Stereochemical equilibration

The mixed dimerization of polyhalogenated alkenes with both activated and nonactivated alkcncs has been well documented (see Houben-Weyl, Vol. 4/4, p 206) and continues to represent a convenient preparative method for polyhalogenated cyclobutanes. Of the polyhalogenated alkenes, the fluorinated ethenes are the most reactive towards [2 + 2] cycloadditions. The method is, however, limited by the nonstereoselectivity due largely to the formation of 1,4-diradical intermediates and the requirement of high temperatures. The observation of stereochemical equilibration is seen in the cycloaddition products of tetrafluoroethene (1) with (island (Z)-but-2-ene and (Z)-l,2-[2H2]ethene where mixtures of stereoisomeric cyclobutanes are obtained.19-20... 

Stereochemical equilibration can arise from bond rotation in the 1,4-diradical and/or reversibility of diradical formation resulting in stereochemical equilibration of the starting alkene. 

The cycloaddition of allenes to symmetrically disubstituted alkenes gives mixtures of cyclobutanes with stereochemical equilibration of the substituents. The reaction of 1,3-dimethylallenc with either diethyl fumarate or diethyl maleate produces a mixture of the /raw.v-bis(ethoxycar-bonyl)cyclobutanes.s The same nonstereoselectivity was observed for phenylallene and 1,1-dimelhylallene cycloadditions to maleic and fumaric acid diesters.9 10... 

Stereochemical equilibration of DCP in DMSO at 343 K in the presence of LiCI yields a mixture containing 36.4 I + 0.3) % of the meso isomer. The statistical weight parameters evaluated from this result are used for theoretical calculation of the proportions of various conformers in meso and racemic DCP, and also in the three diastereoisomers of TCH. Calculations for TCH are compared with estimates of others for NMR coupling constants. It is shown that the less-favoured conformations, often ignored, contribute appreciably to the conformer populations of... 

A RIS model with neighbor interactions is used to calculate mean-square unperturbed dimensions and dipole moments for vinyl chloride chains having degrees of polymerization ranging from x = 1 to 1 50 and stereochemical structures ranging from perfect syndiotacticity to perfect isotacticity. Conformational energies used in these calculations are those which have been established in the analysis based on the stereochemical equilibration of 2,4-dichloro-n-pentane by Flory and Williams (A 002). 

An elegant synthesis of ( )-hirsutene (32) was developed by Cohen and coworkers . The key step of the synthesis is the one pot, completely stereoselective, oxidative cyclopen-tannulation of dienolate 31 with two equivalents of FeCls in dmf (equation 17). CuCl2 was also tested, but proved inferior. The formation of a single diastereoisomer of the triquinane intermediate (31 ) is useful and suggests that stereochemical equilibration may occur at some stage. This annulation procedure can also be extended to cyclohexanone enolates. 

A 3 2 mixture of cis-trans isomers is obtained from the addition of secondary amines to butadiyne in dioxane . The ratio remains constant during the course of the reaction signifying that the isomers are formed in this ratio. This, coupled with the second-order kinetics observed and large negative values for the activation entropy (AS — 50 e.u.), led to the postulation of a mechanism involving ratedetermining attack by the amine on the diyne, followed by stereochemical equilibration of the dipolar ion and proton transfer, as illustrated in Scheme 7. 

It is presumed that the intermediate radicals undergo rapid stereochemical equilibration to the thermodynamically stable form, with axial orientation of the half-filled orbital, which is then reduced to the less stable axial anion. Consequently, 7 is epimerized upon warming to — 30 °C to the equatorial isomer. This is not so for 5 since in this case the lithium can adopt the equatorial position by ring flipping32. 

V. Boundary Conditions for Stereochemical Equilibration of Wittig Intermediates... 

The last item (S) may explain why the independent betaine generation control experiments gave contradictory results. If betaines are high-energy species that lie above the saddle point leading from the ylide to the oxaphosphetane, then experiments that deliberately generate betaines (Schemes 3-5) may encounter pathways for stereochemical equilibration that are not accessible to typical Wittig reactions. 

V. BOUNDARY CONDITIONS FOR STEREOCHEMICAL EQUILIBRATION OF WITTIG INTERMEDIATES... 

Several tests are available to determine whether equilibration of stereochemistry occurs in the course of oxaphosphetane decomposition (methods A-E, Scheme 7), but each method has some limitations. In method A, oxaphosphetane diastereomers are prepared independently by deprotonation of the )S-hydroxyphosphonium salts 27 or 28 with base (NaHMDS, NaNHj, KO-tert-Bu, etc.) (20). If each isomer affords a distinct oxaphosphetane 31 or 32 according to NMR analysis (usually, or H), then the solutions are warmed up to the decomposition temperature. Kinetic control is established if stereospecific conversion to the alkenes can be demonstrated from each diastereomer. A less rigorous version of this test is to perform the experiment only with isomer 27, the precursor of the cis-disubstituted oxaphosphetane 31 (21c). All known examples of significant (> 5%) stereochemical equilibration involve 31 and not the trans-disubstituted isomer 32 (20, 21c). A negative equilibration result with the cis diastereomer 31 can be assumed to apply to 32 as well. 

Both of the above teehniques can be reinforeed by erossover experiments (method C) (12-14,20,2Ic,22,23a). An excess of CIC H CHO (ArCHO) is added to the solution below the temperature for oxaphosphetane decomposition. If stereochemical equilibration occurs exclusively by a retro-Wittig process to give the ylide 33, then an excess of the crossover aldehyde must produee the crossover products. Since 33 would be intercepted by excess ArCHO faster than it can recombine with the original aldehyde, the conversion from one oxaphosphetane diastereomer into the other (i.e., from 31 to 32) by way of any retro-Wittig mechanism will be suppressed using method C. However, it is essential to prove that the oxaphosphetane has not already decomposed prior to the addition of the crossover aldehyde. Otherwise, there is the risk of a false-negative crossover result. 

