Nucleophilic substitutions cryptands

In Chapter 3, we saw that cryptands specifically solvate the alkali metal portion of salts like KF, KOAc, and so on. Synthetic advantage can be taken of this fact to allow anions to be freer, thus increasing the rates of nucleophilic substitutions and other reactions (see p. 455). 

As well as increasing anion nucleophilicity, crown or cryptand complexation can enhance the basicity of the anion. Table 3 exemplifies this effect with 1-bromooctane where base-promoted elimination to 1-octene competes with nucleophilic substitution. Being small and poorly solvated, naked fluoride is a strong and hard base which causes, in the case of certain substrates (e.g. Scheme 6), the elimination product to predominate. As the naked anions increase in size they display less basic characteristics but retain high nucleophilic reactivity (74JA2250). 

Pedersen used reactions of nucleophilic substitution to synthesize most of the crown ethers he has obtained. On the other hand, Lehn and his coworkers [17] (Fig. 7.1.4) carried out cyclization reactions involving amide formation under high dilution conditions in their quest for cryptands such as 54. Pedersen analysis of the selective inclusion of alkali metal cations into the crown ethers cavity... 

To monitor tumor response to capecitabine therapy noninvasively, Zheng and co-workers, from the Indiana University School of Medicine, developed the synthesis of the fluorine- 18-labeled capecitabine as a potential radiotracer for positron emission tomography (PET) imaging of tumors.28 Cytosine (20) was nitrated at the C-5 position with nitric acid in concentrated sulfuric acid at 85°C, followed by neutralization to provide 5-nitrocytosine (27) in moderate yield. This nitro pyrimidine was then carried through the glycosylation and carbamate formation steps, as shown in the Scheme below, to provide the 6/s-protected 5-nitro cytidine 28 in 47% for the three-step process. Precursor 28 was then labeled by nucleophilic substitution with a complex of 18F-labeled potassium fluoride with cryptand Kryptofix 222 in DMSO at 150 °C to provide the fluorine-18-labe led adduct. This intermediate was not isolated, but semi-purified and deprotected with aqueous NaOH in methanol to provide [l8F]-capecitabine in 20-30% radiochemical yield for the 3-mg-scale process. The synthesis time for fluorine-18 labeled capecitabine (including HPLC purification) from end of bombardment to produce KI8F to the final formulation of [18F]-1 for in vivo studies was 60-70 min. 

Nucleophilic substitution in 2,6-dihalopyridines by selected alkoxides can provide a cryptand skeleton. For instance, condensation of 2,6-dichloropyridine and triethanolamine in the presence of sodium hydride afforded the cryptand 29 in 3% yield 32). 

The discussion of the pyridinocryptands has not been restricted, since there are currently only a limited number of cryptands of this type. The major synthetic pathways utilized for their construction have been the condensation of diacyl halides with diamines, nucleophilic substitution of dihalides by glycolates, and quaternization-demethylation of diamines. 

Landini, D., A. Maia, and F. Montanari, Dehydrating Effect of Concentrated Aqueous Alkaline Solutions in Aliphatic Nucleophilic Substitutions Carried Out in Aqueous-Organic Two-Phase Systems The Different Behavior of Various Phase Transfer Catalysts Quaternary Salts, Crown Ethers and Cryptands, Isr.J. Chem., 26, 263 (1985). 

Polymeric cryptands with different porosity, polarity, network density and copolymer compositions have been obtained by polymerization and copolymerization of 5,6-(vinylbenzo)-4,7,13,16,21,24-hexaoxa-l,10-diazabicyclo[8.8.8]hexacosane [87]. It was found that copolymer composition and porosity do not affect the catalytic activity of polymeric cryptands in the nucleophilic substitution reaction between benzyl chloride and solid potassium acetate. Presumingly the reaction occurred on the polymer surface. These polymeric catalysts were more active during the nucleophilic substitution reaction between solid KCN and 1-4-dichlorobutane. 

Nucleophilic substitution of octyl methane sulphonate by anions in biphasic chlorobenzene-water is catalysed by a lipophilic cryptand containing a ,4 alkyl side chain. Lipophilic cryptates exist as monomeric species in low-polarity solvents... 

Nucleophilic Substitutions.—Many of the nucleophilic substitutions covered by equation (1) can be catalysed as effectively in liquid-liquid two-phase systems by crown and cryptand compounds as by quaternary ions. Alkyl substitution on the basic crown skeleton of (28), as in (31), was found to increase the efficiency of catalysis for the conversion of alkyl mesylates to halides, presumably by ensuring partitioning of the crown-salt complex between the phases. A similar observation has been made using alkyl-substituted crown (32) and aza-crown compounds (33) as catalysts in two-phase reactions, for example between iodide, cyanide or thiocyanate aniohs and an alkyl bromide. Alkyl substitution in the macrobicyclic cryptands (34) has the same effect on Sn processes, and in all the above cases systems can be devised with catalytic efficiency comparable to or greater than that achieved by quaternary ion PTC. 

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. 

An interesting alternative approach to the synthesis of a cryptand having nitrogen atoms in the bridges was presented by Newkome and coworkers. This group condensed triethanolamine with 2,6-dichloropyridine in a relatively straightforward but low yield (5%) nucleophilic aromatic substitution to form 7, illustrated below in Eq. (8.6). The identity of the compound was confirmed by X-ray structural analysis. 

Increasing die effective nucleophilicity of an ion allows S 2 substitution reactions to occur under milder conditions. An anion will become a better nucleophile when it is less effectively solvated and when it is further separated from its counterion. Methods that can achieve these changes include selection of a tetraafldammomum counterion [see Eqs. (6) and (6)], addition of a crown ether or a cryptand [see Eq. (7)], and use of a solvent that effectively solvates cations [see Eqs. (1) and (2)]. 

The majority of research on catalysis by anion-exchange resins is devoted to the use of resins in interfacial catalysis reactions [38-43]. In this connection, quaternary ammonium or phosphonium, onium salts have been commonly obtained [44]. Crown-ethers, cryptands and linear polyesters supported on polymers also catalyze similar reactions dealing with the interfacial transfer of reagents. In the simplest case, the mechanism of interfacial catalysis represents a substitution reaction of Sf 2 type typical for the interaction of the nucleophile, T , present in the aqueous solution with the alkyl halogenide, RX, in the organic phase ... 

Newkome et al. used nucleophilic aromatic substitution to incorporate the 2,6-pyrido unit into a triazamacrocycle which was precursor to a series of cryptands (Scheme 11) <81TL3039>. The sequence uses a tertiary aminoalcohol as the nucleophile in a sodium hydride-mediated reaction with 2,6-dichloropyridine. In the second step, the tertiary amines function as nucleophiles in a reaction of triethylene glycol diiodide. The tertiary amines are converted into quaternary ammonium salts in the process. The system must be demethylated to form the neutral crown but conditions must be such that reduction of the pyridine residue does not occur. This was accomplished by using the commercial reagents L-Selectride and Super-Hydride. 

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