Stereomutation determination

FIGURE 4.8 Racemization tests employed for acquiring information on stereomutation. Couplings are carried out, and the isomeric content of the products is determined by a variety of techniques. AAA = amino acid analyzer GLC = gas-liquid chromatography. 

The latest theoretical treatment of cyclopropane stereomutations predicts270 that k, and ki2 are about equal for cyclopropane and for 1,2,3-d3-cyclopropanes, in fair agreement with an experimental value k,.kn - 1.0 0.2 determined with C,d3-labeled cyclopropanes166. 

Thermolysis of l,l-difluoro-2,3-diphenylcyclopropane in supercritical CO2 has allowed the rate of geometrical isomerization [i.e. cis-( 109) to /ra/M-(109)] and racemization [i.e. (/< )-( 109) to (S)-( 109)] to be determined from O2 dependence of the trapping rate of the postulated intermediate 1,3-biradical.246 Above 150 °C, the formation of 2,2-difluoroindane and its decomposition products is reported. A similar thermally induced equilibrating series of stereomutations has been observed with the analogous non-fluorinated cyclopropane in which rate constants and deuterium exchange isotope effects are reported.247 Theoretical studies of this isomerization have focused on classical248 and quasi-classical trajectories.249... 

The activation parameters of the pyramidal inversion have been determined for various dialkyl, diaryl, and alkyl aryl sulfoxides. They vary between 35 and 42 keal/mol for AH, and -8 and +4 cal/(mol-K) for AS. These values indicate that, in most cases, the thermal stereomutation of sulfoxides occurs at a significant rate only at about 200 °C. There are a few exceptions, such as benzyl and allyl sulfoxides, whose racemization is raised at 130-150 and 50-70 °C, respectively. 

Enough substituted cyclopropanes have now been subjected to careful kinetic studies so that a characteristic pattern of reactivity and stereochemical preferences has emerged. Substituents facilitate stereomutations in proportion to their ability to stabilize 1,3-trimethylene diradical structures. The values for both k 2 and (k + k2) stereomutation rate constants relate linearly with consistent measures of substituent radical stabilization energies with equal sensitivities. Experimentally determined (A , + / 2)- i2 ratios do not vary widely they range from 1.4 to 2.5 over a fair diversity of substituents. Neither do kf.kj ratios vary widely. The majority fall between 1 1 and 2.5 1 the largest yet reported gives 2(CHD) a symmetry corrected kinetic advantage over A i(CDPh) in 1-phenyl-1,2,3-d3-cyclo-propanes of 5 1. 

The ultimate test of the theoretical predictions for the mechanism of cyclopropane stereomutation would be to use an optically active disubstituted cyclopropane in which the substituents were just isotopes of hydrogen. This is a challenging problem both from a synthetic standpoint and from an analytical one. The analytical difficulty is particularly acute because one has to analyze a small, volatile molecule for both optical purity and cis-trans isomer ratio, and both measurements have to rely solely on the difference between isotopes. There are no functional groups to be used as handles for an optically active NMR shift reagent and so determination of optical purity must come from direct measurement of rotations—with a probable maximum specific rotation of < 1 ° ... 

One of the nice features of the synthesis used by Berson and Pedersen to prepare optically active trans-cyclopropane-l,2-d2 is that it involved synthesis of optically active trflns-phenylcyclopropane-2-d as an intermediate. It was thus possible from one synthetic sequence to determine not only the mechanism of stereomutation of the dideuterated cyclopropane but also to find out what effect, if any, a phenyl substituent had on the mechanism. 

Person and coworkers followed this study with a related analysis of the stereomutation of phenylcyclopropane-2,3-d2. In this system one can separate 2 from 23 cannot separate ki from ki2- However the two studies together would, in principle, allow complete determination of all of the mechanistic rate constants. In the event, experimental difficulties did not allow this complete dissection of the rate constants. The study did, however, provide an independent measure of /cj, which was found here to be 0.15 x 10" s" again showing correlated double rotation to be by far the dominant process for stereomutation at C(l). 

The stereomutation study of Gilbert showed that some cis-trans isomerization occurred . This fact, taken in combination with the conclusion of preferential 1,2 bond cleavage, requires at least some one-center epimerization to have taken place. The ratio of one-center to two-center epimerization and the question of whether the intermediate is a geometrically equilibrated biradical cannot be determined from the data because no studies on resolved optical isomers were carried out with this compound. The later studies on the substituted spiropentanes were not found to be consistent with the intermediacy of a geometrically equilibrated biradical. ... 

There are at least two fundamentally different mechanisms which may come into play for photochemical stereomutation on direct irradiation. First, there is a-cleavage followed by recombination. The presence of 156 in the above reaction mixture is very strong evidence for just such a process. The work of Guo et al. made that mechanistic assumption in determining the quantum yield of a-cleavage ( 0.4) for aryl benzyl sulfoxides, as the quantum yield for loss of optica] rotation was taken for the quantum yield of cleavage [60]. This is supported by the fact that homolytic cleavage is also the mechanism for thermal racemization of the same compound [71]. 

Additional work needs to be done to develop a theoretical model to represent the trimethylene kinetics. The dynamics in the trimethylene region of the potential energy surface is neither statistical nor direct, and instead contains both these elements. Future work on the kinetics of cyclopropane stereomutation will include developing a theoretical model for trimethylene s dynamics, assessing the accuracy of assuming RRKM dynamics for cyclopropane, and determining a more accurate PES for trimethylene. 

The determination of the exchange rate for the slowest exchanging jMTOton was complicated by the stereomutation at sulphur, which occurred at approximately the same rate as the exchange. This stereomutation, which interconverts H-1 and H-2, and also H-3 and H-4, occurs via pyramidal inversion at sulphur. 

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