Intramolecular electrophilic catalysis

The rate of a bimolecular nucleophilic or electrophilic addition, substitution, elimination, or addition-elimination reaction may be increased by several orders in the presence of an electrophilic catalyst (E+), such as metal ion, if E+ is capable of forming a complex with both reactants (say electrophile Y - Sub - X and nucleophile W - H) in an appropriate molecular geometry, which allows the reaction to proceed intramolecularly as shown in Equation 2.35. 

In an attempt to clarify some vexing points of a complex mechanism of ribozyme (with Mg + as cofactor)-catalyzed hydrolysis of RNA and RNA-model compounds, Bruice et al. studied the rate of divalent metal ion (Mg, Zn, Cu +, and La +)-promoted-hydrolysis of adenosine 3 -[(8-hydroxyquinolyl)methyl phosphate] (38) and adenosine 3 -[2-(8-hydroxyquinolyl)ethyl phosphate] (39). Pseudo-first-order rate constants (kobs) for M +-promoted-hydrolysis of 38 and 39 follow kinetic Equation 2.36 

The occurrence of intramolecular metal ion catalysis is reported in the hydrolysis of adenylyl(3 -5 )adenosine (ApA) under the presence of diaquatetraazaco-balt(lll) complexes [Co(N)4(OH2)2] + (N coordinated nitrogen atom) at pH 7.0. Pseudo-first-order rate constants (ko,J for ApA hydrolysis at 50°C and 0.1 M Co complexes are lO times larger than k.,b 50°C and [Co complex] = 0. 

The catalytic activity is only slightly dependent on the structure of amine ligands. 

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Although PI is a plausible intermediate on the reaction path in such reactions, it has not been detected directly by experiment and, hence, its proposed existence remains largely speculative. However, indirect proof for the presence of PI on the reaction path comes from the observed isomerization between 3, 5 -Unkage and 2, 5 -linkage only under acidic pH where PI can exist in the monoanionic form (PIH). Thus, an alternative mechanism (Scheme 2.26) for the metal-ion-assisted hydroxide-ion- and general base ( B)-catalyzed hydrolysis of RNA and RNA-model compounds cannot be completely ruled out if pentacoordinated intermediate (PIH) does exist on the reaction path. Nearly 10 -fold enhanced catalytic effects of Co " complexes are attributed to the occurrence of intramolecular electrophilic catalysis as shown in the transition state TS,g. 

The lower effective concentrations found in intramolecular base catalysis are due to the loose transition states of these reactions. In nucleophilic reactions, the nucleophile and the electrophile are fairly rigidly aligned so that there is a large entropy loss. In general-base or -acid catalysis, there is considerable spatial freedom in the transition state. The position of the catalyst is not as closely defined as in nucleophilic catalysis. There is consequently a smaller loss in entropy in general-base catalysis, so that the intramolecular reactions are not favored as much as their nucleophilic counterparts. 

Transesterification reactions of 2-alkoxycarbonylethyltin trichlorides and their adducts with neutral donors with alcohols proceed readily. This is attributed to the intramolecular Lewis catalysis by the electrophilic SnCl group owing to the coordination of the ester carbonyl group to the tin atom, C = O —Sn, which decreases the electronic density at the carbonyl carbon atom727,741 745 754. 

The search for electrophilic catalysis could in principle be aided by use of tertiary amines as nucleophiles, in which case an intramolecular or solvent assisted proton shift, formulated in [13] and [14], is eliminated. Thus Ayediran, Bamkole and Hirst (1974) studied salt effects on the reactions of 4-fluoro- and 4-chloronitro-benzene with trimethylamine in DMSO, which proceed according to equations (29) and (30). It had been noted (Suhr, 1967) that the... 

A.R. Hopkins et al., Electrophilic Catalysis of Sulphate (-SOj ) Group Transfer Hydrolysis of Salicyl Sulphate Assisted by Intramolecular Hydrogen Bonding, J. Chem. Soc., Perkin Trans. 2, 1983, 1279. 

So far in this chapter, the chemical biology reader has been introduced to examples of biocatalysts, kinetics assays, steady state kinetic analysis as a means to probe basic mechanisms and pre-steady-state kinetic analysis as a means to measure rates of on-catalyst events. In order to complete this survey of biocatalysis, we now need to consider those factors that make biocatalysis possible. In other words, how do biocatalysts achieve the catalytic rate enhancements that they do This is a simple question but in reality needs to be answered in many different ways according to the biocatalyst concerned. For certain, there are general principles that underpin the operation of all biocatalysts, but there again other principles are employed more selectively. Several classical theories of catalysis have been developed over time, which include the concepts of intramolecular catalysis, orbital steering , general acid-base catalysis, electrophilic catalysis and nucleophilic catalysis. Such classical theories are useful starting points in our quest to understand how biocatalysts are able to effect biocatalysis with such efficiency. 

The transition state for the rapid hydrolysis of the monoanion has been depicted as involving an intramolecular general acid catalysis by the carboxylic acid group, with participation by the anionic carboxylate group, which becomes bound at the developing electrophilic center... 

