Stereomutation studies

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. ... 

The NMR spectroscopy has been widely used in the studies of different types of equilibria like ring-chain tautomerism, racemisation or stereomutation and proton transfer equilibrium in Schiff bases. 

The dynamic NMR (DNMR) spectroscopy has been used in studies of stereomutations of non-symmetrical di-Schiff bases [18].39 It was shown that the hindered Schiff bases exist in DMSO in two chiral conformations. The presence of a pair of conformers being in equilibrium was explained by the existence of two stereogenic axes a g (aligned to Cl—N8 bond) and a 7 (aligned to C6—N7 bond) due to restricted rotation around two Ar—N bonds. The trans to cis interconversion as well as enantio- or diastereoisomerisation barriers for the compounds studied have been established using line shape analysis. 

Although acetylenic bonds are more reactive than C=C bonds, the reactions are often initiated by AIBN or UV radiation. Baldwin and Barden119 have used the latter method to treat a doubly labelled phenylacetylene with triphenyltin deuteride (Scheme 19). The addition of the triphenyltin deuteride was both regiospecific and gave a stereochemically pure product. A five-step synthesis (Scheme 20) converted this product into an optically pure trideuterophenylcyclopropane, which was used to study the thermal stereomutations that these compounds undergo. 

As a result of recent extensive studies, especially that of Mislow (247) on the stereomutation of sulfoxides, it is recognized that racemization of optically active organosulfur compounds occurs under various conditions and according to different mechanisms. 

The molecular mechanisms for the ring openings of various cyclopropanone systems in the gas phase have been studied at the PM3 semiempirical level and shown to be disrotatory processes, while an experimental study of the stereomutation of 1,1-difluoro-2-ethyl-3-methylcyclopropane has confirmed the predicted preference for disrotatory ring opening and ring closure for this system. 

Sixteen years later Baldwin and co-workers published the results of even more elegant experiments in which the stereomutation of optically active 7-l- C-l,2,3-was studied. Because a deuterium atom is attached to each of the carbons in this compound, it was unnecessary for Baldwin to assume the size of a secondary deuterium isotope effect on which bond cleaves, in interpreting his kinetic data. The results of his experiments led him to conclude, the double rotation mechanism does not predominate by a substantial factor. ... 

This example illustrates the importance of the tautomeric P(III) P(V) equilibrium yielding the same result as a stereomutation without bond cleavage. In view of their importance in phosphorane chemistry, we shall therefore study the following equilibria P(III)—P(V), P(IV) P(V), P(V)—P(V) and (Vl) P(V)l... 

The thermal stereomutations of deuterium-labeled phenylcyclopropanes (Scheme 3) were studied in a progressive manner. First, the racemic and both achiral isomers were synthesized to provide material for kinetic work and to verify analytical methods 62. The isomerizations among these three isomers at 309.3 °C were followed using either 2H decoupled H NMR spectroscopy or Raman spectroscopy the two kinetic parameters (k, + k22) = 0.36 x 10 5 s 1 and (k2 + k]2) - 1.07 x 10"5 s 1 at 309.3 °C were measured. Published spectra of both sorts for authentic samples of syn, anti and trans isomers, and of thermal reaction mixtures, provided... 

A complete solution to the kinetic problem was attained through further studies of (2R, 3R)-1,2,3-d3-phenylcyclopropane and (1/ , 2S, 3 R) 1,2,3-d, -phenylcyclopropane-2-13C l6 Reaction mixtures from the first were analyzed by NMR and by Raman spectroscopy, and with the aid of the chiral lanthanide shift reagent Eu(hfc)3 on each derived mixture of deuterium-labeled benzoylcyclopropanes. Concentration versus reaction time data for all four isomers led to k22 = 0 and kx - 0.36 x 10 5 s. From kinetic work based on the l3C, d3-labelled substrate (equation 4) the final distinction between ka and k2 reactions was secured kl2 = 0.20 x 10 5s 1 andk2 0.87 x 10 5 s. Thanks to the 13C,d3 labeling, stereomutations allowed for equilibrations among eight rather than four isomers, and the distinction between k2 and kn products could be made163. 

All of the experimental and theoretical work on the stereomutations of cyclopropanes and vinylcyclopropanes covered above seems consistent with and understandable in terms of kinetically significant involvements of Cj(ts), Cs(ts) and EF(ts) structures and partitionings of EE trimethylene intermediates resulting in the formation of klt k2 and kl2 products at comparable rates. For trans-1,2-disubstituted cyclopropanes, neither the Smith mechanism (one-center stereomutations only) nor any two-center-only formulation can be correct, as demonstrated by Crawford and Lynch in 1968143 and reinforced by numerous subsequent studies (Figures 2 and 3). 

A study of the stereomutations of 1,2-d2-cyclopropanes published in 1990 which claimed, hopefully but unjustifiably, to have measured a k, k, ratio of 1.09 0.05, is now recognized to be of no mechanistic relevance, for the two-parameter, three-data-point least-squares rate constant reported282 for kx is associated with intolerable error limits the 95% confidence interval places k, between 3.9 and 20.8 x 10"5 s"1.282... 

I thank the National Science Foundation for support of our work on cyclopropane stereomutations, now through CHE-9100246, and the coworkers and colleagues who have contributed so invaluably to our studies in this area. 

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... 

After a brief historical recapitulation, the substantial body of experimental and theoretical work on these thermal epimerization reactions reported over the past 40 years is summarized. Of primary concern here are examples of stereomutations involving monocyclic, stereochemically unconstricted and minimally substituted molecules. Experimental studies of more heavily substituted cyclopropanes attempts to generate trimethylene diradical intermediates from pyrazolines " and the fascinating and still incompletely understood thermal chemistry of bicyclo[2.1.0]pentanes, 2-methylenebi-cyclop.l.OJpentanes", bicyclo[3.1.0]hex-2-enes and related reactions such as the pyrolysis of cyclopropane at 1200 °C to give products such as cyclopentadiene and toluene are neglected, in spite of obvious mechanistic interrelationships. 

The experimental and theoretical work published by the early 1970s viewed the stereomutations of cyclopropanes as kinetically competitive one-center and two-center stereomutations some details, especially regarding relative rate constants for one-center epimerizations which defined relative rotational propensities, remained unclear, but all agreed that neither the Smith mechanism (one-center only) nor any two-center-only formulation for stereomutations could be sufficient. Thus when kinetic studies " on the isomerizations shown by chiral samples of l-phenyl-2-d-cyclopropane and 1,2-d2-cyclo-propane purported to show that, actually, two-center stereomutations were kinetically dominant, many were stimulated to fresh speculations and accommodations. Theoretical work at times hinted that the parent hydrocarbon might be an exceptional case and might... 

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. 

Doubleday, C. Bolton, K. Hase, W. L. Direct dynamics quasiclassical trajectory study of the thermal stereomutations of cyclopropane, J. Phys. Chem. A 1998, 102,... 

---