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 in the Department of CHEMISTRY We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA November, 1961. Ih presenting'this thesis in p a r t i a l fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make i t freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. It i s understood that copying or publication of this thesis for financial gain shall not be alloived without my written permission. Department of CHEMISTRY The University of British Columbia, Vancouver 8, Canada. Date DEC. 5/1961 ABSTRACT The structure of the previously reported di-O-benzylidene acetal of a l l i t o l has been established as that of 2,4>3>5-di-O-benzylidene a l l i t o l . An infrared spectroscopic study i n carbon tetrachloride solution of the intramolecular hydrogen bonding existing i n this compound and the related diacetal, l ,3j4>6-di-0-benzylidene dulcitol was made to determine the preferred molecular conformations. An intraring, bifurcated hydrogen bonded conformation was assigned to the dulcitol 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 existing evidence between the two possible intramolecularly hydrogen bonded conformations. A spectroscopic method for the determination of the number of cyclic O-benzylidene groups present per mole of parent alcohol has been developed. ACKNOWLEDGMENT I wish to thank Dr. L. D. Hayward who has will i n g l y assisted and provided encourage-ment to make this research possible. TABLE OF CONTENTS. Page GENERAL INTRODUCTION 1 HISTORICAL INTRODUCTION 2 I. Preparation and Properties of Cyclic 0-Benzylidene Acetals of Glycitols 2 I I . Stereochemistry of Cyclic Acetals 7 A. Stereochemistry of Sis-Membered Acetal Rings 7 B. Stereochemistry of Five-Membered Acetal Rings .16 C. Stereochemistry of Fused Ring Acetals IS III. Stereochemistry of Known O-Benzylidene Acetals of Hexitols 19 A. O-Benzylidene Acetals of Sorbitol 19 B. O-Benzylidene Acetals of 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 Dulcitol 25 F. O-Benzylidene Acetals of A l l i t o l 27 IV. Hydrolysis of Cyclic O-Benzylidene Acetals 27 V. Spectra of O-Benzylidene Acetals 30 A. Infrared Spectra 30 B. NMR Spectra 31 Page RESULTS AND DISCUSSION 33 I. The Struct Tire of Di-O-Benzylidene A l l i t o l 33 I I . Intramolecular Hydrogen Bonding 37 III. The Preferred Conformations of Di-O-Benzylidene Acetals of the Hexitols 37 IV. Synthesis of 2,5-Di-0-Benzoyl-l,4j3,6-Dianhydro-L-Iditol ' 42 V. Attempted Synthesis of 2,5-Di-O-Benzoyl-l,3;4>o-Di-0-Benzylidene A l l i t o l 43 VI. Hydrolysis of O-Benzylidene Acetals 45 EXPERIMENTAL 51 I. Materials and Reagents 51 I I . 2,4j3,5-Di-p-Benzylidene A l l i t o l 52 III. 1,6-Di-0-Methyl-2,4j3 >5-Di-0-Benzylidene A l l i t o l " 53 IV. 1,6-Di-O-Methyl A l l i t o l 54 V. Lead Tetraacetate Oxidation of l,6-Di-0-Methyl A l l i t o l 56 VI. Infrared Spectroscopy 56 VII. 2,5-Di-0-Benzoyl-1,4J 3,6-Dianhydro-L-I d i t o l 57 VIII. Attempted Synthesis of 2,5-Di-O-Benzoyl-l,3;4,6-Di-0-Benzylidene A l l i t o l 57 IX. Tri-O-Benzylidene-D-Mannitol 59 X. Hydrolysis of O-Benzylidene Acetals 60 SUGGESTIONS FOR FURTHER RESEARCH 62 TABLES. TABLE I Graded Acidic Hydrolysis of Acetals TABLE II Absorption Bands Assigned to 1,3-Dioxane Ring TABLE III Infrared Absorptions of Alcohols (OH-Region) TABLE IV Hydrolysis of O-Benzylidene Acetals FIGURES. FIGURE 1 Mechanism of Cyclic Acetal Hydrolysis FIGURE 2 Structural Elucidation of Di-O-Benzylidene A l l i t o l FIGURE 3 Lead Tetraacetate Oxidation of Di-O-Methyl A l l i t o l FIGURE 4 Infrared Spectra of Solutions (OH Region) FIGURE 5 Concentration of Benzylidene Groups Versus Optical Density of Cyclic O-Benzylidene Acetals FIGURE 6 Hydrolysis Curves of Cyclic O-Benzylidene Acetals FIGURE 7 Hydrolysis Curves of Cyclic O-Benzylidene Acetals FIGURE 9 Infrared Spectra of Solid Samples - 1 -GENERAL INTRODUCTION The main objective of this research was to establish the structure and i f possible the preferred conformation of di-O-benzylidene a l l i t o l . This compound was f i r s t synthesized i n 1932 and no previous attempt appears to have been made to 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 for this compound. Both are capable of existing i n two nearly equally probable con-formations which would be stabilized by intramolecular hydrogen bonds. Of the ten isomeric hexitols only a l l i t o l and dul c i t o l f a i l to form tri-O-benzylidene acetals when condensed directly with benzaldehyde. An infrared spectroscopic study of these two di-O-benzylidene acetals i n carbon tetrachloride solution was undertaken to determine the nature of the intramolecular hydrogen bonding i n these compounds and, i f possible, to assign the molecular conforma-tions. In the course of this research a spectroscopic technique for the determination of the number of benzylidene groups i n cyclic O-benzylidene acetals was developed. HISTORICAL INTRODUCTION I. PREPARATION AND PROPERTIES OF CYCLIC-O-BENZILIDENE ACETALS OF GLYCITOLS. Acetals are a general class of organic compounds formed by the condensation of alcohols with the carbonyl group of aldehydes i n the presence of acidic catalysts. Cyclic O-benzylidene acetals w i l l be formed from the conden-sation reaction of benzaldehyde with polyhydroxy alcohols having suitably oriented hydroxyl groups. The reaction i s believed to f i r s t form the hemiacetal (II) which exists as an unstable inter-mediate before proceeding to the acetal (III). RHG-OH RHG-OH + R H p — O PhCHO + (OHOH)n ^ (CHOH) n o ^ CTOH)n)CHPh+ H 2 0 RHG-OH RHWM^-PII R H C — O X)H i n m The condensation reaction i s acid catalyzed, the postulated mechanism involving protonation of the hydroxyl oxygen, and, as the reaction i s reversible, i t i s also f a c i l i t a t e d by dehydrating agents. The standard catalysts employed are concentrated sulfuric, hydrochloric and hydrobromic acids, gaseous hydrogen chloride, zinc chloride, cupric sulfate and phosphorus pentoxide. In the absence of an acidic catalyst the reaction may proceed only as far as the hemiacetal formation; i t continues to the complete acetal only i f water i s removed from the reaction