r e c t i n g a c e t a l formation e x i s t , i t has been possible t o predict with  considerable  accuracy the course of the r e a c t i o n . In 1946  Harm and Hudson (2)  from studies of the known structures  of the methylene acetals of s o r b i t o l , mannitol and d u l c i t o l derived a set of rules which predicted the most favored structure of the product i n c y c l i c a c e t a l formation.  Although these r u l e s were  empirical at the time, stereochemical theory has since placed them on a f i r m b a s i s .  These r u l e s have been regarded as a major contribu-  t i o n t o the stereochemistry The  of a c y c l i c molecules.  system of nomenclature followed here i s that employed by  - 6 Barker and Bourne ( 4 , 8 ) . j  Yrings  }  are rings formed by the engagement of hydroxy!  groups attached t o carbon atoms which are adjacent, separated by one atom and separated by two atoms r e s p e c t i v e l y .  For secondary  hydroxyl groups, C ( c i s ) r e f e r s t o rings formed by the closure at hydroxyl groups on the same side of the Fischer projection formula} s i m i l a r l y T (trans) w i l l r e f e r t o r i n g closure at hydroxyl groups on opposite sides of the Fischer projection formula.  The parts  of the p o l y o l carbon chain not involved i n the formation a c e t a l r i n g are referred t o as residues.  of the  Fused rings r e f e r t o  rings i n which two carbon atoms are i n common. Barker and Bourne ( 4 ) i n 1952 modified the o r i g i n a l Hann and Hudson rules t o include a l l of the cases of benzylidenation, ethylidenation and methylenation known t o that date.  The modified  rules are: (1)  The most favored structure i s a ^ - C r i n g .  (2)  The second most favored structure i s f o r a ^3 r i n g ,  (3) The t h i r d most favored structure i s f o r a n ^ , ^ - T , ^?-T or Y~1 r i n g . (4)  In methylenation a B-1 ^<-T or y-T r i n g .  (5)  In benzylidenation and ethylidenation an c<-1 r i n g takes precedence over a or ^-T r i n g .  (6)  Rules ( 4 ) and ( 5 ) may not apply when one or both of the carbon atoms carrying the hydroxyl groups concerned i s already part of a r i n g system.  r i n g takes precedence over an  Of i n t e r e s t i s the f a c t that these r u l e s do not apply t o the isopropylidene ketals which exist predominantly as five-membered rings. Hann and Haskins ( 2 ) pointed out that the O-benzyHdene acetals  would be expected t o be more complicated than the methylene acetals as i n each O-benzylidene a c e t a l r i n g there i s the p o s s i b i l i t y of an asymmetric carbon atom which would give r i s e t o stereoisomerism. Conformational analysis of the c y c l i c a c e t a l rings i s necessary t o provide a t h e o r e t i c a l basis f o r these empirical r u l e s and t o enable one t o answer the following questions:  II.  (1)  What i s the most probable r i n g structure of an O-benzylidene a c e t a l formed from a polyhydroxy alcohol of known configuration?  (2)  How many conformations are l i k e l y t o be favored f o r the a c e t a l and which of these i s l i k e l y t o be the more stable?  STEREOCHEMISTRY OF CYCLIC ACETALS. Recent advances i n the stereochemistry of carbohydrates and  t h e i r c y c l i c derivatives are reviewed by M i l l s ( 9 ) , Overend (10),  and I s b e l l and Tipson  F e r r i e r and  (11).  Condensation of benzaldehyde with a polyhydric alcohol generally r e s u l t s i n the formation of a six-membered c y c l i c a c e t a l r i n g although f i v e and seven membered rings are known.  A.  STEREOCHEMISTRY OF SIX-MEMBERED ACETAL RINGS. A considerable amount of information i s now available about  the stereochemistry of six-membered rings from studies with cycle— hexane and cyclohexane derivatives (12).  The chair form (I) i s  i n v a r i a b l y the preferred conformation having minimized non-bonded repulsions.  Other possible six-membered r i n g conformations include  the boat ( I I ) , planar ( H I ) , sofa (IV), h a l f chair (V) and skewed (VI) forms.  Substituents w i l l tend t o occupy equatorial rather  than a x i a l positions t o minimize d i a x i a l repulsions.  -  .  - 9-  The substitution of two oxygen atoms i n the cyclohexane r i n g t o form a 1,3-dioxane r i n g as found i n c y c l i c acetals does not appear t o a l t e r these rules s u b s t a n t i a l l y .  However, the  p o s s i b i l i t y of s l i g h t d i s t o r t i o n s from the cyclohexane conformat i o n s exists since C-0 w i l l give a shorter bond distance than C-C and replacement of two hydrogen atoms by lone p a i r s of electrons on oxygen might be expected to decrease non-bonded ring interactions.  Thus the 1,3-dioxane r i n g (VII) i s probably  l e s s strained and somewhat more distorted than the cyclohexane ring. Examining the ^ -C r i n g (VIII) both  and R£ may be i n  equatorial positions while i n a ^3 -T r i n g (IX) i f R^ i s equatorial R  2  must be a x i a l .  Since the equatorial positions are energetically  favored over a x i a l positions then i t i s reasonable that £3-0, rings w i l l be favored over ^ -T r i n g s .  Examining the a c e t a l carbon atom,  the favored p o s i t i o n f o r the bulky phenyl group of a c y c l i c O-benzylidene acetal w i l l be i n the equatorial (e) p o s i t i o n .  Thus (VIII)  (R^= phenyl) w i l l represent the predicted most stable six-membered O-benzylidene a c e t a l where the two residues and the bulky phenyl group are a l l on the same side of the r i n g .  Assuming that the r e -  pulsive forces from the unshared electrons of the r i n g oxygen i n the 1,3-dioxane r i n g are l e s s than those from a hydrogen atom, then the equatorial p o s i t i o n at the a c e t a l carbon atom w i l l be favored over the a x i a l p o s i t i o n much; more i n a 1,3-dioxane r i n g than i n a cyclohexane r i n g . of a ^-C  I t i s therefore highly u n l i k e l y that the isomer  O-benzylidene a c e t a l having the phenyl group i n an a x i a l  p o s i t i o n would be stable enough t o i s o l a t e .  This i s i n agreement  - 10 with experimental r e s u l t s i n d i c a t i n g only one diastereoisomer i s formed i n most benzylidenation reactions affording six-membered rings. Comparing the positions of groups Rtj and R^ of (7111), one sees that although both RJJ and R^ suffer repulsions from R-^ and R» 2  only Rej suffers repulsions from two hydrogen atoms.  repulsion between R  Q  The  and the oxygen atoms cannot be accurately  assessed but i s assumed t o be l e s s than repulsions from two hydrogen atoms.  The p r o b a b i l i t y i s thus seen that the a x i a l group  R^ w i l l be more favored than the equatorial group R^ and hence a x i a l hydroxyl groups i n 0-benzylidene a c e t a l rings may occur.  From conformational considerations alone M i l l s  predicted that 2,4-O^methylene-D-glucitol,  readily (9)  l,3j4,6-di-0-methylene  d u l c i t o l and the related ethylidene and benzylidene derivatives were stable acetals with a x i a l hydroxyl groups. As previously stated only one diastereoisomer i s obtained from most benzylidenation reactions which produce six-membered rings.  However, i n c e r t a i n cases two products have been i s o l a t e d  and c i t e d as being diastereoisomers.  Gluco-gulo-heptitol reported-  l y yielded a mono O-benzylidene acetal which could be converted t o 3,5-O-benzylidene-gluco-gulo-heptitol on r e c r y s t a l l i z a t i o n from ethanol (13).  S i m i l a r l y D-perseitol  (D-manno-D-gala-heptitol)  has been reported to y i e l d two l,3j5,7-di-0-benzylidene acetals (14). However, both of these compounds gave indistinguishable i n f r a r e d spectra i n n u j o l mulls and potassium bromide disks, had o p t i c a l  o rotations d i f f e r i n g by only 0.1  , and one form could be converted  - 11 i n t o the other by repeated r e c r y s t a l l i z a t i o n s from ethanolpyridine (15).  This evidence indicates that the l a t t e r reported  p a i r of diastereoisomers probably exist as polymorphic forms. Of considerable i n t e r e s t i s the isomerism encountered i n the benzylidene acetals of g l y c e r o l .  