Isomerism in bicyclic diacetals. Part I. 1,3:2,4- and 1,4:2,3-Di-O-methylene-erythritol

摘要

666 J.C.S. Perkin IIsomerism in Bicyclic Diacetals. Part I. 1,3 :2,4- and I ,4 :2,3- Di-O-methylene-erythritolBy Ian J. Burden and J. Fraser Stoddart,” Department of Chemistry, The University, Sheffield S3 7HFAcid-catalysed methylenation of erythritol affords 1.3 2.4- and 1.4 :2,3-di-O-methylene-erythritol and a smallamount of 1.4-anhydro-2.3-0-methylene-erythritol. Constitutional assignments have been made to the diacetalson the basis of their l H n.m.r. and mass spectra. Deuteriation studies and the Janthanide shift reagent, Eu(fod),,have been employed to investigate the conformational behaviour of the 1.4 :2,3-diacetal in solution by lH n.m.r.spectroscopy. Acid-catalysed equilibration of the 1.3 :2,4- and I ,4 :2,3-diacetals indicates that there is a freeenergy difference of 1 a37 kcal mol-l in favour of the former at room temperature. The significance of these resultsis discussed in terms of electronic effects associated with the -0-C-C-O-fragments as well as steric effects.I II IALDITOLS containing four or more hydroxy-groups canform bicyclic diacetals when they undergo acid-catalysedcondensations with aldehydes or ketones. By limitingconsideration to those acet alations involving all thehydroxy-groups of the tetritols, four contiguous hydroxy-groups of the pentitols, and all four secondary hydroxy-groups of the hexitols, two categories of constitutionallyisomeric bicyclic diacetals can be identified (Figure 1) onthe basis of the relative configurations of the inner pairof hydroxy-groups in the alditols.(i) &Fused 2,4,7,9-tetraoxabicyclo[4.4.O]decane (1) and trans-fused 3,5,8,10-tetraoxabicyclo(5.3.0jdecane (2) ring systems in additionto a 4,4’-bis-1,3-dioxolan (3) may result when carbonatoms previously associated with hydroxy-groups in thethmo configuration form the ring junctions. (ii) trans-Fused 2,4,7,9-tetraoxabicyclo[4.4.0]decane (4) and cis-fused 3,5,8,10-tetraoxabicyclo[5.3.0]decane (5) ring sys-tems in addition to a 4,4’-bis-1,3-dioxolan (6) may resultt D-Arabinitol displays category (i) reactivity if the hydroxy-groups on C-1, -2, -3, and -4 are involved, and category (ii)reactivity if the hydroxy-groups on C-2, -3, -4, and -6 areinvolved.when carbon atoms previously associated with hydroxy-groups in the erythro configuration form the ring junc-tions.Examples of alditols which fall into the first categoryof reactivity are D-threitol, D-XyfitOl, D-arabinitol,f D-glucitol, D-iditol, and D-mannitol; examples of alditolswhich fall into the second category are erythritol, D-arabinitol, ribitol, galactitol, allitol, and D-altritol.Bicyclic diacetals containing the cis-fused 2,4,7,9-tetraoxabicyclo[4.4.O]decane ring system are known inthe threo, xylo, arabino, gluco, ido, and mamo configur-ational series.Acid-catalysed methylenation of L-threitol has yielded 1,3:2,4-di-O-methyIene-~-threitol(7) with a cis-fused [4.4.0] ring system. Although twoconformations, which have been termed the O-inside ’and the H-inside,’ axe possible for (7), dipole momentmeasurements in benzene and lH n.m.r.spectroscopy inJ. F. Stoddart, ‘ Stereochemistry of Carbohydrates,’ Wiley,R. U. Lemieux and J. Howard, Canad. J. Chem., 1963, 41,J. A. Mills, Adv. Carbohydrate Chem., 1966,10, 1.New York, 1971, p. 210.3931976 667deuteriochloroform have shown2 that (7) exists pre-dominantly as the ' O-inside ' conformation in solution.It has also been established4 that the configurationalisomer of 1,3:2,4-di-O-benzylidene-~-threitol with equa-torial phenyl groups in the ' O-inside ' conformation is( i 1 threoRIOHCHOHRIinside ' conformation, a conclusion which is in agreementwith experimental observation.2Molecular models show 193 that 1,3:2,4-di-O-methylene-DL-Xylitol (8) ,17 2,4:3,5-&-0-methylene-~-glucitol (9) ,laand 2,4:3,5-di-O-methylene-~-iditol (10) l9 must alsoI i i) erythroRIOHCHOMR1121FIGURE 1 The two categories (i) and (ii) of constitutional isomers resulting from bicyclic diacetal formation in (i) thethreo series, and (ii) the erythro seriesobtained on acid-catalysed benzylidenation of L-threitol.It was argued 2 some time ago that the ' O-inside ' con-formation is preferred on the basis of steric consider-ations.There are three gauche oxygen-oxygen inter-tactions associated with the -0-b-C-O- fragments in thisI 1conformation whereas the ' H-inside ' conformation in-corporates three anti oxygen-oxygen orientations. Theconformational behaviour of molecules of the typeRO-CH,*CH,*OR' has been the subject of numerous in-vestigations &-16 in the last few years.It has been estab-lished that anti-gazcche equilibria in solution depend onthe nature of R and R' and also on solvent polarity.Solvent effects suggest that electronic factors as well assteric factors are important in determining the positionsof conformational equilibria. Such