Substrate preorganization

The mechanisms for metal-catalyzed and organocatalyzed direct aldol addition reactions differ one from another, and resemble the mode of action of the type 11 and type I aldolases, respectively. Some metal-ligand complexes, for example, 1-4 and 9 are considered to have a bifunctional character [22], embodying within the same molecular frame a Lewis acidic site and a Bronsted basic site. Whereas base would be required to form the transient enolate species as an active form of the carbonyl donor, the Lewis acid site would coordinate the acceptor aldehyde carbonyl, increasing its electrophilicity. By this means, both transition state stabilization and substrates preorganization would be provided (see Scheme 5 for a proposal). 

Enzymes are, however, much more than just a combination of substrate binding site and the catalytically active site. Important contributions to enzymatic catalysis arise from substrate preorganization, restriction of substrate motion, catalyst dynamics, transition state binding, and desolvation of the substrates, and natural evolution has used these... 

Confinement of the substrate next to the active site in a supramolecular environment enhances reactivity. Indeed, the calculations performed on the Cu-ZSM-5 system also show that, upon CH4 approach, one of the SOMO orbitals develops a strong oxygen p character and is oriented toward the C-Tl bond of methane. The dicupric core is thus activated for H-abstraction, as a result of both host constraints (stabilization of the reactive core) and substrate preorganization. 

The microenvironment within the enzyme cavity has a great influence on the reaction catalyzed by enzymes. Most of the effective parameters on enzyme operation—such as substrate preorganization, restricted substrate motion, protein dynamics, covalent binding of the transition state, and desolvation of the substrate—are induced by this microenvironment [5]. Therefore, designing a binding cavity in the structure of artificial enzymes is of great importance [2,6]. 

Dydio P, Reek JNH. Supramolecular control of selectivity in transition-metal catalysis through substrate preorganization. Chem Sci 2014 5 2135—45. 

From the kinetic point of view the facts are different and the order is reverse, ie, the rigid highly preorganized spherands are slow, as contrasted with the flexible barely preorganized podands that are fast both in formation and decomposition of the receptor—substrate (host—guest) complex (20,21). 

The use of chiral ruthenium catalysts can hydrogenate ketones asymmetrically in water. The introduction of surfactants into a water-soluble Ru(II)-catalyzed asymmetric transfer hydrogenation of ketones led to an increase of the catalytic activity and reusability compared to the catalytic systems without surfactants.8 Water-soluble chiral ruthenium complexes with a (i-cyclodextrin unit can catalyze the reduction of aliphatic ketones with high enantiomeric excess and in good-to-excellent yields in the presence of sodium formate (Eq. 8.3).9 The high level of enantioselectivity observed was attributed to the preorganization of the substrates in the hydrophobic cavity of (t-cyclodextrin. 

Type (820) dinickel complexes offer the opportunity of substrate binding within the bimetallic pocket, and highly preorganized complexes of this type have also been employed as model systems for the urease metalloenzyme (see Section 6.3.4.12.7). The Ni—Ni separation in type (820) complexes can be... 

The four oxygen donor atoms preorganized in a quasiplanar geometry have a major effect in determining the set and relative energy of the frontier orbitals available at the metal for the substrate activation (see Chart 2). 

The highest rate acceleration in the nonenzymatic hydrolysis of a phosphate monoester was reported by Chin s group [35]. In the dinuclear cobalt(III) complex 9 the metal ions are much more rigidly preorganized than in complexes 6 and 8. At pH 7 and 25 °C coordinated phenyl phosphate (PP) hydrolyzes 1011 times faster than free PP under the same conditions. There is good evidence for a reaction mechanism which has already been suggested for 2. The higher reactivity of 9 compared to 2 may be attributed to the proximity of substrate and M-OH nucleophile. 

Hydrogen bonds can preorganize the spatial arrangement of the reactants In cases where hydrogen bond donor/acceptor functions are attached to a (chiral) scaffold, they can steer the assembly of a well-defined catalyst-substrate complex. The positions of hydrogen bond donors and acceptors determine the stereoselechvity of the reaction. 

The synthesis of a molecular knot 6 [11], olympiadane 7 [12], and many other topological molecules discussed in Sections 2.3 and 8.1 would not be possible without preorganization of substrates forcing their appropriate orientation. In this case the preorganization is accomplished by the complexation of phenanthroline fragments with a metal ion (Figure 1.2). 

As stated above, simple catenanes were first obtained by a statistical approach. However, the successful syntheses of more complicated topological molecules would not have been possible without an enforcement of spatial orientation of reaction substrates called preorganization, introduced in Section 2.3. The latter effect can be achieved by... 

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