postulated (I), on the basis of the antiperiplanar lone-pair hypothesis, that a-glycosides (axial anomer) are hydrolyzed via their ground state chair conformation ...
1994 R.U. Lemieux Award Lecture Hydrolysis of acetals and ketals. Position of transition states along the reaction coordinates, and stereoelectronic effects1 PIERREDESLONGCHAMPS,~ YVESL. DORY,AND SHIGUILI Luboratoire de syndkse organique, Dkpartement de chimie, Facultk des sciences, Universite' de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada
Received June 1, 1994
PIERREDESLONGCHAMPS, YVESL. DORY,and SHIGUI LI. Can. J. Chem. 72,2021 (1994). Past and recent experimental results on the formation or hydrolysis (or isomerization) of various acetals and ketals including
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a-and P-glycoside models are presented. Ab initio investigations of simple acetals are also briefly reviewed as well as recent
experimental and theoretical support evidence for a synperiplanar effect. A detailed study using the semi-empiricalHamiltonian AM1 defining the reaction pathway in the hydrolysis of various acetals and ketals is reported. This overall study shows that the hydrolysis of acetals and ketals is controlled by powerful stereoelectronic effects.
PIERRE DESLONGCHAMPS, YVESL. DORYet SHIGUILI. Can. J. Chem. 72,2021 (1994). Des rksultats expCrimentaux anciens et nouveaux sur la formation ou l'hydrolyse (ou l'isom6risation) de divers acetals et cttals incluant des modbles d'a- et P-glycosides sont presentis. Des Ctudes ab initio d'acttals simples sont aussi bribvement rapportkes ainsi que de rCcentes evidences experimentales supportCes theoriquement de l'effet synpCriplanaire. Une Ctude dCtaillCe, A l'aide de 1'Hamiltonian semi-empirique AM1, des chemins rCactionnels d'hydrolyse de divers acCtals et cCtals est rapportCe. Cette Ctude globale montre que I'hydrolyse dlacCtals et de cCtals est contr61Ce par de puissants effets stCrCoClectroniques.
Introduction It has been generally accepted that stereoelectronic effects play a major role in acetal hydrolysis (1, 2). We previously postulated (I), on the basis of the antiperiplanar lone-pair hypothesis, that a-glycosides (axial anomer) are hydrolyzed via their ground state chair conformation whereas P-glycosides (equatorial anomer) must first assume a twist-boat conformation in order to have the ring oxygen with a lone pair properly oriented to eject the leaving group. Since it is well known (3,4) that a - and P-glycosides are hydrolyzed at similar rates, it follows that these compounds must be hydrolyzed via transition states that resemble more closely the geometry of the cyclic oxocarbonium ions rather than that of the protonated glycosides. It was therefore necessary to obtain experimental evidence and theoretical support to establish the position of the transition state along the reaction coordinates in the hydrolysis of acetals and related functions. In this paper, we wish to review our recent published work in this area and to present an AM1 molecular modelling study (5). We recently discovered (6-8) that a series of hydroxy-en01 ethers can undergo cyclization to provide the corresponding spiroketals either under kinetically (CH3COOH-benzene) or thermodynamically (CF3COOH-benzene) controlled conditions. For instance, taking bicyclic hydroxy-en01 1as an example (Scheme I), this compound gave exclusively spiroketal 8 under thermodynamic control and a 2:3 mixture of 5 and 8 under kinetic control. Spiroketal8 being much more stable than 5 for steric and stereoelectronic reasons (9), it is the only isomer observed under equilibrating conditions. Under kinetically controlled conditions, upon protonation, 1 must first give the cyclic oxocarbonium ion 2, which can then be converted into spiroket-
h his is an invited review article based on the R.U. Lemieux Award Lecture presented by Professor Pierre Deslonghcamps at the annual conference of the Canadian Society for Chemistry, Winnipeg, Manitoba, June 1994. 2 ~ u t h o to r whom correspondence may be addressed. Telephone: (819) 821-7002. Fax: (819) 821-7910.