considerations, how-ever, do not alter the general conclusion1$2 that the' O-inside ' conformation of 1,3:2,4-di-O-methylene-~-threitol (7) should be much more stable than the ' H -A. B. Foster, A. H. Haines, and J. Lehmann, J . Chem. SOG.,1961, 6011.6 J. E. Mark and P. J. Florey, J . Amer. Chem. SOG., 1966, 87,1416; 1966,88, 3702.R. G. Snyder and G. Zerbi, Spectrochim. Acta, 1967, =A,391.C.B. Anderson, D. T. Sepp, M. P. Geis, and A. A. Roberts,Chem. and Ind.. 1968, 1806.E. L. Eliel and M. K. Kaloustian, Chem. Comm., 1970, 290.9 E. L. Eliel, Accounts Chem. Res., 1970, 8, 1.lo R. J. Abraham and K. Parry, J . Chem. SOC. (B), 1970, 639.11 E. L. Eliel, Pure AfiflZ. Chem., 1971,25,609.le R. J. Abraham, H. D. Banks, E. L. Eliel, 0. Hofer, andla E. L. Eliel and R. M. Enanoza, J . Amer. Chem. Soc., 1972,M. K. Kaloustian, J . Amer. Chem. Soc., 1972, 94, 1913.94, 8072.exist in ' O-inside ' conformations, as the ' H-inside 'conformations all have axial hydroxymethyl groupswhich would have to be accommodated in the stericallycrowded ' inside ' portion of the molecule.2,4:3,5-Di-O-methylene-~-rnannitol (1 1) can existeither in the ' O-inside ' conformation with two axialhydroxymethyl groups or in the ' H-inside ' conform-ation with two equatorial hydroxymethyl groups.Coupling constant data from the lH n.m.r.spectrum of1 ,6-dideoxy-2,4:3,5-d-O-methylene-~-mann~tol (12) in&-cate that the ' H-inside ' conformation is the predomin-ant contributor to the conformational equilibrium atroom temperature in deuteriochloroform solution. How-ever, when the temperature is lowered to -59"' the ' 0-inside ' conformation is preferred. The temperaturedependence of this conformational equilibrium has beeninterpreted 21 in terms of the ' H-inside ' conformationbeing more flexible and thus having a higher entropythan the ' O-inside ' conformation.14 E. L. Eliel, Angew.Chem. Internat. Edn., 1972, 11, 739.l5 E. L. Eliel and 0. Hofer, J . Amer. Chem. SOC., 1973, 94,l6 L. Phillips and V. Wray, J . C . S . Chem. Comm., 1973, 90.R. M. Hann, A. T. Ness, and C . S. Hudson, J . Amer. Chem.SOL, 1944, 66, 670.l 8 W. N. Haworth and L. F. Wiggins. J . Chem. SOG., 1944, 68;R. M. Hann, J. K. Wolfe, and C. S . Hudson, J . Amer. Chem. Soc.,1944, 66, 1898.R. M. Ham and C . S. Hudson, J . Amer. Chem. SOC., 1945,87,602.20 W. T. Haskins, R. M. Hann, and C . S. Hudson, J . Amer.Chem. SOG., 1943, 65, 67; W. N. Haworth and L. F. Wiggins, J .Chem. SOC., 1944, 58.21 D. M. Kilburn, M.Sc. Thesis, Queen's University, Kingston,Ontario, 1969.8041668 J.C.S. Perkin IIn principle, D-arabinitol could display category (i) orcategory (ii) reactivity .In practice, acid-cat a1 ysedcondensation of D-arabinitol with formaldehyde yields 221,3:2,4-di-O-rnethylene-~-arabinitol (13) in low yieZd,*and so category (i) reactivity has been observed. Thenature of the potential conformational equilibriumbetween the ‘ 0-inside ’ conformation with an axialhydroxymethyl group and the ‘ H-inside ’ conformationwith an equatorial hydroxymethyl group has not beeninvestigated.Although no transfused 3,5,8,10-tetraoxabicyclo-[5.3.0]decane derivatives have been isolated as thermo-dynamically stable bicyclic diacetals after acid-catalysed‘0- inside’ ( 7 ) ‘ H - inside’110)‘0 - i n s i d e ’ ‘//-insides111 R=CH;OH(12) R=Me‘ 0 - inside’ (13 1 ‘H- inside’acetalations, a number of derivatives of 3,4-0-benzyl-idene-2,6-0-methylene-~-mannitol (14) and 3,4-O-iso-* Recently, one of us has been incorrectly attributed l6 theelaim that the 1,3 : 2,4-diacetal (13) is the thermodynamicallyfavoured product in this reaction.It should be emphasised thatZissis and RichtmeyerZ2 isolated this diacetal from the acid-catalysed methylenation of D-arabinitol in 49% yield only afterthree successive equilibrations of the same reaction mixture. Otherproducts may be present in the reaction mixture under equili-brium conditions and it is our belief that this work should berepeated before conclusions are drawn about the nature of thethermodynamically favoured product.propylidene-2,5-O-methylene-~-mannitol (15) have beenprepared indirectly.=-25R R(1L)a; R= C H i OH 115)a; R=CHiOHb; R=CHiOBz b; R=CHiOBzc; R=CH;OTsd; R=MeH116) R ~ C H ~ O H , R ~ = H ; (18 1or R’=H, RZ-CH; OH11 7) R’= R~=CH;OHBicyclic diacetals containing the trans-fused 2,4,7,9-tetraoxabicyclo[4.4.0]decane system have been charac-terised in only the ribo and aZZo series.Acid catalysedmethylenation of ribitol and allitol has yielded 1,3:2,4-di-0-methylene-m-ribitol (16) 26 and 2,4:3,5-di-O-methyl-ene-allitol (17) 27 with trans-fused [4.4.0] ring systems andequatorial hydroxymethyl groups. When our presentinvestigations were initiated no cis-fused 3,5,8,10-tetra-oxabicyclo[5.3.0]decane derivatives had been fullycharacterised.This paper describes results obtained from the acid-catalysed methylenation of erythritol.The succeedingpaper discusses some closely related