mixture. The nature of the derived acetal i s usually independent of the acidic 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 derivative of 1 ,6-dibenzoyl d u l c i t o l whereas zinc chloride as catalyst yielded at room temperature an isomeric dibenzylidene compound, which when subjected to zinc chloride and benzaldehyde at 60°C reverted into the former isomer (1). Cyclic O-benzylidene acetals generally form crystalline, high-melting derivatives of polyols and hence are useful for characterization purposes. These acetals are readily hydrolysed back to the parent alcohol by aqueous acid as their acid catalyzed formation i s reversible. Under mild conditions acetals are stable to bases such as hydroxides, alkoxides, ammonia and pyridine. This characteristic of acid l a b i l i t y and base stabi-l i t y makes cyclic acetals extremely useful as intermediates i n the synthesis of p a r t i a l l y substituted polyhydric alcohols. As protective substituents cyclic acetal linkages may be employed to block pairs of hydroxyl groups with a high degree of specificity. 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 oxidising agents employed i n carbohydrate chemistry such as lead tetraacetate and the periodates. Similarly acetals appear to be stable toward reducing agents. An example i s the preparation of 2,4-O-benzylidene-D-xylitol by reduction of 2,4-0-benzylidene-D-xylose with hydrogen and Raney nickel 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»6-diisopropylidene-D,L-galactitol was subjected to benzoylation in quinoline at elevated temperatures and yielded l,6-dibenzoyl-2,3»4»5-diisopropylidene d u l c i t o l . Barker and Bourne (4) accordingly state that although treatment of an acetal or ketal with a basic reagent i s unlikely to cause structural rearrangements, this pos s i b i l i t y should not be ignored. Interest in cyclic acetal formation has up to the present been concerned mainly with either stereochemical studies in the determination of the most stable structures of these compounds or with their use as intermediates in the synthesis of p a r t i a l l y substituted polyhydric alcohols. Very l i t t l e industrial use has so far been found for these compounds. Since this research has been mainly concerned with the stereochemistry of the cyclic acetals this aspect -will be considered in detail. The formation of cyclic acetals from polyhydric alcohols -will theoretically produce many isomeric products that w i l l d i f f e r in structures, configuration, and conformation. The effect of configura-tion of the reactants on the course of the reaction depends consider-ably on whether the reaction i s reversible or irreversible. Cyclic acetal formations are examples of reversible reactions where, pro-viding a true equilibrium i s attained, the composition of the products i s independent of mechanism and determined by the relative thermodynamic st a b i l i t i e s of the constituents. The conversion of benzylidene (5) and ethylidene acetals (6) into the corresponding methylene analogues gives evidence for the reversible nature of the reaction. However, i t i s not always possible to assess whether a true equilibrium has been reached for 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 reversible equilibrium involving several acetals w i l l be reached. Should one of these acetals crystallize during the reaction then the equilibrium con-ditions may cause this solid phase to be the principal product. In predicting the most probable structures and conformations of cyclic acetals several important factors should be considered. The major considerations w i l l be: (1) The configuration of the hydroxyl groups in the polyhydric alcohol. (2) The structure of the carbonyl component. (3) The conditions under which the acetalation occurs. Although i t appears that many variable factors directing acetal formation exist, i t has been possible to predict with considerable accuracy the course of the reaction. In 1946 Harm and Hudson (2) from studies of the known structures of the methylene acetals of sorbitol, 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 cyclic acetal formation. Although these rules were empirical at the time, stereochemical theory has since placed them on a firm basis. These rules have been regarded as a major contribu-tion to the stereochemistry of acyclic molecules. The 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 to carbon atoms which are adjacent, separated by one atom and separated by two atoms respectively. For secondary hydroxyl groups, C (cis) refers to rings formed by the closure at hydroxyl groups on the same side of the Fischer projection formula} similarly T (trans) w i l l refer to ring closure at hydroxyl groups on opposite sides of the Fischer projection formula. The parts of the polyol carbon chain not involved i n the formation of the acetal ring are referred to as residues. Fused rings refer to rings i n which two carbon atoms are i n common. Barker and Bourne (4) i n 1952 modified the original Hann and Hudson rules to include a l l of the cases of benzylidenation, ethylidenation and methylenation known to that date. The modified rules are: (1) The most favored structure i s a ^ -C ring. (2) The second most favored structure i s for a ^3 ring, (3) The third most favored structure i s for a n ^ , ^ -T, ^?