- Email: [email protected]
Further observations on the acid-catalysed benzaldehyde-glycerol reaction
Carbohydrale Research
216
Ekevier
FURTHER
OBSERVATIONS
BENZALDEHYDE-GLYCEROL N. BAGGEIT,
J.
ON THE
Publishing
Company, Amsterdam Printed in Edgium
ACID-CATALYSED
REACTION
M. DUXBURY, A. B. FOSTER, AND J. M. WEBBER
Chemisrry Department, The Umkersity, Birmingham 15 (Grear Britain)
(Received January rzth, 1966)
INTRODUCTION The acid-catalysed condensation of aldehydes with tetritols and higher, acyclic, polyhydric alcohols yields derivatives of 1,3-dioxan in preference to those of 1,3dioxolanl. Glycerol is exceptional in that I&dioxolan derivatives (I,a-acetals) are reported to be preponderant at equilibrium *a_ In extending 3 study of benzylidene acetalss, we have re-examined the acid-catalysed condensation of benzaldehyde and glycerol in order to clarify the apparently anomalous situation. The benzylidenation of glycerol was first described by Fischer*, and, subsequently, Irvine et aZ.5concluded that the product was preponderantly, if not exclusively, cis,trans-4-hydroxymethyl-2-phenyl-1,3-dioxolan. However, Hibbert and his co-workers*a found that a crystalline 5-hydroxy-2-phenyl-1,3-dioxan (later shown6 to be cis> formed a sign&cant percentage of the O-benzylideneglycerol mixture. On the basis of the isolation of the crystalline cis-r,3-dioxan derivative from various equilibrium mixtures of the O-benzylideneglycerols, the Canadian worker@ conthe 4-hydroxymethyl-2-phenyl-r ,3-dioxolans were cluded that, in each case, markedly preponderant, although the inaccuracy of the method was recognised. The observation7 that each component of an O-benzylideneglycerol mixture may be identified by the chemical shift of the benzyl protonsigna1inthen.m.r. spectrum allows an easy and reasonably RESULTS AND
accurate
analysis
of an equilibrium
mixture.
DISCUSSION
The benzyl proton signals for trans- (I) and cis-5-hydroxy-2-phenyl-1,3dioxan (II) and cis- (III) and trans-4-hydroxymethyI-2-phenyl-I,3-dioxolan (IV), present in an equilibrium mixture [A, acetal ratio (I)--(II)-(III)-(IV), cu. I:I:3:2.7, see below], occurred at t 4.84, 4.72, 4.41, and 4.25, respectively*, for 3 c(t. 25% solution (total solute) in carbon tetrachloride. The signals were readily assigned since the acetals (Q6. (II)6, and (III)* have been isolated, and their structures determined.
*In dioxan (internal tetramethylsilane), the corresponding signals (t 4.78, 4.66, 4.42, and 4.27) appeared at appreciably lower field than those previously recorded7 relative to an external reference (6% tetramethylsilane in chloroform). Curboh_wfruteRes., 2 (1966) 216-223
N. BAGGEl-l-,
218
J. M. DUXBURY,
A. B. FOSTER,
J. M. WEBBER
6.5-7.0 c.p.s. for the axial (a) and equatorial @) anomeric hydroxyl groups, respectively. The same trend, although not so marked, was shown by the +phenylcyclohexanols [cis (axial OH), 5.74 (Jca. 3 c.p.s); tram (equatorial OH), 5.53 (Jca. 4 c.p.s.)]. The reverse trend is observed for the I&acetals, in that the coupling constant for the &-isomer (II) is the larger, and this difference may be due to a hydroxyl-group orientation effect. Thus, for cz&+-phenylcyclohexanol, in the preferred chair conformation (equatorial phenyl groupl3), the hydrogen atom of the axial hydroxyl group is likely (c$ the results of Cole and Jefferiesla) to be oriented away from the synaxial15 hydrogen atoms in the cyclohexane ring, so that the dihedral angle H-O-C-I-H is ca. o”. On the other hand, if the axial hydroxyl group in the cis-5-hydroxy-z-phenylI,3-dioxan (II) is oriented to allow hydrogen bonding to the ring oxygen atom@, in addition to solvent molecules, the dihedral angle O-H-C-5-H is ca 180~. In the literature, various methods are given for the condensation of benzaldehyde and glycerol. The compositions of the acetal mixtures obtained by repetition of three of these methods are given in Table II. Thus, the mixture (A) obtainedpa by
TABLE II COMPOSITION
Mixture
OF
VARIOUS 0-BENZYLIDENEGLYCEROL
C A. Gerhardt C, storage
r,j-Dio_rolon-r,3-dioxon ratio
AceraZ(o/,) cis-r,j
A B
MIXTURES
(II)
trans-r,j
(I)
cis-r,t
(III)
trans-r,z(IV)
This work ca.
13.1
13.0
38.7
35.2
20.5
14.1 22.8
34-9
30-S
36.6
method16
of mixture
(CO2
sweep
B (without
22.0
at cu.