findings in thegalacto, arabino, and ribo series. The whole investigationhas been the subject of a preliminary communication.28RESULTS AND DISCUSSIONProlonged acid-catalysed methylenation of erythritolafforded two of the three possible [(4)-(6); R = HIconstitutionally isomeric diacetals shown in Figure 1.Both isomers are crystalline and the isomer with m.p.100” has been reported 29 previously (lit. m.p. 97-98’),although its constitution was not determined. The otherisomer, with m.p. 88-89”, is a new compound. A thirdnon-crystalline product, isolated in low yield (7%) bypreparative g.l.c., was characterised as 1,4-anhydro-2,3-0-methylene-erythritol (18) by spectroscopic methods.76, 5516.Soc., 1943, 65, 2215.22 E.Zissis and N. K. Richtmeyer, J. Amer. Chem. Soc., 1964,23 A. T. Ness, R. M. Hann, and C. S. Hudson, J. Amev. Chew.24 B. Wickberg, Acta Chem. Scand., 1958, 12, 1187.25 J. F. Stoddart and W. A. Szarek, J. Chem. SOC. (B), 1971,26 R. M. Hann and C. S. Hudson, J. Amer. Chem. Soc., 1944,66,27 M. L. Wolfrom, B. W. Lew, and R. M. Goepp, J. Amer.28 I. J. Burden and J. F. Stoddart, J.C.S. Chem. Comm., 1974,29 M. Schulz and B. Tollens, Annalen, 1896,289,’20.437.1906.Chem. Soc., 1946, 68, 1443.8631975 669Constitutional assignments of the diacetals were basedupon the nature of the lH n.m.r. signals for their dioxy-methylene protons 30 and were confirmed 31 by massspectrometry. The chemical shift patterns characterisethe topic relationships 32 between the disxymethylenegroups, and the magnitudes of the geminal couplingconstants between the dioxymethylene protons are alsodiagnostic of a given bicyclic diacetal.It is well estab-lished30 that the geminal coupling constant for dioxy-methylene protons in 1,3-dioxolan rings is close to 0,whereas in 1'3-dioxan and 1,3-dioxepan rings numericalvalues * of around 6 Hz are to be expected.The 1H n.m.r. spectrum of the compound with m.p.88-89" exhibits two anisochronous 32 AB systems withJAB (I 1.0 Hz and JAB 6.1 Hz for the constitutionallyhterotofiic 3, dioxymethylene groups and so this isomeris identified as 1,4:2,3-di-O-methylene-erythritol (5;R = H). The two isochronous 32 AB systems in the lHn.m.r. spectrum of the compound with m.p.100" withJAB 6.0 Hz for the enantiotopic 32 dioxymethylene groupsnecessitate that this isomer be 1,3:2,4-di-O-methylene-erythritol (4; R = H). No evidence was obtained forthe formation of the other possible constitutional isomer,1,2:3,4-di-O-methylene-erythritol (6; R = H), under theconditions of thermodynamic control employed in thisinvestigation.Analysis of the fragmentation patterns produced in themass spectrum of the bicyclic diacetals often allow 31 adistinction to be made between constitutional isomers.The important aspects of the fragmentation pattern (seeExperimental section) of the 1,4:2,3-diacetal ( 5 ; R = €3)are accounted for in Scheme 1. Loss of two formaldehydemolecules from the molecular ion (m/e 146) by rupture ofthree bonds gives a fragment f, (m/e 86) which maysubsequently lose a hydrogen atom to yield fragment f,(m/e 85).There are also important peaks to be found inthe high mass range particularly at m/e 145 (fragmentb,/b',) and 115 (fragment b,/b',). As shown in Scheme1, fragments b, and b', result from loss of a hydrogenatom from the 1,3-dioxolan and I ,3-dioxepan ringsrespectively of the molecular ion. Both these fragmentsmay then lose formaldehyde to give fragments b, and b,',respectively, with nz/e 115. A significant feature of themass spectrum of the 1,4:2,3-diacetal ( 5 ; R = H) is therelatively low abundance of a ' half-ion ' peak at nzle 73.In the case of the 1,3:2,4-diacetal (4; R = H), this is themost intense peak in the mass spectrum (see Experi-mental section) and arises 31 from electron shifts whichresult in the rupture of three bonds t o give a stable ' half-radical ' and the ' half-ion ' (h,) at m/e 73.Loss of car-bon monoxide from the fragment h, gives an ion withm/e 45. Loss of formaldehyde from the molecular ion* Geminal coupling constants usually assume negative values ;i n this paper, however, we shall present numerical values only.30 J. A. Pople and A. A. Bothner-By, J . Chevt. Pirys., 1965, 42,1339; A. A. Bothner-By, Adv. Magnetic Resonance, 1965, 1, 195;R. C. Cookson and T. A. Crabb, Tetrahedron Letters, 1964, 679;Tetrahedron, 1968, 24, 2385; R. C. Cookson, T. A. Crabb, J. J.Frenkel, and J . Hudec, Tetvahedron, Suppl.No. 7, pp. 356, 1966;R. Cahill, H. C. Cookson, and T. A. Crabb, TetralzedrotL, 1969, 25,4681.gives fragment e (m/e 116). Loss of two formaldehydemolecules from the molecular ion gives fragment f,+. +m / e 1L6 \ + +b ( ( m / e i ~ 5 ) b i [m/e 11 5 1SCHEME 1 Fragmentation patterns for1,4:2,3-di-O-rnethylene-erythritol (5; R = H)m / e[c:m / e 146\ -2 ncnoke ( m / e 116)m/e L5Q +fz I m/e 85 1SCHEME 2 Fragmentation patterns for1,3:2,4-di-O-methylene-erythritol (4; R = H)(m/e 86) which