-T or Y~1 ring. (4) In methylenation a B-1 ring takes precedence over an ^<-T or y-T ring. (5) In benzylidenation and ethylidenation an c<-1 ring takes precedence over a or ^ -T ring. (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 ring system. Of interest i s the fact that these rules do not apply to the isopropylidene ketals which exist predominantly as five-membered rings. Hann and Haskins (2) pointed out that the O-benzyHdene acetals would be expected to be more complicated than the methylene acetals as i n each O-benzylidene acetal ring 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 to stereoisomerism. Conformational analysis of the cyclic acetal rings i s necessary to provide a theoretical basis for these empirical rules and to enable one to answer the following questions: (1) What i s the most probable ring structure of an O-benzylidene acetal formed from a polyhydroxy alcohol of known configura-tion? (2) How many conformations are l i k e l y to be favored for the acetal and which of these i s l i k e l y to be the more stable? I I . STEREOCHEMISTRY OF CYCLIC ACETALS. Recent advances in the stereochemistry of carbohydrates and their cyclic derivatives are reviewed by M i l l s ( 9 ) , Ferrier and Overend (10), and Isbell and Tipson (11). Condensation of benzaldehyde with a polyhydric alcohol generally results i n the formation of a six-membered cyclic acetal ring although five 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 invariably the preferred conformation having minimized non-bonded repulsions. Other possible six-membered ring conformations include the boat (II), planar ( H I ) , sofa (IV), half chair (V) and skewed (VI) forms. Substituents w i l l tend to occupy equatorial rather than axial positions to minimize diaxial repulsions. - . - 9 -The substitution of two oxygen atoms in the cyclohexane ring to form a 1,3-dioxane ring as found i n cyclic acetals does not appear to alter these rules substantially. However, the po s s i b i l i t y of slight distortions from the cyclohexane conforma-tions exists since C-0 w i l l give a shorter bond distance than C-C and replacement of two hydrogen atoms by lone pairs of electrons on oxygen might be expected to decrease non-bonded ring interactions. Thus the 1,3-dioxane ring (VII) i s probably less strained and somewhat more distorted than the cyclohexane ring. Examining the ^ -C ring (VIII) both and R£ may be i n equatorial positions while i n a 3^ -T ring (IX) i f R^ i s equatorial R 2 must be axial. Since the equatorial positions are energetically favored over axial positions then i t i s reasonable that £3-0, rings w i l l be favored over ^ -T rings. Examining the acetal carbon atom, the favored position for the bulky phenyl group of a cyclic O-benzyl-idene acetal w i l l be i n the equatorial (e) position. Thus (VIII) (R^= phenyl) w i l l represent the predicted most stable six-membered O-benzylidene acetal where the two residues and the bulky phenyl group are a l l on the same side of the ring. Assuming that the re-pulsive forces from the unshared electrons of the ring oxygen i n the 1,3-dioxane ring are less than those from a hydrogen atom, then the equatorial position at the acetal carbon atom w i l l be favored over the axial position much; more i n a 1,3-dioxane ring than i n a cyclohexane ring. It i s therefore highly unlikely that the isomer of a ^-C O-benzylidene acetal having the phenyl group i n an axial position would be stable enough to isolate. This i s i n agreement - 10 -with experimental results indicating 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 R2» only Rej suffers repulsions from two hydrogen atoms. The repulsion between RQ and the oxygen atoms cannot be accurately assessed but i s assumed to be less than repulsions from two hydrogen atoms. The probability i s thus seen that the axial group R^ w i l l be more favored than the equatorial group R^ and hence axial hydroxyl groups in 0-benzylidene acetal rings may readily occur. From conformational considerations alone Mills (9) predicted that 2,4-O^methylene-D-glucitol, l,3j4,6-di-0-methylene du l c i t o l and the related ethylidene and benzylidene derivatives were stable acetals with axial hydroxyl groups. As previously stated only one diastereoisomer i s obtained from most benzylidenation reactions which produce six-membered rings. However, i n certain cases two products have been isolated and cited as being diastereoisomers. Gluco-gulo-heptitol reported-l y yielded a mono O-benzylidene acetal which could be converted to 3,5-O-benzylidene-gluco-gulo-heptitol on recrystallization from ethanol (13). Similarly D-perseitol (D-manno-D-gala-heptitol) has been reported to yield two l,3j5,7-di-0-benzylidene acetals (14). However, both of these compounds gave indistinguishable infrared spectra i n nujol mulls and potassium bromide disks, had optical o rotations differing by only 0.1 , and one form could be converted - 11 -into the other by repeated recrystallizations from ethanol-pyridine (15). This evidence indicates that the latter reported pair of diastereoisomers probably exist as polymorphic forms. Of considerable interest i s the isomerism encountered i n the benzylidene acetals of glycerol. Fischer i n 1894 (16) was the f i r s t to describe a definite condensation product from glycerol and benzaldehyde which he suggested was either the 1,3-or 1,2-O-benzylidene derivative. However, Fischer's product was probably a mixture of both derivatives for Hibbert and H i l l (17) and Verkade and van Roon (18) later isolated two separate 1,3-0-benzylidene acetals as well as the predominant 1,2-0-benzylidene acetal. The two 1,3-0-benzylidene glyceritols possess a cis-trans relationship but i t should be pointed out that i n these acetals (X and XI) the acetal 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 tetrachloride solutions <^0.005M at which concentrations intermolecular hydrogen bonding i s eliMnated (20). From the infrared stretching frequency i n the hydroxyl region they have been able to assign cis and trans configurations to 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 ring oxygen in a series of monohydroxy derivatives of tetrahydropyran, tetrahydro-furan and 1,3-dioxanes under similar conditions. Absorptions near 3630 cm ''"and 3590 cm ^ were associated with free and intramolecularly bonded hydroxyl groups respectively. - 12 -xn xm X3ZI -13 -Examination of the infrared spectra of l,3-dioxane-5-ol -1 -1 showed absorptions at 3635 cm and 3594 cm with relative extinction coefficients of 21 and 100 respectively. The relative extinction coefficients indicate that an equilibrium of chair conformations exist (XII and XIII) which favors the conformation (XIII) having an intramolecularly hydrogen bonded axial hydroxyl group. From this evidence i t would appear that an equatorial substituent on C 2 i n conformation (XIII) of l,3-dioxane£-ol would effectively f i x this conformation thus causing