B, hydrogen
for 12 h at room
2.8:1
Ccz.
co. 1.g:r
18.6
1500);
neutralisation)
Hibberf et aI.=
CCI.0.68:r
chloride
catalyris
7.51
-
5_5:1
for
I h at
100~
temperature.
sweeping out the water of condensation from a benzaldehyde-glycerol
mixture at
ca. 150” with carbon dioxide (Gerhardt methodl6), and that (B) obtained by hydrogen
chloride-catalysed equilibrationza at IOOO, contain preponderantly &tram-1,3dioxolan derivatives (73.9 and 65.4x, respectively). When mixture i3 was subsequently storedza (without neutralisation) at room temperature for 12 hours, a new mixture (C) was obtained in which cis,trans-r,3-dioxan derivatives are preponderant &g-4%)_ The effect of temperature is further illustrated by equilibration of an O-benzylideneglycerol mixture at ca. 180~ in the presence of hydrogen chloride. The product (E) is mainly c&rrans-4-hydroxymethyl-z-phenyl-r,3-dioxolan containing (20% of the 1,3-acetals (I) and (II). The r,3-dioxan-r,3-dioxolan ratios recorded by Hibbert et aZ.2afor various O-benzylideneglycerol mixtures are seriously in error (Table II). Presumably, all of the c&1,3-acetal (II) was not isolated from a particular mixture, and the substantial proportion of the tram-r,3-acetal (I), now shown to be present, was included with the r&dioxolan fraction. van Roonl7 observed a temperature Carbohydrate Res.,
2 (1966)
216-223
BENZALDEHYDE-GLYCEROL
REACTION
219
effect in the acid-catalysed ethylidenation of glycerol; above o”, r,3-dioxolan derivatives were preponderant and, at r7g”, were the exclusive products. By comparison with other benzaldehyde-diol reactions, the presence of a substantial proportion of 1,3-dioxolan derivatives in mixture C suggests the operation of an effect additional to that of temperature. Thus, in the competition reactio@ of equimolar proportions of ethane-r ,2-diol and propane- I ,3-diol with one molecuiar proportion of benzaldehyde, a-phenyl- r ,3-dioxan is the preponderant product. Also, benzylidenation of butane-r,2,4-trio118 yields the 2,4-acetal as the major product, with only ~-IO% of the r,2-acetal. The benzaldehyde-glycerol reaction pattern may be rationalised by a consideration of intermolecular hydrogen-bonding. In the above, competition experiment and in the butane-r,2,4-trio1 reaction, intermolecular hydrogen-bonding would not be a significant factor since, after formation of r,3-dioxan or r,3-dioxolan derivatives, only primary hydroxyl groups remain unsubstituted. For the glycerol derivatives, however, the five- and six-membered acetals contain primary and secondary hydroxyl groups, respectively. It is possible that the stronger acidity and greater steric accessibility of the primary hydroxyl groups facilitate more effective, intermolecular hydrogen-bonding for cis- and tracts-4-hydroxymethyl-2-phenyl-r,pdioxolan, so that their thermodynamic stabilities, relative to those of the cis- (II) and trans-;,3-dioxan derivative (I), are increased. It follows that, on acid-catalysed equilibration of an O-benzylideneglycerol mixture in an inert solvent (i.e., a solvent which is a weak proton-acceptor in hydrogen bonding), as concentration diminishes, intermolecular hydrogen-bonding will diminish, and intramolecular hydrogen-bonding will become dominant. Hence, as the dilution is increased, and if the latter effect is important, ci.s-5-hydroxy-2-phenyl1,3-dioxan (II) should begin to preponderate at equilibrium since this is the only member of the acetal series (I)-(IV) in which complete, intramolecular hydrogznbonding can occurGa. Preliminary result+*, which suggested that such a trend was, indeed, operative, are now amply confirmed. A series of equilibrations was effected in carbon tetrachloride, which was ca. 0.015~ with respect to hydrogen chloride, at 3”, 37”, and 7o”, with total solute concentrations in the range O.OOI-5.0~. The equilibria were approached from two sides using cis-5-hydroxy-2-phenyl-i,3-dioxan (II) and the mixture E which contained mainly cis,trans-4-hydroxymethyl-2-phenyl-1,3-dioxolan. The proportions of the acetals @-(IV) in the neutralised, equilibrated mixtures were determined by integration of the benzyl proton signals in the n.m.r. spectra. The results are depicted in Fig. I, which clearly shows certain trends. Thus, as the temperature of equilibration increases, and for a given molarity of total solute, the combined proportions of six-membered acetals decreases. For example, at o.05~ and at 3”, 37”, and 70”, the percentages of acetals were as follows: c&r,3 (II), 57-5, 45.5, 32-5; trans-I,3 (I) II, 10.5, 12; cis-I,2 (III), 18, 25, 30.5; trans-I,2 (IV), 13.5, 19, 25. Little has been reported19 Is on the effect of temperature on the pattern of acid-catalysed acetalations of polyhydric alcohols other than glycerol, and this aspect of cyclic acetal chemistry merits further investigation. Carbohydrate Res., 2 (1966) 216-223
N.
220
BAGGEZT,
J. M. DUXBURY,
A. B. FOSTER,
J. M. WEBBER
Another trend, especially noticeable at 3” and 37O,is that, as the concentration of total solute diminishes, the proportion of the cis-r,3-acetal (II) increases at the expense of the tram-isomer Cl), whereas the proportions of the cis- (III) and tram-1,2acetals (IV) remain relatively constant. At 37’, for example, the dilution effect is 70”
37O
C
I
1 a0005
0.005 \
A-
e
a015 .,%gg_ MO5
a05
aoo& O50
z; a005 Molarity
a05 (total
05
ap
.,.