can eliminate a hydrogen atom to yieldfragment f, (m/e 85).Molecular models of 1,4:2,3-di-O-met hylene-eryt hritol31 0. S. Chizov, L. S. Golovkina, and N. S. Wulfson, Carbo-hydrate Res., 1968, 6, 138, 143; N. S. Wulfson, 0.S. Chizov, andL. S. Golovkina, Zhur. org. khim., 1968, 4, 744.32 K. Mislow and M . Raban, Topics Stereochenz., 1967, 1, 1;E. L. Eliel, ' Elements of Stereochemistry,' Wiley, New York,1969, p. 20; D. Arigoni and E. L. Eliel. Topics Stereochem., 1969,4, 127; E. L. Eliel, J . Chem. Edztc., 1971, 48, 163; H. Hirsch-mann and K. R. Hanson, J . Ovg. Chenz., 1971, 38, 3293; Ezcro-pean J . Biochem., 1971, 22, 301; J. F. Stoddart, MTP Inter-national Review of Science, Organic Chemistry, Series One, vol. 1,ed. W. D. Ollis, 1973, p. 1670 J.C.S. Perkin I(6; R = H) reveal that there are three conformationswhere torsional energy and nonbonded interactions ap-pear to be approximately minimal. In all these con-formations, the 1,340xepan ring adopts a favourabletwist-chair conformation with the cis-fused I ,3-dioxolanring in a twist conformation.If attention is focused onthe relative conformational dispositions of the oxygenatoms in the -O-C-$-O- units between the five- andseven-membered rings, then the three conformations(Figure 2) may be identified as the gauche,gauche (19),gauche,anti (20), and anti,anti (21) conformations. Thegauche,ga.uche conformation (19) may be regarded as a‘ conformational relative ’ of the ‘ O-inside conform-ation of 1,3:2,4-di-O-methylene-~-threitol (7).In view of this situation it was of interest to investigatethe conformational behaviour of 1,4:2,3-di-O-methylene-erythritol (5; R = H) in solution by lH n.m.r. spectro-scopy. The partial lH n.m.r.spectra in deuteriochloro-form and in carbon disulphide are shown in Figures 3and 4, respectively. In order to aid the assignment ofchemical shifts to the bridgehead and C-methylene pro-tons, 1 ,4:2,3-di-0-methylene[l,l,4,4-2HkJerythritol (26)was prepared by the procedure outlined in Scheme 3.Comparisons of the experimental spectra in Figures 3 and4 with computed spectra have provided the couplingconstant data summarised in Table 1. The problem nowarises of equating this information with the conform-ational behaviour of the molecule. The possibility mustbe recognised that the gauche,gauche (19), gawhe,anti (20),I 1I 8Hgauche ,, gauche gauche, a n t i(19) I201a n t i , a n t iI211FIGURE 2 The gaztche,gauclze (19), gauclze,anti (ZO), and anti,anti (21) conformations of 1,4 : 2,3-di-O-rnethylene-erythritol(5; R = H) ; the gaztche -0-d-d-O- fragments are identifiedI Iby the thickened bondsand anti,anti (21) conformations-and for that matter,other conformations-may be of approximately equalenergies and, in view of the conformational flexibility of* Such a process involves boat-like intermediates for theseven-membered ring.35 W.E. Willy, G. Binsch, and E. L. Eliel, J. Amer. Chem. SOL,1970,92, 6394.34 V. Tabacik, Tetvahedron Letters, 1968, 555, 561.the molecule, may also be undergoing rapid inter-conversion.* If this is the case, then the calculation ofH-2/H-3 H-1’IH-L‘I I f H-VH-41‘ I5.80 5-88 6.21 r5-80 5.88 6.217FIGURE 3 The experimental and computed partial lH n.m.r,spectra of 1,4:2,3-di-O-methylene-erythritol ( 5 ; R = H) indeuteriochloroformspecific coupling constants would be imprudent ,% sincecoupling constants should be summed 34 over the wholepseudorotational itinerary and not just over the mostTABLE 1Vicinal coupling constants observed for 1,4: 2,3-di-0-methylene-erythritol (5 ; R = H) in deuteriochloro-form and carbon disulphideJ I H zVicinal - protons CDCl, CS,1,2 3.0 4.0l’, 2 5.0 7.02, 3 8.0 8.03, 4 3.0 4.03, 4‘ 5.0 7.0stable conformations. In addition, the dependence 35 ofcoupling constants on the orientation of the protons with36 K.L. Williamson, J, Amer. Chem. Soc., 1963, 85, 516;P. Laszlo and P. von R. Schleyer, ibid., p. 2709; D. H. Williamsand N. S.Bhacca, ibid., 1964, 86, 2742; H. Booth, Tetrahedron:Letters, 1966, 411; S . Sternhell, Quart. Rev., 1969, 23, 2361975 67 1respect to the electronegative oxygen atoms is also un-certain. These factors render the Karplus relationship 36unreliable for the quantitative determination of torsionI I /5.94 r 6:21 6:30FIGURE 4 Experimental and computed partial 1H n.m.r.R = H) in spectra of 1,4:2,3-di-O-methylene-eryth~tol (6;carbon disulphideangles, and hence of conformation, in 1,4:2,3-di-O-methylene-erythritol (5; R = H). In six-memberedrings, and to some extent in five-membered rings, thisproblem may be circumvented by employing the R-valuemethod 37 provided certain structural criteria are fulfilled.Unfortunately, 1,4:2,3-di-O-methylene-erythritol (5 ;R = H) is not amenable to such an analysis.However,the significant difference amongst conformations (19)-(21) in Figure 2, lies in the torsion angles involving theH(l')?-?