Template kinetic coordination

The template centre plays the key role in matrix reactions. If the steric course of macrocyclisation, or other multistep reaction, is directed and facilitated by the ligsons spatial structures, and their activation by coordination to the metal ion or another centre, then the process is controlled by the kinetic coordination template effect. If the metal ion (or another centre) sequesters one of the components from an equilibrium mixture (starting ligsons and oilier competing molecular species) and, as a consequence, shifts the position of the equihbriiun towards the formation of the desired product in the form of its metal complex, then the thennodynamic (or equilibrium) coordination template effect is considered to be operative for the reaction. 

Reactions with a pronounced kinetic coordination template effect are found, in particular, in cases of preparation of macrocycUc compounds by ring-closure of chelate precursors. For example, when the complex [Ni(L4)] is electrophilically alkylated with l,2-bis(bromomethyl)benzene, the macrocyclic product [Ni(L5)Br2] is isolated ( q. 1.1). 

In the above examples of the kinetic coordination template effect, the metal ion serves to transfer information to interacting compoimds, so the structure of the reaction product is predetermined. In such cases the strict geometry of the metal ion eoordination sphere [2, 11] may be considered as an information source. 

It should be noted that uncoordinated allylphosphine does not cyclise when treated with initiator, This gives evidence for the kinetic coordination template effect operating in this process. In conditions of kinetic control (enforced by spatial effects resulting from coordination to the metal), macrocyclic product formation by addition of P-H to the C=C double bond of a neighbouring coordinated allylphosphine proceeds contrary to Markovnikov s rule (phosphorus as a more electronegative element bonded to a less substituted carbon atom). This template process is notable for its exceptional regiospecific character in that the formation of Markovnikov addition products is not detected. 

Thus, when we say that, for instance, a kinetic coordination template effect is responsible for the production of some product, it does not mean that a possible contribution from the thermodynamic coordination template effect is ruled out. The role of the matrix does not depend on one or other of the two coordination template effects prevailing. It consists not only in the strict suppression of side effects, but also in directing the process to its most favourable pathway [2, 4]. 

The chelate [Ni(L4)] transformation into the macrocyclic product [Ni(L5)Br2] [36, 37] belongs to those coordinated ligand reactions which are also template transformations. The latter are realised as a result of the kinetic coordination template effect with formation of a new chelate ring, whereas the alkylation of [Ni( L4)] with methyl iodide or benzyl bromide is merely a reaction of a coordinated ligand. 

The product is kinetically rather stable, due to the lack of (or reduced) nucleophilic properties of the coordinated primary amine group. However, in basic media, it easily turns into [Cu(L15)](C104)2. The kinetic coordination template effect is presumably manifested at this key step of macroc clisation if one assumes that, in the presence of base, the nucleophilic amido ligand is generated in sufficient concentration to allow the ring-closure reaction to proceed at a reasonable rate. 

Thus, introduction of electron-withdrawing groups into the y position of y -diketonate residues results in considerable activation of the coordinated CO groups and creates conditions favourable for the kinetic coordination template effect to operate. Chelates [M(L6)] and [M(L228)], where M = Ni or Cu, also interact with 1,3-diaminopropane forming 15-membered macrocyclic systems [273, 285]. 

Scheme 2-35. Illustration of the kinetic coordination template effect in the synthesis of phthalo-cyanines.

The kinetics and mechanisms of template reactions are rarely studied in depth - they are often merely assumed to be genuine template reactions rather than a metal-activated reaction at a coordinated ligand. The best evidence for a true template mechanism is the isolation and characterization of intermediates with both reactants and with the macrocyclic product complexed with the template cation. 

Structures have been determined for [Fe(gmi)3](BF4)2 (gmi = MeN=CHCF[=NMe), the iron(II) tris-diazabutadiene-cage complex of (79) generated from cyclohexanedione rather than from biacetyl, and [Fe(apmi)3][Fe(CN)5(N0)] 4F[20, where apmi is the Schiff base from 2-acetylpyridine and methylamine. Rate constants for mer fac isomerization of [Fe(apmi)3] " were estimated indirectly from base hydrolysis kinetics, studied for this and other Schiff base complexes in methanol-water mixtures. The attenuation by the —CH2— spacer of substituent effects on rate constants for base hydrolysis of complexes [Fe(sb)3] has been assessed for pairs of Schiff base complexes derived from substituted benzylamines and their aniline analogues. It is generally believed that iron(II) Schiff base complexes are formed by a template mechanism on the Fe " ", but isolation of a precursor in which two molecules of Schiff base and one molecule of 2-acetylpyridine are coordinated to Fe + suggests that Schiff base formation in the presence of this ion probably occurs by attack of the amine at coordinated, and thereby activated, ketone rather than by a true template reaction. ... 