Fischer i n 1894  the f i r s t to describe a d e f i n i t e condensation  product  (16)  was  from  g l y c e r o l and benzaldehyde which he suggested was either the  1,3-  or 1,2-O-benzylidene d e r i v a t i v e . However, Fischer's product  was  probably a mixture of both derivatives f o r Hibbert and H i l l  (17)  and Verkade and van Roon (18) l a t e r i s o l a t e d two separate 1,3-0benzylidene acetals as w e l l as the predominant 1,2-0-benzylidene acetal.  The two 1,3-0-benzylidene g l y c e r i t o l s possess a c i s - t r a n s  r e l a t i o n s h i p but i t should be pointed out that i n these acetals (X and XI) the a c e t a l carbon atom i s not asymmetric, Brimacorribe, Foster and Stacey (19) have exaroined the isomeric 1,3-0-benzylidene-glyceritols (2-phenyl-5-hydroxy-l,3-dioxanes) spectrophotometrically i n carbon t e t r a c h l o r i d e solutions <^0.005M at which concentrations intermolecular hydrogen bonding i s e l i M n a t e d (20).  From the i n f r a r e d stretching frequency i n the hydroxyl region  they have been able to assign c i s and trans configurations t o the two isomers by examining the extent of intramolecular hydrogen bonding.  Brimacombe, Foster et.al.(21) f i r s t examined the extent  of hydrogen bonding between hydroxyl groups and r i n g oxygen i n a series of monohydroxy derivatives of tetrahydropyran, tetrahydrofuran and 1,3-dioxanes under similar conditions.  Absorptions near  3630 cm ''"and 3590 cm ^ were associated with f r e e and intramolecularly bonded hydroxyl groups r e s p e c t i v e l y .  - 12 -  xn  xm  X3ZI  -13  -  Examination of the i n f r a r e d spectra of l,3-dioxane-5-ol  -1 showed absorptions at  3635  cm  -1 and  3594 cm  with r e l a t i v e  extinction c o e f f i c i e n t s of 21 and 100 r e s p e c t i v e l y .  The r e l a t i v e  extinction c o e f f i c i e n t s indicate that an equilibrium of chair conformations exist (XII and XIII) which favors the conformation (XIII) having an intramolecularly hydrogen bonded a x i a l hydroxyl group.  From t h i s evidence i t would appear that an equatorial  substituent on C  2  i n conformation (XIII) of l,3-dioxane£-ol would  e f f e c t i v e l y f i x t h i s conformation thus causing complete  intra-  molecular hydrogen bonding. Spectroscopic examination of the two 1,3-O-benzylidene —  84°C  g l y c e r i t o l isomers showed that the isomer of m.p. one hydroxyl stretching absorption at  3590  cm  1  gave only  i n d i c a t i n g conforma-  t i o n (X) while the other isomer (m.p. 63 - 64°C) gave two hydroxyl stretching frequencies at  3633  cm"  1  (£ = 79) and  3601  cm""  1  (£=26)  i n d i c a t i n g an equilibrium between the bonded (XIV) and non-bonded (XV ) conformations.  From t h i s spectroscopic examination the isomer  o of m.p.  84 C was allocated the c i s configuration and the other  o isomer (m.p.  o  63 - 64 C) the trans configuration.  The conformation (XIV) contains the phenyl group i n the s t e r i c a l l y unfavorable a x i a l p o s i t i o n and the observation that a proportion of the molecules exist i n t h i s conformation r e f l e c t s the strength of the intramolecular hydrogen bond.  The non-bonded  interactions associated with the a x i a l phenyl group i n conformation (XIV) could p o s s i b l y r e s u l t i n some deformation of the chair structure but the extent would probably be s l i g h t and would adversely affect the intramolecular hydrogen bond.  - 14 In the hydrogen bonds the hydroxyl groups are shown bonded t o both r i n g oxygens forming a bifurcated bond.  Experimental  evidence suggests that bifurcated bonds are present but does not confirm t h e i r existence. Brimacombe, Foster ety a l . (21) have shown the importance of both r i n g oxygens i n 5-hydroxyj-1,3-dioxane structures as intramolecular hydrogen bonding between the hydroxyl group and the r i n g oxygen i n tetrahydropyran-3-ol occurs t o the extent of approximately  50$ (<£?=40  and  50  f o r free and bonded  hydroxyl groups respectively) whereas the introduction of a second r i n g oxygen giving 1,3-dioxane-5-ol gives more extensive intramolecular hydrogen bonding (<£ = 21 and 100 f o r free and bonded hydroxyl. groups r e s p e c t i v e l y ) . Dobinson and Foster (22) have compared the hydrogen bonding effects i n derivatives of trans-cyclohexane-l,2-diol (XVI) and 5-hydroxy 1,3-dioxane (XIII). T  Intramolecular hydrogen bonding i n  both of these compounds involves five-membered rings and as t h e i r A  pvalues (arithmetical difference between free and bonded  hydroxyl absorption frequencies) were found t o be s i m i l a r ^ i t  appears  that these bonds are of equal strength. However, the bulk of the isopropyl group i n trans-l-isopropylcyclohexane-l 2-diol was <  found  t o be s u f f i c i e n t to anchor the molecule exclusively i n the chair conformation with the isopropyl group equatorial and the hydroxyl groups a x i a l .  The bulk of the phenyl group appears somewhat l e s s  than that of the isopropyl group as i t has been shown by Brimacombe, Foster e t ^ a l . (21) that i t i s not s u f f i c i e n t to anchor 2-phenyl-l,3-dioxane  i n conformation (XV).  trans-5-hydroxy-  Dobinson and Foster  are currently attempting the synthesis of trans-5-hydroxy-2-t-butyl-  - 15 1,3-dioxane t o determine i f the bulky t - b u t y l group w i l l exist only i n an equatorial p o s i t i o n . The spectroscopic observations made by Brimacombe, Foster et.al.  (21,22,23,24)  have thus pointed out the significance of  intramolecular hydrogen bonding i n s t a b i l i z i n g conformations which otherwise would be considered  unfavorable.  The condensation of aldehydes with g l y c e r o l s i g n i f i c a n t l y d i f f e r s from the pattern observed with higher polyhydric alcohols as the proportion of five-membered r i n g c y c l i c acetals of g l y c e r o l always markedly exceeds the proportion of six-membered r i n g acetals providing the reaction mixture remains l i q u i d .  One noted  exception  i s the O-methylene g l y c e r o l which when acid e q u i l i b r a t e d , produced the six-membered c y c l i c a c e t a l i n greater y i e l d .  Thus, although  intramolecular hydrogen bonding undoubtedly influences the reaction behaviour of c e r t a i n higher polyhydric alcohols with aldehydes, i t i s probably not the determining influence with g l y c e r o l . I f t h i s was  so, cis-l,3-0-benzylidene  g l y c e r o l (X) would be expected t o be  the major condensation product of benzaldehyde with g l y c e r o l . Piantadosi e t | a l . (25) have shown that i n c a t a l y t i c amounts of acid an equilibrium e x i s t s between the 1,2-  and 1,3-0-benzylidene  glycerols and have calculated an equilibrium constant. indicate an equilibrium r a t i o of approximately 9:1  Their r e s u l t s  favoring the  1,2-0-benzylidene-glycerol thus i n d i c a t i n g the preference f o r the five-membered r i n g configuration. An example where the empirical r u l e s regarding c y c l i c a c e t a l formation f a i l t o d i f f e r e n t i a t e a preferred structure i s the formation of a 1,3-0-benzylidene-(XVII) and 1,3-O-methylene a c e t a l  - 16 of D and L a r a b i t o l i n preference t o the corresponding substituted acetals (XVIII).  Since both the 1,3-  3,5-  and 3,5-  struc-  tures have @ rings the acetal formation rules w i l l not d i f f e r e n t i a t e between them.  From an examination of the stereochemistry  of both structures i t i s seen that the p o s s i b i l i t i e s of i n t r a -  "in molecular hydrogen bonding are greater i n the 1,3-  thanAthe  3,5-  derivative since the former contains an a x i a l hydroxyl group which can intramolecularly bond with the r i n g oxygens. B.  STEREOCHEMISTRY OF FIVE-MEMBERED ACETAL RINGS. The p o s s i b i l i t i e s of isomerism i n five-membered rings are  shown i n the M i l l s projection formulae (XIX) and five-membered r i n g i s nearly planar the c^-T favored over the positions.  (XX).  As the  r i n g w i l l be  -C r i n g which w i l l have R^ and R2 i n eclipsed  The ^ - T  r i n g , being more symmetrical, should be more  stable than a terminal c(. r i n g .  Evidence f o r t h i s i s the rearrange-  ment of l,2j4,5-di-0-isopropylidene-D,L-galactitol t o  2,3j4,5-di-0-  isopropylidene d u l c i t o l when catalyzed by pyridinium chloride or quinolinium  chloride  (26).  Stereoisomerism at the a c e t a l carbon atom w i l l be ijiipossible i f R3 = R^ and impossible i n an eC -T r i n g i f R]_ = R . 2  In a l l other  cases isomerism i s possible and i t i s d i f f i c u l t to predict a favored isomer.  