50
solute)
Fig. I. Composition of equilibrium O-benzylideneglycerol mixtures with variation in temperature and molarity of total solute. Equilibrations were performed at the molarities recorded above the ordinate. A, cis-5-hydroxy-z-phenyEr&dioxan; B, trans-isomer; C, cis-4-hydroxymethyl-z-phenyl1,3-dioxolan; D, trans-isomer-
minimal at concentrations (
2
(1966) 216-223
BENZALDEHYDE-GLYCEROL
REACTION
221
cis-diols), and other examples are being studied. Evidence and argument has been presented8 which indicate that hemi-acetal formation preferentially involves the primary hydroxyl group of terminal vicinal diols, and further evidence was sought from the n.m.r. spectra of diols in dimethyl sulphoxide. In this solvent, the signalsll for the primary (triplet, r 5.60) and secondary hydroxyl groups (doublet, 5.64) of propane-r+diol were partially superimposed and gave an unsymmetrical triplet. Glycerol gave a more complex signal pattern C5.61 (2-proton triplet), 5.53 (r-proton doublet)]. It was hoped that addition of a suitable aldehyde to a solution of propaner,z-diol in dimethyl sulphoxide would result in diminution in intensity of the primary hydroxyl signal as hemi-acetal formation proceeded_ However, trichloroacetaldehyde and pentafluorobenzaldehyde, which readily form hemi-acetals, could not be freed from traces of acid, and their separate addition caused coalescence of the hydroxyl proton signals. Coalescence occurred gradually when acetaldehyde was used, and was complete when equimolar amounts of the diol and aldehyde were present. At equilibrium in NJV-dimethylformamide at room temperature, the cis- (II) and the trans-r,3-acetal (I) are present in comparable proportions, in contrast to the situation in carbon tetrachloride (e.g., Fig. 2) where the cis-r,3-acetal was preponderant. When equilibrium was effected in sulpholane, using the cis-r,3-acetal (II) or the mixture E as starting material, the acetal ratio [(I)-(II)-(III)-(IV), ca. x.4:1.7:1.2: r-o] was not significantly different from the ratio noted above for N,N-dimethylfor-man-ride, but, with dimethyl sulphoxide at room temperature, the ratio was ca. 2.4: 1.3:1.2:1.0, showing a preponderance of the Pans-1,3-acetal (I). The ratio was little different when the equilibration was effected at 0“. Hydrogen bonding effects may be responsible, at least in part, for these differences. In carbon tetrachloride, significant hydrogen-bonding can occur intramolecularly or between solute molecules, and the favoured component (cis-1,3-acetal) is that which can undergo the most extensive, intramolecular hydrogen-bonding, whereas, in dimethyl sulphoxide, strong hydrogen-bonding to the solvent occurs, and the preponderant isomer (transr,3-acetal) is that which would be expected.on conformational grounds. The effect of solvent on the equilibration of other cyclic acetal systems is being investigated. EXF’ERIMENTAL
Unless otherwise stated, n.m.r. spectra were obtained on ca. 20% solutions (internal tetramethylsilane) by using a Varian A60 spectrometer under normal working conditions. Equilibration experiments A series of separate solutions of cis-5-hydroxy-2-phenyl-1,3-dioxd$ (0.45 g) and cis,trarzs-4-hydroxymethyl-2-phenyl-r,3-dioxolan (0.45 g, mixture E, see DISCUSSION) in carbon tetracbloride (volume determined by the desired molarity of solute), which was ca. 0.015~ with respect to hydrogen chloride, was stored for suitable Carbohydrate
Res.,
2 (I 966) 216423
222
N. BAGGEilT,
J. M. DUXBURY,
A. B. FOSTER, J. M. WEBBER
periods at 3” (5 days), 37” (24 h), and 70~ (5 h). The solutions were then neutralized with ammonia gas and, after storage at 37” for 30 min, filtered, concentrated (to ca. 0.5 ml) under diminished pressure, and analysed by n.m.r. spectroscopy. Control experiments showed that no change in the composition of an equilibrium mixture occurred after the ammonia treatment_ The benzyl proton signals for cis- and trans-5-hydroxy-2-phenyl-r,3-dioxan and cis- and trans-+hydroxymethyl-z-phenyl-I,g-dioxolan
occur at t 4.72,
4.84,
4.41,
and 4.25, respectively, in carbon tetrachloride. The relative proportions of each acetal were determined from the average of several integrations of the relevant peak areas, using a sweep width of IOOc.p.s. The results are shown in Fig. I _
