Crystallization induced reaction

However, interchange reactions appear to be rather slow at temperatures below Tm(15). We(50) observed that thermal treatment of some of liquid crystalline, aromatic copolyesters at the temperatures substantially lower than Tm did not lead to any changes in the comonomer sequence even after a prolonged period of time. A copolyester especially of 4-hydroxybenzoic acid, however, can undergo a special type of sequence changes below Tm, which is called the crystallization induced reaction(51). 

R.W.Lenz and A.N.Schuler, Crystallization-induced reactions of copolymers. Important reaction variables in the reorganization of random to block copolymers, J.Polym.Sci., Polym.Symp. 

It has been found previously that isomerization reactions may occur in cis/trans CDM terephthalate polyesters just below the melting point. These crystallization-induced reactions may lead to replacement of cis by trans units and an increase in the degree of crystallinity and melting point. Thus caution should be exercised in interpreting the result of annealing since chemical changes may actually be introduced. Also, these effects have... 

Lenz et studied the crystallization-induced reactions of copolymers. Their articles... 

Measurements of thermal analysis are conducted for the purpose of evaluating the physical and chemical changes, which may take place as a result of thermally induced reactions in the sample. This requires that the operator subsequently interpret the events observed in a thermogram in terms of plausible thermal reaction processes. The reactions normally monitored can be endothermic (melting, boiling, sublimation, vaporization, desolvation, solid-solid phase transitions, chemical degradation, etc.) or exothermic (crystallization, oxidative decomposition, etc.) in nature. 

Diastereoselective Slrecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an In situ crystallization-induced asymmetric transformation, whereby one diastereomer selecliveiy precipitates and can be isolated in 76-33% yield and dr > gsti. The diastereomeilcaily pure a-amino nitrtie obtained from pivaidehyde (R, = t-Bu, Rj = H) was converted in three steps to (S)-tert-leucine in 73% yieid and >98% ee. 

Because in methanol crystallization of amino nitrile 3 did not take place, first the solvent was varied in order to attempt to find conditions for a crystallization-induced asymmetric transformation. At a MeOH/2-PrOH ratio of 1/9, the amino nitrile (R,S)-3 was isolated in 51% yield and dr 99/1 (entry 2). Other combinations of alcoholic solvents failed to lead to a higher yield of precipitated (R,S)-3 in high dr (entries 3 and 4). On further screening of solvents, it was observed that upon addition of HjO to the methanol solution selective precipitation of amino nitrile (R,S)-3 occurred giving (R,S)-3 and (R,R)-3 in a ratio of 81 19 and 69% yield (entry 5). The asymmetric Strecker reaction was further studied in HjO alone using temperature as a variable. The results of these experiments are given in Table 1 (entries 6-9). After addition of NaCN/AcOH at 23-28 °C... 

The observed diastereoselectivity in the asymmetric Strecker step via the crystallization-induced asymmetric transformation can be explained as shown in Figure 2. Apparently, the re face addition of CN to the intermediate imine 4 is preferred at room temperature in methanol and results in a dr 65/35. At elevated temperatures in water, the diastereomeric outcome and yield of the process are controlled by the reversible reaction of the amino nitriles 3 to the intermediate imine and by the difference in solubilities of both diastereomers under the applied conditions. . .. 

In summary, (R)-phenylglycine amide 1 is an excellent chiral auxiliary in the asymmetric Strecker reaction with pivaldehyde or 3,4-dimethoxyphenylacetone. Nearly diastereomerically pure amino nitriles can be obtained via a crystallization-induced asymmetric transformation in water or water/methanol. This practical one-pot asymmetric Strecker synthesis of (R,S)-3 in water leads to the straightforward synthesis of (S)-tert-leucine 7. Because (S)-phenylglycine amide is also available, this can be used if the other enantiomer of a target molecule is required. More examples are currently under investigation to extend the scope of this procedure. ... 

Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and... 