This i s e s p e c i a l l y so i n an  closely similar.  <J*(-T r i n g where R-j_ and R  2  are  Stereoisomerism i n the five-membered r i n g i s  probably the reason f o r variable melting points being reported f o r  l,3j2,4j5,6-tri-0-benzylidene-D-glucitol (26,27).  - 17 -  - 18 C.  STEREOCHEMISTRY OF FUSED RING ACETALS. Fused b i - and t r i - c y c l i c rings are quite common i n acetals  of higher polyhydric alcohols. two  The most common fusion i s with  six-membered r i n g s , however, examples of s i x and seven  membered fused rings are known. Fusion of two m-dioxane rings as found i n  1,3,2,4-  and  2»4j3,5-diaeetals of hexitols w i l l give either a trans (XXI) or c i s (XXII) r i n g junction.  These r i n g fusions w i l l be analogous  with either c i s or trans d e c a l i n . Trans decalin has a r i g i d conformation with sharply defined a x i a l and equatorial p o s i t i o n s . I t would be expected that a fused trans b i c y c l i c m-dioxane r i n g system having both residues R-j_ and R would be a favorable conformation.  2  equatorial (XXIII)  Thus i f di-O-benzylidene  a l l i t o l has a 2,4j3»5-acetal r i n g structure i t should exist i n a stable symmetrical configuration. Trans fused b i c y c l i c acetals having one residue equatorial should be s l i g h t l y l e s s favorable.  An example of such a conforma-  t i o n i s l,3j2,4-D,L-ribitol (XXIV). Trans fused b i c y c l i c acetals having an a x i a l residue w i l l be l e s s stable. 2,4-diacetal  Evidence of t h i s i s the f a i l u r e t o i s o l a t e the 1,3; of mannitol or the 3,5j4,6-diacetal o f g l u c i t o l .  Trans fused b i c y c l i c acetals having both residues a x i a l would be expected t o be extremely unstable and are probably not formed since under these conditions, more stable a c e t a l rings could be produced.  - 19 Fused six-membered b i c y c l i c acetals with a c i s r i n g junction can produce two possible conformations (XXV) and (XXVT). the  (XXV) i s  "O-inside" conformation while (XXVI) i s the "H-inside" confor-  mation.  Evidence indicates that the 0-inside conformation i s the  more favorable as the repulsive forces caused by the close approach of the four endg hydrogen atoms i n the H-inside conformation appears quite unfavorable.  The p o s s i b i l i t y of an i n s i d e a x i a l substituent  can be dismissed as i t would be extremely unfavorable compared t o other conformations. Ill,  STEREOCHEMISTRY OF KNOWN O-BENZYLIDENE ACETALS OF HEXITOLS. Ten possible stereoisomeric hexitols can exist and a l l have  been synthesized. CIHgOH  H 0H 2  ALLITOL CH OH 2  HO-C-H HO-C-H H-C-OH H-C-OH  6H OH 2  D-MANNTTOL  A.  H-C-OH H-C-OH H-C-OH CHgOH D-TALITOL (D-ALTRITOL) CHgOH  2  9HgOH  2  H-C-OH HO-C-H HO-C-H CRjOH  CH 0H H-C-OH H0-C-H HO-C-H HO-C-H CH 0H  CH 0H H-C-OH HO-C-H H-C-OH H-C-OH CH 0H  L-TALITOL (L-ALTRITOL)  SORBITOL (D-GLUCITOL)  2  2  L-GLUCITOL  H 0H  H 0H  2  2  H-C-OH H-C-OH HO-C-H HO-C-H  JH OH 2  L-MANNITOL  D-3DIT0L  L-IDITOL  DULCITOL (GALACTITOL)  O-BENZYLIDENE ACETALS OF SORBITOL. In 1935 Vargha (28) i s o l a t e d a mono-O-benzylidene acetal of  s o r b i t o l which was i d e n t i f i e d as the 2,/^derivative.  Wolfe, Hann  and Hudson (29) i n 1942 i s o l a t e d a di-O-benzylidene derivative which they i d e n t i f i e d only as a 1,2,3,4-O-benzylidene a c e t a l .  1IIAXX  MXX  T7TXX  AXX  - .02 ~  - 21 Angyal and Lawler (26) i n 1944 c a r e f u l l y hydrolysed t h i s a c e t a l and i s o l a t e d a mono-O-benzylidene acetal i d e n t i c a l t o Vargha's, thus showing the di-O-benzylidene a c e t a l t o be l , 3 j 2 , 4 - d i - 0 - b e n z y l i d e n e sorbitol.  In a similar manner they obtained an i d e n t i c a l di-O-  benzylidene a c e t a l from controlled hydrolysis of a tri-G-benzylidene sorbitol.  Variations f o r the melting point of t h i s compound have 0  0  been reported with values ranging from 191 C t o 204 C.  A 4,6-0-  benzylidene derivative has also been synthesized but from the reduction of 4»6-0-benzylidene-D-glucose  so i t cannot be stated  that t h i s i s a more favorable configuration of mono-O-benzylidene sorbitol (30). The mono-O-benzylidene s o r b i t o l i d e n t i f i e d as a 2,4-derivative should possess a very stable conformation (XXVTI) having a ^ -C r i n g with both residues equatorial and an a x i a l hydroxyl group i n a position t o introjmolecularly hydrogen bond t o the r i n g oxygens. The l,3j2,4-0-benzylidene  s o r b i t o l w i l l be a fused r i n g  d i a c e t a l with c i s r i n g junction and should possess the preferred  of 0-inside conformation having the residueAC^ and  equatorial (XXVIII).  l , 3 ; 2 , 4 j 5 , 6 - ^ r i - 0 - b e n z y l i d e n e s o r b i t o l should exist i n a s i m i l a r conformation t o that of l , 3 j 2 , 4 - d i - 0 - b e n z y l i d e n e s o r b i t o l  that e x c e p t i t w i l l have a five-membered a c e t a l r i n g i n an equatorial A  p o s i t i o n t o the fused c i s d i a c e t a l rings (XXIX), As mentioned previously, the p o s s i b i l i t y of isomerism at the a c e t a l carbon atom of the five-membered r i n g may account f o r the v a r i a t i o n i n reported melting point of the tri-O^benzylidene a c e t a l .  - 22 B.  O-BENZILLDENE ACETALS OF MANNITOL. Direct condensation of mannitol with benzaldehyde y i e l d s  a tri-O-benzylidene a c e t a l .  Tri-O-benzylidene-D-mannitol was  f i r s t synthesized i n 1888 by Meunier (31) and t h i s was the f i r s t reported synthesis of an O-benzylidene a c e t a l .  The analysis  of Meunier's a c e t a l indicated that the t r i a c e t a l was contaminated with a d i a c e t a l and l a t e r workers have reported a higher point  (32,33).  melting  The structure of tri-O-benzylidene mannitol has  not as yet been elucidated but tri-O-methylene-D-mannitol i s known to possess a  1,3;2,5;4,6-  structure which i s also the probable  structure f o r the tri-O-benzylidene a c e t a l .  This would consist  of two six-membered rings fused trans-anti-trans t o a sevenmembered r i n g (XXX),  The trans-anti-trans configuration i s known  t o be a stable structure with three cyclohexane r i n g s .  5,6-  or  1,2J3,5J4,6-  A  1,3J2,4J  structure (XXXI) would lead t o a conformation  having a five-membered a c e t a l r i n g a x i a l i n a fused b i c y c l i c s i x membered a c e t a l r i n g system with a trans r i n g junction which i s not expected t o be favorable.  Similarly a  l,2;3,4j5,6-  structure  would not be expected t o be favorable as six-membered rings generally take precedence over five-membered rings when both are p o s s i b l e . C.  O-BENZILIDENE ACETALS OF TALITOL. Direct condensation of benzaldehyde and t a l i t o l y i e l d s a  tri-O-benzylidene a c e t a l .  E.Fischer i n 1894 (34) f i r s t  synthesized  a tri-O-benzylidene a c e t a l of D - t a l i t o l but was unable t o obtain a product having a sharp melting point a f t e r several r e c r y s t a l l i x a t i o n s . Lobry de Bruyn and Alberda van Ekenstein i n 1899 (35) and Bertrand  - iz -  - 24 and Bruneau (36)  i n 1908  also synthesized the t r i a c e t a l and  obtained a melting point of 210°C.  No attempt has as yet been  made t o determine the structure of t h i s compound.  The most  probable structure appears to be the l,2j3,5j4,6-0-benzylidene a c e t a l (XXXII) which w i l l consist of two fused six-membered rings with a trans r i n g junction and a five-membered acetal r i n g i n an equatorial p o s i t i o n .  I f t h i s i s the conformation then possible  isomerism exists at the a c e t a l carbon atom of the five-membered ring.  Another possible structure would be l,3}2,5j4,6-G-benzylidene  t a l i t o l (XXXIII).  This structure would have two  six-membered rings  fused t o a seven-membered r i n g with both a c i s and a trans r i n g junction. D.  O-BENZYLIDENE ACETALS OF IDITOL. D- and L - i d i t o l have both been reported t o form a t r i - O -  benzylidene acetal when condensed with benzaldehyde i n the presence of either hydrochloric or s u l f u r i c a c i d . a c e t a l i s not known.  The  structure of t h i s  A di-O-benzylidene a c e t a l has also been pre-  pared and has been found to be the major product i n the condensation of L - i d i t o l with benzaldehyde (37).  