High dilution synthesis, cryptands

Scheme 3.16 High-dilution synthesis of diaza[18]crown-6 and thence [2.2.2] and [2.2.1] cryptands. Note the use of acid chloride groups to enhance reaction rate.9...

Synthesis by high-dilution techniques requires slow admixture of reagents ( 8-24 hrs) or very large volumes of solvents 100 1/mmol). Fast reactions can also be carried out in suitable flow cells (J.L. Dye, 1973). High dilution conditions have been used in the dilactam formation from l,8-diamino-3,6-dioxaoctane and 3,6-dioxaoctanedioyl dichloride in benzene. The amide groups were reduced with lithium aluminum hydride, and a second cyclization with the same dichloride was then carried out. The new bicyclic compound was reduced with diborane. This ligand envelops metal ions completely and is therefore called a cryptand (B. Dietrich, 1969). 

The synthesis of 1,10-diaza-l 8-crown-6 (9) has been an important problem because this is the key starting material in the synthesis of numerous cryptands (see Chap. 8). Although first synthesized some years ago, the process has recently been patented. Di-azacrown 9 is prepared by a high dilution condensation of 1,8-diamino-3,7-dioxaoctane with ethylene glycol diacetyl chloride. The resulting diamide is then reduced with lithium aluminum hydride to give 9 in 56% overall yield from the open-chained diamine. The synthesis is illustrated In Eq. (4.8), below. 

Although Lehn and his coworkers prepared a large number of cryptands and derived complexes over the years, the synthetic approach to these compounds remained essentially similar for most of them. Details are presented for a number of such compounds in ref. 26. The essential features of these syntheses were use of amide-forming reactions in the absence of templating ions with reliance on a high dilution step to form the second ring. An alternative approach for the synthesis of cryptands was developed by Dye and his coworkers. Their approach involved the use of a flow synthesis to replace the high dilution step. 

Shortly after their first report of all-oxygen bridged cryptands, Dietrich, Lehn and Sauvage reported incorporation of sulfur in the strands. The experimental methods used were essentially similar to those applied in the syntheses of the parent cryptands. As in previous cases, a diacyl chloride was condensed with a diamine under high dilution conditions. In this case, however, the diamine contained sulfur atoms rather than oxygen. The synthesis of compound 5 was accomplished in two stages as illustrated below in Eq. (8.3). The first cyclization step affords the macrocyclic amine in 55% yield. The macrobicyclic product (5) is formed in 25% yield from the monocyclic diamine and the acid chloride. 

The parent series of cryptands may be represented by (213) - a stepwise increase in cavity size occurs along this series. High-dilution procedures are employed for the synthesis of these cages. 

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... 

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 synthesis of some coronands and cryptands involve several synthetic steps and, sometimes, high dilution techniques to avoid unwanted polymerisation, which considerably adds to the cost of the synthesis. In some instances, it is possible to simplify the synthetic procedure by using a templating agent, that is, a metal ion which pre-organizes the reactants in such a way that they do not polymerise and have the right orientation to yield the desired compound. One of the first examples of such template reaction in lanthanide macrocyclic chemistry was demonstrated by Wanda Radecka-Paryzek who isolated via a one-pot pro-... 

Scheme 1 The synthesis of simple cryptands via the high-dilution addition of acyl chlorides to azacrownethers...

The first synthesis of molecules of this kind was reported independently by Vogtle [52] and Hall [51] and both involved condensation of 34 with a range of diazamacrocycles 37 under high dilution conditions to form the corresponding amide cryptands 38 together with dimeric analogues 39 and some polymers. The compounds were easily separated by column chromatography on alumina and were fully characterised by mass spectrometry, elemental analysis, and multinuclear NMR... 

The commonly adopted methods for cryptand synthesis are (1) high dilution,... 

The one-pot synthesis of polymers via Ugi-4CR can only be performed if either two bifunctional AA-type components or one AB-type component are used. Moreover, highly concentrated reaction mixtures are needed because otherwise ring formations occur, as thoroughly investigated by Wessjohann and coworkers. Here, the directed synthesis of macrocycles or cryptands under classic or pseudo high dilution conditions, or even without dilution exploiting metal template effects were demonstrated [66, 67]. 

Scheme 12.74 Synthesis under high-dilution conditions of cryptand 214...

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