Preparation of equilibrium mixtures (a) Water was removed during I h from a mixture of benzaldehyde (150 g) and glycerol (120 g) at 145-155” by a stream of carbon dioxide (Gerhardt methodIT) and then for a further 30 min at r 65’. Distillation of the residue gave the acetal m.ixtureeaA (173 g), b-p. 152-160°/ca. 12 mm. (b) The procedure of Hibbert et aZ.25 was repeated as exactly as possible. Thus, cis-5-hydroxy-2-phenyl-r,3-dioxan was equilibrated by heating for I h at IOO” in the presence of hydrogen chloride (mixture B, after neutralisation with cont. ammonia) and then stored at room temperature for 12 h (mixture C, after neutralisation). An ethereal solution of the product was neutralised with solid potassium carbonate and concentrated (mixture 0). The procedure was repeated with cis,frm.s4-hydroxymethyl-2-phenyl-r,3-dioxolan (mixture E) to give the corresponding products, B’, c’, and D’. Some of the results are recorded in Table II. The composition of the mixture pairs B,B’, C,C’, and D,D’ were closely similar, as were mixtures C and D. (c) The equilibrations in sulpholane and dimethyl sulphoxide involved, in each case, a mixture of the solvent (0.5 ml), cis-r,3-acetal (II, 0.45 g) or mixture E (0.45 g), and toluene-p-sulphonic acid (5 mg). The homogeneous benzylidenation involved N,N-dimethylformamide (2 ml), benzaldehyde (3 g), glycerol (2 g), and toluene-p-&phonic acid (5 mg). ACKNOWLEDGEMENTS
The authors thank Professor M. Stacey, F. R. S., for his interest and the S. R. C. for a research studentship (J. M.D.). SUhlhfARY
The proportions of cis- and trans-5-hydroxy-2-phenyl-r.3-dioxan and cis- and trans-4-hydroxymethyl-2-phenyl-1,3-dioxolan in acid-catalysed, equilibrated, Obenzylideneglycerol mixtures are critically dependent on solvent and temperature. In carbon tetrachloride, elevation of temperature increases the proportion of dioxolan Carbohydrare Res,
2
(x966)
216-223
BENZALDEHYDE-GLYCEROL
REACTION
223
derivatives and, at a given temperature, diminishing concentration increases the proportion of the cis-r,3-acetal at the expense of the tra~zs-isomer. At equilibrium in dimethyl sulphoxide, the rrans-r,3-acetal is preponderant. On acid-catalysed benzylidenation of glycerol under homogeneous conditions (~&dimethylformamide), the ~,a-acetals form rapidly in the initial, kinetic phase, and the IJ-acetals are preponderant at equilibrium. A rationalisation of some of these observations is presented.
REFERENCES I S. A. BARKER AND E. J. BOURNE, Adoan. Carbohydrate Cltem., 7 (1952) 137. S. HILL, M. S. WHELM, AND H. HIBBERT, J. Am. Chem. Sot., 50 (1928) 2235; (b)H. HIBBERT AND J. A. TIMM, J. Am. Chem. Sot., 46 (1924) 1283. 3 N. BAGGEIT, K. W. BUCK, A. B. FOSTER, AND J. M. WEBBER, J. Chem. Sot., (1965) 3401. 4 E. FISCHER, Ber., 27 (1894) 1536. 5 J. C. IRVINE, J. L. A. MACDONALD, AND C. W. SOUTAR, J. Chem. Sot., 107 (Igi5) 337. 6(a) N. BAGGEIT, J. S. BRIMACO~~BE,A.B. FOSTER, M. STACEY, AND D. H. WHIFFEIV,J. C/tern.Sot., (1960) 2574 ; (b) A. B. FOSTER, A. H. HAIMS, AND J. LEHMANN, J. Chem. Sot., (1961) 5011. 7 N. BAGGETT, K. W. BUCK, A. B. FOSTER, M. H. RANDALL, AND J. M. WEBBER, J. Clrem. Sot., 2 (a)H.
(1965) 33948 N. BAGGET, A. B. FOSTER, J. M. DUXBURY, AND J. M. WEBBER, J. Chem. Sot. (C), (1966) 208. g A. B. FOSTER, A. H. HAINES, J. HohfER, J. LEHMANN, AND L. F. THOMAS, J. Cfrem. Sot., (1961) IO P. E. VERKADE
II
AND J. D. VAN ROON, Rec. Tram. Chirn., 61 (1942) 831.
0. L. CHAPMAN AND R. W. KING,
12 B.
CASU,
M.
REGGIANI,
G.
G.
J. Am. Chenz. Sot., 86 (1964) 1256. GALLO, AND A. VIGEVANI, Tetralzedron Letters,
(1964) 2839;
(1965) 2253.
GARBISCH AND D. B. PA-RSON, f. Am. Chem. Sot., 85 (1963) 3228. 14 A. R. H. COLE AND P. R. JEFFERIES, J. C/rem. Sot., (1956) 4391. 15 E. L. ELIEL, Angetu. CJzem. Intern. Ed., 4 (1965) 761. 16 W. GERHARDT, Germm Pat., 255,083 (1913)~ 17 J. D. VAN ROON, Rec. Trau. CJnin., 48 (1929) 173. 18 A. B. FOSTER, A. H. HAINES, AND M. STACEY, Tetralredron, 16 (1961) 177. 19 J. A. MILLS, Adcan. C’arbolzydrare Chem., IO (1955) I. 20 L. P. KUHN, J. Am. Chem. Sot., 74 (1952) 2492; 76 (1954) 4323_ 21 J. S. BRIMACOLIBE, A. B. FOSTER, AND A. H. HAINES, J_ Chem. Sot., (1960) 2582. 22 B. DOBINSON AND A. B. FOSIZR, J. CJlem. Sot., (1961) 2338. 23 F. S. AL-JEBOURY, N. BAGGETT, A. B. FOSTER, AND J. M. WEBBER, CkenI. Comm~irr., (1965) 13 E. W.