The d i a c e t a l was  shown t o have  the 2 , 3 , 4 , 5 - structure and thus undoubtedly i s 2,4j3»5~di-0-benzylidene iditol.  This molecule would have two fused six-membered rings with  a c i s r i n g junction and equatorial residues (XXXIV).  I t i s of  i n t e r e s t t o compare the conformation of t h i s a c e t a l with a proposed l,3j4,6-di-0-benzylidene i d i t o l (XXXV) which should also be a stable structure, being s i m i l a r t o the stable conformation of the benzylidene a c e t a l of d u l c i t o l .  di-O-  Such a conformation would have two  - 25 separate six-membered rings with an equatorial-equatorial r i n g junction and with a x i a l hydroxyl groups capable of intramolecularly hydrogen bonding with the r i n g oxygens.  The preference f o r the  2 , 4 , 3 , 5 - structure seems t o indicate that fused rings are  favored  over i s o l a t e d r i n g s . The tri-O-benzylidene  i d i t o l w i l l probably have either the  I , 3 j 2 , 4 ; 5 , 6 - or the 1,3J2,5J4,6- configuration.  A 1,3;2,4}5,6-  configuration would have as the most favorable conformation two fused six-membered r i n g s , O-inside conformation, c i s r i n g junction and an equatorial five-membered r i n g (XXXVI). A l , 3 j 2 , 5 ; 4 , 6 - structure (XXXVII) would consist of  two  six-membered rings fused c i s - a n t i - c i s t o a seven_membered r i n g . E.  O-BENZYLIDENE ACETALS OF DUICITOL. Direct condensation of d u l c i t o l with benzaldehyde i n the  presence of a c i d i c c a t a l y s t s y i e l d s a di-O-benzylidene a c e t a l (38).  There has not been any reported synthesis of the t r i - O -  benzylidene d u l c i t o l , although a a c e t a l has been reported  (39).  tri-O-(o-nitrobenzylidene) The di-O-benzylidene d u l c i t o l  has the 1,3;4,6~ structure of which D. Livingstone  (40)  has made  a conformational study and predicted the most stable conformation t o be (XXXVIII).  This conformation, as mentioned when discussing  the di-O-benzylidene acetals of i d i t o l , should be quite having two i s o l a t e d six-membered rings with an  favorable  equatorial-equatorial  trans r i n g junction and also having a x i a l hydroxyl groups capable of intramolecularly hydrogen bonding to the r i n g oxygens. Livingstone confirmed the reported f a i l u r e of d u l c i t o l t o form  - 27 a tri-O-benzylidene  derivative under f o r c i n g conditions with  a v a r i e t y of c a t a l y s t s and recorded the u l t r a v i o l e t and i n f r a red spectra of the l,4;3,6-di-0-benzylidene d u l c i t o l . F.  O-BENZYLIDENE ACETALS OF ALLITOL. Direct condensation of a l l i t o l with benzaldehyde i n the  presence of concentrated  hydrochloric a c i d , as i n the case of  d u l c i t o l , leads t o the formation a tri-O-benzylidene a c e t a l (41).  of a di-O-benzylidene and not A conformational  study of  t h i s compound was made i n the present research as i t was thought that the preferred structure was p o s s i b l y the 1,3j4,6- since t h i s could lead t o a conformation analagous t o that of l,3j4,6di-O-benzylidene d u l c i t o l (XXXVTII) but having equatorial hydroxyl groups.  The other p o s s i b i l i t y i s the 2,4;3,5- structure  which i s predicted from the established r u l e s f o r a c e t a l formation. IV.  HYDROLYSIS OF CYCUC-O-BEMZYIJDENE ACETALS. The hydrolysis of c y c l i c O-benzylidene acetals i s believed  t o proceed v i a the mechanism outlined i n FIGURE 1. Few workers have been concerned with rate  determination  studies of the hydrolysis of these acetals and i n most cases f o r c i n g conditions are employed f o r rapid and complete hydrolysis. With hot N-hydrochloric within one hour.  acid the hydrolysis i s u s u a l l y complete  The a c i d s t a b i l i t y of such acetals w i l l depend  upon such factors as: 1.  Size and p o s i t i o n of r i n g .  2.  S o l u b i l i t y of the a c e t a l and hydrolysed products i n the a c i d i c medium.  ~'2* MECHA"IS! CF CYCLIC ACTUAL HYDROLYSIS T  CHOH\,  HPh + H<  pKPh  RH(  RHG-O-H (qHOH)  n  pHPh  SLOW  (CHOH)  n  RH(  RHG-O-CHPh  RHC—OH  RHG—O-H-  (dHOH)  H- H 0  n  2  O H OH)  n  '  RHG-0=CHPh  RHG-O—CHPh  RHC—OH  RHG-OH  OOH)„ RHb-  (<^HOH)  H HPh  n  RHfe-O-H  FIGURF 1  :,. f  K  PhCHO  - 29 3.  V o l a t i l i t y of the carbonyl compound.  From thermodynamic considerations the difference i n a c t i v a t i o n energies necessary f o r the synthesis of a c e t a l rings of different types w i l l be the energy required to d i s t o r t the zig-zag carbon chain which controls the energy differences i n the products.  Acetal rings which are most r e a d i l y formed  should be those that are most stable to hydrolysis.  TABLE I  shows c y c l i c acetals which have been subjected to graded a c i d i c hydrolysis: TABLE I GRADED ACIDIC HYDROLYSIS OF ACETALS Order of Ring S c i s s i o n  Parent Acetal  1st  2nd  3rd  1,3 J 2,4;5,6-tri-O-benzylidene s o r b i t o l  o(  (26)  1,3j2,4j5,6-tri-O-methylene s o r b i t o l  *<  (42)  l,3;2,4~di-0-ethylidene  sorbitol  l,3;2,5j4,6-tri-O-ethylidene  mannitol  e  e  f<or These data indicate that p f t h e benzylidene,  ethylidene  and methylene acetals of the two h e x i t o l s the order of r i n g hydrolysis i s cK ,  ^> ^  ^5-C  which i s i n the order of  decreased r i n g s t a b i l i t y . The only studies on rates of hydrolysis of c y c l i c O-benzylidene acetals appear to be those r e c e n t l y reported Brimacombe, Foster and Haines (45) of 1,2-  who  by  followed the hydrolysis  and 1,3-0-methylene g l y c e r o l and c i s - and trans- 1,3-0-  benzylidene g l y c e r o l . These workers hydrolysed a 1% solution  (43) (44)  - 30 of 1,2-  and 1,3-0-methylene g l y c e r o l i n N-sulfuric acid at  o 89 C and observed t i values of 42 and 129  minutes respectiv-  ely, i n d i c a t i n g the preferred s t a b i l i t y of the six-membered over the five-membered r i n g .  They also observed that both  c i s - and trans-1,3-0-benzylidene g l y c e r o l hydrolysed extremely r a p i d l y haviag t i values of 17 minutes i n 0.02N s u l f u r i c a c i d  o at 35 C.  The 1,3-0-methylene and 1,3-O-benzylidene acetals  appear to r e f l e c t extremes of acid l a b i l i t y and s t a b i l i t y among cyclic acetals. The hydrolysis was  followed at time i n t e r v a l s by n e u t r a l i z -  ing aliquot samples of the reaction mixture, o x i d i z i n g with sodium meta-periodate and determining periodate  consumption  by addition of standard arsenite and back t i t r a t i n g with iodine. V. A.  SPECTRA OF O-BENZYLIDENE ACETALS. INFRARED SPECTRA (21)  As mentioned previously, Brimacombe, Foster, et,/ a l . have examined the i n f r a r e d spectra i n carbon t e t r a c h l o r i d e solution of several c y c l i c acetals of g l y c e r o l . were i n solutions l e s s than  0.005M and  These spectra  were only concerned  with the hydroxyl stretching frequency region. I s b e l l , Stewart and Tipson (46)  have examined the i n f r a r e d  spectra of a series of 1-methoxyethylidene and isopropylidene acetals to determine i f i t was possible to unequivocally the 1,3-dioxane r i n g .  r  cyclic  detect  They also reviewed r e l a t e d spectra obtained  by other workers to determine i f other correlations existed. They found that the absorption bands were not highly c h a r a c t e r i s t i c  - 31 of the type of r i n g present and that there were no r e a d i l y distinguishable bands suitable f o r the assignment of r i n g structure or f o r the study of r i n g conformations i n these compounds. TABLE II l i s t s the absorption bands assigned to the o tiler dioxane r i n g by I s b e l l ety a l . and related workers.  1,3-  TABLE I I ABSORPTION BANDS ASSIGNED TO 1,3-DIOXANE RING WAVENUMBER (CM ) OF SPECTRAL REGION OF ABSORPTION BANDS -1  B  A  C  D  1190-1151  1161-1123  1105-1077  1052-  1190-1158  1143-1124  1098-1063  1056-1038  1173-1151  1151-1132  1105-1077  1053-  DOUBLE F BETWEEN 1160 and 1120  1181-1153  B.  NMR  1126-1104  1038  1038  DOUBIET BETWEEN 111C and 1050 1093-1070  1055-1029-  SPECTRA  Foster e t / a l . (50) have reported the NMR hydroxy-l,3-dioxane and some r e l a t e d compounds.  spectra of 5These spectra  o were obtained at 34 C from ca. M solutions of these compounds i n chloroform with tetramethylsilane as the i n t e r n a l reference. They published the spectra of c i s - (XXXIX) and t r a n s - (XL) 5-acetoxy-2-phenyl-l,3-dioxane.  