als 5 and 8 while respecting the antiperiplanar hypothesis. On that basis, 5 is formed via a twist-boat (3 4 4) and 8 via a chair pathway (6 4 7). If the transition states were late, their geometry would be near that of 4 and 7, their energy difference would be quite large due to steric reasons, and the exclusive formation of 8 would have resulted. The 2:3 ratio of 5 and 8 observed can only be explained by transition states that are near the structures of the oxocarbonium ions 3 and 6, respectively. Thus, these results can be explained by postulating early transition states, the early chair-like (near 6) transition state being slightly favored over the early boat-like (near 3) transition state. The above results differ from those previously observed (10, 11) with hydroxypropyl acetal9 (Scheme 2), as this compound led to the exclusive formation of cis-tricyclic acetal 1 3 under kinetically controlled conditions @-TSOH-CH30H, room temperature). An equilibrium mixture (45%) of cis and trans acetals 1 3 and 1 6 was obtained under reflux conditions. The kinetically controlled formation of 13 can be explained in the following way: upon protonation, 9 gave the cyclic oxocarbonium ion 10, which can then lead to the cis and the trails acetals 1 3 and 16, respectively, via a chair-like (11 4 12) pathway and a twist-boat-like (14 4 15) pathway while assuming the antiperiplanar hypothesis. Again, it is relatively easy to understand the exclusive formation of cis acetal 13 via an early transition state provided that the incoming hydroxyl group is properly aligned with the n-orbital of the cyclic oxocarbonium ion. Such an alignment, which corresponds closely to the Biirgi-Dunitz angle of attack of a nucleophile on a n-system (12, 13), can be easily attained with 11 but not with 14, a conclusion that was supported by a molecular modelling study (6). Concurrent to these experiments, a theoretical study on the anomeric effect in acetals was started in collaboration with F. Grein. In the first study (14), geometry optimizations at the 631G** level were performed on various conformers of H,,XCH2-YH, and their protonated counterparts H,X-CH2-YHII,+,+ where X and Y a r e N and 0. The relative energies for the neutral systems are shown in Table 1. As expected, conformers having two anomeric effects are more stable than those having only
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CAN. J. CHEM. VOL. 72, 1994
+ ii 11
14
TABLE1. Relative energy A E in kcallmol obtained by 6-31G** geometry optimization on system XH,,-CH,-YH,. Values in parentheses come from a simple energy decomposition model Simple model parameters
one, which in turn are more stable than conformers without an anomeric effect. The energy difference does not vary a great deal when oxygen is replaced by nitrogen. Using simple pararneters, an energy analysis was performed to explain such different behavior. Energy differences between various conformers
chair
twit-boat
12
15
16
can be explained by taking into account an electronic stabilizing term (eo or e,), a 1,3-diaxial H-H repulsion term (r), a 1,3diaxial lone pair - lone pair repulsion term (l),and an intramolecular hydrogen bonding term (h) (see Table 1). Based on ab initio calculations, approximate values r G 1G -h G 1 kcaVmol were obtained. Applying this model to the systems given in Table 1 led to eo = -2 kcaVmol and eN= -2.5 kcaVmo1. The energy values obtained by this simple model are shown in parentheses in Table 1 and are remarkably close to the ab initio values. Overall, this study led to a simple model from which it was possible to estimate qualitatively the underlying electronic energy of stabilization due to the anomeric effect and to separate it from other forms of energy, such as steric and electrostatic energy. The validity of this simple model was confirmed by application to methanetriol and arninomethanediol. Studies of theprotonated systems led to a theoretical interpretation of the reverse anomeric effect (15), which would be the result of an electrostatic attraction between a positively charged heteroatom and the electron lone pairs of thk neighboring heteroatom. In a second article (16), more detailed studies were performed on systems H,X-CH2-OH with X = N, 0 , F, C where the OH group was rotated about the C-0 bond. This was followed by a Fourier analysis of the energy as a function of the rotation
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S Y ~
TABLE2. Energy parameters eo, e N for electronic component of anomeric effect due to 0 , N and vo, vN, for reverse anomeric effect due to 0 , N, in kcaVmol
Y = OH, NH2
"C stands for complex formation, which prevents the reverse anomeric effect from taking place.