-H(2) and H(3)-C-C-H(4') fragments. Ifthese are directly associated with gauche -0-C-C-O-fragments, then the torsion angle relating the protons toeach other is 38339 synclinal; * if they are associated withanti -0-k-C-O- fragments, then the torsion angle relat-ing the protons to each other antiperiplanar."* Conformations are described as synclinal or antiperifllanar ifthe torsion angle is within *30° of -+ 60" or & 180", respectively. t Tris-( l,l, 1,2,2,3,3-heptafluoro-7,7-dimethyloctane-4,8dion-ato)europiurn(m).1 1 I I1 1 1 1I tII IThus, by applying the Karplus equation in a qualitativesense and making allowance for the conformationalaveraging which is presumably occurring betweenenantiomeric conformations, it would be expected thatthe coupling constant J1r,2 (= J3,4p) would increase inmagnitude on going from the gauche,gauche (19), throughthe gauche,anti (ZO), to the anti,anti (21) conformation.Thus, qualitatively at least, an increase in the magnitudeof observed values for (= J3,4$) from 5.0 to 7.0 Hz(Table 1) on going from deuteriochloroform to carbondisulphide solution indicates that contributions from con-formations with oxygen atoms in the -0-C-C-O- frag-ments in the anti relationship is more important in carbondisulphide.This conclusion is supported by results obtained for1,4:2,3-di-O-methylene-erythritol (5; R = H) in thepresence of the lanthanide shift reagent, Eu(fod),,t indeuteriochloroform and in carbon disulphide solution.Although comparison (Table 2) of the lanthanide-inducedshifts indicates that a similar conformational picture per-tains in both solvents in the presence of Eu(fod),, thedramatic change (Table 3) in the magnitude of J1t,2(= J3,4t) from 7.0 to 4.0 Hz, as Eu(fod), is added pro-gressively to the carbon disulphide solution, is consistentI tI 1C02Me COzMel22)JI7D;OH CDiOHIy y oD D'ox$o'D D125) (26)SCHEME 3 Preparation of 1,3:2,4- (26) and 1,4:2,3- (26)di-O-methylene[ 1, 1,4, 4-aH,]erythritolonly with a perturbation in the conformational equilib-rium towards the gauche,guuche conformation (19).36 M.Karplus, J . Chem. Phys., 1969, 80, 11; J . Amev. Chsm.37 J. B. Lambed, Accounts Chem. Res., 1971, 4, 87.38 W. Klyne and V. Prelog, Experientia, 1960, 16, 621.39 IUPAC 1968 Tentative Rules, Section E, FundamentalSOC., 1963,85. 2870.Stereochemistry, J . Org. Chem., 1970, 55, 2849672 J.C.S. Perkin IInteractions between substrates and lanthanide shiftreagents are known40 to influence the positions of con-formational equilibria involving diastereoisomeric con-formations. The gauchegauche conformation (19) pro-vides the best geometrical situation for simultaneous co-ordination of all four oxygen atoms with the europiumion and is presumably stabilised as a consequence.TABLE 2Comparison of the lanthanide-induced shifts for 1,4:2,3-di-O-methylene-erythritol (5; R = H) with Eu(fod),in deuteriochloroform and in carbon disulphideCDCl, CS,Proton -- H-1/H-4 3-79 4.18 3.70 5.34H-l'/H-4' 4.12 5.16 3.79 6.73H-2/H-3 4.20 4-14 4.06 6-24H A / ~ , ~ - O * C H ~ * O 4.96 2-10 4-60 3.14HB/1,4-O*CH,*O 4.61 2.88 4.60 3-65HA/~,~-O*CH,.O 5.22 1-65 5.01 2.24HB/~,~-O*CH~.O 4.86 2.33 4.72 3.92(1 Plots of lanthanide-induced shifts against molar ratios (p)of complex to substrate gave excellent linear relationships upto at least p = 0.5.Thus, we have defined AW5 = 6" solvent -Kif%;,.TABLE 3Vicinal coupling constants J 1 r , 2 (G J 3 , 4 p ) in CS, for 1,4:2,3-di-O-methylene-erythritol (5; R = H) at variousdifferent molar ratios (p) of Eu(fod),P J1t.z (~J3.4'1IHz0.00 7.00.15 6-90.34 5.00.55 4.00.80 4.0It is instructive to compare these results with thoseobtained (Table 4) for 1,3:2,4-di-O-rnet hylene-~-t hrei t 01TABLE 4Lanthanide-induced shifts for 1,3:2,4-di-O-methylene-~-threitol (7) and 1,6-dideoxy-2,4:3,5-di-O-methylene-~-mannitol (12) in deuteriochloroformCompound (7) Compound (1 2)A AI \ I \ Proton a'eolveat A8°*5 a Proton 8Osolvent ArS0'5H-2/H-3 3.62 4.22 H-2/H-5 4.21 3.62H-laxlH-4ax 3-78 4-27 H-3/H-4 3-67 2.83H-lcqlH-4eq 4.15 6.35 HB 4.83 2-50HB 4.77 3.36 HA 4.83 2-60HA 6.16 3.43 CH, 1-34 1.46a Footnote as for Table 2.(7) and 1,6-dideoxy-2,4:3,5-d~-O-methylene-~-rnann~tol(12) in deuteriochloroform on addition of Eu(fod),.The' O-inside ' conformations of these molecules resemble thegauchegauche conformation (19) of 1,4:2,3-di-O-methyl-40 R.R. Fraser and Y. Y. Wigfield, Chem. Comm., 1970, 1471;J. F. Caputo and A. R. Martin, Tetrahedron Letters, 1971, 4547;W. G. Bentrude, H.-W. Tan, and K. C. Yee, J. Amer. Chem. SOC.,1972,94, 3265; T. Sat0 and K. Goto, J.C.S. Chem. Comm., 1973,494; B. L. Shapiro, M. D. Johnstone, jun., and M. J . Shapiro, J.Org. Chem., 1974, 59. 