With the trans a c e t a l the  a x i a l and equatorial protons on C/^ and C5 are not equivalent and were found to couple together and with H5 giving a complex  - 32 pattern.  With the c i s a c e t a l no coupling was  observed and a  single broad peak was formed from the protons on  and  which indicated that these p a i r s had l o s t t h e i r a x i a l - e q u a t o r i a l character and that the c i s form r a p i d l y interconverts between n  two conformations.  No further NMR  acetals have been reported.  spectra of cyclic-O-benzylidene  The low s o l u b i l i t y of acetals of  higher polyhydric alcohols w i l l make i t d i f f i c u l t to obtain solutions of s u f f i c i e n t concentration to obtain t h e i r spectrum with present day equipment.  NMR  - 33 RESULTS I.  AND  DISCUSSION  THE STRUCTURE OF DI-O-BENZILLDENE ALLITOL. As previously mentioned, conformational analysis indicated  two probable structures f o r di-O-benzylidene a l l i t o l . structures were l,3;4,6-di-0-benzylidene 3,5-di-O-benzylidene  These  a l l i t o l (XLII) and  2,4j  a l l i t o l (XLI) and no decision between them  could be made on conformational grounds alone. FIGURE 2 indicates the steps followed i n the s t r u c t u r a l elucidation.  Hydrolysis of 'methylated 2,4J3,5-di-O-benzylidene  a l l i t o l (XLIII) would y i e l d l,6-di-0-methyl a l l i t o l (XLIV) while hydrolysis of methylated l,3j4,6-di-0-benzylidene a l l i t o l would y i e l d the 2,5-di-O-methyl isomer (XLV).  1,6-Di-O-methyl a l l i t o l  (XLIV) has four v i c i n a l hydroxyl groups while 2,5-di-O-m.ethyl a l l i t o l (XLV) has only two.  Since lead tetraacetate i s a selective  o x i d i s i n g agent f o r the cleavage of the carbon chain between p a i r s of v i c i n a l hydroxyl groups and one mole of lead tetraacetate i s consumed per p a i r of such groups then (XLIV) would consume three moles of o x i d i s i n g agent per mole while (XLV) would consume only one mole. Experimentally a maximum value of 3.05  moles of lead t e t r a -  acetate per mole of di-0-methyl a l l i t o l was consumed during 18 hours (FIGURE 3).  Since the conditions of methylation and hydro-  l y s i s were selected to r u l e out migration of either the  O-benzylidene  or methyl ether groups, t h i s result may be taken as proof of the 2,4J3,5-di-O-benzylidene a l l i t o l structure (XLI).  - 34 STRUCTURAL ELUCIDATION OF DI-O-BEHZYLIDEKE ALLITOL  XU7  3 Pb(OAc)  1 PbCOAc)  4  CHgOH 2 hhCHDCH CHO  4  2  JHJOO+J +  3  2 HCOOH FIGURE 5  MOLES  Pb(OAc)  4  CH-Q-METHYL ALLITOL O  CONSUMED u>  ireyy  2EXX  - 37  II.  -  INTRAMOLECULAR HYDROGEN BONDING. The examination of the i n f r a r e d spectra of 2 , 4 ; 3 , 5 - d i -  O-benzylidene a l l i t o l (XLI) and l , 3 j 4 , 6 - d i - 0 - b e n z y l i d e n e d u l c i t o l (XXXVIII) i n the region 3500 cm"  1  to 3700 cm  -1  was  conducted to determine the type and extent of intEamolecular hydrogen bonding e x i s t i n g i n these compounds.  The following  solutions i n carbon t e t r a c h l o r i d e were prepared: 3 . 1 x 10 M _A  -4 cyclohexanol, 2 . 0 x 10  M 2,4j3,5-di-0-benzylidene  allitol  -4 and 1.0 x 10  M l,3j4,6-di-0-benzylidene dulcitol.  From the  plot of the difference i n percentage transmittance of solution and solvent against wave length the hydroxyl stretching absorpt i o n frequency of these compounds was determined (FIGURE 4 ) . The following absorption maxima were determined:  cyclohexanol  ( p = 3 6 2 4 ± 2 cm" ), 2 , 4 j 3 , 5 - d i - 0 - b e n z y l i d e n e a l l i t o l ( p = 3 6 0 3 ± 2 cm" ), 1  l>3j4,6-di-0-benzylidene d u l c i t o l ( P=3579  1  ±  2 cm ). -1  The appearance of single absorption peaks f o r both 2 , 4 j 3 , 5 di-0-benzylidene a l l i t o l and l , 3 j 4 , 6 - d i - 0 - b e n z y l i d e n e d u l c i t o l indicated unique conformations f o r these compounds and the f r e quencies of maximum absorption indicated that r e l a t i v e l y strong introm&lecular hydrogen bonds are present i n both compounds. III. EHE PREFERRED CONFORMATIONS OF DI-O^BENZYLIDENE ACETALS OF THE HEXIT0LS. From the known structures of the di-O-benzylidene acetals of a l l i t o l , d u l c i t o l and i d i t o l i t appears that several factors operate t o favor one structure and conformation over others which have approximately equal non-bonded i n t e r a c t i o n s . appear to include:  These factors  - 38 1.  Preference f o r 6- over 5-membered r i n g s .  2.  Preference f o r a symmetrical structure,  3.  Preference f o r fused rings over i s o l a t e d r i n g s .  4.  Enhancement of s t a b i l i t y of a conformation by i n t r a molecular hydrogen bonds.  The conformation of 2,4J3,5-di-O-benzylidene  allitol  (XLI) appears t o be very favorable, being symmetrical with a trans-fused 6-membered r i n g system and equatorial hydroxymethyl groups which are intramolecularly hydrogen bonded t o the oxygen atom of the meta-dioxane rings (XLIa or b ) . Examination of molecular models indicated that  hydrogen  bonding could occur betwean the primary hydroxyl groups and the oxygen atom of the same r i n g (XLIa) or the oxygen atom of the adjacent r i n g (XLIb).  In the former case a 5-membered hydrogen  bonded r i n g resulted and i n the l a t t e r case a 6-membered hydrogen bonded r i n g .  Hydrogen bond lengths calculated from accepted  bond distances and bond angles (51) agreed with those measured d i r e c t l y on Cenco-Pftersen scale models and were r(OH*"0) = 1.80A  f o r conformation (XLIa) and r(OH*•*0)= 1.35A f o r conforma-  t i o n (XLIb). The i n f r a r e d spectral data compiled by Brimacombe e t / a l . (21) andAKuhn (20) (TABLE I I I ) indicates that both 6- and 5membered r i n g hydrogen bonds of t h i s type occur.  Of i n t e r e s t  i s the observation that 2-hydroxymethyl-tetrahydropyran and 2-hydroxymethyl-tetrahydrofuran exist i n completely hydrogen bonded 5-membered r i n g conformations while the 1,2-O-acetals of g l y c e r o l which can take up similar 5-membered r i n g hydrogen  bonded conformations a c t u a l l y exist i n both free and bonded forms.  The hydroxyl stretching frequencies of  2-hydroxymethyl-  tetrahydropyran and 2-hydroxymethyl-tetrahydrofuran and the bonded conformations of the 1,2-0-acetals of glycerol range  -1 from 3597 cm  -1 t o 3603 cm  .  The value observed f o r 2,4;3>5-  di-O-benzylidene a l l i t o l , (3603 cm ) -1  middle of t h i s range.  f a l l s p r e c i s e l y i n the  No data are at present available f o r  3-hydroxymethyl-tetrahydropyran which would be the model f o r the 6-membered hydrogen bonded conformation (XLIb). We are therefore unable t o make a f i n a l assignment of either (XLIa) or (XLIb) as the more preferred conformation f o r allitol.  2,4;3>5-di-0-benzylidene  The predicted conformation f o r l,3j4»6-di-0-benzylidene  a l l i t o l (XLII) shows that i t also could be s t a b i l i z e d by j n t r a molecular hydrogen bonding.  In t h i s case a 6-membered hydrogen  bonded r i n g with the hydroxyl of one r i n g bonding t o the oxygen atom of the other r i n g would occur.  I t thus appears that although  both conformations (XLI) and (XLII) are symmetrical and can both be s t a b i l i z e d by intramolecular hydrogen bonding the fused b i c y c l i c r i n g system i s a more stable structure than two separate r i n g s . The known conformation of l , 3 j 4 , 6 - d i - 0 - b e n z y l i d e n e d u l c i t o l (XXXVIII) i s an example where a structure with two separate rings i s favored over one with two fused rings (XLIII).  The  2,4,3,5-di-  O-benzylidene d u l c i t o l structure (XLIII) i s not favored since i t would have two a x i a l hydroxymethyl groups.  Furthermore, the  observed hydroxyl stretching frequency of 3579 cm"  1  for  l , 3 j 4 , 6 - d i - 0 - b e n z y l i d e n e d u l c i t o l indicates a strong intramolecular  - 42 hydrogen bond which s t a b i l i z e s t h i s conformation. Calculations show r(OH* 0) = 2.42A i n (XXXVXLI). ,#  The reason that t h i s 5-  membered r i n g intramolecular hydrogen bond i s unusually strong may possibly be due t o i t s bifurcated nature. It should be pointed out when discussing intramolecular hydrogen bonds that a l i n e a r arrangement of (0H««»0) which has been shown t o be the e n e r g e t i c a l l y favored arrangement i n c r y s t a l s i s undoubtedly not obtainedj i t would be formed only with considerable s t r a i n on the conformation. A compromising non-linear minimum energy configuration probably occurs (52). For  di-O-benzylidene i d i t o l the occurrence of the 2,4;3»5-  structure (XXXIV) rather than the 1,3;4>6- (XXXV) appears to place more importance on the preference f o r fused b i c y c l i c rings than on s t a b i l i z a t i o n by intramolecular hydrogen bonding, f o r the  l,3;4,6-di-0-benzylidene i d i t o l should possess a favorable  bifurcated intramolecular hydrogen bond similar to that i n l,3}4,6-di-0-benzylidene d u l c i t o l .  