complete in t r a -molecular hydrogen bonding. Spectroscopic examination of the two 1,3-O-benzylidene — glyceritol isomers showed that the isomer of m.p. 84°C gave only one hydroxyl stretching absorption at 3590 cm 1 indicating conforma-tion (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) indicating an equilibrium between the bonded (XIV) and non-bonded (XV ) conformations. From this spectroscopic examination the isomer o of m.p. 84 C was allocated the cis configuration and the other o o isomer (m.p. 63 - 64 C) the trans configuration. The conformation (XIV) contains the phenyl group in the st e r i c a l l y unfavorable axial position and the observation that a proportion of the molecules exist i n this conformation reflects the strength of the intramolecular hydrogen bond. The non-bonded interactions associated with the axial phenyl group in conformation (XIV) could possibly result i n some deformation of the chair struc-ture but the extent would probably be slight and would adversely affect the intramolecular hydrogen bond. - 14 -In the hydrogen bonds the hydroxyl groups are shown bonded to both ring oxygens forming a bifurcated bond. Experimental evidence suggests that bifurcated bonds are present but does not confirm their existence. Brimacombe, Foster ety a l . (21) have shown the importance of both ring oxygens in 5-hydroxyj-1,3-dioxane structures as intramolecular hydrogen bonding between the hydroxyl group and the ring oxygen in tetrahydropyran-3-ol occurs to the extent of approximately 50$ (<£?=40 and 50 for free and bonded hydroxyl groups respectively) whereas the introduction of a second ring oxygen giving 1,3-dioxane-5-ol gives more extensive intramole-cular hydrogen bonding (<£ = 21 and 100 for free and bonded hydroxyl. groups respectively). Dobinson and Foster (22) have compared the hydrogen bonding effects i n derivatives of trans-cyclohexane-l,2-diol (XVI) and 5-hydroxyT 1,3-dioxane (XIII). Intramolecular hydrogen bonding i n both of these compounds involves five-membered rings and as their A pvalues (arithmetical difference between free and bonded hydroxyl absorption frequencies) were found to be similar^it appears that these bonds are of equal strength. However, the bulk of the isopropyl group in trans-l-isopropylcyclohexane-l <2-diol was found to be sufficient to anchor the molecule exclusively i n the chair conformation with the isopropyl group equatorial and the hydroxyl groups axial. The bulk of the phenyl group appears somewhat less than that of the isopropyl group as i t has been shown by Brimacombe, Foster et^ a l . (21) that i t i s not sufficient to anchor trans-5-hydroxy-2-phenyl-l,3-dioxane i n conformation (XV). Dobinson and Foster are currently attempting the synthesis of trans-5-hydroxy-2-t-butyl-- 15 -1,3-dioxane to determine i f the bulky t-butyl group w i l l exist only in an equatorial position. The spectroscopic observations made by Brimacombe, Foster et.al. (21,22,23,24) have thus pointed out the significance of intramolecular hydrogen bonding in stabilizing conformations which otherwise would be considered unfavorable. The condensation of aldehydes with glycerol significantly differs from the pattern observed with higher polyhydric alcohols as the proportion of five-membered ring cyclic acetals of glycerol always markedly exceeds the proportion of six-membered ring acetals providing the reaction mixture remains l i q u i d . One noted exception i s the O-methylene glycerol which when acid equilibrated, produced the six-membered cyclic acetal i n greater yi e l d . Thus, although intramolecular hydrogen bonding undoubtedly influences the reaction behaviour of certain higher polyhydric alcohols with aldehydes, i t i s probably not the determining influence with glycerol. I f this was so, cis-l,3-0-benzylidene glycerol (X) would be expected to be the major condensation product of benzaldehyde with glycerol. Piantadosi e t | a l . (25) have shown that i n catalytic amounts of acid an equilibrium exists between the 1,2- and 1,3-0-benzylidene glycerols and have calculated an equilibrium constant. Their results indicate an equilibrium ratio of approximately 9:1 favoring the 1,2-0-benzylidene-glycerol thus indicating the preference for the five-membered ring configuration. An example where the empirical rules regarding cyclic acetal formation f a i l to differentiate a preferred structure i s the formation of a 1,3-0-benzylidene-(XVII) and 1,3-O-methylene acetal - 16 -of D and L arabitol i n preference to the corresponding 3,5-substituted acetals (XVIII). Since both the 1,3- and 3,5- struc-tures have @ rings the acetal formation rules w i l l not differen-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 axial hydroxyl group which can intramolecularly bond with the ring oxygens. B. STEREOCHEMISTRY OF FIVE-MEMBERED ACETAL RINGS. The p o s s i b i l i t i e s of isomerism in five-membered rings are shown i n the M i l l s projection formulae (XIX) and (XX). As the five-membered ring i s nearly planar the c^-T ring w i l l be favored over the -C ring which w i l l have R^ and R2 i n eclipsed positions. The ^-T ring, being more symmetrical, should be more stable than a terminal c(. ring. Evidence for this i s the rearrange-ment of l,2j4,5-di-0-isopropylidene-D,L-galactitol to 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 acetal carbon atom w i l l be ijiipossible i f R3 = R^ and impossible i n an eC -T ring i f R]_ = R2. 