796; K. L. Williamson, D. R. Clutter, R.Erich, M. Alexander, A. E. Burroughs, C. Chua, and M. E. Bogel,J. Amer. Chem. SOC., 1974, 96, 1471.41 H. Hibbert and N. M. Carter, J. Amer. Chem. SOC., 1028, 50,3120.ene-erythritol(5; R =: H) in as far as they also provide agood disposition of the oxygen atoms for simultaneousco-ordination with europium ions.The lanthanide-induced shifts for (5; R = H) and (7) are similar in asmuch as the signals due to protons on C-1, -2, -3, and-4 are shifted downfield more rapidly than those of theO-methylene protons. Coupling constant data from thelH n . m. r. spectrum of 1,6-dideoxy-2,4: 3,5-di-O-me thyl-ene-D-mannitol (12) show 21 that the ' H-inside ' con-formation is an important contributor to the conform-ational equilibrium at room temperature in deuterio-chloroform solution. However, when Eu(fod), is added,a decrease in the magnitude of J2,3 (= J4,J is observed(Table 5) indicating a perturbation in the conformationalTABLE 5Vicinal coupling constants J2. ( ez J4, J for 1,6-dideoxy-2,4: 3,5-di-O-methylene-~-mannitol ( 12) at variousmolar ratios (p) of Eu(fod),P Jz.3(= J4.JlHZ0.00 5.90.1 1 5.50.27 4-80.43 4.70-58 4.20-74 3.8equilibrium towards the ' O-inside ' conformation.Thisbehaviour appears Yo have a close analogy with thatalready noted for 1,4:2,3-di-O-methylene-erythritol (5 ;R = H) in carbon disulphide solution.Acid-catalysed equilibration of the 1,3:2,4- (4; R = H)and 1,4:2,3- ( 5 ; R = H) diacetals indicates that there isa free energy difference of 1.37 kcal mol-l in favour of the1,3:2,4-diacetal (4; R = H) at room temperature.Coupling constant data (see Experimental section) for the1,3:2,4-diacetal (4; R = H) are consistent with a trans-decalin-like conformation (27) which incorporates threeanti oxygen-oxygen orientations.(271It is known that formaldehyde 41 and acetaldehyde 42943will condense with glycerol to give approximately equi-molar mixtures of 1,3-dioxan and 1,3-dioxolan deriva-tives at equilibrium.Thermodynamic data obtainedfrom the polymerisation of 1,3-dioxolan 44 and 1,3-dioxepan 45 indicate ( c j . ref. 46) that the strain energiesare of the same order of magnitude in these ring systemsas well. Thus, the relatively small free energy differencebetween the 1,3:2,4- (4; R = H) and 1,4:2,3- (5; R = 14)42 H. S. Hill and H . Hibbert, -1. Amev. Cltem. SOC., 1923, 45,3117; H. S. Hill, H. C. Hill, and H. Hibbert, ibid., 1928, 50, 2242.43 G. Aksnes, P. Albriktsen, and P. Juvvik, Ada Chem. Scand.,1966, 19, 920.44 P. H. Plesch and P. H. Westermann, J.Polymer Sci., 1968,C16, 3837; W. K. Bushfield, R. M. Lee, and D. Merigold, Makro-mol. Chem., 1972, 156, 183.45 P. H. Plesch and P. H. Westermann, PoZymer, 1969,10, 105:W. K. Bushfield and R. M. Lee, Makromol. Chem., 1973,169, 199.46 G. Borgen and J . Dale, J.C.S. Cltem. Comm., 1974, 4841975 673diacetals is not surprising.* It would certainly appearthat the gauche oxygen-oxygen interactions in thegaucke,gaztche (19) and gauche,anti (20) conformations ofthe 1,4:2,3-diacetal (5; R = H) do not result in anyappreciable relative stabilisation of this isomer under theequilibrium conditions employed. This is in spite of thefact that the gnuche,unti conformation (20) also accom-modates a favourable orientation for the dioxymethylenegroup in the seven-membered ring.This is the only con-formation in Figure 2 where the 1,3-dioxa-grouping inthe seven-membered ring avoids an unfavourable syn-axial lone pair i n t e r a ~ t i o n . ~ J 1 ~ ~ ~ * ~ There are, of course,two syn-axial interactions associated with the 1,3-dioxa-groupings in the trans-decalin-like conformation (27) ofthe 1,3:2,4-diacetal(4; R = H). This problem does notarise in 2-isopropyl-5-methoxy-l,3-dioxan (28) which isprobably the most suitable model compound avail-able 8r12914915 at present with which to compare thestereoclieinical behaviour of the di-0-methylene deriva-tives [(4) and (5) ; R = H] of erythritol. Studies on theposition of the configurational equilibrium between cis-(28a) and trans- (28b) 2-isopropyl-5-methoxy-l,3-dioxanin 17 different solvents indicate 8*12914715 values for theconformational free energies of the methoxy-groupranging from -0.01 in acetonitrile to 1.06 in n-hexane.These data seem to suggest that there is an ztnfuvoztrableelectronic interaction 8*1291*9 l5 resulting in a small relativedestabilisation of isomers with gauche oxygen-oxygeninteractions and leading to a small preference for the antiarrangement of vicinal oxygen substituents.OMeAlthough it has been claimed16 that in solution thegauche arrangement is always preferred for vicinal oxygensubstituents, there is no evidence that vicinal oxygensubstituents are a stabilising feature in any of the com-pounds discussed in this paper.EXPERIMENTALM.p.s were determined using a Reichart hot-stageapparatus.Optical rotations were measured using aPerkin-Elmer 14 1 automatic polarimeter a t ambient tem-peratures. T.1.c. was carried out on glass plates (20 x 5cm) coated with Merck silica gel G. Developed plates wereair-dried, sprayed with a cerium(1v) sulphate-sulphuric acidreagent, and heated at about 110". Hopkin and WilliamsThey are (i) thefavouring of the 1,4: 2,3-diacetal (5; K = H) on entropygrounds on account of its greater flexibility, and (ii) the destabili-sation of the 1,3 : 2,4-diacetal (4; R = H) relative to trans-decalin due to thc incompatibility of flattening of the C(4)-C(5)-C(6) regions 9 3 1 1 9 1 4 * 4 7 of the 1,3-dioxan rings because of the transring junction between them.Flattening of one 1,3-dioxan ringwould have to be accompanied by unfavourable puckering in theother. Presumably a compromise situation pertains where aconsiderable amount of strain energy is associated centrosym-metrically with the tvans ring junction.