However, the greater symmetry  of conformation (XXXIV) compared t o (XXXV) may also be a contributing factor. IV.  SYNTHESIS OF 2,5-DI-O-BENZOYL-l,4;3,6-DIANHYDRO-L-IDIT0L. The conversion of  2,5-di-0-(£-toluenesulphonyl)-l,4;3,6-  dianhydro-D-mannitol t o 2,5-di-0-benzoyl-l,4j3>6-dianhydro-Li d i t o l i s a second example of the recently reported (53>54)  2 SJ\J  displacement of a tosyloxy group by a benzoate i o n . Reist  and Baker (54)  successfully displaced with inversion both  tosyloxy groups of  2,3-di-0-benzoyl-4,6-di-0-(£-toluenesulphonyl)  -e/v-D-galactopyranoside by benzoate ion employing sodium benzoate  - 43 i n N,N-dimethyl forroamide.  Since the tosyloxy group on carbon  4 was i n an a x i a l position t h i s reaction i s quite unusual.  Few  nucleophiles are powerful enough to displace the tosyloxy groups without neighbouring group p a r t i c i p a t i o n .  Sodium iodide gener-  a l l y does not react with i s o l a t e d secondary tosylates and sodium hydroxide or sodium methoxide upon reaction hydrolyses the t o s y l a t e with retention of configuration  (55).  The conversion of 2,5-di-0-(pytoluenesulphonyl)-l,4$3»6dianhydro-D-mannitol  (XLIV) t o 2,5-di-0-benzoyl-l,4;3»6-dian-  h y d r o - L - i d i t o l (XLV) was probably a p a r t i c u l a r l y favorable case since two endo tosyloxy groups were replaced with inversion by benzoyloxy groups which assumed exo p o s i t i o n s .  This i s i n  agreement with the observation that the tosyloxy groups of 2,5-di-0-(p-toluenesulphonyl)-l,4j3» 6-dianhydro-D-mannitol r e a d i l y replaceable with sodium iodide  V.  are  (56).  ATTEMPTED SYNTHESIS OF 2,5-DI-0-BENZ0Y L - l , 3 J 4 ,6-DI-0BENZYLIDENE ALLITOL. The attempted replacement of the tosyloxy groups of  2,5-di-0-tosyl-l,3j4,6-di-0-benzylidene d u l c i t o l (XLVT) to form 2,5-di-0-benzoyl-l,3j4,6-di-O-benzylidene a l l i t o l  (XLVTI)  would be expected to be a favorable replacement as the a x i a l tosyloxy groups would be replaced by equatorial benzoyl groups. However, on the basis of several experimental attempts t h i s replacement does not appear t o take place. The importance of t h i s reaction i s that i f t h i s replacement did occur the configuration at carbon atoms 2 and 5 would be  -  -  - 45 inverted and hence t h i s synthesis would provide a method of preparing VI.  the rare h e x i t o l , a l l i t o l , from the more common d u l c i t o l . HYDROLYSIS OF O-BENZYLIDENE ACETALS. The hydrolysis of the several c y c l i c O-benzylidene acetals  (TABLE IV) was followed spectophotometrically. TABLE IV. HYDROLYSIS OF O-BENZILIDENE ACETALS O-BENZYLIDENE ACETAL  (MIN) OBSERVED MOLES  tl  12  Tri-O-benzylidene-D-mannitol Tri-O-b en zyliden e-D-t a l i t o l  BENZY LIDENE GROUP PER MOLE  2.97 i . 0 3  <3  2.93 i .03  5  2.01 +.02  1,6-Di-O-methyl-2,4} 3,5-di-0-benzylidene allitol  <3  1.95 t .02  l,3;4,6-di-0-benzylidene d u l c i t o l  <3  2.04 *- .02  2,4j3,5-Di-0-benzylidene  allitol  2,5-Di-O-met h y l - 1 , 3 J 4,6-di-0-benzylidene dulcitol  6.5  1.81* .03  2,5-Di-O-benzyl-l,3;4,6-di-O-benzylidene dulcitol  8  1.85 2 . 0 3  <3  1.04 i .01  8 .  3 .  Methyl-4,6-0-benzylidene- p  -D-glucopyranoside  Prepared i n t h i s laboratory by E. Premuzic ( 5 7 ) . Prepared by G. Creamer ( 5 8 ) . From the rate p l o t s (FIGURES 6 AND 7)> values of t i were calculated and also the number of moles of benzylidene group per mole of a c e t a l a f t e r complete hydrolysis. using a value of 1 0 , 2 0 0 i l 0 0 f o r £  This value was calculated  (FIGURE 5 ) .  - 46 Due to the high a c i d concentration (1.25M hydrochloric acid) the hydrolysis of these compounds was very rapid and the rates may be compared only q u a l i t a t i v e l y . The mono-O-benzylidene a c e t a l , methyl-4>6—0-benzylidene - >3 -D-glucopyranoside, appeared t o hydrolyse f a s t e s t while tri-O-benzylidene-D-mannitol was the slowest. Since the concentration of a l l of these  O-benzylidene  the sue. p<* a  acetals was approximately the same^and a l l poooooo 6-momborod aootal r i n g s , tho number of rings and the position and type of substituents attached should account f o r the differences i n hydrolysis rates. The presence of substituents i n the a c e t a l r i n g appears to decrease the ease of hydrolysis (e.g. larger t i values f o r 2,5-di-0-methyl-l,3j446-di-0-benzylidene  d u l c i t o l and 2 , 5 - d i - 0 -  benzyl-l,3j4,6-di-0-benzylidene d u l c i t o l than f o r 1 , 3 - 4 , 6 - d i - 0 benzylidene d u l c i t o l . 2,4j3,5-Di-0-benzylidene  a l l i t o l possessing two ^ -C-rings  as expected hydrolysed more slowly than l , 3 j 4 , 6 - d i - 0 - b e n z y l i d e n e d u l c i t o l which possesses two ^ - r i n g s . The reason f o r the rapid hydrolysis of tri-O-benzylideneD - t a l i t o l compared t o tri-O-benzylidene-D-mannitol does not appear t o be r e a d i l y explainable. As the purpose of t h i s portion of the research was t o develop a method f o r determination of the number of moles of benzylidene group per mole of h e x i t o l , the acid concentration employed was too high t o enable only p a r t i a l hydrolysis t o be  - 47 detected and to permit a good comparison of the acid s t a b i l i t y of each of the O-benzylidene a c e t a l s . It would be of i n t e r e s t to follow the hydrolysis of the tri-O-benzylidene  acetals at such an acid concentration  that  graded hydrolysis of the acetal rings could be exajriined.  FIGURE 5 -  CONCENTRATION OF BENZYLIDENE GROUPS VERSUS OPTICAL DENSITY OF CYCLIC 0-HEN7YLIDENE ACETALS.  *  O  A D  X +  SLOPE - 10,200  TRI-Q-BENZYLIDENE-D-MANNITOL BENZALDEHYDE 1.3.4.6-Dl-Q-BENZYLIDEHE DULCITOL 2,5-DI-Q-METHYL-l.3; 4.&-DI-Q-BENZYLIDENE 2.5-Df-Q-BENZYL-|,3-,4.6-DI-Q-BENZYLlDENE  DULCITOL DULCITOL  CONC. (PhCH) X 10" M/L 5  $  fe—-7-  — - t — i b -  IT  ife—ft  *r  -  -  Ai.JSN3Q IVDUdO  Q2-  0.1  TIME (MIN.) 10  20  30  40  K)  60  70  80  90  100  110  120  130  140  l£o  160 170  180  190 200  - 51 EXPEEIMENTAL I.  MATERIALS AND REAGENTS.  BENZAIDEHIDE. Reagent grade benzaldehyde was p u r i f i e d as recommended by Vogel (59), d i s t i l l e d under nitrogen at reduced pressure and stored i n the dark under nitrogen,  n ^ 1.5470 ( l i t . value n ^ 1.5463  (60) ). ALLITOL. The a l l i t o l sample was prepared i n t h i s laboratory by W. Bowering from D-ribose i n a previous research (61). recrystallized  I t was  from ethanol-water and melted at 148 C.  D-MANNITOL. Reagent grade D-mannitol, (Matheson, Coleman and B e l l Co.,) O  was r e c r y s t a l l i z e d ( l i t . value  0  from absolute ethanol, m.p. 165 - 165.5 C  166°C (62)).  TRI-O-BENZYLIDENE-D-T ALITOL. This compound was prepared i n a previous research (63) m.p. of  186.0^186.5°C  Analysis:  ( l i t . value  Calcd. f o r Found:  The infrared  210°C (35,36).  C27H26O6:  C,  72.63j  H,  5.87$  C,  71.97J  H,  5.82$  spectrum indicated no hydroxyl groups t o be present  and a chromatopiate run i n pyridine and developed with s u l f u r i c a c i d - n i t r i c a c i d spray reagent showed only one spot. CYCLOHEXANOL. Reagent grade cyclohexanol (Fisher S c i e n t i f i c Co.,) was d i s t i l l e d under reduced pressure and a middle f r a c t i o n  (b.p. 76.5 C)  - 52 22  was c o l l e c t e d ,  6  1.4649 ( l i t . value  *  22  1.4650 (60) ).  CARBON TETRACHLORIDE. A n a l y t i c a l reagent carbon t e t r a c h l o r i d e was d i s t i l l e d over  o b.p. 76.0 C  phosphorus pentoxide.  n  1 5 D  15 1.4631 ( l i t . value  1.46305 (60) ).  