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 especially so i n an ^ ^ ^5-C which i s i n the order of decreased ring s t a b i l i t y . The only studies on rates of hydrolysis of cyclic O-ben-zylidene acetals appear to be those recently reported by Brimacombe, Foster and Haines (45) who followed the hydrolysis of 1,2- and 1,3-0-methylene glycerol and c i s - and trans- 1,3-0-benzylidene glycerol. These workers hydrolysed a 1% solution - 30 -of 1,2- and 1,3-0-methylene glycerol i n N-sulfuric acid at o 89 C and observed t i values of 42 and 129 minutes respectiv-ely, indicating the preferred s t a b i l i t y of the six-membered over the five-membered ring. They also observed that both c i s - and trans-1,3-0-benzylidene glycerol hydrolysed extremely rapidly haviag t i values of 17 minutes i n 0.02N sulfuric acid o at 35 C. The 1,3-0-methylene and 1,3-O-benzylidene acetals appear to reflect 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 intervals by neutraliz-ing aliquot samples of the reaction mixture, oxidizing 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. SPECTRA OF O-BENZYLIDENE ACETALS. A. INFRARED SPECTRA As mentioned previously, Brimacombe, Foster, et,/ a l . (21) have examined the infrared spectra i n carbon tetrachloride solution of several cyclic acetals of glycerol. These spectra were in solutions less than 0.005M and were only concerned with the hydroxyl stretching frequency region. I s b e l l , Stewart and Tipson (46) have examined the infrared spectra of a series of 1-methoxyethylidene and isopropylidene r c y c l i c acetals to determine i f i t was possible to unequivocally detect the 1,3-dioxane ring. They also reviewed related spectra obtained by other workers to determine i f other correlations existed. They found that the absorption bands were not highly characteristic - 31 -of the type of ring present and that there were no readily distinguishable bands suitable for the assignment of ring struc-ture or for the study of ring conformations i n these compounds. TABLE II l i s t s the absorption bands assigned to the 1,3-o t i l e r dioxane ring by Isbell ety a l . and related workers. TABLE II ABSORPTION BANDS ASSIGNED TO 1,3-DIOXANE RING WAVENUMBER (CM - 1) OF SPECTRAL REGION OF ABSORPTION BANDS A 1190-1151 1190-1158 1173-1151 DOUBLE 1160 1181-1153 B 1161-1123 1143-1124 1151-1132 F BETWEEN and 1120 1126-1104 C 1105-1077 1098-1063 1105-1077 DOUBI 111C 1093-1070 D 1052- 1038 1056-1038 1053- 1038 ET BETWEEN and 1050 1055-1029-B. NMR SPECTRA Foster et/ a l . (50) have reported the NMR spectra of 5-hydroxy-l,3-dioxane and some related compounds. These spectra o were obtained at 34 C from ca. M solutions of these compounds in chloroform with tetramethylsilane as the internal reference. They published the spectra of c i s - (XXXIX) and trans- (XL) 5-acetoxy-2-phenyl-l,3-dioxane. With the trans acetal the axial 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 cis acetal no coupling was observed and a single broad peak was formed from the protons on and which indicated that these pairs had lost their axial-equatorial character and that the cis form rapidly interconverts between n two conformations. No further NMR spectra of cyclic-O-benzylidene acetals have been reported. The low solubility 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 sufficient concentration to obtain their NMR spectrum with present day equipment. - 33 -RESULTS AND DISCUSSION I. THE STRUCTURE OF DI-O-BENZILLDENE ALLITOL. As previously mentioned, conformational analysis indicated two probable structures for di-O-benzylidene a l l i t o l . These structures were l,3;4,6-di-0-benzylidene a l l i t o l (XLII) and 2,4j 3,5-di-O-benzylidene 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 structural elucidation. Hydrolysis of 'methylated 2,4J3,5-di-O-benzylidene a l l i t o l (XLIII) would yield 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 yield the 2,5-di-O-methyl isomer (XLV). 1,6-Di-O-methyl a l l i t o l (XLIV) has four vi 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 oxidising agent for the cleavage of the carbon chain between pairs of v i c i n a l hydroxyl groups and one mole of lead tetraacetate i s consumed per pair of such groups then (XLIV) would consume three moles of oxidising agent per mole while (XLV) would consume only one mole. Experimentally a maximum value of 3.05 moles of lead tetra-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 rule out migration of either the O-benzylidene or methyl ether groups, this 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 1 PbCOAc)4 CHgOH 2 hhCHDCH3 CHO 3 Pb(OAc)4 2 J H J O O + J + 2 HCOOH FIGURE 5 MOLES Pb(OAc)4 CH-Q-METHYL ALLITOL O CONSUMED u> ireyy 2 E X X - 37 -I I . INTRAMOLECULAR HYDROGEN BONDING. The examination of the infrared spectra of 2 , 4 ; 3 , 5-di-O-benzylidene a l l i t o l (XLI) and l , 3 j 4 , 6-di - 0-benzylidene 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 existing i n these compounds. The following solutions i n carbon tetrachloride were prepared: 3 . 1 x 10 _AM - 4 cyclohexanol, 2 . 0 x 10 M 2 ,4j3,5-di-0-benzylidene a l l i t o l - 4 and 1 .0 x 10 M l , 3 j 4 , 6-di - 0-benzylidene d u l c i t o l . From the plot of the difference i n percentage transmittance of solution and solvent against wave length the hydroxyl stretching absorp-tion frequency of these compounds was determined (FIGURE 4 ) . The following absorption maxima were determined: cyclohexanol ( p=3624±2 cm"1), 2 ,4j3,5-di-0-benzylidene a l l i t o l ( p=3603±2 cm"1), l>3j4,6-di-0-benzylidene du l c i t o l ( P=3579 ± 2 cm - 1). The appearance of single absorption peaks for both 2 , 4 j 3 , 5 -di-0-benzylidene a l l i t o l and l , 3 j 4 , 6-di - 0-benzylidene dulcitol indicated unique conformations for these compounds and the fre-quencies of maximum absorption indicated that relatively 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 lcitol and i d i t o l i t appears that several factors operate to favor one structure and conformation over others which have approximately equal non-bonded interactions. These factors appear to include: - 38 -1. Preference for 6- over 5-membered rings. 2. Preference for a symmetrical structure, 3. Preference for fused rings over isolated rings. 