*Two other factors should be considered.silica gel (MFC) was used as the chromatographic mediumfor all column separations. G.1.c. analyses were carried outusing a Perkin-Elmer F 11 gas chromatograph equippedwith a flame-ionisation detector. Low resolution massspectra were determined with an A.E.I. MS12 spectrometer,and high resolution spectra with an A.E.I. MS 9 instrument.1.r. spectra were recorded for KBr discs using a Perkin-Elmer 137 spectrophotometer (NaC1 optics). lH N.m.r.spectra were recorded on a Varian HA-100 or HR-220spectrometer with tetramethylsilane as ' lock ' and internalstandard. Theoretical lH n.m.r.spectra were calculatedwith an ICL 1907 computer by use of the LAOCOON I1program. 491,3:2,4- (4; R = H) and 1,4:2,3- (5; R = H) Di-O-methylene-erythritol.-Concentrated sulphuric acid (6 ml)was added t o erythritol (10.0 g) and paraformaldehyde (10.0g). After 3 days at room temperature, the mixture wasrefluxed with methanol (180 ml) for 2 h. On cooling, thesolution was neutralised with barium carbonate, the bariumsalts were filtered off, and the methanol was removed to givea white solid (4.0 g). T.1.c. indicated the presence of twomajor components, RF 0.90 and 0.67 in ethyl acetate-lightpetroleum (b.p.60-80") (3 : 1 v/v). A portion (2.0 g ) ofthis product was chromatographed on a silica gel column(75 x 2-5 cm) with ethyl acetate-light petroleum (b.p.60-80") (1 : 4 v/v) as eluant to give three fractions.Fraction 1, on recrystallisation from ethyl acetate-lightpetroleum (b.p. 6L8Oo), yielded long needles of the 1,3:2,4-diacetal (4; R = H) (757 mg), m.p. 100" (lit.,29 97-98").(Found: C, 49-1; H, 6.6%; M+', 146. C,Hl0O4 requiresC, 49.3; H, 6.9%; M , 146), T (100 MHz; CDCI,) 6.00 and5.30 (4H, AB systems, JAB 6-0 Hz, O*CH,*O), 5-86 (2H, m,Jieq.iax = Juq.4az = 8.0, Jieq.2 = J3.4eq = 1.6HzP H-leq and-4eq), 6.46 (2H, m, Jieq.iaz = J4ep.4az = 8.0, J i a z . 2 =Jieq.2 = J3.4eq = 1.6, J 1 w 2 . 2 = J3.4az = 9.2, J2.3 = 9.2 Hz,J3,& = 9.2 Hz, H-lax and -4ax), and 6.47 (2H, m,H-2 and -3), m/e 146 (5%), 116 (36), 85 (58), 83 (91), 73(loo), and 45 (38).Fraction 2, on recrystallisation from ethyl acetate-lightpetroleum (b.p.60-80"), yielded the 1,4:2,3-dzacetaE (5;R = H) (106 mg), m.p. 88-89" (Found: C, 48.8; H, 6.7%;M+', 146), T (220 MHz; CDCI,) 4.78 and 6.14 (2H, ABsystem, JAB 1.0 Hz, 2,3-O0CH2*0), 5.08 and 5.39 (2H, ABsystem, J a ~ 6.1 H z , 1,4-0*CH2*0), 5.80 (2H, m, J 2 . 3 8.0,J1ts2 = J3,4t = 5.0, J1,2 = J3,4 = 3.0 Hz, H-2 and -3),5.88 (2H, m, J1t,2 = J3,4. = 5.0, J1,lt = J4,4t = 13.0 H z ,H-1' and -a'), and 6.21 (2H, q, J1,2 = J3,4 = 3.0,J1,l# = J4,4i. = 13.0 Hz, H-1 and -4), T (220 MHz; CS,)4.99 and 5.28 (2H, AB system, JAB 1.0 Hz, 2,3-0*CHS*0),5-40 (2H, s, 1,4-0.CH2-O), 5.94 (2H, m, J2,3 8-0, J3,4 4-0,J1#,a = J3,4t = 7.0 H z , H-2 and -3), 6-21 (2H, m, Jl,ln =J 4 , ~ .= 13.0, J1t,2 = J3,4' = 7.0 Hz, H-1' and -4'), and6.30 (2H, m, JlV1t = J 4 , 4 r = 13-0, = J s , r r = 4.0 Hz,H-l and -4), m/e 146 (4%), 145 (6), 115 (85), 101 (21), 86(loo), 85 (17), 83 (21), 73 (30), 70 (60), and 55 (92).Dimethyl 2,3-0-CycZohexyZidene-meso-tartrate (22) .-Amixture of dimethyl meso-tartrate (4.5 g) , cyclohexanone47 E. L. Eliel and Sr. PVI. C. Knoeber, J. Amer. Chem. SOC., 1968,90, 3444; E. L. Eliel, Svensk kern. Tidskr., 1969, 81, 617, 22;F. W. Nader and E. L. Eliel, J. Amer. Chem. Soc., 1970,92, 3050;A. J . de Kok and C. Romers, Rec. Trav. chim., 1970,89, 313.48 J. F. Stoddart, MTP International Review of Science.Organic Chemistry, Series One, vol.7, ed. G . 0. Aspinall, 1973,49 S. Castellano and A. A. Bothner-By, J. Chevn. Phys., 1964,p. 1.41, 3863674 J.C.S. Perkin I(15.0 ml), toluene-p-sulphonic acid (150 mg), and lightpetroleum (b.p. 40-60") (15.0 ml) was refluxed in a Soxhletextractor containing molecular sieves for 48 h. On cooling,the mixture was washed with sodium carbonate solution, andafter the light petroleum had been removed by evaporation,the residue was subjected to fractional distillation. Thesecond fraction collected was characterised as dimethyl 2,3-O-cyclohexylidene-meso-tartrate (22) (3.36 g, 52y0), b.p. 110-120" at 2 mmHg (Found: M+', 258.1104. C12H,,0, re-quires M , 258.1103).2,3-O-CycZohexyZidene[ 1, 1,4,4-2H,]erythritoZ (23) .