Cyclization template reaction

Fig. 3a,b. Template cyclization reactions of a crown ethers and b CPOs. The coordination bonds are illustrated by black arrows. In the crown ether synthesis, ethylene glycols coordinate toward the metal acting as the template (normal template reaction) however, the template coordinates to the incorporated metals of porphyrin In CPO synthesis (inverse-template reaction)... 

Other template cyclizations. In another Schiff-base template reaction, 1,3-diaminopropane monohydrochloride was reacted with biacetyl in methanol in the presence of Ni(n) to yield the nickel complex of the corresponding cyclic tetraimine - see [2.16] (Jackels et al., 1972). The success of the procedure illustrated is quite dependent on the reaction conditions employed. Attempts to isolate the metal-free macrocycle were unsuccessful - this once again emphasizes the stabilizing role of the metal... 

Cyclization of coordinated primary amines on to coordinated aminoacetone has also been investigated in bis(l,2-diaminpethane)cobalt(ni) complexes, and the results show selectivity with respect to attack of the monoamine or 1,2-diaminoethane (equation 38).218 A similar complex with two coordinated aminoacetone molecules undergoes the same type of stereoselective kinetic template reactions and yields complexes primarily of a new quadridentate ligand (Scheme 48).219... 

An extensive series of neutral macrocyclic complexes, mainly of nickel(II), copper(II), platinum(II) and palladium(II), has been developed by Dziomko and coworkers. The cyclization step in the template reaction is a nucleophilic aromatic substitution of an arylamine on to a haloaryl azo compound. A variety of aryl and heteroaryl rings can be incorporated in different combinations. For instance, a diaminoazo compound can be combined with a dihaloazo compound (Scheme 58).246 247 Another synthetic strategy involves the dimerization of an aminohaloazo compound and leads to more symmetrical macrocyclic complexes (Scheme 59).248 249 Most recently, dihalodiazo compounds have been synthesized from dihydrazines and pyrazolinediones and undergo template reactions with simple 1,2-diamines (Scheme 60).249 250... 

Kinetic templates accelerate reaction of bound substrates, which makes it tempting to quantify template effects in terms of rate enhancement . In this section, we will show how this can be misleading because such rate enhancements are concentration dependent. We will elucidate the parameters which determine the rate enhancement achieved with a kinetic template, by analyzing the thermodynamic and kinetic behavior of simple theoretical models, and applying these models to published template systems. Our theoretical models are similar to the Michaelis-Menten analysis of enzyme catalyzed reactions [51], except that we assume there is no catalytic turnover. First, we consider linear templates, then cyclization templates. In general, the rate of reaction varies as the reaction proceeds whenever we refer to rates in the following discussion, we mean initial rates. 

Template reactions are those in which formation of a complex places the ligands in the correct geometry for reaction. One of the earliest was for the formation of phthalocyanines (Figure 12.17). The study of this chanistry began in 1928, after discovery of a blue impurity in phthalimide prepared by reaction of phthalic anhydride with ammonia in an enameled vessel. This impurity was later discovered to be an iron phthalocyanine complex, created from iron released into the mixture via a scratch in the enamel surface. A similar reaction takes place with copper intermediates isolated from this reaction are shown in Hgure 12.17. Phthalic acid and ammonia first form phthalimide, then l-keto-3-iminoisoindoline, and then l-amino-3-iminoisoindolenine. The cyclization reaction then occurs, probably with the assistance of the metal ion, which holds the chelated reactants in position. This is confirmed by the lack of cyclization in the absence of the metals. The essential feature of these reactions is the formation of the cyclic compound by coordination to a metal ion. 

Although many synthetic routes have been adopted for the preparation of azacycloalkanes and -cyclophanes, the vast majority of cyclization procedures can be grouped into two major categories (i) direct synthesis by conventional organic reactions and (ii) metal ion-promoted (template) reactions. 

In an analogous (but slightly altered) manner, the synthesis of 60 (Scheme 4.14) started with l,5-dibromo-2,4-diiodobenzene 57 [76] as a C2v-symmetric template. Reaction with TMSA and deprotection gave l,5-dibromo-2,4-diethynylbenzene. Another Sonogashira coupling, this time with l-bromo-2-iodobenzene, provided the tetrabrominated 58. This material underwent a four-fold exchange of bromides with TMSA and, after fluoride-assisted deprotection, yielded hexayne 59. The cyclization to 60 proceeded smoothly under the conditions of [CpCo(eth)2] catalysis (see Experimental Section). 

In 1977, Mandolini and Masci reported clear kinetic evidence that a template effect was important to the cyclization of o-hydroxyphenyl-3,6,9,12-tetraoxa-14-bromotetra-decyl ether. The starting material and its subsequent reactions are illustrated in Eq. (2.4). 

An approach to isobacteriochlorins1 ln-e makes use of Pd(II) or metal-free bilatrienes 1 as starting materials. Cyclization of the corresponding bilatriene derivatives is induced by base in the presence of palladium(II) or zinc(II) which exercise a template effect. Zinc can be readily removed from the cyclized macrotetracycles by acid whereas palladium forms very stable complexes which cannot be demetalated. Prior to the cyclization reaction, an enamine is formed by elimination of hydrogen cyanide from the 1-position. The nucleophilic enamine then attacks the electrophilic 19-position with loss of the leaving group present at the terminal pyrrole ring. 

The yield of the cyclization step under the influence of a metal template can be increased when the corresponding dialdehyde 19 of the tetrapyrrole 16 is used. The reaction sequence is initiated by insertion of palladium(II) or nickel(II) into the tetrapyrrole to give 20 followed by Michael addition of one acrylaldehyde side chain to the other yielding the macrotetracycle 21 from which in a retro-Michael reaction acetaldehyde is eliminated to give 22. 

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