4. Enhancement of s t a b i l i t y of a conformation by int r a -molecular hydrogen bonds. The conformation of 2,4J3,5-di-O-benzylidene a l l i t o l (XLI) appears to be very favorable, being symmetrical with a trans-fused 6-membered ring system and equatorial hydroxy-methyl groups which are intramolecularly hydrogen bonded to 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 ring (XLIa) or the oxygen atom of the adjacent ring (XLIb). In the former case a 5-membered hydrogen bonded ring resulted and i n the latter case a 6-membered hydrogen bonded ring. Hydrogen bond lengths calculated from accepted bond distances and bond angles (51) agreed with those measured directly on Cenco-Pftersen scale models and were r(OH*"0) = 1.80A for conformation (XLIa) and r(OH*•*0)= 1.35A for conforma-tion (XLIb). The infrared spectral data compiled by Brimacombe et/ a l . (21) andAKuhn (20) (TABLE III) indicates that both 6- and 5-membered ring hydrogen bonds of this type occur. Of interest i s the observation that 2-hydroxymethyl-tetrahydropyran and 2-hydroxymethyl-tetrahydrofuran exist i n completely hydrogen bonded 5-membered ring conformations while the 1,2-O-acetals of glycerol which can take up similar 5-membered ring hydrogen bonded conformations actually 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 -1 from 3597 cm to 3603 cm . The value observed for 2,4;3>5-di-O-benzylidene a l l i t o l , (3603 cm - 1) f a l l s precisely i n the middle of this range. No data are at present available for 3-hydroxymethyl-tetrahydropyran which would be the model for the 6-membered hydrogen bonded conformation (XLIb). We are therefore unable to make a f i n a l assignment of either (XLIa) or (XLIb) as the more preferred conformation for 2,4;3>5-di-0-benzylidene a l l i t o l . The predicted conformation for l ,3j4»6-di-0-benzylidene a l l i t o l (XLII) shows that i t also could be stabilized by jntra-molecular hydrogen bonding. In this case a 6-membered hydrogen bonded ring with the hydroxyl of one ring bonding to the oxygen atom of the other ring would occur. It thus appears that although both conformations (XLI) and (XLII) are symmetrical and can both be stabilized by intramolecular hydrogen bonding the fused bicyclic ring system i s a more stable structure than two separate rings. The known conformation of l ,3 j4 ,6-di -0-benzylidene dulcitol (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 du l c i t o l structure (XLIII) i s not favored since i t would have two axial hydroxymethyl groups. Furthermore, the observed hydroxyl stretching frequency of 3579 cm"1 for l ,3 j4 ,6-di -0-benzylidene du l c i t o l indicates a strong intramolecular - 42 -hydrogen bond which stabilizes this conformation. Calculations show r(OH* , #0) = 2.42A i n (XXXVXLI). The reason that this 5-membered ring intramolecular hydrogen bond i s unusually strong may possibly be due to i t s bifurcated nature. It should be pointed out when discussing intramolecular hydrogen bonds that a linear arrangement of (0H««»0) which has been shown to be the energetically favored arrangement i n crystals i s undoubtedly not obtainedj i t would be formed only with con-siderable strain 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 for fused bicyclic rings than on stabilization by intramolecular hydrogen bonding, for 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 in l ,3}4,6-di-0-benzylidene d u l c i t o l . However, the greater symmetry of conformation (XXXIV) compared to (XXXV) may also be a con-tributing 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 to 2,5-di-0-benzoyl-l,4j3>6-dianhydro-L-i 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 ion. 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 axial position this reaction i s quite unusual. Few nucleophiles are powerful enough to displace the tosyloxy groups without neighbouring group participation. Sodium iodide gener-a l l y does not react with isolated secondary tosylates and sodium hydroxide or sodium methoxide upon reaction hydrolyses the tosylate with retention of configuration (55). The conversion of 2,5-di-0-(pytoluenesulphonyl)-l,4$3»6-dianhydro-D-mannitol (XLIV) to 2,5-di-0-benzoyl-l ,4;3»6-dian-hydro-L-iditol (XLV) was probably a particularly favorable case since two endo tosyloxy groups were replaced with inversion by benzoyloxy groups which assumed exo positions. 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 are readily replaceable with sodium iodide (56). V. ATTEMPTED SYNTHESIS OF 2,5-DI-0-BENZ0Y L-l,3 J 4 ,6-DI-0-BENZYLIDENE ALLITOL. The attempted replacement of the tosyloxy groups of 2,5-di-0-tosyl-l ,3j4,6-di-0-benzylidene du 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 axial tosyloxy groups would be replaced by equatorial benzoyl groups. However, on the basis of several experimental attempts this replacement does not appear to take place. The importance of this reaction i s that i f this replacement did occur the configuration at carbon atoms 2 and 5 would be - -- 45 -inverted and hence this synthesis would provide a method of prepar-ing the rare hexitol, a l l i t o l , from the more common dul c i t o l . VI. HYDROLYSIS OF O-BENZYLIDENE ACETALS. The hydrolysis of the several cyclic O-benzylidene acetals (TABLE IV) was followed spectophotometrically. TABLE IV. HYDROLYSIS OF O-BENZILIDENE ACETALS O-BENZYLIDENE ACETAL t l (MIN) OBSERVED MOLES BENZY LIDENE GROUP PER MOLE Tri-O-benzylidene-D-mannitol 12 2.97 i . 0 3 Tri-O-b en zyliden e-D-t a l i t o l < 3 2.93 i .03 2,4j3,5-Di-0-benzylidene a l l i t o l 5 2.01 +.02 1,6-Di-O-methyl-2,4} 3,5-di-0-benzylidene a l l i t o l < 3 1.95 t .02 l ,3 ;4 ,6-di -0-benzylidene d u l c i t o l < 3 2.04 *- .02 2,5-Di-O-met hyl - 1 , 3 J 4,6-di-0-benzylidene d u l c i t o l 8 . 6.5 1.81* .03 2,5-Di-O-benzyl-l,3;4,6-di-O-benzylidene d u l c i t o l 3 . 