-A solu-tion of dimethyl 2,3-U-cyclohexylidene-meso-tartrate (22)(1.0 g) in dry tetrahydrofuran (2-0 ml) was added to a solu-tion of lithium aluminium deuteride (346 mg) in dry tetra-hydrofuran (10.0 ml) during 10 min.The mixture was re-fluxed for 30 min before the excess of lithium aluminiumdeuteride was destroyed with ethyl acetate (2.0 ml).Potassium hydroxide (1.0 g) in water (4.0 ml) was added andafter stirring the residue was isolated by decantation. Thisresidue was extracted with ether (3 x 5.0 ml) and the com-bined organic layers were washed, dried, and concentratedto give the tetradeuteriated derivative (23) (860 mg), b.p.175-180" a t 1.5 mmHg (Found: M+', 206.1456.C,,H,,D,O, requires M , 206.1456) as a viscous oil which wasused in the next step without further purification.El, 1,4,4-2HJErythritoE (24).-A solution of the crude 2,3-O-cyclohexylidene[l, 1,4,4-,H Jerythritol (23) (860 mg) inhydrochloric acid ( 0 .1 ~ ; 15-0 ml) was refluxed for 2 h,cooled, and extracted with ether (10.0 ml) to remove cyclo-hexanone. The ether was removed under reduced pressureto leave an oil, which, on addition of ether-ethanol(1 : 1 v/v;7 ml) crystallised to give [I, 1,4,4-2H4]erythritoZ (24) (260 mg,45%), m.p. 119-121'.1,3: 2,4- (25) and 1,4: 2,3- (26) Di-O-methyZene[ 1, 1,4,4-,H4]-erythritot.-Tetradeuteriated erythritol (24) (300 mg) wasmixed with paraformaldehyde (300 mg) and concentratedsulphuric acid (0-18 ml). The mixture was kept for 3 daysa t room temperature. Chloroform (20 ml) was added andthen sodium hydrogen carbonate solution untiI the mixturewas alkaline.The chloroform layer was separated,extracted with more sodium hydrogen carbonate solution(10 ml), dried (MgSO,), and evaporated to yield a white solid(220 mg). T.1.c. revealed the same spectrum of products asobtained from the methylenation of erythritol. The di-acetal components were separated chromatographically bythe procedure described for the undeuteriated analogues.Fraction 1 contained 1,3:2,4-di-O-methylene[ 1, 1,4,4-2H3]-erythritd (25) (75 mg), m.p. loo", z (100 MHz; CDCl,) 5.00and 5.28 (4H, AB systems, JAB 6.0 Hz, O*CH,*O) and 6.47(2H, s, H-2 and -3) ,T (100 MHz; CS,) 5.15 and 5.43 (4H,AB systems, J A B 6-0 Hz, O*CH,*O) and 6.65 (2H, s, H-2 and-3), 7 (100 MHz; C,D,) 5.26 and 5.80 (4H, AB systems,JAB 6.0 Hz, O*CH,*O) and 6.77 (2H, s, H-2 and -3).Fraction 2 contained 1,4:2,3-di-O-unethyZene[ 1, 1,4,4-2H4]-erythritol (26) (44 mg), m.p.88-90', 7 (100 MHz; CDCI,)4.78 and 5.15 (2H, AB system, JAB 1.0 Hz, 2,3-0*CH2*0),Erythritol has 6o m.p. 121.5".5.04 and 5-37 (2H, AB system, JAB 6.0 Hz, 1,4-0*CH2*0),and 5-81 (2H, s, H-2 and -3), T (100 MHz; CS,) 4.99 and5.28 (2H, AB system, JAB 1.0 Hz, 2,3-0*CH2-0), 5.40 (2H,s, 1,4-0*CH2-0), and 5.94 (2H, s, H-2 and -3), T (100 MHz;C,D,) 4.99 and 5.41 (2H, AB system, JAB la0 Hz, 2,3-O*CH,*O), 5.49 and 5-65 (2H, AB system, JAB 6.0 Hz, 1,4-O*CH,*O), and 6-24 (ZH, s, H-2 and -3).Acid-catatysed Equilibration of the Methylent? Diacetals (4 ;R = H) and (5; R = H) of ErythritoZ.-Six reaction mix-tures were prepared containing erythritol (500 mg), para-formaldehyde (500 mg), and concentrated sulphuric acid(0.3 ml) and stored at ca. 25'. Periodically (4-7 weeks)two samples were quenched by addition of sodium hydrogencarbonate followed by extraction with chloroform. Theextracts were analyed by g.1.c. on columns (0.125 in x 6 f t )containing 20% Carbowax 20M washed with 2% potassiumhydroxide. A minimum of three analyses were carried outon each sample. The g.1.c. system was calibrated byTABLE 6Acid-catalysed equilibration of the methylene diacetals(4; R = H) and (5; R = H) of erythritolEquili-bration AGO/Sample time No. of Isomer ratio kcalno. (weeks) analyses [1,3:2,4-] : [1,4:2,3-] K mol-11 4 3 91.3 : 8.7 10.50 1-362 4 3 90.9 : 9.1 9.99 1.373 5 3 91-6 : 8.4 10.90 1.424 5 3 91.6 : 8.4 10.90 1.426 7 6 90.4 : 9.6 9.42 1.336 7 5 90-4 : 9.6 9-42 1.33= 1.37Average valueanalysing known mixtures of methylene diacetals of erythri-tol. The experimental data are summarised in Table 6together with the calculated K and AGO values.During the g.1.c. analyses a small amount (ca. 7%) of avolatile fast-moving component was observed. Since it wassuspected that this component might correspond to the so-far undetected 1,2:3,4-di-O-methylene-erythritol, it wasisolated by preparative g.1.c. Spectroscopic examinationindicated however that it was 1,4-anhydro-2,3-O-methyZene-erythritol (18) (Found: M+', 116.0469. C,H,O, requires M ,116.0473), T (100 MHz; CDCl,) 4.98 and 5.14 (2H, AB sys-tem, JAB la0 Hz, 2,3-0*CH2-0) and 5.24-6.66 (6H,AA'MM'XX' system).1,3:2,4-Di-O-methyEene-~-threitoZ (7) .-Compound (7){m.p. 173-174", [E], -51' (G 0.8 in CHCl,)} was preparedaccording to ref. 2.( 11) .-Compound (11) {m.p. 57-59", [a], +61.8" (c 2.0 in CHC1,) 1was prepared according to ref. 20.[4/1934 Received, 20th September, 197411 , 6-Dideoxy-2,4: 3,5-di-O-methyZene-~-mannitoZ' Heilbron's Dictionary of Organic Compounds,' vol. 3, 1965,Eyre and Spottiswoode, London, p. 1354