Application of classical type of kinetic equations to the template polymerization was demonstrated by Kabanov at al It was shown that 4-vinylpyridine, in the presence of poly(methacrylic acid), poly(acrylic acid), poly(l-glutamic acid), and polyphosphate, polymerizes according to the classical equation and the order of reaction with respect to the monomer is 2 as demonstrated in the Figure 8.1. In log-log coordinates, for the all sets of polymerizations, experimental points fit straight lines. In the same paper dependence of the initial rate on the molar ratio of acid to monomer was examined. This relationship is shown on the Figure 8.2. The rate of polymerization in the presence of the poly(acrylic acid) is much higher than that for the low molecular analogue (acetic acid). The polymerization rate riches its maximum for the molar ratio [acid]/[monomer] 2. The authors found kinetic equation for template polymerization of 4-vinylpyridine in the presence of different polyacids in the form ... 

The kinetic template effect is observed in reactions in which the metal ion acts by coordinating the reactants. This effect has also been described as a coordination template effect. A more direct description of a kinetic template reaction is one which involves Combination of two Ligands Attached to the same. Metal ion. Such a description leads to the useful acronym CLAM reaction , which graphically portrays the key reaction step. The process can be generalized and compared with the non-template reaction in Scheme 30. 

The most important reaction of this type is the formation of imine bonds and Schiff bases. For example, salicylaldehyde and a variety of primary amines undergo reaction to yield the related imines, which can be used as ligands in the formation of metal complexes. However, it is often more desirable to prepare such metal complexes directly by reaction of the amine and the aldehyde in the presence of the metal ion, rather than preform the imine.113 As shown in Scheme 31, imine formation is a reversible process and isolation of the metal complex results from its stability, which in turn controls the equilibrium. It is possible, and quite likely, that prior coordination of the salicylaldehyde to the metal ion results in activation of the carbonyl carbon to amine nucleophilic attack. But it would be impossible for a precoordinated amine to act as a nucleophile and consequently no kinetic template effect could be involved. Numerous macrocyclic chelate systems have been prepared by means of imine bond formation (see Section 61.1.2.1). In mechanistic terms, the whole multistep process could occur without any geometrical influence on the part of the metal ion, which could merely act to stabilize the macrocycle in complex formation. On the other hand,... 

New chelate rings can be formed by the nucleophilic addition of alcohols to imine complexes. For example, the nickel(II) TAAB complex is susceptible to attack by bis-alkoxides (equation 31).127 It is not clear whether or not a kinetic template effect operates by prior coordination of the central oxygen or sulfur atom. However, such an effect is not necessary, as simple alkoxides undergo a similar addition reaction.128... 

The situation is even more clear cut in the formation of thioethers by alkylation of thiolate complexes. Such reactions have been described in Section 7.4.2.1.2, but in those examples new chelate rings were not formed. The reaction which led Busch to propose the kinetic template effect is a thiolate complex alkylation, which does indeed produce a new chelate ring (equation 40).110 162 163 This reaction is an example of the general type shown in equation (35) and it has been established clearly that the sulfur atoms remain coordinated to the metal ion throughout the... 

Dziomko and coworkers have utilized the nucleophilic aromatic substitution of aryl amines to chloropyrazoles or chloropyridines in the template step of their macrocycle syntheses.174 175 The nature of the template process is unclear and it could simply be thermodynamic. However, a kinetic effect is a distinct possibility and would require attack of a coordinated aryl amine (Scheme 52). 

Kinetic template effects have been postulated in more typical organic aldol condensations, where metals such as lithium and zinc are likely to coordinate both the enolate or enamine nucleophile and the aldehyde in the transition state. The examples shown in Schemes 58184 and 59185 are illustrative of these reactions and the degree of selectivity obtained. The carboxylation of ketones and nitroalkanes by methyl magnesium carbonate to produce P-keto acids and a-nitro acids respectively provides early examples of similar reactions (Scheme 60).186 187 See also Section 61.1.4.4. 

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... 

The use of metal ions as kinetic synthetic templates is extremely widespread, and is an excellent way in which to bring about the organisation of a number of reacting components in order to direct the geometry of the product. Because some metal ions, such as the transition metals, often have preferred coordination geometries (e.g. tetrahedral, square planar, octahedral etc), changes in metal ion may have a profound effect on the nature of the templated product. Metal-ion-templated syntheses may be classified more generally as examples of self-assembly with covalent postmodification. For example, the synthesis of the artificial siderophore 10.2 is effected by the use of an octahedral Fe3+ template.8 In this case, the macrobicyclic product is obtained as the Fe3+ complex from which it is difficult to separate. 

A reaction is described as proceeding by a kinetic template effect if it provides a route to a product that would not be formed in the absence of the metal ion and where the metal ion acts by coordinating the reactants. An alternative description for this process is the coordination template effect that more aptly describes how the stereochemistry imposed by the metal ion, through coordination, promotes a series of controlled steps in a multistep reaction, e.g., Scheme 1 17, 136, 137). 

---