Schiff base template reaction

The diastereodifferentiating effect of the galactosylamine template in these Strecker reactions is rationalized in terms of a preferred conformation 5 of the Schiff bases which is stabilized by a (7i-double bond into the carbohydrate ring. This conformation is supported by a strong NOE in the H-NMR spectrum between the anomeric and the iminc proton. 

A selection from the large number of template reactions published following the original report by Curtis will now be described. Schiff-base and related condensations have figured prominently in these reactions. For ease of presentation, it is convenient to separate examples involving non-Schiff-base condensation from those involving Schiff-base formation. The next two subsections are devoted to descriptions of examples from each of these respective types. 

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... 

The ligand reaction step may occur either with the template metal still intact or may take place after removal of the metal ion from the ring. As already mentioned, many of the Schiff-base macrocycles are unstable in the absence of a coordinated metal ion. However, for such systems, it has often been possible to hydrogenate the coordinated imine functions directly. The resulting saturated ligands will not be subject to the hydrolytic degradation which occurs for the imine precursors in the absence of their metal ion. 

The Schiff base complex [SrL](BPh4)2 (L = (188)) was obtained by an in situ metal template procedure." This species undergoes a transmetallation reaction in dry ethanol to yield [Mn2NCS4] (L = (188)). No evidence for a magnetic exchange interaction was observed in this case. 

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. ... 

The highest flexibility for a variation of the functional group and the chains X and Y (i.e. the size of the rim of the lamp shade) will be realiad when the synthesis of 3 is convergent and modular (Scheme 1). Amide bonds can easily be formed in macrocyclizations [13], therefore macrocyclic diamines 7 and diacyl dichlorides 8 had to be prepared. For the synthesis of macrocyclic diamines 7, also a large number of reactions are known. However, in this case a reduction of a macrocyclic diamide could not be achieved [11]. Therefore, another route was used the formation of macrocyclic diimines 6 (bis-Schiff bases) followed by NaBH4 reduction to the macrocyclic diamines 7. This approach has the advantage that for the construction of macrocyclic diimines 6, the metal ion template effect [14] may be exploited. 

Aspinall, H. C. Black, J. Dodd, I. Harding, M. M. Winkley, S. J. A lanthanide-templated Schiff-base condensation reaction to give a trinuclear macrocyclic complex. J. Chem. Soc., Dalton Trans. 1993, 709—714. 

The crystal structures of alkaline earth metal complexes of several (1 + 1) and (2 + 2) Schiff base macrocycles have been reported. These macrocycles are formed by the metal template-controlled condensation of the required heterocyclic dicarbonyl derivative and a, co functional diamine in alcoholic solution. (1 +1) complexes arise from the condensation reaction of one dicarbonyl with one diamine and (2 + 2) complexes from the condensation of two dicarbonyls with two diamines. 

Most nickel(II) complexes with the various Schiff bases derived from salicylaldehyde and different amines have usually been easily prepared by three general methods (i) the reaction of a nickel(II) salt, usually hydrated nickel(II) acetate, with the preformed Schiff base using water, EtOH, MeOH or their mixtures as reaction medium (ii) the condensation reaction of bis(salicylaldehydato)nickel(II) with the appropriate amine in refluxing EtOH or H20/EtOH mixture (iii) the template reaction of the aldehyde with the appropriate amine in the presence of a nickel salt. In Table 97 the formulas, synthetic methods and some physicochemical properties for a number of nickel(II) salicylaldiminato complexes are reported. Examples of dinuclear complexes formed with Schiff bases are specifically reported in Section 50.5.8.5. 

Template and capping reactions feature in recent work. A number of sterically hindered H20 and N4 ligands have been prepared in which a quadridentate Schiff base is capped by condensation of salicylaldehyde or pyrrole-2-carbaldehyde with a series of bis(8-aminonaphthyl)alkyl ethers. These ligands combine the versatility of the Schiff base with the protective features well known for certain model porphyrin systems, and appear to be of some interest. The zinc(II) complex and other transition metal complexes have been prepared.340... 

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,... 

The synthetic routes may often involve template directed condensations, a widely used reaction being the (carbonyl + amine) to imine condensation that efficiently leads to a variety of Schiff-base macrocycles [2.58-2.60, A.7, A.14], macrobicyclic cryptands [2.61-2.63] and lacunar cyclidene ligands [2.60, 2.64]. 

