ENERGY BARRIERS AND STRUCTURE OF cis-, MUCO-, AND ALLO-INOSITOL HEXAACETATES IN SOLUTION'

Transcription

1 ENERGY BARRIERS AND STRUCTURE OF cis-, MUCO-, AND ALLO-INOSITOL HEXAACETATES IN SOLUTION' S. BROWNSTEIN Division of Applied Chemistry, National Research Cozcncil, Ottawa, Canada Received September 29, 1961 ABSTRACT The proton resonance spectra of cis-, muco-, and allo-inositol hexaacetates as a function of tenlperature yield enthalpies of activation and Arrhenius factors for sorne of the sbeleta1 oscillatiolls of the sis-membered ring. INTRODUCTION When the location of substituents on a cyclohexane ring is such that one conformation is strongly favored, proton resonance spectroscopy may often be used to determine axial and equatorial substituents and the conformation of the ring (1-4). In those cases where rapid inversion of the chair form of the cyclohexane ring exchanges the substituents between. axial and equatorial positions only an averaged signal is observed. However, by lowering the temperature to reduce the rate of inversion it is often possible to observe the individual co~lfor~nations and determine the rate of inversion (5-9). When the rate of exchange of a substituent between an axial and equatorial position is comparable to the difference in chemical shift between them, the spectral lines corresponding to the individual positions merge to a single averaged line. This yields a single rate measurement, and an Arrhenius factor of 1013 has been assumed to obtain the enthalpy of activation. Quantitative calculatioils of line shape as a function of exchange rate have been made (10-12), enabling exchange rates to be deternlined over a temperature range. In the cyclohexa~le system for those cases where the Arrhenius factor was obtained by nuclear magnetic resonance methods values of 1010,1, 101L3, and were found (6, 9). The results obtained in the present study also indicate that the "normal" Arrhenius factor may be a poor approximation in the cyclohexane system. An investigation of ring inversions for some ~nollosubstituted cyclohexanes by ultrasonic relaxation yields "normal" Arrhenius factors (13). The activation energies are in agreement with those obtained by proton resonance measurernellts (7). From the limited results available it is difficult to determine under what circulnstances "normal" Arrhenius factors may be assumed. It is also proposed that the ring inversion may occur via a chair-planar-chair pathway a~lalogous to the Alg vibrational mode in cyclohexaile (13). The limited data presently available suggest that a solutio~l of the problem of ring inversions in the cyclohexane system will require careful examination of many more coinpounds. The results for a few compounds are presented in this paper. DISCUSSION The geometrical relationship of the substitue~lts in cis-, allo-, and muco-inositol hexaacetate as a planar model and in the chair forms is shown in Fig. 1. The acetate groups are shown but the protons attached to the cyclohexane ring are not indicated. In these three isomers an illversio~l of the chair form of the cyclohexane ring causes the three 'l'ssued as N.R.C. No Canadian Journal of Chemistry. Volume 40 (1902) 870

2 BROWNSTEIN : INOSITOL HEXAACETATES cis W FIG. I.-[ The relationship of the substituents ill cis-, allo-, and muco-inositol hesaacetates. axial substituents to become equatorial and vice versa, resulting in an identical conformation. Therefore changes in the proton resonance spectrum with temperature will only reflect a change in the inversion rate since contributions from varying amounts of two conformations cannot occur. In Fig. 2 some representative spectra of these con~pou~lds are shown. The rate constants are obtained by fitting the observed spectra with those theoretically calculated in the cis ring cis acetate allo ring 0110 ac,etate muco ring muco acetate FIG. 2. Proton resonance spectra of i~~ositol hexaacetates. case of the cis and a110 isomers (12, 14). For the nluco isomer two magnetic averaging mechanisms are occurring. The one which is observed at low temperatures yields a complex pattern of overlapping lines which cannot be rigorously analyzed. However, the rate of this averaging process can be estinlated as 12.5 sec-' at 197.2' K from the coalescence of the individual peaks at this temperature. If the assumption is made that the Arrhenius factor for this averaging process is the mean of those observed for the cis and a110 isomers an enthalpy of activation of 4.7 ltcal/mole is obtained. There will be considerable uncertainty in this value because of the approximate nature of the rate and the assumptio~l of a value for the Arrhenius factor. The magnetic averaging which is observed at high telnperatures causes the merging of the two sharp peaks due to the acetate protons. It was not possible to obtain sufficiently high telnperatures to cause complete lnerging of the separate acetate peaks in the ~nuco isomer. The rates were calculated from the decrease in separation of the lines, assullling they had a negligible width (15). The results