222.
Carbohydrate Res.. 2 (1966) 216-223
216
Ekevier
FURTHER
OBSERVATIONS
BENZALDEHYDE-GLYCEROL N. BAGGEIT,
J.
ON THE
Publishing
Company, Amsterdam Printed in Edgium
ACID-CATALYSED
REACTION
M. DUXBURY, A. B. FOSTER, AND J. M. WEBBER
Chemisrry Department, The Umkersity, Birmingham 15 (Grear Britain)
(Received January rzth, 1966)
INTRODUCTION The acid-catalysed condensation of aldehydes with tetritols and higher, acyclic, polyhydric alcohols yields derivatives of 1,3-dioxan in preference to those of 1,3dioxolanl. Glycerol is exceptional in that I&dioxolan derivatives (I,a-acetals) are reported to be preponderant at equilibrium *a_ In extending 3 study of benzylidene acetalss, we have re-examined the acid-catalysed condensation of benzaldehyde and glycerol in order to clarify the apparently anomalous situation. The benzylidenation of glycerol was first described by Fischer*, and, subsequently, Irvine et aZ.5concluded that the product was preponderantly, if not exclusively, cis,trans-4-hydroxymethyl-2-phenyl-1,3-dioxolan. However, Hibbert and his co-workers*a found that a crystalline 5-hydroxy-2-phenyl-1,3-dioxan (later shown6 to be cis> formed a sign&cant percentage of the O-benzylideneglycerol mixture. On the basis of the isolation of the crystalline cis-r,3-dioxan derivative from various equilibrium mixtures of the O-benzylideneglycerols, the Canadian worker@ conthe 4-hydroxymethyl-2-phenyl-r ,3-dioxolans were cluded that, in each case, markedly preponderant, although the inaccuracy of the method was recognised. The observation7 that each component of an O-benzylideneglycerol mixture may be identified by the chemical shift of the benzyl protonsigna1inthen.m.r. spectrum allows an easy and reasonably RESULTS AND
accurate
analysis
of an equilibrium
mixture.
DISCUSSION
The benzyl proton signals for trans- (I) and cis-5-hydroxy-2-phenyl-1,3dioxan (II) and cis- (III) and trans-4-hydroxymethyI-2-phenyl-I,3-dioxolan (IV), present in an equilibrium mixture [A, acetal ratio (I)--(II)-(III)-(IV), cu. I:I:3:2.7, see below], occurred at t 4.84, 4.72, 4.41, and 4.25, respectively*, for 3 c(t. 25% solution (total solute) in carbon tetrachloride. The signals were readily assigned since the acetals (Q6. (II)6, and (III)* have been isolated, and their structures determined.
*In dioxan (internal tetramethylsilane), the corresponding signals (t 4.78, 4.66, 4.42, and 4.27) appeared at appreciably lower field than those previously recorded7 relative to an external reference (6% tetramethylsilane in chloroform). Curboh_wfruteRes., 2 (1966) 216-223
N. BAGGEl-l-,
218
J. M. DUXBURY,
A. B. FOSTER,
J. M. WEBBER
6.5-7.0 c.p.s. for the axial (a) and equatorial @) anomeric hydroxyl groups, respectively. The same trend, although not so marked, was shown by the +phenylcyclohexanols [cis (axial OH), 5.74 (Jca. 3 c.p.s); tram (equatorial OH), 5.53 (Jca. 4 c.p.s.)]. The reverse trend is observed for the I&acetals, in that the coupling constant for the &-isomer (II) is the larger, and this difference may be due to a hydroxyl-group orientation effect. Thus, for cz&+-phenylcyclohexanol, in the preferred chair conformation (equatorial phenyl groupl3), the hydrogen atom of the axial hydroxyl group is likely (c$ the results of Cole and Jefferiesla) to be oriented away from the synaxial15 hydrogen atoms in the cyclohexane ring, so that the dihedral angle H-O-C-I-H is ca. o”. On the other hand, if the axial hydroxyl group in the cis-5-hydroxy-z-phenylI,3-dioxan (II) is oriented to allow hydrogen bonding to the ring oxygen atom@, in addition to solvent molecules, the dihedral angle O-H-C-5-H is ca 180~. In the literature, various methods are given for the condensation of benzaldehyde and glycerol. The compositions of the acetal mixtures obtained by repetition of three of these methods are given in Table II. Thus, the mixture (A) obtainedpa by
TABLE II COMPOSITION
Mixture
OF
VARIOUS 0-BENZYLIDENEGLYCEROL
C A. Gerhardt C, storage
r,j-Dio_rolon-r,3-dioxon ratio
AceraZ(o/,) cis-r,j
A B
MIXTURES
(II)
trans-r,j
(I)
cis-r,t
(III)
trans-r,z(IV)
This work ca.
13.1
13.0
38.7
35.2
20.5
14.1 22.8
34-9
30-S
36.6
method16
of mixture
(CO2
sweep
B (without
22.0
at cu.
