The High Dilution Method

In a bimolecular reaction, for example, the reaction between A and B, the reaction rate depends on the concentrations of A and B. Therefore, at very low concentrations or in high dilution conditions, the reaction rate decreases significantly and mixing becomes relatively faster than reaction. 

In this case, the desired reaction is an intramolecular reaction, and the undesired intermolecular reaction might be avoided under these high-dilution conditions. The high-dilution technique might also be effective for improving the selectivity of competitive consecutive reactions, although the overall reaction time should be greatly reduced in comparison with that required under normal conditions. 

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The high-dilution method (for technical details see for example Ref. 21) has been used not only to form simple cryptands, but also in the syntheses of more complex systems — cylindrical macrotricyclic molecules24), lateral macrobicycles 25), spherical macrotetracyclic systems 26), and speleands 27). Nevertheless, the important drawback of the method is the last step, e.g. reduction with diborane. That means only compounds which do not interfere with this reagent can be formed in this manner. Also, even a small contamination of the solvents and reactants with water has a significant influence on the yield. 

Diaza[12]coronand-4 (21) was condensed with diethylene glycol bismesylate 22 in the presence of butyllithium. Precipitation, occuring during the reaction course, afforded the proton cryptate 24 H+ c= [1.1.1] in 40% yield. It should be noted that [1.1.1] was obtained only in 10% yield via the high-dilution method 23). Lithium promoted cyclization was excluded (as an alternative mechanism) by an additional experiment in which KH served as a base instead of BuLi. Identical yield was achieved, indicating that intramolecular hydrogen bonding was responsible of the cyclization. 

All the methods presented in this Chapter have their merits and drawbacks. The most important factor in the synthesis of cryptands is the yield. As it was shown, the high-dilution technique is superior to all remaining methods in this respect (except for the [1.1.1] cryptand case). Furthermore, the high-dilution method has been applied... 

Fig. 1 First macrocycle synthesized in 1912 by the high dilution method.

The high-dilution and template methods are frequently used in the synthesis of cyclic compounds with the aim of increasing the yield. The former method is carried out at substrate concentrations lower than 1 mM [18-20]. This reaction condition decreases the contact of the substrate molecules in the solution. The linear intermediate produced prefers the intramolecular cyclization reaction rather than the intermolecular reaction. Therefore, this reaction condition is useful for the intramolecular reaction, method B (Fig. 2). 

Recently, Dolbie2"21 reported a new, nonpyrolytic method for the synthesis of PA-F dimer [Eq. (4)]. This method allows easy laboratory preparation of gram quantities of PA-F dimer but still presents difficulties with regard to commercialization because of the high-dilution methodology that is required for a good yield of high-purity product. 

The third method which provides evidence for a knotted structure is mass spectrometry.42 With electrospray ionization (ESI) it is possible to ionize the knot and other similar molecules by protonation and to transfer them into the highly diluted gas phase of a mass spectrometer. In a so-called tandem-MS experiment, the parent ion, i.e. the protonated knot, is isolated and subjected to collisions with a stationary gas inside the... 

It may be noted that for calibration each analyte is needed to be spiked with its labeled analog. This enhances the cost of the analysis. High cost and often unavailability of labeled analogs are the major drawbacks of isotope dilution method as compared with external and internal standard calibration methods. The isotope dilution method should be, theoretically, more accurate than the internal standard method, as the chromatograpic response and the retention times of the labeled analogs are closest to the compounds. 

The principle of the high-dilution (h.d.) method consists in the condensation of macrocyclic diamines with highly reactive acid dichlorides or, alternatively, 2,4-dinitrophenyl diesters in an inert solvent like toluene 22). The yields of the resulting diamides are usually good, although [1.1. ljcryptand was obtained in this manner only in 10% yield, accompanied by a dimer (30% yield)23. ... 

The saturated aza-oxa crown ethers were first synthesised as intermediates in the synthesis of the nitrogen cryptands.1 The reaction conditions used for the formation of these macrocycles involved the high-dilution technique. In this versatile method, a diamine and a diacid chloride are simultaneously added in the presence of triethylamine to a large volume of solvent, usually toluene, over an extended period of time. The major product from such a reaction is the [1+1] cyclised product, although the [2+2] adduct can often be isolated as well, in low yield. Whilst this method is still sometimes used,2,3 particularly for cryptand synthesis (Chapter 5), it has been superseded by methods that are more convenient and which proceed under medium dilution. 

The oxa-thiacrown ether having bicyclo[2.2.2]octane units was prepared from a mixture of dichloro sulfides 28 and 29 <2002CHE261>. The reaction of the mixture with diethylene glycol by a high-dilution method led to the formation of only one stereoisomer of 30 in 40% yield (Scheme 3). 

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