3 872 C.-1NADIAN JOURNAL OF CHEMISTRY. VOL. 40, 1962 are plotted in Fig. 3 and the thermodynamic quantities are listed in Table I. These were derived froin a least-squares fit of the experirne~ltal points except for the low-temperature 2.0 log k FIG. 3. Temperature dependence of the inversion rate. TABLE I Activation enthalpies and Arrhenius factors for ring oscillations of some inositol hexaacetates Isomer AH* log A cis 6.60~t all0 5.48f n~uco f averaging for the nluco isomer, as described previously. The greater uncertainties for the high-temperature averaging for the inuco isomer are readily explained by the error inherent in measuring the separation of two lines which are at most 1.91 cycles apart. The assumption of negligible line width may also be expected to introduce an error. In the chair form of the cis isomer there are two groups of three geonzetrically identical acetate substituents and a similar arrangement of hydrogens attached to the cyclohexane ring. The proton resollance spectrum, when iiiversioil is sufficiently slow, has two pealcs of equal intensity for both the acetate groups and the ring protons, which agrees with this structure. For the chair form of the a110 isomer there are three equatorial and three axial acetate groups but all those in a given group are no longer identical. Nevertheless two peaks of equal intensity ruay be observed for the acetate protons. A complex trace is obtained for the ring protons which indicates the variety of environments. This too agrees with the chair structure for the a110 isomer. In the chair forin of the ~IIUCO isomer there are also three equatorial and three axial acetate groups, with those in a given group not identical. Therefore when inversion is slow one would expect either two pealcs of equal intensity or more than two pealcs. Similarly for the ring protons a complex trace might be expected. If inversion between the two chair forms of the cyclohexane ring is rapid this still does not average all the acetate groups. In a given conformatioil there is one equatorial acetate group which has an

4 BROWNSTEIN: INOSITOL I-IEXAXCETATES 873 equatorial acetate on each side of it. There is also an axial group with axial acetate groups 011 each adjacent ring carbon atom. When inversion to the other chair conformation occurs these two groups exchange environments and appear in an average magnetic environment if the rate of exchange is sufficiently rapid. Similarly there are two equatorial and two axial acetate groups, each of which is situated between an axial and an equatorial group. I~lversio~l of the cyclohexa~le ring can also average the environment of these four acetate groups. However, the environments of the two and the four acetate groups remain unique. This can be visualized by inspection of the chair conformation of muco-inositol hexaacetate shown in Fig. 1. The observed spectra agree with this interpretation. At the lowest temperature a complex spectrum containing at least three pealcs is observed, as shown in Fig. 2. A total of four peaks with intensity ratio 1:2:2:1 might occur. I-Iowever, overlap of two of these would give rise to the observed spectrum. As the temperature is raised a two-line pattern is eventually obtained, with intensity ratio of 2:l. This correspo~lds to rapid inversioll of the chair form of the cyclohexane ring. At still higher tenlperatures the separation between the lines decreases from 1.9 to 1.4 cycles at the highest temperature reached. This requires an additional averaging mechanism. Conversion to the boat form might possibly be such a mechanism. In Fig. 4 are shown four possible conformations when the ring is in a boat configuration. FIG. 4. Boat conformations of muco-inositol hexaacetate. In confornlation I all six acetate groups are in a pseudoequatorial location. I-Iowever, the two distinguished by marl;s are not equivalent to the other four. If the ring inverts confor~nation IV is obtained. This is not equivalent to confornlation I since now all six acetate groups are in pseudoaxial positions. A great deal of steric repulsion may reasonably be expected between the acetate groups, causing this conformation to have a much higher energy than conformation I. The ring protons in confornlation I will all be axial and will have the same configuration as shown for the acetate groups in conformation IV. Another mode of motion for the boat form of the cyclohexane ring allows an infinite nunlber of intermediate configurations without altering the carbon-carbon bond angles (16). When substituents are placed on the cyclohexane ring to give the stereochelnistry of muco-inositol hexaacetate the possibilities are reduced to those shown by conformations Confornlation I1 may be generated from conformation I by a rotation about all the carbon-carbon bonds of the cyclohexane ring. Atoms 3 and 6 are now at the prows of the boat instead of 1 and 4. By a further rotation atonls 2 and 5 talce up this position as shown in conformation 111. Conformations I1 and I11 are identical, except for a mirror inlage transformation because labels are on two of the acetate groups. However, they are not the same as conformation I. The two acetate groups which are averaged by chair-chair inversion of the cyclol~exane ring correspond to those at the prows of the boat. They will still be different from the other four acetate groups. Even though the same groups of two and four remain non-equivalent