B, hydrogen
for 12 h at room
2.8:1
Ccz.
co. 1.g:r
18.6
1500);
neutralisation)
Hibberf et aI.=
CCI.0.68:r
chloride
catalyris
7.51
-
5_5:1
for
I h at
100~
temperature.
sweeping out the water of condensation from a benzaldehyde-glycerol
mixture at
ca. 150” with carbon dioxide (Gerhardt methodl6), and that (B) obtained by hydrogen
chloride-catalysed equilibrationza at IOOO, contain preponderantly &tram-1,3dioxolan derivatives (73.9 and 65.4x, respectively). When mixture i3 was subsequently storedza (without neutralisation) at room temperature for 12 hours, a new mixture (C) was obtained in which cis,trans-r,3-dioxan derivatives are preponderant &g-4%)_ The effect of temperature is further illustrated by equilibration of an O-benzylideneglycerol mixture at ca. 180~ in the presence of hydrogen chloride. The product (E) is mainly c&rrans-4-hydroxymethyl-z-phenyl-r,3-dioxolan containing (20% of the 1,3-acetals (I) and (II). The r,3-dioxan-r,3-dioxolan ratios recorded by Hibbert et aZ.2afor various O-benzylideneglycerol mixtures are seriously in error (Table II). Presumably, all of the c&1,3-acetal (II) was not isolated from a particular mixture, and the substantial proportion of the tram-r,3-acetal (I), now shown to be present, was included with the r&dioxolan fraction. van Roonl7 observed a temperature Carbohydrate Res.,
2 (1966)
216-223
BENZALDEHYDE-GLYCEROL
REACTION
219
effect in the acid-catalysed ethylidenation of glycerol; above o”, r,3-dioxolan derivatives were preponderant and, at r7g”, were the exclusive products. By comparison with other benzaldehyde-diol reactions, the presence of a substantial proportion of 1,3-dioxolan derivatives in mixture C suggests the operation of an effect additional to that of temperature. Thus, in the competition reactio@ of equimolar proportions of ethane-r ,2-diol and propane- I ,3-diol with one molecuiar proportion of benzaldehyde, a-phenyl- r ,3-dioxan is the preponderant product. Also, benzylidenation of butane-r,2,4-trio118 yields the 2,4-acetal as the major product, with only ~-IO% of the r,2-acetal. The benzaldehyde-glycerol reaction pattern may be rationalised by a consideration of intermolecular hydrogen-bonding. In the above, competition experiment and in the butane-r,2,4-trio1 reaction, intermolecular hydrogen-bonding would not be a significant factor since, after formation of r,3-dioxan or r,3-dioxolan derivatives, only primary hydroxyl groups remain unsubstituted. For the glycerol derivatives, however, the five- and six-membered acetals contain primary and secondary hydroxyl groups, respectively. It is possible that the stronger acidity and greater steric accessibility of the primary hydroxyl groups facilitate more effective, intermolecular hydrogen-bonding for cis- and tracts-4-hydroxymethyl-2-phenyl-r,pdioxolan, so that their thermodynamic stabilities, relative to those of the cis- (II) and trans-;,3-dioxan derivative (I), are increased. It follows that, on acid-catalysed equilibration of an O-benzylideneglycerol mixture in an inert solvent (i.e., a solvent which is a weak proton-acceptor in hydrogen bonding), as concentration diminishes, intermolecular hydrogen-bonding will diminish, and intramolecular hydrogen-bonding will become dominant. Hence, as the dilution is increased, and if the latter effect is important, ci.s-5-hydroxy-2-phenyl1,3-dioxan (II) should begin to preponderate at equilibrium since this is the only member of the acetal series (I)-(IV) in which complete, intramolecular hydrogznbonding can occurGa. Preliminary result+*, which suggested that such a trend was, indeed, operative, are now amply confirmed. A series of equilibrations was effected in carbon tetrachloride, which was ca. 0.015~ with respect to hydrogen chloride, at 3”, 37”, and 7o”, with total solute concentrations in the range O.OOI-5.0~. The equilibria were approached from two sides using cis-5-hydroxy-2-phenyl-i,3-dioxan (II) and the mixture E which contained mainly cis,trans-4-hydroxymethyl-2-phenyl-1,3-dioxolan. The proportions of the acetals @-(IV) in the neutralised, equilibrated mixtures were determined by integration of the benzyl proton signals in the n.m.r. spectra. The results are depicted in Fig. I, which clearly shows certain trends. Thus, as the temperature of equilibration increases, and for a given molarity of total solute, the combined proportions of six-membered acetals decreases. For example, at o.05~ and at 3”, 37”, and 70”, the percentages of acetals were as follows: c&r,3 (II), 57-5, 45.5, 32-5; trans-I,3 (I) II, 10.5, 12; cis-I,2 (III), 18, 25, 30.5; trans-I,2 (IV), 13.5, 19, 25. Little has been reported19 Is on the effect of temperature on the pattern of acid-catalysed acetalations of polyhydric alcohols other than glycerol, and this aspect of cyclic acetal chemistry merits further investigation. Carbohydrate Res., 2 (1966) 216-223
N.
220
BAGGEZT,
J. M. DUXBURY,
A. B. FOSTER,
J. M. WEBBER
Another trend, especially noticeable at 3” and 37O,is that, as the concentration of total solute diminishes, the proportion of the cis-r,3-acetal (II) increases at the expense of the tram-isomer Cl), whereas the proportions of the cis- (III) and tram-1,2acetals (IV) remain relatively constant. At 37’, for example, the dilution effect is 70”
37O
C
I
1 a0005
0.005 \
A-
e
a015 .,%gg_ MO5
a05
aoo& O50
z; a005 Molarity
a05 (total
05
ap
.,.