The most useful of the insertion processes is the intramolecular reactions that occur with high selectivity for the formation of five-membered ring products. The electrophilic nature of the process is suggested by C-H bond reactivity in competitive experiments (3°>20 >1°) [76, 77]. Asymmetric catalysis with Rh2(MPPIM)4 has been used to prepare a wide variety of lignans that include (-)-enterolactone (3) [8], as well as (R)-(-)-baclofen (2) [7],2-deoxyxylolactone (31) [80,81],and (S)-(+)-imperanane (32) [82].Enantioselectivities are 91-96%... 

Of the many reagents, both heterogeneous and homogeneous, that can facilitate chemical reactions, the cycloamyloses stand out. Reactions can be catalyzed with many species such as hydronium ions, hydroxide ions, general acids, general bases, nucleophiles, and electrophiles. More effective catalysis can sometimes be achieved by combinations of catalytic species as in multiple catalysis, intramolecular catalysis, and catalysis by com-plexation. Only the latter catalysis can show the real attributes of an efficient catalytic system, namely speed and selectivity. In analogy to molecular sieves, selectivity can be attained by stereospecific complexation and speed can be likewise attained if the stereochemistry within the complex is correct. The cycloamyloses, of any simple chemical compound, come the closest to these goals. 

Products of a so-called vinylogous Wolff rearrangement (see Sect. 9) rather than products of intramolecular cyclopropanation are generally obtained from P,y-unsaturated diazoketones I93), the formation of tricyclo[2,1.0.02 5]pentan-3-ones from 2-diazo-l-(cyclopropene-3-yl)-l-ethanones being a notable exception (see Table 10 and reference 12)). The use of Cu(OTf), does not change this situation for diazoketone 185 in the presence of an alcoholl93). With Cu(OTf)2 in nitromethane, on the other hand, A3-hydrinden-2-one 186 is formed 160). As 186 also results from the BF3 Et20-catalyzed reaction in similar yield, proton catalysis in the Cu(OTf)2-catalyzed reaction cannot be excluded, but electrophilic attack of the metal carbene on the double bond (Scheme 26) is also possible. That Rh2(OAc)4 is less efficient for the production of 186, would support the latter explanation, as the rhodium carbenes rank as less electrophilic than copper carbenes. 

The intramolecular arylation of sp3 C-H bonds is observed in the reaction of l-/ r/-butyl-2-iodobenzene under palladium catalysis (Equation (71)) 94 94a 94b The oxidative addition of Arl to Pd(0) gives an ArPdl species, which undergoes the electrophilic substitution at the tert-butyl group to afford the palladacycle. To this palladacycle, another molecule of Arl oxidatively adds, giving the Pd(iv) complex. 

Three salicylate (2-hydroxybenzoate) anions, which have unusual reactivity towards bromine that has been attributed to intramolecular proton transfer assisting electrophilic attack (Tee and Iyengar, 1985, 1990), exhibit modest catalysis (k /k2u = 3 to 10) and have KTS values similar to phenols. Pyridones and their /V-methyl derivatives, three heteroaromatic acid anions, and four phenoxy derivatives show comparable catalysis (k //c2u = 1.7 to 9.5) and Krs values (Table A4.4). 

As we have seen (Section 4, p. 191) the range of effective molarities associated with ring-closure reactions is very much greater than that characteristic of intramolecular general acid-base catalysis the main classification is therefore in terms of mechanism. By far the largest section (I, Tables A-D) gives EM s for intramolecular nucleophilic reactions. These can be concerted displacements (mostly at tetrahedral carbon), stepwise displacements (mostly addition-elimination reactions at trigonal carbon), or additions, and they have been classified in terms of the nucleophilic and electrophilic centres. 

General acid catalysis is schematized in Fig. 7J,b. Here, an acid A-H increases the polarity of the carbonyl group and, hence, the electrophilicity of the carbonyl C-atom. For entropy reasons, the reaction is greatly facilitated when it is an intramolecular one (Fig. 7J,b2), in other words, when the general acid catalyst is favorably positioned within the molecule itself. Such a mechanism is the one exploited and refined by nature during the evolution of the hydrolases, with the general acid catalyst and the H20 molecule replaced by adequate amino acid side chains, and the enzymatic transition state being de facto a supermolecule (see Chapt. 3). 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

In contrast, the closely related palladium acetate-promoted intramolecular alkylation of alkenes by tri-methylsilyl enol ethers (Scheme 4)6,7 has been used to synthesize a large number of bridged carbocyclic systems (Table 1). In principle, this process should be capable of being made catalytic in palladium(II), since silyl enol ethers are stable to a range of oxidants used to carry the Pd° -> Pd11 redox chemistry required for catalysis. In practice, catalytically efficient conditions have not yet been developed, and the reaction is usually carried out using a full equivalent of palladium(II) acetate. This chemistry has been used in the synthesis of quadrone (equation 2).8 With the more electrophilic palladium(II) trifluoroace-tate, methyl enol ethers underwent this cyclization process (equation 3).9... 

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