angle. Again, a decomposition of the energy into a stabilizing electronic component, as a steric component (interaction of rotating OH with neighboring CH2X group) and a steric-electrostatic component (interaction of OH with XH,) was performed. The stabilizing electronic component considered to be the fundamental driving force of the anomeric effect was related to the ability of the CH20H portion of the molecule to form a double bond. The mechanism leading to anomeric stabilization is thus explained by partial n-bonding. The ideas described in these two papers were combined and extended by Grein (17), leading to much improved values for the electronic portion of the anomeric stabilization energy, which are summarized in Table 2. These values are larger for nitrogen (eN)than for oxygen (eo) because the former is a better electron donor. The eNand eo values also increase with the leaving-group ability of the XH, group. In the protonated series, these values become quite large and in some cases protonation of XH, leads to the formation of n-complexes due to the high electronegativity of the protonated group. As a result, stereoelectronic effects in acetals are put on a more solid theoretical basis. The n-bonding model also indicated that the syn and the anti periplanar effects are energetically similar, although processes with the aid of the former are normally sterically disfavored over the latter, eclipsed conformers (syn process) being higher energetically' than gauche conformers (anti process) (Scheme 3). Also, due to the large C-XH,+I+ bond increase found in the protonated species, these calculations suggested that in acetal hydrolysis the geometry of
anli
the transition state for the cleavage reaction is likely to be closer to the oxocarbonium ion than to~theacetal. Having obtained theoretical evidence for the synperiplanar effect, tricyclic acetal 17 was synthesized in order to verify whether this effect is operative both in the ozonolysis and the hydrolysis of acetals. Due to its bridged nature, tricyclic acetal 17 has the two lone pairs of the ring oxygen oriented syn to both and the C(1)-0CH3 bonds. The the anomeric C(1)-H CH,-0 bond must also be antiperiplanar to the C(1)-C(2) bond as a result of the exa anomeric effect and minimal steric interaction for the CH3 group. Thus, acetal 17 has one lone pair synperiplanar and one lone pair antiperiplanar to the C(1)-H bond. Normally, acetals that have a lone pair on each oxygen atom antiperiplanar to the C-H bond are very reactive toward ozone (18-20). Since it was observed (21) that acetal 17 is also already oxidized at -78"C, this result constitutes unequivocal ex~erihentalevidence that a svn stereoelectronic effect can also be operative in the ozonolysis of acetals. It was also found (22) that tricyclic acetal 17 undergoes hydrolysis under mild acidic conditions (HCl, 0.01 N in wateracetone), yielding the corresponding lactol 20. Since the endocyclic oxygen of 17 has one lone pair synperiplanar to the C-0CH3 bond, this result constitutes the first unambiguous experimental evidence that a synperiplanar lone pair can accelerate the hydrolysis of acetals. Accepting the fact that acetals are hydrolyzed via a late transition state, the hydrolysis of 17 must take place via a transition state (18) having a geometry near the tricyclic oxocarbonium ion 19. Following this work, we studied the reaction pathway for the acid hydrolysis of various acetals using the semi-empirical Hamiltonian AM^.^ We have examined specific conformations of acetals, their protonated forms, and corresponding oxocarbonium ions, and have looked for transition structures (23) for the cleavage steps. We first examined the hydrolytic pathway of acetals 13 and 16 (Fig. 1). In acetal 13, the C-O(1) bond is shorter (1.41 A) than the C-O(2) bond (1.43 A) due to the anomeric effect (O(1) has one lone pair antiperiplanar to the C-O(2) bond). O(2) is thus more basic, and upon protonation (21) the C-O(1) bond shortens (1.36 A) and the C-O(2) bond komputational procedure: All the calculations were done at the RHF level. The first input files for MOPAC 6.00 were created by means of SYBYL 6.01 (Tripos Associates, Inc.: 16995 Hanley Rd., Suite 303, St. Louis, Missouri 63 144-2913) for IBM RISC 6000 computers. The gradients of the norm of these draft structures were then fully optimized using EF or TS subroutines. Finally, all the transition structures were characterized by only one negative force constant. The calculations were carried out on IBM RISC 6000 computers.
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CAN. J. CHEM. VOL. 7 2 , 1994
lengthens (1.59 A) considerably. This is in agreement with Grein's findings (14, 16, 17) that the anomeric electronic stabilizing effect greatly increases in protonated acetals. As a result, the middle ring flattens considerably and it appears better to draw, for this protonated acetal, an sp2 hybridized O(1) and a p orbital periplanar to the C-O(2) bond. Transition structure 22 bond distances of 1.32 was then found with C-O(1)lC-O(2) and 1.86 A with an energy of 38.75 kcaVmo1. The geometry of this transition structure is now very close to that of the cyclic oxocarbonium ion 23 found at 38.02 kcal/mol and with CO(1)lC-O(2) distances of 1.30 and 2.22 A. The transition structure 22 is about 1.0 kcaVmol higher than the protonated acetal 21 and 0.7 kcaVmol higher than the oxocarbonium ion 23. Having no anomeric effect, the two C-0 bonds in acetal16 are of equal length. Upon protonation, 16 provides 24, with ring B now appearing in a boat form as a result of a strong anomeric effect and a periplanar p orbital. In this case, there is a very small energy barrier after protonation, 24 being at 44.33 and 25 at 44.64 kcallmol. What is even more important is the comparison between the cis and trans acetal transition structures. It can be seen that 25 from the trans acetal 16 is at a much higher energy (44.64 kcaVmo1) than 22 (38.75 kcaVmo1) from cis acetal13. This large difference, which is steric in nature, is a direct consequence of the required periplanar alignment of the p orbital with the neighboring C--0 bond. The specific formation of cis acetal 13 under kinetically controlled conditions is thus well understood on this basis.