50
solute)
Fig. I. Composition of equilibrium O-benzylideneglycerol mixtures with variation in temperature and molarity of total solute. Equilibrations were performed at the molarities recorded above the ordinate. A, cis-5-hydroxy-z-phenyEr&dioxan; B, trans-isomer; C, cis-4-hydroxymethyl-z-phenyl1,3-dioxolan; D, trans-isomer-
minimal at concentrations (
2
(1966) 216-223
BENZALDEHYDE-GLYCEROL
REACTION
221
cis-diols), and other examples are being studied. Evidence and argument has been presented8 which indicate that hemi-acetal formation preferentially involves the primary hydroxyl group of terminal vicinal diols, and further evidence was sought from the n.m.r. spectra of diols in dimethyl sulphoxide. In this solvent, the signalsll for the primary (triplet, r 5.60) and secondary hydroxyl groups (doublet, 5.64) of propane-r+diol were partially superimposed and gave an unsymmetrical triplet. Glycerol gave a more complex signal pattern C5.61 (2-proton triplet), 5.53 (r-proton doublet)]. It was hoped that addition of a suitable aldehyde to a solution of propaner,z-diol in dimethyl sulphoxide would result in diminution in intensity of the primary hydroxyl signal as hemi-acetal formation proceeded_ However, trichloroacetaldehyde and pentafluorobenzaldehyde, which readily form hemi-acetals, could not be freed from traces of acid, and their separate addition caused coalescence of the hydroxyl proton signals. Coalescence occurred gradually when acetaldehyde was used, and was complete when equimolar amounts of the diol and aldehyde were present. At equilibrium in NJV-dimethylformamide at room temperature, the cis- (II) and the trans-r,3-acetal (I) are present in comparable proportions, in contrast to the situation in carbon tetrachloride (e.g., Fig. 2) where the cis-r,3-acetal was preponderant. When equilibrium was effected in sulpholane, using the cis-r,3-acetal (II) or the mixture E as starting material, the acetal ratio [(I)-(II)-(III)-(IV), ca. x.4:1.7:1.2: r-o] was not significantly different from the ratio noted above for N,N-dimethylfor-man-ride, but, with dimethyl sulphoxide at room temperature, the ratio was ca. 2.4: 1.3:1.2:1.0, showing a preponderance of the Pans-1,3-acetal (I). The ratio was little different when the equilibration was effected at 0“. Hydrogen bonding effects may be responsible, at least in part, for these differences. In carbon tetrachloride, significant hydrogen-bonding can occur intramolecularly or between solute molecules, and the favoured component (cis-1,3-acetal) is that which can undergo the most extensive, intramolecular hydrogen-bonding, whereas, in dimethyl sulphoxide, strong hydrogen-bonding to the solvent occurs, and the preponderant isomer (transr,3-acetal) is that which would be expected.on conformational grounds. The effect of solvent on the equilibration of other cyclic acetal systems is being investigated. EXF’ERIMENTAL
Unless otherwise stated, n.m.r. spectra were obtained on ca. 20% solutions (internal tetramethylsilane) by using a Varian A60 spectrometer under normal working conditions. Equilibration experiments A series of separate solutions of cis-5-hydroxy-2-phenyl-1,3-dioxd$ (0.45 g) and cis,trarzs-4-hydroxymethyl-2-phenyl-r,3-dioxolan (0.45 g, mixture E, see DISCUSSION) in carbon tetracbloride (volume determined by the desired molarity of solute), which was ca. 0.015~ with respect to hydrogen chloride, was stored for suitable Carbohydrate
Res.,
2 (I 966) 216423
222
N. BAGGEilT,
J. M. DUXBURY,
A. B. FOSTER, J. M. WEBBER
periods at 3” (5 days), 37” (24 h), and 70~ (5 h). The solutions were then neutralized with ammonia gas and, after storage at 37” for 30 min, filtered, concentrated (to ca. 0.5 ml) under diminished pressure, and analysed by n.m.r. spectroscopy. Control experiments showed that no change in the composition of an equilibrium mixture occurred after the ammonia treatment_ The benzyl proton signals for cis- and trans-5-hydroxy-2-phenyl-r,3-dioxan and cis- and trans-+hydroxymethyl-z-phenyl-I,g-dioxolan
occur at t 4.72,
4.84,
4.41,
and 4.25, respectively, in carbon tetrachloride. The relative proportions of each acetal were determined from the average of several integrations of the relevant peak areas, using a sweep width of IOOc.p.s. The results are shown in Fig. I _