DI0XANE. Reagent grade dioxane ( B r i t i s h Drug Houses) was p u r i f i e d as recommended by Vogel (59) and stored over sodium i n a nitrogen  o  o  atmosphere (b.p. 100.5-101 C ) . ANHYDROUS PYRIDINE. Reagent grade pyridine was d i s t i l l e d from calcium hydride, b.p. 112.0°- 112.5°C METHYL IODIDE. Methyl iodide (Eastman Kodak Co.,) was dried over phosphorus pentoxide and the middle f r a c t i o n (b.p. 42.0 C) was c o l l e c t e d . POWDERED SODIUM. Freshly cut sodium was powdered following the procedure of Fieser (64)• The xylene was decanted o f f and the sodium suspension was stored i n dry dioxane. THIN LAYER CHROMATOGRAPHY. Thin layer chromatopiates were prepared on glass plates from a s l u r r y of s i l i c i c a c i d , plaster of p a r i s and water i n the proportions  (4:1:8) and dried overnight at 100°C as described by  A l l e n t o f f and Wright (65). II.  2,4j3,5-DI-0-BENZYLIDEIffi ALLITOL. Allitol  (0.246 g, 0.00135 mole) was dissolved i n 0.49 g  concentrated hydrochloric a c i d a f t e r mechanically shaking f o r  10  minutes.  Freshly d i s t i l l e d benzaldehyde  was then added dropwise with shaking.  (0.49 g, 0,0046  inole)  The solution became t u r -  partially bid  almost immediately and the contents of f l a s k formed a/| s o l i d  white mass a f t e r 2-3 minutes. for  The mixture was shaken vigorously  one hour and then placed i n a r e f r i g e r a t o r overnight.  The  crude a c e t a l was washed acid-free with i c e water and was further washed with ether followed by i c e water and dried overnight i n vacuo over phosphorus pentoxide.  92.7$  (0.448 g,  The crude product  y i e l d ) was r e c r y s t a l l i z e d from absolute ethanol.  235.0^236.5°C Analysis:  (Reported m.p.  Calcd. f o r  249-250°C (41) ).  C 0 22°6 H  m.p.  :  C  2  Found:  »  6 7  C,  *  0 2  J  67.19j  H  »  » -9$J  6  H,  3  6.07$.  A chromatopiate of the r e c r y s t a l l i z e d di-O-benzylidene a l l i t o l run  i n methanol and developed with sodium periodate-potassium  permanganate spray reagent showed one long, t h i n spot near the solvent f r o n t .  Another chromatoplate run i n chloroform showed  one spot near the o r i g i n ( R f ^ 0.15) spot just below (Rf -z-  and a trace of another  0.06).  The i n f r a r e d spectrum of the compound i s shown i n FIGURE 8. /  III.  l,6-DI-0-METHYL-2,4;3,5-DI-0-BMZYLIDENE ALLITOL. 2,4;3,5-Di-0-benzylidene a l l i t o l was methylated according to  the  procedure of Freudenberg (66).  (0.100  Di-O-benzylidene a l l i t o l  g) was dissolved with heating and s t i r r i n g i n  dioxane.  A large excess of powdered sodium ^(0.2  3.0  ml. of  g) was added  to the cooled solution which was then refluxed and magnetically  - 54 stirred.  In the f i r s t 10 minutes a powdery s o l i d appeared t o  form i n the f l a s k and on the surface of the sodium. hrs.  After 6  the contents of the f l a s k were evaporated under reduced  pressure to a yellowish residue containing f i n e l y divided metallic sodium.  Methyl iodide (4 ml.) was added and the mixture refluxed  and s t i r r e d f o r a further 6 hrs.  Evaporation gave a sodium-free  yellowish residue which was extracted 5 times with 8 ml. portions of hot benzene.  The f i l t e r e d extracts were combined and evaporated  to a white c r y s t a l l i n e residue which was dried overnight i n vacuo over phosphorus pentoxide.  The crude di-0-methyl-di-O-benzylidene  a l l i t o l (98$ average y i e l d ) was r e c r y s t a l l i z e d from absolute ethanol  o as c o l o r l e s s , needle-like c r y s t a l s , Analysis:  Calcd. f o r C 2H26°6 2  :  c  m.p.  202.0-203.5 C.  » 6S.37; C, 68.52;  Found:  o  H, 6.78;  H, 6.90;  OCR^,  15.57$.  OCH3, 16.04$.  The i n f r a r e d spectrum showed no hydroxyl stretching absorption (FIGURE 8 ) .  A chromatoplate showed only one spot when run i n  chloroform and developed with potassium permanganate-sodium p e r i o date spray reagent. IV.  l,6-DI-0-METHYL ALLITOL. l,6-Di-0-methyl-2,4;3,5-di-0-benzylidene a l l i t o l , 0.100  g,  was dissolved i n dioxane, 4.0 ml., and N hydrochloric a c i d , 1.0 was added.  ml.,  The solution was refluxed f o r 3 hrs., the hydrochloric  acid was neutralized with excess s i l v e r carbonate, 10 ml. dioxane was added and the hot solution was f i l t e r e d through a C e l i t e pad on a sintered glass funnel.  The f i l t r a t e was evaporated t o a  -56syrup which c r y s t a l l i z e d on dpying i n vacuo over phosphorus pentoxide.  The crude product was r e c r y s t a l l i z e d from benzene  o  0  as c o l o r l e s s p l a t e - l i k e c r y s t a l s having a m.p. Analysis:  Calcd. f o r  CgH 0 : 18  6  Found:  of  103.0-104.5 C.  C,  45.71J  H,  8.63;  OCH^,  29.53$  C,  45.02;  H,  8.25;  OCR^,  29.60$  Paper chromatography of the compound i n butanol-acetic a c i d -  (4:1:5) showed one spot corresponding i n R.^ value t o that  water  of other di-0-methyl hexitols when sprayed with potassium permanganate-sodium periodate reagent. V.  LEAD TETRAACETATE OXIDATION OF l,6-DI-0-METHYL ALLITOL. 1,6-Di-O-methyl a l l i t o l ,  ml. of a  0.0100 g, was dissolved i n 25.0  0.0738 M solution of lead tetraacetate i n g l a c i a l acetic  a c i d (mole r a t i o of lead tetraacetate to di-0-methyl a l l i t o l  3.88:1). The reaction mixture was kept at 25.0±1°C i n a constant temperature bath and 2.00  ml. aliquots were withdrawn at i n t e r -  v a l s , excess potassium iodide solution was added, and the l i b e r ated iodine was t i t r a t e d with standard sodium t h i o s u l f a t e solution with starch i n d i c a t o r . VI.  The r e s u l t s are shown i n FIGURE 3.  INFRARED SPECTROSCOPY. The i n f r a r e d spectra were measured i n the  region on a Perkin-Elmer No. 112-G i n a 9.0  3500 to 3700 cm""  single beam spectrophotometer  cm. pyrex c e l l with sodium chloride windows. The con-  centrations of the solutions were s u f f i c i e n t l y low (1.0 to 3.1 (20,  1  x  10"^  x 10 M) that intramolecular hydrogen bonding was excluded _4  21).  Complete spectra of the s o l i d compounds were run on  - 57 the PerkLn-Elmer No. 21 double-beam spectrophotometer i n potassium bromide windows. VII.  2,5-DI-0-BENZ0YL-l,4j3,6-DIANHYDR0-I^IDrr0L. A sample of 2,5-di-0-(£-toluenesulphonyl)-l 4;3#6-dianhydro>  D-mannitol (l.OOg, 0.00220 mole) previously prepared i n t h i s laboratory by M. Jackson (67) was dissolved i n 30 ml. of N,Ndimethyl formamide.  The solution was magnetically s t i r r e d and  heated t o just below r e f l u x temperature. Sodium benzoate (0.793g» 0.00551 mole) was slowly added t o the solution over a period of one hour.  The sodium benzoate slowly dissolved and  a f t e r a few minutes the solution became l i g h t yellow i n c o l o r . After 3 hrs. the solution was cooled to room temperature, whereupon a white, flocculent p r e c i p i t a t e s e t t l e d out of the solution. D i s t i l l e d water was added dropwise to the reaction mixture u n t i l a l l of the p r e c i p i t a t e had dissolved  (5 ml.). Further addition  of water (30 ml.) produced a colorless c r y s t a l l i n e p r e c i p i t a t e which was washed with water and dried i n vacuo overnight over phosphorus pentoxide.  The crude product, 0.718g (92.3$), was  r e c r y s t a l l i z e d from absolute ethanol and melted at 109-110°C. A mixed melting with an authentic sample of 2,5-di-0-benzoyll,4}3»6-dianhydro-L-iditol was 109-110°C.  The two samples gave  indistinguishable i n f r a r e d spectra.  VIII.  ATTEMPTED SYNTHESIS OF BENZYLIDENE ALLITOL.  2,5-DI-0-BENZ0YL-l,3J4,6-DI-0-  2, 5-Di-O-(p_-toluenesulphonyl)-l,3J4, 6-di-O-benzylidene d u l c i t o l was prepared according to the procedure of Hann, HaskLns and  - 58 Hudson ( 6 8 ) . Di-O-benzylidene d u l c i t o l ( l . 0 0 7 g ) prepared by E.  Premuzic i n t h i s laboratory'(57) was dissolved i n 10 ml. of  anhydrous pyridine and 1.3g of p_-toluenesulfonyl chloride was slowly added t o the ice-cooled solution.  The p-toluenesulfonyl  chloride r e a d i l y dissolved with shaking.  Upon standing overnight  c r y s t a l s had deposited on the sides of the reaction f l a s k . D i s t i l l e d water (25 ml.) was added dropwise t o the f l a s k .  After  approximately 5 ml. of water had been added a white powdery p r e c i p i t a t e appeared.  The contents of the f l a s k were poured  into 200 ml. of d i s t i l l e d water and vigorously s t i r r e d . The product was recovered on a f i l t e r and dried i n vacuo over phosphorus pentoxide, (1.704g, 91.3$ y i e l d ) .  The crude 2,5-di-O-  p_-toluenesulfonyl)-l,3j4,6-di-0-benzylidene d u l c i t o l was r e c r y s t a l l i z e d from 70 parts of pyridine; m.p. 213-215 C (decomposition). L i t . value 215°C (decomposition).