A similar analysis was made for the hydrolysis of spiroketals 5 and 8 (Fig. 2). Each oxygen having one anomeric effect, the two C-0 bonds are of equal length in 8. In 5, the ring C oxygen having one anomeric effect, the C-0 bond lengths vary = 1.4211.43). Upon protonaaccordingly (C-O(2)lC-O(1) tion, 8 gives 27 at 29.92 kcallmol; then there is essentially no further energy barrier (28 = 29.96 kcaVmo1) to yield the oxocarbonium ion 29 (25.55 kcaVmo1). It can be seen that ring B in 27 (or 28) is almost a half-chair (or the end of a chair form), which completely flattens in oxocarbonium ion 29. Upon protonation, 5 provides 30, with a flattened boat-like conformation, which then provides the half-chair oxocarbonium ion 31. In this case, no energy barrier was observed between 30 and 31. Since 30 is about 1 kcaVmol higher than 27, it follows that the formation of acetal 8 should be slightly favored over acetal 5, a result in accord with experimentation (8:s ratio = 3:2). The most stable conformers 32 and 36 (Fig. 3) of the axial and equatorial methoxytetrahydropyrans were next examined as theoretical models for a-and P-glycosides. The bond length difference in 36 is due to the exo anomeric effect. In 32, each oxygen has one anomeric effect, but the C-OMe bond length was found to be slightly longer. This may be due to a stronger endo anomeric effect and (or) to the fact that the C-OMe bond is not part of a ring. As expected, 33 corresponds to a flattened chair and 37 to a flattened boat, 33 and 37 giving then the cyclic oxocarbonium ions 35 and 39 via their respective transition structures 34 and 38. Since transition structure 38 is slightly 4 than 34, it follows that the rate higher in energy ( ~ 0 . kcaYmo1)
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1.4311.42A
30.92 kcallmol
1.36 / 1.67
b
25.20 1.31 1 2.57
FIG.2
of hydrolysis of 32 should be slightly faster than 36. This is in complete accord with the reported hydrolysis of bicyclic acetals 40 and 41 (Scheme 4), which was reported by Eikeren (24). Indeed, the a-anomer 40 is more stable than the p-anomer 41 by 0.45 kcallmol; on the other hand, 40 is hydrolyzed faster by a 5 The difference in energy factor of 1.5 ( ~ 0 . 2 kcallmol). between the two transition states should thus be approximately 0.7 kcallmol in favor of the a-anomer 40, in complete agreement with the AM1 calculation. The relative rates of hydrolysis of a - and P-glycosides (3,4) can thus be explained on the basis that the geometries of their late transition states are close to the half-chair cyclic oxocarbonium ion. In P-glycoside, this transition state can be reached either from a half-chair with a synperiplanar lone pair or via a twist-boat conformation with an antiperiplanar lone pair. Since the twist-boat is attained from the chair via the half-chair, it is thus likely that P-glycosides are hydrolyzed via a syn pathway. Such a pathway was previously suggested by Fraser-Reid and co-workers (25, 26) for the hydrolysis of a conformationally rigid P-n-pentenylglycoside under neutral conditions by the use of an electrophilic reagent. On the other hand, in a-glycoside the transition state geometry can be obtained directly from the chair conformation with an antiperiplanar lone pair.
Conclusion The above experimental and molecular modelling studies c o n f i i that proper alignment of an oxygen lone pair periplanar
to the leaving group is one of the main driving forces in acetal and ketal hydrolysis. In acetals, molecular modelling indicates that there is an energy barrier for the cleavage of the protonated form and the transition structure should be late, having a geometry near that of the oxocarbonium ion. More specifically, this transition structure corresponds to a flattened chair in a-glycosides and to a flattened boat in P-glycosides. Also, the hydrolysis of the a isomer takes place via an antiperiplanar pathway whereas that of the p-isomer probably follows a synperiplanar route. The relative rate hydrolysis of a - and P-glycosides (3,4) can be readily explained on that basis. In ketals, AM1 calculations indicate that there is essentially no energy barrier after the protonation step (see Fig. 2); the transition state for the ketal hydrolysis must be very early, having a geometry close to that of their protonated form. The fact that there would be essentially no energy barrier after protonation would be the result of a steric decompression effect of the two alkyl groups present in ketal. As a result and in accord with experimental results, ketals are hydrolyzed at a much faster rate than acetals (27). Also, this rationalization is in accord with the fact that spiroketals such as 5 and 8 are very readily equilibrated with mild acid, whereas isomeric acetals such as 13 and 16, or the a - and P-glycoside models 40 and 41, require stronger acidic conditions for equilibration. Work is now in progress to establish that the slow steps in acetals and ketals are not the same.
