Cryptands synthesis methods

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 Whilst this method is still sometimes used,2,3 particularly for cryptand synthesis (Chapter 5), it has been superseded by methods that are more convenient and which proceed under medium dilution.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 commonly adopted methods for cryptand synthesis are (1) high dilution,... 

Mention has to be given to the synthetic aspects of cryptands. It is obvious that after the intellectual process of ligand design and despite the various new (efficient) modelization tools found for the computer, the necessity still exists to obtain the actual compound. Numerous methods were developed over the years. Many symmetrical cryptands can be obtained in a few steps and with high yields. For the more elaborate cryptands, synthesis is usually more cumbersome, and the number of steps is high. 

It should be noted here that the brevity of this section is due in part to the fact that essentially this single method is utilized in the synthesis of most cryptands which have... 

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. 

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 preparation of crown ethers differs principally owing to the presence or absence of nitrogen. The preparation of all-oxygen heteromacrocycles has largely involved the Williamson ether synthesis. The preparation of aza-, diaza-, or triazacrowns has usually required the formation of cyclic amides, followed by reduction. The latter method applies to cryptands as well and has been used for that purpose since 1969. The methods are well known and shown in the lower panel of Figure 4. 

The template synthesis represents an elegant method that uses metal ions to direct reactions of ligands and provides a useful route to macrocyclic structures. Several books159-161 describe the template processes that involve reactions on matrices used to synthesize polyazamacrocyles, crown ethers, cryptands, rotaxanes, knots,159 clathrochelates,160 phthalocyanines,161 etc. which are applied, e.g., as molecular switches, in ion exchange, electron transfer or catalysis. An example of clathrochelate synthesis is given in Chapter 1.33... 

Miscellaneous Methods of Preparing Phosphines. - The synthesis and properties of phosphorus-containing cryptand ligands has been reviewed. The basic principles for the synthesis of functionalised phosphorus-containing heterocyclic systems have been summarised, relating to the chemistry of phosphabicyclohexanes, dihydrophosphinines, phosphabicyclooctadienes, and phosphabicyclooctenes °. Ethylene acetals (108) of the 9-oxa-2-phosphabicyclo[4.4.0]-5-one system have been prepared. Methods for the... 

So far, much research has gone into finding new synthetic routes, new products and novel selective syntheses, and in the analysis of important factors affecting yield and in some cases selectivity. However, other practical constraints relevant to process development for industrial-scale synthesis have to be tackled. For example, new insights are needed to develop cost-effective, stable, and selective PT catalysts (especially effective immobilized triphase catalysts). Other relevant factors include the recovery and recycle of the PT catalyst, catalyst decomposition, environmental issues such as catalyst toxicity, and ease of product recovery. Catalyst costs are not very high when quats are used, as against the more expensive crown ethers or cryptands. In most cases, the overall process is more than cost-effective since PTC allows the use of cheap alternative raw materials, prevents the use of costly dipolar solvents, is less energy intensive (due to lower temperatures) than alternative methods, alleviates the need... 

Krakowiak and Bradshaw (1991) have observed that the reaction of certain diamines with the diiodide derivative of tetraethylene glycol gave the bis(aza-12-crown-4)s as by-products in the one-step synthesis of cryptands (method D-8). More work needs to be done on this interesting new one-step synthesis... 

The synthetic route to iV-aryl [3.2.2] cryptands 5a and 5b is shown in the Scheme. Starting from the A-aryl diethanolamine, reaction with two equivalents of chloro-acetic and /-BuOK in t-BuOH followed by conversion of the diacid to the diester for purification gave la and lb in yields of 49 and 25%, respectively. Subsequent acid-catalyzed hydrolysis produced the dicarboxylic acid amine hydrochlorides 2a and 2b quantitatively. Attempts to form the diacid chloride of 2a resulted in an unreactive deep blue-colored substance of unknown identity. Ring closure was effected by adaptation of a method from peptide synthesis [8]. Mixed anhydrides 3a and 3b formed by reaction with two equivalents of isobutyl chloroformate in the presence of triethylamine were cyclized with l,10-diaza-18-crown-6 in toluene to produce the corresponding cryptand diamides 4a and 4b in 36 and 32% yields, respectively. Reduction with borane-dimethyl sulfide in THF provided 74% yields of 5a and 5b. 

Introduction.—The ability of certain molecules, such as the macrocyclic crown ethers, e.g. 18-crown-6 (28), and the macrobicyclic cryptands, e.g. [2,2,2] cryptand (29), to form complexes with metal and ammonium cations has been extensively investigated in recent years. Since the original discovery by Pedersen, in 1967, of the crown group,some reviews and many papers have appeared on the syntheses and complexing properties of different classes of ligands, but it is not the intention here to go into detail concerning these aspects. Laboratory syntheses of the polyether class are dependent on the Williamson ether synthesis (Equation 11), but methods for production of commonly used compounds, such as (28), have been improved, and many representatives of both the crown and cryptand groups are now commercially available. 

One-Step synthesis 2-fluoropyridine (7) from 2-chloropyridine (4) in HF at temperature 350 °C with use as catalyst MgO is of interest for the industry [42] (Schane 15). This method is the advanced of three-steps method [43], For synthesis 2-F -pyridines (46) reactions of nucleophilic substitution of F-, NO2- and NH2-groups by F are used [44-46] (Scheme 16). The effective reagent - catalyst in synthesis 2-F -pyridines appeared 2,2,2-Cryptand (49) at the presence of which time of reaction is reduced up to 20 min. It is necessary to note, that 2-P -pyridines are used in radiobiology of a cancer, and half-life period of F is equal to 12 h. 

Gas-liquid phase-transfer catalysis (GL-PTC) is a new synthetic organic method that has similarities both with phase-transfer catalysis (PTC) and with gas-liquid chromatography (GLC) in that anion transfer processes and partition equilibria between gaseous and liquid phases both take place and affect the synthesis. Using GL-PTC, nucleophilic substitution reactions have been so far carried out under operative conditions and with synthetic results, making this method different from the well known liquid-liquid (LL-) and solid-liquid (SL-) phase-transfer catalysis. As regards these latter, phase-transfer catalysts (onium salts, crown ethers and cryptands) transfer the reactive anion from an aqueous liquid (LL-PTC) or a solid salt (SL-PTC) phase into the organic one in which the substitution reaction occurs. In the case of GL-PTC, where no solvent is used, the catalyst always acts as an anion transfer (between solid and liquid phases) but, as it works in the molten state it also constitutes the medium in which the reaction proceeds. 

The GL-PTC synthesis of carboxylate esters is justified by some advantages aprotic polar solvents in which the synthesis is conducted with classical nucleophilic substitution methods need not be used and moreover, in comparison with analogous reactions carried out under gTC conditions, the use of either a large carboxylate excess (LL- TC) or of expensive catalysts like 18-crown-6 and cryptands (SL-PTC) is avoided. 

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