(68). 2,5-Di-0- (p_-t oluenesulf onyl ) - l ,3 J 4 , 6-di-0-benzylidene d u l c i t o l (l.OOg) was dissolved i n 30 ml. of N,N-dimethyl formamide, heated t o just below r e f l u x temperature and magnetically stirred.  The compound dissolved a f t e r 20 minutes heating.  Sodium benzoate (0.540g, mole r a t i o of sodium benzoate to 2 , 5 - d i 0-(p-toluenesulfonyl)-l,3j4,6-di-0-benzylidene d u l c i t o l of 2.5:1) was added slowly t o the solution which changed color from colorless to dark orange and then black i n a few minutes a f t e r the i n i t i a l sodium benzoate addition.  The solution was refluxed f o r 3 h r s . and  cooled t o room temperature. to  initiate crystallization.  D i s t i l l e d water was added dropwise After 25 ml. of water had been added  - 59 a flocculent black p r e c i p i t a t e formed.  A further 50 ml. of  water was added and the product was f i l t e r e d through a sintered glass funnel.  The product was f i n e l y divided, dark brown i n  color and d i d not appear to be c r y s t a l l i n e .  Upon r e d i s s o l v i n g  the product i n f r e s h N,N-dimethyl formamide and r e p r e c i p i t a t i n g with water i t remained dark brown and d i d not c r y s t a l l i z e .  No  sharp melting point of product was observed as i t appeared to start decomposing "i-i60 C.  Three further attempts t o prepare 2 , 5 - d i -  0-benzoyl l , 3 j 4 , 6 - d i - 0 - b e n z y l i d e n e a l l i t o l by t h i s procedure were made with the following modifications:  The r e f l u x i n g  temperature was decreased from 148°C t o 125°C, the sodium benzoate was f i r s t dissolved i n N,N-dimethyl formamide before addition of the 2,5-di-pj-(£-toluenesvilfonyl)-l,3j4,6-di-0-benzylidene d u l c i t o l , the time of r e f l u x i n g the reaction mixture was varied.  In a l l of these cases the i s o l a t e d product was brown  i n color and y i e l d s varying from 24$ to 68$ of o r i g i n a l material were recovered.  The product when r e c r y s t a l l i z e d from dioxane-  water was shown to be 2 , 5 - d i - 0 - ( p _ - t o l u e n e s u l f o n y l ) - l , 3 ; 4 , 6 - d i - 0 benzylidene d u l c i t o l by i t s melting point and t h i n layer chromatography.  IX.  TRI-O-BENZILIDENE-D-MANNITOL. The procedure followed f o r the synthesis was that employed  by Patterson and Todd  (33).  D-Mannitol (2.995g* 0.0164 mole) was dissolved with shaking i n 9.0 ml. of concentrated hydrochloric a c i d .  Freshly d i s t i l l e d  - 60 benzaldehyde  (6.30g,  0.0594 mole) was added dropwise with shaking.  The f l a s k was stoppered and shaken mechanically f o r 30  minutes.  A s o l i d white product appeared to form a f t e r approximately minute of shaking.  one  The reaction v e s s e l was placed i n a r e f r i g e r -  ator f o r 12 hrs. a f t e r which time the contents of the f l a s k had formed a s o l i d white mass.  The product was transferred to a  sintered glass funnel and washed with i c e water and ether.  The  washing was continued u n t i l the f i l t r a t e gave a negative test f o r chloride i o n .  The crude product, 6.277g (85.5$ y i e l d ) ,  r e c r y s t a l l i z e d from carbon t e t r a c h l o r i d e and had a m.p.  was  of 206  C ( l i t . v a l u e 218^219°C) (32);  30  l i t . value  [X]  D  =16.65  (CHC1 ,  [<<]  D  =16.5  (CHCI3, 1.  3  1. 2.00, 1.00,  c. 3.512) c. 7.0192)  Analysis cal6d.for C2<jE2(Ps'- C, 72.63;  H, 5.87$  C, 72.35;  H, 5.72$  Found:  (69)  The i n f r a r e d spectrum indicated the absence of hydroxyl groups and t h i n layer chromatography showed a single spot when run i n pyridine and developed with concentrated s u l f u r i c a c i d - n i t r i c a c i d spray reagent. X.  HYDROLYSIS OF 0-BENZYLIDENE ACETALS. Several c y c l i c 0-benzylidene acetals were hydrolyzed with  1.25M  hydrochloric a c i d i n ethanol solution and the hydrolysis  was followed spectophotometrically by the appearance of the carbonyl absorption peak i n the u l t r a v i o l e t spectrum.  The  procedure was as follows: A standard solution of the a c e t a l  (2.94 x  1CT\)  i n absolute ethanol was prepared.  A  6.25M  solution of hydrochloric a c i d was prepared by d i l u t i n g one volume of hydrochloric a c i d with an equal volume of absolute ethanol.  The solutions were kept i n a constant  temperature  O  bath at 25.0  i ,1 C.  was pipetted i n t o a  The standard a c e t a l solution (1.00  10 ml.  volumetric f l a s k ,  2.00 ml.  of  ml.)  6.25M  hydrochloric acid was added and the volume was made to the mark with absolute ethanol.  The f i n a l concentration of a c e t a l was  -5  2.94 x 10  M  and of hydrochloric acid was  was transferred to a 1.00  1.25M.  The solution  cm. stoppered quartz c e l l which was  balanced i n a Beckmann D.U. spectrophotometer  against a matched  c e l l containing a blank solution of hydrochloric acid i n absolute ethanol.  Reapongs of o p t i c a l density  regular time i n t e r v a l s .  at/\246mu were  recorded at  From the plot of time versus o p t i c a l  density (FIGURES 6 and 7 ) , the time required f o r complete hydrol y s i s was measured and from the value of o p t i c a l density maximum and the extinction c o e f f i c i e n t ( €. ), the number o f benzylidene groups per a c e t a l molecule could be calculated.  The value of  was determined by preparing standard solutions of benzaldehyde i n 1.25M  hydrochloric acid i n absolute ethanol and measuring the o p t i c a l  density maximum at /\  246mu  as w e l l as by measuring the o p t i c a l den-  s i t y maximum of hydrolysed standard solutions o f : tri-O-benzylideneD-mannitol,  l,3;4,6-di-0-benzylidene  4,6-di-0-benzylidene benzylidene d u l c i t o l .  d u l c i t o l and  dulcitol,  2,5-di-0-methyl-l,3j  2,5-di-0~benzyl-l,3j4,6-di-0-  From the plot of o p t i c a l density versus  concentration of benzylidene groups was drawn having a slope (£!) of  (FIGURF2J5) a  10,200.  straight l i n e  SUGGESTIONS FOR FURTHER RESEARCH.  1.  The synthesis of l , 3 j 4 , 6 - d i - 0 - b e n z y l i d e n e a l l i t o l  could be carried out under more f o r c i n g conditions and with d i f f e r e n t a c i d i c catalysts t o see i f a tri-O-benzylidene acetal could be formed. 2.  Graded a c i d i c hydrolysis of tri-O-benzylidene i d i t o l  t o di-O-benzylidene i d i t o l would be of i n t e r e s t as the possi b i l i t y exists f o r the i s o l a t i o n of a di-O-benzylidene derivative which does not possess the most favored structure. 3.  The hydrolysis of O-benzylidene acetals at varying  hydrogen i o n concentration would be of i n t e r e s t t o determine the acid s t a b i l i t y of d i f f e r e n t types and sizes of a c e t a l r i n g s . Graded hydrolysis of the tri-O-benzylidene acetals of mannitol and t a l i t o l could provide a route for t h e i r s t r u c t u r a l elucidation.  BIBLIOGRAPHY. 1. W.T. Haskins, R.M. Hann, and C.S. Hudson. Soc. 64, 136 (1942). 2. R.M. Hann, A.T. Ness, and C.S. Hudson. 68, 1769 (1946). 3.  R.M. Hann, W.D. Maclay,and C.S. Hudson. 61, 2432 (1939).  4.  S.A. Barker and E.J. Bourne. 7, 137 (1952).  E . J . Bourne and L.F. Wiggins.  7.  R.M. Hann and C.S. Hudson.  8.  S.A. Barker and E . J . Bourne.  9.  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E.D. Bergman and S. Pinchas.  Rec. t r a v . chim. 71, 161 (1952).  48.  S.A. Barker, E.J. Bourne, and D.H. Whiffen. Biochemical Analysis. 3 . 219 (1956).  49.  H. Tschambe and R. Leuter.  50.  N. Baggett, B. Dobinson.  51.  Interatomic Distances. Chem. Soc. London, Spec. Publ. 11 (1958).  52.  G.C. Pimentel and A.L. McLellan. The Hydrogen Bond. Freeman and Co. San Francisco (i960).  53.  E . J . R e i s t , L. Goodmann and B.R. Baker.  Monstsh.  Methods of  83, 1502 (1952).  Chem. and Ind.  106 ( l 9 6 l ) .  W.H.  J . Am. Chem. Soc.  80, 5775 (1958). 54.  E . J . R e i s t , R.R. Spenser, and B.R. Baker.  J . Org. Chem. 24,  1618 (1959). Advances i n Carbohydrate Chemistry. 8, 107 (1953).  55.  R.S. Tipson,  56.  M. Jackson and L.D. Hayward.  57.  E . Premuzic and L.D. Hayward.  58.  G. Creamer. Personal Communication. Columbia (1949).  59.  A.I. Vogel. P r a c t i c a l Organic Chemistry. Green, London (1959).  60.  H.M. Bunbury and I . Heilbron.  V o l . I (1946).  Can. J . 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