The asymmetric synthesis of a-amino acids is an important topic due to their extensive use in pharmaceuticals and agrochemicals and as chiral ligands. The Strecker reaction is historically one of the most versatile ways to produce a-amino acids, but this method has a maximum yield of only 50% for a single enantiomer. Higher yields can be achieved by using chiral auxiliaries, but auxiliaries have other drawbacks, such as high cost, low availability, the need for purification, and high loss rates. A possible solution to these problems would be to use a chiral auxiliary in a crystallization-induced asymmetric transformation. 

A subsequent paper (05TA1969) reported the preparation of four pyrrolo fused TBs, 34a, 34b, 35a and 35b from 33a,b (no chiral induction was observed) (see reaction of 30, 31a,b and 32). The absolute configuration of 34a, [a]o = -193, was determined by X-ray crystallography. A CIAT experiment (crystallization-induced asymmetric transformation) allows the transformation of the crude mixture of 34b and 35b into pure 35b (Scheme 7). The thiophene derivative WADPIB (03AX(E)o745) (see VI.A) also belongs to this section. 

In a second example using 3,4-dimethoxyphenylacetone (8) and (R)-PGA (1), it was found that an equilibrium composition of 55 45 exists between the two diastereoisomers (R,S)-9 and (R,R)-9 in methanol as solvent. By fine-tuning the reaction, it was found that in a mixture of methanol and water (6 1), almost diastereoisomerically pure (de >98%) amino nitrile (R,S)-9 precipitated in 76% isolated yield (Scheme 25.4). Clearly, in this case a crystallization-induced asymmetric transformation has also occurred. 

Few examples of crystallization-induced asymmetric transformations in Strecker reactions based on arylalkyl-methyl ketones have been reported a) Weinges, K., Gries, K., Stemmle, B., Schrank, W. Chem. Ber. 1977, 110, 2098 b) Weinges, K., Klotz, K-P., Droste, H. Chem. Ber. 1980, 113, 710. 

As mentioned, asymmetrically pure compounds are important for many applications, and many different strategies are pursued. However, in spite of many methods being developed, the classic resolution technique of diastereomeric crystallization is still preferentially used to prepare optically active pure compounds in bulk quantity. Crystallization is commonly used in the last purification steps for solid compounds because it is the most economic technique for purification and resolution. Attempts to achieve crystallization after completed reaction without workup and extraction is called a direct isolation process. This technique can be cost-effective even though the product yield obtained is lower. Special conditions may be needed in this case, and the diastereomers can be classified into two types diastereomeric salts and covalent diastereomeric compounds, respectively. Diastereomeric salts can, for example, be used in the crystallization of a desired amine from its racemic mixture using a chiral acid. Covalent diastereomers can, on the other hand, be separated by chromatography, but are more difficult to prepare. Another advantage of crystallization is the possibility of combining in situ racemi-zation reactions and diastereomeric formation reactions to get the desired pure compounds. This crystallization-induced resolution technique is still under development because of its requirements for optimized conditions [55, 56],... 

The dynamic crystallization-induced diastereomeric resolution was further investigated in order to develop practical approaches to obtain one diastereomer by exploiting more diversity of the diastereomeric nitroaldol adducts in the dynamic system [77]. A larger and more diverse dynamic nitroaldol system (CDS-5C) was generated by equimolar amounts of nine different benzaldehydes, nitroethane 38, and triethylamine was used as catalyst as shown in Scheme 15. A total of 36 nitroaldol diastereomers were formed under thermodynamic control in chloroform-d, and the reaction was followed by H-NMR spectroscopy. 

The above examples demonstrate the DSR concept as a useful approach to generate and interrogate simultaneously complex systems for different applications. A range of reversible reactions, in particular carbon-carbon bond-formation transformations, was used to demonstrate dynamic system formation in both organic and aqueous solutions. By applying selection pressures, the optimal constituents were subsequently selected and amplified from the dynamic system by irreversible processes under kinetic control. The DSR technique can be used not only for identification purposes, but also for evaluation of the specificities of selection pressures in one-pot processes. The nature of the selection pressure applied leads to two fundamentally different classes external selection pressures, exemplified by enzyme-catalyzed resolution, and internal selection pressures, exemplified by transformation- and/or crystallization-induced resolution. Future endeavors in this area include, for example, the exploration of more complex dynamic systems, multiple resolution schemes, and variable systemic control. 

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