8 1.85 2 .03 Methyl-4,6-0-benzylidene- p -D-glucopyranoside < 3 1.04 i .01 Prepared i n this laboratory by E. Premuzic (57). Prepared by G. Creamer (58). From the rate plots (FIGURES 6 AND 7)> values of t i were calculated and also the number of moles of benzylidene group per mole of acetal after complete hydrolysis. This value was calculated using a value of 10,200il00 for£ (FIGURE 5 ) . - 46 -Due to the high acid concentration (1.25M hydrochloric acid) the hydrolysis of these compounds was very rapid and the rates may be compared only qualitatively. The mono-O-benzylidene acetal, methyl-4>6—0-benzylidene - >3 -D-glucopyranoside, appeared to hydrolyse fastest while tri-O-benzylidene-D-mannitol was the slowest. Since the concentration of a l l of these O-benzylidene the sue. ap<* acetals was approximately the same^and a l l poooooo 6-momborod aootal rings, tho number of rings and the position and type of substituents attached should account for the differences i n hydrolysis rates. The presence of substituents i n the acetal ring appears to decrease the ease of hydrolysis (e.g. larger t i values for 2,5-di-0-methyl-l ,3j446-di-0-benzylidene d u l c i t o l and 2 , 5-di - 0 -benzyl-l ,3 j4,6-di-0-benzylidene dulcitol than for 1 , 3 - 4 , 6-di - 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 j4 ,6-di -0-benzylidene dul c i t o l which possesses two ^ -rings. The reason for the rapid hydrolysis of tri-O-benzylidene-D - t a l i t o l compared to tri-O-benzylidene-D-mannitol does not appear to be readily explainable. As the purpose of this portion of the research was to develop a method for determination of the number of moles of benzylidene group per mole of hexitol, the acid concentration employed was too high to enable only par t i a l hydrolysis to 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 acetals. It would be of interest 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. * SLOPE - 10,200 O A D X + 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 DULCITOL 2.5-Df-Q-BENZYL-|,3-,4.6-DI-Q-BENZYLlDENE DULCITOL CONC. (PhCH) X 10"5 M/L $ fe—-7- — - t — i b - IT i f e — f t * 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 purified as recommended by Vogel (59), d i s t i l l e d under nitrogen at reduced pressure and stored in 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 th i s laboratory by W. Bowering from D-ribose i n a previous research (61). It was recrystallized from ethanol-water and melted at 148 C. D-MANNITOL. Reagent grade D-mannitol, (Matheson, Coleman and Be l l Co.,) O 0 was recrystallized from absolute ethanol, m.p. 165 - 165.5 C ( l i t . value 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 ( l i t . value 210°C (35,36). Analysis: Calcd. for C 2 7 H 2 6 O 6 : C, 72.63j H, 5.87$ Found: C, 71.97J H, 5.82$ The infrared spectrum indicated no hydroxyl groups to be present and a chromatopiate run i n pyridine and developed with sulfuric acid-nitric acid spray reagent showed only one spot. CYCLOHEXANOL. Reagent grade cyclohexanol (Fisher Scientific Co.,) was dis-t i l l e d under reduced pressure and a middle fraction (b.p. 76.5 C) - 52 -22 6 22 was collected, * 1.4649 ( l i t . value 1.4650 (60) ). CARBON TETRACHLORIDE. Analytical reagent carbon tetrachloride was d i s t i l l e d over o 15 phosphorus pentoxide. b.p. 76.0 C 1.4631 ( l i t . value n D 1 5 1.46305 (60) ). DI0XANE. Reagent grade dioxane (British Drug Houses) was purified as recommended by Vogel (59) and stored over sodium in 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 fraction (b.p. 42.0 C) was collected. POWDERED SODIUM. Freshly cut sodium was powdered following the procedure of Fieser (64)• The xylene was decanted off and the sodium suspension was stored i n dry dioxane. THIN LAYER CHROMATOGRAPHY. Thin layer chromatopiates were prepared on glass plates from a slurry of s i l i c i c acid, plaster of paris and water in the pro-portions (4:1:8) and dried overnight at 100°C as described by Allentoff and Wright (65). I I . 2,4j3,5-DI-0-BENZYLIDEIffi ALLITOL. A l l i t o l (0.246 g, 0.00135 mole) was dissolved i n 0.49 g concentrated hydrochloric acid after mechanically shaking for 10 minutes. Freshly d i s t i l l e d benzaldehyde (0.49 g, 0,0046 inole) was then added dropwise with shaking. The solution became tur-p a r t i a l l y bid almost immediately and the contents of flask formed a/| solid white mass after 2-3 minutes. The mixture was shaken vigorously for one hour and then placed i n a refrigerator overnight. The crude acetal was washed acid-free with ice water and was further washed with ether followed by ice water and dried overnight i n vacuo over phosphorus pentoxide. The crude product (0.448 g, 92.7$ yield) was recrystallized from absolute ethanol. m.p. 235.0^236.5°C (Reported m.p. 249-250°C (41) ). Analysis: Calcd. for C20H22°6: C» 6 7 * 0 2 J H» 6»3-9$J Found: C, 67.19j H, 6.07$. A chromatopiate of the recrystallized 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, thin spot near the solvent front. Another chromatoplate run i n chloroform showed one spot near the origin ( R f ^ 0.15) and a trace of another spot just below (Rf -z- 0.06). The infrared spectrum of the compound i s shown in 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). Di-O-benzylidene a l l i t o l (0.100 g) was dissolved with heating and s t i r r i n g in 3.0 ml. of dioxane. A large excess of powdered sodium ^(0.2 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 solid appeared to form i n the flask and on the surface of the sodium. After 6 hrs. the contents of the flask were evaporated under reduced pressure to a yellowish residue containing fi n e l y divided metallic sodium. Methyl iodide (4 ml.) was added and the mixture refluxed and stirred for 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 crystalline residue which was dried overnight in vacuo over phosphorus pentoxide. The crude di-0-methyl-di-O-benzylidene a l l i t o l (98$ average yield) was recrystallized from absolute ethanol o o as colorless, needle-like crystals, m.p. 202.0-203.5 C. Analysis: Calcd. for C22H26°6 : c» 6S.37; H, 6.78; OCR^, 15.57$. Found: C, 68.52; H, 6.90; OCH3, 16.04$. The infrared spectrum showed no hydroxyl stretching absorption (FIGURE 8 ) . A chromatoplate showed only one spot when run in chloroform and developed with potassium permanganate-sodium perio-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 acid, 1.0 ml., was added. The solution was refluxed for 3 hrs., the hydrochloric acid was neutralized with excess silver carbonate, 10 ml. dioxane was added and the hot solution was f i l t e r e d through a Celite pad on a sintered glass funnel. The f i l t r a t e was evaporated to a -56-syrup which crystallized on dpying i n vacuo over phosphorus pentoxide. The crude product was recrystallized from benzene 0 o as colorless plate-like crystals having a m.p. of 103.0-104.5 C. Analysis: Calcd. for CgH 1 8 0 6 : C, 45.71J H, 8.63; OCH^, 29.53$ Found: C, 45.02; H, 8.25; OCR^, 29.60$ Paper chromatography of the compound i n butanol-acetic acid-water (4:1:5) showed one spot corresponding i n R.