High dilution reactions

Knops, P., Sendhoff, N., Mekelburger, H.-B., Vogtle, F. High Dilution Reactions - New Synthetic Applications 161, 1-36(1991). 

Further investigation of model reactions revealed that the reaction of aromatic acid chlorides with diols such as butanediol or ethylene glycol was too slow to be useful for kinetically controlled p.vcMdo-high-dilution reactions carried out... 

Phase-transfer catalysis can be used to mimic high dilution reaction conditions and has been utilized to good effect in the synthesis of large ring lactones [67J. Macrocyclic nitrolactones have also been obtained by rearrangement of 2-(3-hydroxy-propyI)-2-nitrocycloalkanones using a stoichiometric amount of tetra-n-butyl-ammonium fluoride [68]. 

Knops P, Sendhoff N, Mekelburger H-B, Vogtle F (1991) High Dilution Reactions - New Synthetic Applications. 161 1-36 Koca J, see Hladka E (1993) 166 121-197 Koepp E, see OstrowickyA (1991) 161 37-68... 

A special feature of the synthesis described here is the glass apparatus used to achieve high-dilution reaction conditions (Figure 1).4 This "trident" is simple but effective and can be fabricated quite easily from standard parts. The one shown here is designed to accept an overhead mechanical stirrer. 

The addition rate is sufficiently slow that virtually no starting material remains. The procedure avoids the need for excessively large volumes Of solvent that are normally required in high dilution reactions. 

In order to circumvent the unwanted intermolecular reactions that are usually observed, syntheses are often performed under conditions of moderate to very great dilution. Under these circumstances, the intramolecular reaction becomes more likely than the intermolecular process. It is more likely for the reactive end of a molecule to encounter the other end of the same molecule as opposed to the reactive site of another molecule. In extreme cases, milligrams of reactants are dissolved in litres of solvent. This places extreme constraints upon the purities of reactants and solvents and also upon the quantities of products which may reasonably be obtained. A further synthetic problem is associated with the observation that many of the reactive precursors are water sensitive it is very difficult to completely exclude water from a reaction vessel, and many of the solvents used are hygroscopic. Think about a high dilution reaction with 0.1 mmol of a hydrolytically unstable compound in one litre of solvent. It would only require 1.8 mg of water to completely destroy the reactant. This corresponds to 0.0002 % (w/v) of water in the solvent ... 

Similar results are obtained with 2-adamantanol which rearranges to 1 -ada-mantanol (> 98 %) at 28°C in sulfuric acid. An equilibrium mixture containing small amounts of 2-adamantanol is rapidly achieved fromeither direction67 6 K This isomerization is one of the mechanistic bases for the preparation of ada-mantanone by the reaction of adamantane with sulfuric acid at 77°C (see Section V.A.l) 57> 67> 691. The Koch-Haaf carboxylation of 2-adamantanol similarly results in predominant 1-adamantyl carboxylic acid formation unless highly dilute reaction conditions are employed 57> 7°). 

Treatment of II in THF with two equivalents of ri-butyllithium generated V, which gave VI and VII upon high dilution reactions (6) in THF with bis(3-methanesulfonyloxypropyl)sulfide and bis(3-chloropropyl)methylamine, respectively in yields of about 80%. 

Initially, it was assumed that the diazacoronand with secondary nitrogen functions incorporating D-mannopyranosidic unit 49) could serve as a precursor for the synthesis of the chiral [2.2.ljcryptand (10) according high-dilution method43 . Indeed, high-dilution reaction of 49 with diglycolic acid dichloride provided the bisamide 50 in 65 % yield (Scheme 14). 

The following procedure for the synthesis of macrocycle 4 is representative of a high dilution reaction. 

Cryptand syntheses require ultrahigh purity reagents, water-free conditions, and highly dilute reaction conditions in order to quell partial reactions and polymerizations. Also, a template species such as metal ions or nonreactive guest species is useful. 

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