The standard synthesis for cyclam was developed by Barefield and Wagner in 1976.29 They used similar starting materials to the van Alphen procedure but the cyclisation yield is improved through the use of a nickel (II) template. Glyoxal completes the macrocycle by a Schiff base condensation reaction. The resulting imine functionalities are reduced with sodium borohydride to leave the complexed macrocycle. The metal ion is then removed by reaction with cyanide and the free ligand extracted with chloroform (Scheme 3.19). Yields are typically in the region of 60%. 

We have already looked at three key Schiff base macrocycles (Figure 3.56), which were amongst the first artificial metal macrocycle compounds to be synthesised. These compounds are generally formed by thermodynamic template effects because, unless water is removed during the course of the reaction, the condensation is reversible, allowing complexation to sequester the most stable metal-product... 

Scheme 3.22 Schiff base reactions (a) 1 1 cyclocondensation templated by small metal ions (b) larger macrocycles are obtained with larger templates.

Both porphyrins and phthalocyanines are prepared by template Schiff base type condensation rections. For example, the use of a large template is evident in the synthesis of the superphthalocyanine 3.83, in which five repeat units are organised about the pentagonal bipyramidal U022+ core, instead of four as in more traditional phthalocyanine complexes such as 3.82. Smaller templates result in the formation of the trimeric subphthalocyanine 3.84. The reversible nature of the condensation reaction means that both 3.83 and 3.84 can be converted into normal tetrameric phthalocyanine, 3.85, Scheme 3.23. 

Ni(II) salts give rise to trimeric 31 and tetrameric 32 macrocycles (Fig. 16B).45 111 116 There was some speculation about the mechanism of the condensation, although when the reaction was run with cyclic intermediate 33114 there was a predominant formation of trimeric 31. Apparently, a rapid interconversion of oligomeric Schiff bases would in the presence of Ni(II) cations become directed to form thermodynamically stable and metallated 31 and 32. Since these pioneering discoveries, there have been many reports about using templating molecules for directing the outcome of reversible covalent processes.42,44,66... 

Figure 28 shows another two examples of trivalent Schiff base ligands. The macrocyclic ligand was generated in a template condensation of 2,6-diacetyl-pyridine with l,3-diamino-2-hydroxypropane in the presence of lanthanide salts [187]. The La(N03)3 H20-reaction yielded a trinuclear complex of composition [La3U/ 3-0HX0H)(N03)4]-7H20 [188]. 

Myriad polydentate aza-macrocycles have been reported 41. The extent of the subject forces limitation of this discussion to only macrocycles containing a pyridine or dipyridine subunit. Most of these coronands have been synthesized by a SchifF base condensation of an aldehyde or ketone with a hfc-primary amine in the presence of a metal ion. The metal ion acts as a template, resulting in dramatic increases in yield of the desired cyclic product over linear polymerization products42 46. Lindoy and Busch45 have described this effect in two ways, kinetic and thermodynamic. If the metal ion controls the steric course of a series of stepwise reactions, the template effect is considered to be kinetic. If the metal ion influences an equilibrium in an organic reaction sequence by coordination with one of the reactants, the template effect is termed thermodynamic. It is the kinetic effect that is believed to be operative in most metal ion-assisted (in situ) syntheses of... 

Principally, the same ring closure reactions as for tetraazacycles (Section 14.11.5.3) can be applied for preparation of larger polyazamacrocycles however, mostly tosylamide and peptide-like syntheses are employed. In addition, metal template or cyclization reactions between carbonyl compounds and amines (and reduction of intermediate Schiff base) are often utilized. 

Macrocycles that are saturated or have double bonds in only one part of the ring can be made independently or can be made by template synthesis96 where the presence of a metal ion controls the ligand synthesis. An important route is the Schiff base condensation reaction (eq. 9-3),... 

Metal ion template mediation in macrocyclic synthesis has been a part of the field since its inception, its importance having been realized early in the development of this area. Two specific roles for the metal ion in template reactions have been proposed. These are, in turn, kinetic and thermodynamic in origin." In the kinetic template effect, the arrangement of ligands already coordinated to the metal ion provides control in a subsequent condensation during which the macrocycle is formed. The thermodynamic effect serves to promote stabilization of a structure which would not be favored in the absence of a metal ion. Schiff base condensations tend to be dependent on this latter type of template effect. Some of the more routine and general synthetic procedures will be described here. A more in-depth treatment can be found in a review by Curtis, with particular emphasis on general methods as well as modifications of preformed macrocycles." ... 

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