Preparation of equilibrium mixtures (a) Water was removed during I h from a mixture of benzaldehyde (150 g) and glycerol (120 g) at 145-155” by a stream of carbon dioxide (Gerhardt methodIT) and then for a further 30 min at r 65’. Distillation of the residue gave the acetal m.ixtureeaA (173 g), b-p. 152-160°/ca. 12 mm. (b) The procedure of Hibbert et aZ.25 was repeated as exactly as possible. Thus, cis-5-hydroxy-2-phenyl-r,3-dioxan was equilibrated by heating for I h at IOO” in the presence of hydrogen chloride (mixture B, after neutralisation with cont. ammonia) and then stored at room temperature for 12 h (mixture C, after neutralisation). An ethereal solution of the product was neutralised with solid potassium carbonate and concentrated (mixture 0). The procedure was repeated with cis,frm.s4-hydroxymethyl-2-phenyl-r,3-dioxolan (mixture E) to give the corresponding products, B’, c’, and D’. Some of the results are recorded in Table II. The composition of the mixture pairs B,B’, C,C’, and D,D’ were closely similar, as were mixtures C and D. (c) The equilibrations in sulpholane and dimethyl sulphoxide involved, in each case, a mixture of the solvent (0.5 ml), cis-r,3-acetal (II, 0.45 g) or mixture E (0.45 g), and toluene-p-sulphonic acid (5 mg). The homogeneous benzylidenation involved N,N-dimethylformamide (2 ml), benzaldehyde (3 g), glycerol (2 g), and toluene-p-&phonic acid (5 mg). ACKNOWLEDGEMENTS
The authors thank Professor M. Stacey, F. R. S., for his interest and the S. R. C. for a research studentship (J. M.D.). SUhlhfARY
The proportions of cis- and trans-5-hydroxy-2-phenyl-r.3-dioxan and cis- and trans-4-hydroxymethyl-2-phenyl-1,3-dioxolan in acid-catalysed, equilibrated, Obenzylideneglycerol mixtures are critically dependent on solvent and temperature. In carbon tetrachloride, elevation of temperature increases the proportion of dioxolan Carbohydrare Res,
2
(x966)
216-223
BENZALDEHYDE-GLYCEROL
REACTION
223
derivatives and, at a given temperature, diminishing concentration increases the proportion of the cis-r,3-acetal at the expense of the tra~zs-isomer. At equilibrium in dimethyl sulphoxide, the rrans-r,3-acetal is preponderant. On acid-catalysed benzylidenation of glycerol under homogeneous conditions (~&dimethylformamide), the ~,a-acetals form rapidly in the initial, kinetic phase, and the IJ-acetals are preponderant at equilibrium. A rationalisation of some of these observations is presented.
REFERENCES I S. A. BARKER AND E. J. BOURNE, Adoan. Carbohydrate Cltem., 7 (1952) 137. S. HILL, M. S. WHELM, AND H. HIBBERT, J. Am. Chem. Sot., 50 (1928) 2235; (b)H. HIBBERT AND J. A. TIMM, J. Am. Chem. Sot., 46 (1924) 1283. 3 N. BAGGEIT, K. W. BUCK, A. B. FOSTER, AND J. M. WEBBER, J. Chem. Sot., (1965) 3401. 4 E. FISCHER, Ber., 27 (1894) 1536. 5 J. C. IRVINE, J. L. A. MACDONALD, AND C. W. SOUTAR, J. Chem. Sot., 107 (Igi5) 337. 6(a) N. BAGGEIT, J. S. BRIMACO~~BE,A.B. FOSTER, M. STACEY, AND D. H. WHIFFEIV,J. C/tern.Sot., (1960) 2574 ; (b) A. B. FOSTER, A. H. HAIMS, AND J. LEHMANN, J. Chem. Sot., (1961) 5011. 7 N. BAGGETT, K. W. BUCK, A. B. FOSTER, M. H. RANDALL, AND J. M. WEBBER, J. Clrem. Sot., 2 (a)H.
(1965) 33948 N. BAGGET, A. B. FOSTER, J. M. DUXBURY, AND J. M. WEBBER, J. Chem. Sot. (C), (1966) 208. g A. B. FOSTER, A. H. HAINES, J. HohfER, J. LEHMANN, AND L. F. THOMAS, J. Cfrem. Sot., (1961) IO P. E. VERKADE
II
AND J. D. VAN ROON, Rec. Tram. Chirn., 61 (1942) 831.
0. L. CHAPMAN AND R. W. KING,
12 B.
CASU,
M.
REGGIANI,
G.
G.
J. Am. Chenz. Sot., 86 (1964) 1256. GALLO, AND A. VIGEVANI, Tetralzedron Letters,
(1964) 2839;
(1965) 2253.
GARBISCH AND D. B. PA-RSON, f. Am. Chem. Sot., 85 (1963) 3228. 14 A. R. H. COLE AND P. R. JEFFERIES, J. C/rem. Sot., (1956) 4391. 15 E. L. ELIEL, Angetu. CJzem. Intern. Ed., 4 (1965) 761. 16 W. GERHARDT, Germm Pat., 255,083 (1913)~ 17 J. D. VAN ROON, Rec. Trau. CJnin., 48 (1929) 173. 18 A. B. FOSTER, A. H. HAINES, AND M. STACEY, Tetralredron, 16 (1961) 177. 19 J. A. MILLS, Adcan. C’arbolzydrare Chem., IO (1955) I. 20 L. P. KUHN, J. Am. Chem. Sot., 74 (1952) 2492; 76 (1954) 4323_ 21 J. S. BRIMACOLIBE, A. B. FOSTER, AND A. H. HAINES, J_ Chem. Sot., (1960) 2582. 22 B. DOBINSON AND A. B. FOSIZR, J. CJlem. Sot., (1961) 2338. 23 F. S. AL-JEBOURY, N. BAGGETT, A. B. FOSTER, AND J. M. WEBBER, CkenI. Comm~irr., (1965) 13 E. W.
222.
Carbohydrate Res.. 2 (1966) 216-223