^ value to that of other di-0-methyl hexitols when sprayed with potassium perman-ganate-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 , 0.0100 g, was dissolved i n 25.0 ml. of a 0.0738 M solution of lead tetraacetate i n glacial acetic acid (mole ratio 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 inter-vals, excess potassium iodide solution was added, and the l i b e r -ated iodine was tit r a t e d with standard sodium thiosulfate solution with starch indicator. The results are shown in FIGURE 3. VI. INFRARED SPECTROSCOPY. The infrared spectra were measured i n the 3500 to 3700 cm""1 region on a Perkin-Elmer No. 112-G single beam spectrophotometer in a 9.0 cm. pyrex c e l l with sodium chloride windows. The con-centrations of the solutions were sufficiently low (1.0 x 10"^ to 3.1 x 10_4M) that intramolecular hydrogen bonding was excluded (20, 21). Complete spectra of the solid 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,N-dimethyl formamide. The solution was magnetically stirred and heated to just below reflux temperature. Sodium benzoate (0.793g» 0.00551 mole) was slowly added to the solution over a period of one hour. The sodium benzoate slowly dissolved and after a few minutes the solution became light yellow in color. After 3 hrs. the solution was cooled to room temperature, where-upon a white, flocculent precipitate settled 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 precipitate had dissolved (5 ml.). Further addition of water (30 ml.) produced a colorless crystalline precipitate which was washed with water and dried i n vacuo overnight over phosphorus pentoxide. The crude product, 0.718g (92 .3$), was recrystallized from absolute ethanol and melted at 109-110°C. A mixed melting with an authentic sample of 2,5-di-0-benzoyl-l ,4}3»6-dianhydro-L-iditol was 109-110°C. The two samples gave indistinguishable infrared spectra. VIII. ATTEMPTED SYNTHESIS OF 2,5-DI-0-BENZ0YL-l,3J4,6-DI-0-BENZYLIDENE ALLITOL. 2, 5-Di-O-(p_-toluenesulphonyl)-l,3J4, 6-di-O-benzylidene dulcitol was prepared according to the procedure of Hann, HaskLns and - 58 -Hudson (68). Di-O-benzylidene dulcitol (l .007g) prepared by E. Premuzic i n this laboratory'(57) was dissolved i n 10 ml. of anhydrous pyridine and 1.3g of p_-toluenesulfonyl chloride was slowly added to the ice-cooled solution. The p-toluenesulfonyl chloride readily dissolved with shaking. Upon standing overnight crystals had deposited on the sides of the reaction flask. D i s t i l l e d water (25 ml.) was added dropwise to the flask. After approximately 5 ml. of water had been added a white powdery precipitate appeared. The contents of the flask were poured into 200 ml. of d i s t i l l e d water and vigorously stirred. The product was recovered on a f i l t e r and dried i n vacuo over phosphorus pentoxide, (1.704g, 91.3$ yield). The crude 2,5-di-O-p_-toluenesulfonyl)-l ,3j4,6-di-0-benzylidene du l c i t o l was recr y s t a l l -ized 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 forma-mide, heated to just below reflux temperature and magnetically stirred. The compound dissolved after 20 minutes heating. Sodium benzoate (0.540g, mole ratio of sodium benzoate to 2 ,5-di-0-(p-toluenesulfonyl)-l ,3 j4,6-di-0-benzylidene dulcitol of 2.5:1) was added slowly to the solution which changed color from colorless to dark orange and then black i n a few minutes after the i n i t i a l sodium benzoate addition. The solution was refluxed for 3 hrs. and cooled to room temperature. D i s t i l l e d water was added dropwise to i n i t i a t e crystallization. After 25 ml. of water had been added - 59 -a flocculent black precipitate 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 finely divided, dark brown in color and did not appear to be crystalline. Upon redissolving the product i n fresh N,N-dimethyl formamide and reprecipitating with water i t remained dark brown and did not cr 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 to prepare 2 ,5-di-0-benzoyl l ,3 j4 ,6-di -0-benzylidene a l l i t o l by this procedure were made with the following modifications: The refluxing temperature was decreased from 148°C to 125°C, the sodium ben-zoate 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 refluxing the reaction mixture was varied. In a l l of these cases the isolated product was brown in color and yields varying from 24$ to 68$ of original material were recovered. The product when recrystallized from dioxane-water was shown to be 2 ,5-di -0-(p_-toluenesulfonyl)-l ,3 ;4 ,6-di -0-benzylidene du l c i t o l by i t s melting point and thin layer chrom-atography. IX. TRI-O-BENZILIDENE-D-MANNITOL. The procedure followed for the synthesis was that employed by Patterson and Todd (33). D-Mannitol (2.995g* 0.0164 mole) was dissolved with shaking in 9.0 ml. of concentrated hydrochloric acid. Freshly d i s t i l l e d - 60 -benzaldehyde (6.30g, 0.0594 mole) was added dropwise with shaking. The flask was stoppered and shaken mechanically for 30 minutes. A solid white product appeared to form after approximately one minute of shaking. The reaction vessel was placed i n a refriger-ator for 12 hrs. after which time the contents of the flask had formed a solid white mass. The product was transferred to a sintered glass funnel and washed with ice 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 for chloride ion. The crude product, 6.277g (85.5$ yield), was recrystallized from carbon tetrachloride and had a m.p. of 206 C (lit.value 218^219°C) (32); 30 [ X ] D =16.65 (CHC13, 1. 2.00, c. 3.512) l i t . value [<<]D =16.5 (CHCI3, 1. 1.00, c. 7.0192) (69) Analysis cal6d.for C2 1707 (1919). 63. D. Conder. B. Sc. Thesis. University of Bri t i s h Columbia (1959). - 66 -64. L. Fieser. Experiments in Organic Chemistry. Heath and Co. New York (1955). 65. N. Allentoff and G.F. Wright. Can. J. Chem. 35, 900 (1957). 66. K. Freudenburg. Ber. deut. chem. Ges. 56, 2125 (1923). 67. M. Jackson, Ph.D. Thesis. University of Bri t i s h Columbia (1959). 68. W.T. Haskins, R.M. Hann, and C.S. Hudson. J. Am. Soc. 64, 132 (1942). 69. J.W. Pette. Rec. trav. chim. 53, 967 (1934).