5 874 C-4NADIAN JOURNAL OF CHEMISTRY. VOL during a chair-boat conversion magnetic averaging will still occur provided that the magnetic environment of the two acetate groups is different in the boat conforlnation I than in the average of the two chair conformations. A similar situation will apply for the four equivalent acetate groups. An averaging of all six acetate groups could occur by transforn~ations among conforinations I, 11, and 111. Since confor~nations I1 and 111 contain two axial acetate groups they might be of higher potential energy than conforination I and the extent of this type of inagiletic averaging is difficult to estimate. In the chair-chair inversion of cis-inositol hexaacetate all six acetate groups have to pass by each other. In the a110 isoiner four pairs are adjacent during inversion and in the muco isoiner only two pairs. The observed enthalpies of activation also decrease in this order. Since a chair-chair inversion is presuinably involved in all three of these averaging processes it may be safe to assume a similar Arrhenius factor for the muco isomer. The magnetic averaging observed at high temperatures for the muco isomer must occur by a different mechanism, resulting in a very different Arrhenius factor. EXPERIMENTAL The proton resonance spectra were obtained on a Varian Associates high-resolution nuclear magnetic resonance spectrometer operating at 56.4 Mc/sec. The spectra were calibrated using side-band nlodulation, with the modulating frequency altered during recording of the spectra. The modulating frequencies were determined to 0.1 cycle/sec by counting with a Hewlett Paclzard Model 521C frequency counter. By averaging many determillations peak positions were determined to an accuracy of 0.1 cycle/sec for mucoinositol hexaacetate. This accuracy was not necessary for the other isomers since line shapes rather than peak positions were used to calculate the inversion rates. Since the widths of the resonance lines due to the inositol acetates were often temperature dependent they could not be used as a criterion of instrument resolution. The width at half height of a modulation sideband from the solvent signal was used to determine resolution. This width was between 0.5 and 1.1 cycle/sec in all the measurements. The thermostated probe assembly has been described previously, but was inodilied by using polyurethanefoam-jacketed glass tubes to introduce the thermostating gas, and by attaching the outlet to a water aspirator to increase the pressure differential across the probe assembly (1'7). A temperature range of f 140" C could be obtained. Chloroform solutions of the acetates were used. Purity of the inositol acetates was determined by vapor phase chromatography to be 97% for the a110 isomer, 99% for the cis isomer, and 99.8y0 for the muco isomer. ACKNOWLEDGMENTS The author is indebted to Professor S. J. Angyal for kindly supplying the inositol hexaacetates and a description of their purity. A referee suggested the low-temperature measuren~ents of the inuco isomer. REFERENCES 1. R. U. LEMIEUX, R. I<. I~ULLNIG, H. J. BERNSTEIN, and W. G. SCHNEIDER. J. Am. Chem. Soc. 79, 1005 (1957); 80, 6098 (1958). 2. R. U. LEMIEUX, R. I<. I<ULLNIG, and R. Y. MOIR. J. Am. Chem. Soc. 80, 2237 (1958). 3. S. BROWNSTEIN. J. Am. Chem. Soc. 81, 1606 (1959). 4. E. L. ELIEL. Chem. & Ind. (London), 568 (1959). 5. F. R. JENSEN, D. S. NOYCE, C. H. SEDERHOLM, and A. J. BERLIN. J. Am. Chem. Soc. 82, 1256 (1960). 6. G. V. D. TIERS. Proc. Chem. Soc. 389 (1960). 7. L. W. REEVES and I<. 0. STROMME. Trans. Faraday Soc. 57, 390 (1961). 8. W. B. MONIZ and J. A. DIXON. J. Am. Chem. Soc. 83, 1671 (1961). 9. G. CLAESON, G. ANDROES, and M. CALVIN. J. Am. Chem. Soc. 83, 4357 (1961). 10. H. S. GUTOWSKY and C. H. HOLM. J. Chem. Phys. 25, 1228 (1956). 11. E. GRUNWALD, A. LOEWENSTEIN, and S. MEIBOOM. J. Chenl. Phys. 27, 630 (1957). 12. S. MEIBOOM. Tables of exchange broadened nmr multiplets. ASTIA No. AD J. E. PIERCY. J. ACOUS~. SOC. Am. 33, 198 (1961). 14. A. LOEWENSTEIN and S. MEIBOOM. J. Chem. Phys. 27, 831 (1957). 15. S. BROWNSTEIN and A. E. STILLMAN. J. Phys. Chem. 63, 2061 (1959). 16. P. HAZEBROEIC and L. J. OOSTERHOFF. Discussions Faraday Soc. 10, 87 (1951). 17. S. BROWNSTEIN. Can. J. Chem. 37, 1119 (1959).