Methods A, D, and E suffer from the inherent limitation that they deliberately generate a betaine as the precursor of the oxaphosphetane. Since there is no assurance that the reaction of an ylide with an aldehyde would involve the same ionic intermediate (19,21) these control experiments may provide opportunities for stereochemical equilibration that may not be available to the corresponding Wittig reactions. If the oxaphosphetane generated by methods A or E is stable enough to observe directly, then it is usually possible to distinguish between oxaphosphetane equilibration, betaine equilibration, and other mechanisms for loss of stereochemistry (21 c). However, this is not possible for oxaphosphetanes that contain unsaturated substituents at Cj because oxaphosphetane decomposition is fast at — 78°C (21c). In these examples, method A (like method D or E) can only establish an upper limit for equilibration of all of the conceivable intermediates betaines, betaine lithium halide adducts, oxaphosphetanes, and so on. 

Tables 6 and 7 summarize results from stereochemical equilibration studies performed over the past decade by MaryanofT et al. (22,23), and Vedejs et al. (20, 21c, 39-42). A few other convincing examples are included to expand the scope of the systems covered. Table 6 lists those examples where control experiments establish at least 90% retention of stereochemistry from intermediates-to alkene products. As already discussed, the percentage of equilibration represents the upper limit for loss of stereochemistry from all possible pathways in the control experiments. No attempt has been made to determine whether the minor levels of stereochemical leakage in Table 6 occur at the stage of oxaphosphetanes, betaines, or other potential intermediates. Table 6 includes entries corresponding to all of the principal families of Wittig reagents nonstabilized ylides (entries 1-12, 24, 25, 29, and 30), benzylic ylides (entries 13-17 and 28), allylic ylides (entries 22, 23, 26, and 27), and ester-stabilized ylides (entries 18-21). The corresponding Wittig reactions must take place under dominant kinetic control.

There are also some examples where significant reversal and stereochemical equilibration of intermediates has been demonstrated in aldehyde Wittig reactions (Table 7, subset 1). Several additional examples of reversal from betaine generation experiments may also be relevant, depending on whether the same betaines play any role in the Wittig process (Table 7, subset 2). The following generalizations follow from the comparison of Tables 6 and 7. 

By the same logic, it is unlikely that the stabilized ylide reactions can be influenced by stereochemical equilibration. It would be difficult for any equilibration process to compete with the exceptionally rapid oxaphosphetane decomposition step. Partial loss of stereochemistry does occur in some of the high-temperature control experiments at the betaine stage, as listed in Table 7, but oxaphosphetane decomposition takes place with retention of stereochemistry (Table 6, entries 18-21) (21c). 

The observations summarized in Table 8 have important preparative consequences. To achieve the highest possible ( )-alkene selectivity in a system that is capable of stereochemical equilibration, it is essential to provide sufficient time for oxaphosphetane equilibration below the decomposition temperature. This is best done by monitoring the diastereomer mixture using NMR methods to establish the temperature thresholds for diastereomer equilibration as well as for alkene formation from the more reactive cis-diastereomer. Once these temperatures are known, equilibration can be allowed to proceed below the temperature for (Z)-alkene formation until the optimum ratio of trans-cis oxaphosphetanes is obtained. Subsequent warming completes the optimized E-selective alkene synthesis in an equilibrating system (Table 7). 

Several puzzling entries in Table 14 remain to be explained, including reactions where hydroxylic solvents or alkoxide bases are used (entries 11-14). Betaine reversal was demonstrated under hydroxylic conditions in the original Trippet-Jones experiment (Scheme 4) (13), and it is conceivable that interconversion between oxaphosphetanes and betaines could be fast enough in hydroxylic solvents to allow significant betaine reversal to the ylide and aldehyde in some cases. However, there is no clear evidence to implicate stereochemical equilibration of benzylide-derived Wittig intermediates in ether solvents. 

Similar hydride transfers occur with sodium alkoxides on heating. This constitutes an important means of effecting stereochemical equilibration of a hydroxyl group. The normal procedure is to add a small amount of a carbonyl compound, frequently benzophenone, to act as the initial hydride acceptor and thus catalyze the... 

The stereochemistry of the di-7r-methane reaction has been investigated. Reactions via the singlet state are stereospecific with respect to the stereochemistry about the participating double bonds." This stereospecificity means that any diradical species formed by 2,4-bridging must not live long enough for stereochemical equilibration at the radical center. Stereospedficity is also exhibited with respect to... 

The necessary amount of detail required in the RIS model may depend on the physical property that is calculated from the model. For example, the dependence of Coo on stereochemical composition in poly(methyl methacrylate) is described nearly as well by a relative simple three-state model [94] and by a much more complex six state model that contains many more parameters [93]. However, the six-state model is superior to its simpler relative in the description of the scattering function, F(/t), which is sensitive to the precise description of the conformations of relatively short subchains [159]. fri the case of polypropylene, the stereochemical composition achieved after epimeiization to stereochemical equilihrium is captured correctly by a three-state model [71], but accurate description of the behavior of Coo with changes in stereochemical compositiOTi is better achieved with a five-state model [72]. The stereochemical composition at stereochemical equilibration does not depend explicitly on the geometry (/, 0, ) when it is calculated with the RIS model [71], but Coo is obviously sensitive to this geometiy [72]. In particular, the manner in which Coo depends on the probability of a meso dyad, as Pm can be improved by going from a three-state to a five-state model. 

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