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CAN. I. CHEM. VOL. 72. 1994
Acknowledgements This work was supported financially by the Natural Sciences and Engineering Research Council of Canada (NSERCC) and by the Fonds pour la Formation de Chercheurs et 1'Aide 2 la Recherche (FCAR) du QuCbec. 1. P. Deslongchamps. IIZStereoelectronic effects in organic chemistry. Edited by J.E. Baldwin. Organic Chemistry Series. Vol. 1. Pergamon Press, Oxford, England. 1983. 2. A.J. Kirby. In The anomeric effect and related stereoelectronic effects at oxygen. Springer-Verlag, Berlin. 1983. 3. J.N. BeMiller. Adv. Carbohydr. Chem. 22,25 (1967). 4. J.N. BeMiller. Adv. Carbohydr. Chem. 25,544 (1970). 5. M.J.S. Dewar, E.G. Zoebisch, E.F. Healy, and J.J.P. Stewart. J. Am. Chem. Soc. 107,3902 (1985). 6. N. Pothier, S. Goldstein, and P. Deslongchamps. Helv. Chim. Acta, 75,604 (1992).
7. P. Deslongchamps. Pure Appl. Chem. 65, 1161 (1993). 8. P. Deslongchamps. In The anomeric effect and associated stereoelectronic effects. Intramolecular strategies and stereoelectronic effects. Glycosides and orthoesters hydrolysis revisited. Edited b y G.R.J. Thatcher. ACS Symp. Ser. 539, Washington, D.C. 1993. pp. 26-54. Chap. 3. 9. P. Deslongchamps, D.D. Rowan, N. Pothier, G. SauvC, and J.K. Saunders. Can. J. Chem. 59, 1105 (1981). 10. N. Beaulieu, R.A. Dickinson, and P. Deslongchamps. Can. J. Chem. 58,2531 (1980). 11. P. Deslongchamps and D. Guay. Can. J. Chem. 63,2757 (1985). 12. H.B. Biirgi, J.D. Dunitz, and E. Shefter. J. Am. Chem. Soc. 95, 5065 (1973). 13. H.B. Biirgi and J.D. Dunitz. Acc. Chem. Res. 16, 153 (1983). 14. F. Grein and P. Deslongchamps. Can. J. Chem. 70, 1562 (1992). 15. R.U. Lemieux and A.R. Morgan. Can. J. Chem. 43,2205 (1965). 16. F. Grein and P. Deslongchamps. Can. J. Chem. 70,604 (1992). 17. F. Grein. In The anomeric effect and associated stereoelectronic effects. Anomeric and reverse anomeric effect in acetals and related functions. Edited by G.R.J. Thatcher. ACS Symp. Ser. 539, Washington, D.C. 1993. pp. 205-225. Chap. 11. 18. P. Deslongchamps and C. Moreau. Can. J. Chem. 49,2465 (1971). 19. P. Deslongchamps, C. Moreau, D. Frkhel, and P. Atlani. Can. J. Chem. 50,3402 (1972). 20. P. Deslongcharnps, P. Atlani, D. FrChel, A. Malaval, and C. Moreau. Can. J. Chem. 52,365 1 (1974). 21. S. Li and P. Deslongchamps. Tetrahedron Lett. 34,7759 (1993). 22. S. Li, A.J. Kirby, and P. Deslongchamps. Tetrahedron Lett. 34, 7757 (1993).
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23. K.N. Houk, Y. Li, and J.D. Evanseck. Angew. Chem. Int. Ed. Engl. 31,682 (1992). 24. P.v. Eikeren. J. Org. Chem. 45,4641 (1980). 25. A.J. Ratcliffe, D.R. Mootoo, C.W. Andrews and B. Fraser-Reid. J. Am. Chem. Soc. 111,7661 (1989). 26. C.W. Andrews, B. Fraser-Reid, and J.P. Bowen. In The anomeric
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