Tetrahedral intermediates stabilization

The mechanism of methanolysis at 25 °C of / -nitrophenyl acetate (PNA) by a Zn2+ (MeO-) complex of 1,5,9-triazacyclododecane (79 M = Zn) involves pre-equilibrium binding of PNA to (79 M = Zn) followed by rate-limiting intramolecular attack of the coordinated methoxide to form a tetrahedral intermediate stabilized via coordination to the Zn2+.79... 

Figure 9. Proposed catalysic mechanism for carboxypeptidase A where water acts as the nucleophile, (a) nucleophilic attack by a water molecule on the carbonyl carbon of the substrate promoted by zinc and assisted by Glu270 with concommitant transfer of i proton to Glu270 (b) a tetrahedral intermediate, stabilized by interactions with Argl27 and the zinc ion, collapses with a proton donated by Glu270 (c) a second proton transfei results in product formation (d).

Stage 2 Water adds to the carbonyl group of the peptide bond. The rate of this nucleophilic addition is accelerated by coordination of the carbonyl oxygen to Zn and/or to one of the N—protons of Arg-127 (not shown). The product is a tetrahedral intermediate stabilized by coordination to zinc. Stabilization of the tetrahedral intermediate may be the major factor for the rapid rate of the carboxypeptidase-catalyzed hydrolysis. 

The elucidation of the molecnlar bases responsible for the different snbstrate specificities observed in the PHA synthases belonging to class 11 (Rehm 2003) has been approached by different anthors (Wahab et al. 2006 Arias et al. 2008). Some structural studies have revealed the participation of a serine residue (Sef297) in the catalytic process, and the formation of two tetrahedral intermediates, stabilized by the formation of an oxyanion hole during PHA biosynthesis, has been... 

There are large differences in reactivity among the various carboxylic acid derivatives, such as amides, esters, and acyl chlorides. One important factor is the resonance stabilization provided by the heteroatom. This decreases in the order N > O > Cl. Electron donation reduces the electrophilicity of the carbonyl group, and the corresponding stabilization is lost in the tetrahedral intermediate. 

Transition-state stabilization in chymotrypsin also involves the side chains of the substrate. The side chain of the departing amine product forms stronger interactions with the enzyme upon formation of the tetrahedral intermediate. When the tetrahedral intermediate breaks down (Figure 16.24d and e), steric repulsion between the product amine group and the carbonyl group of the acyl-enzyme intermediate leads to departure of the amine product. 

Q The enzyme active site contains an aspartic acid, a histidine, and a serine. First, histidine acts as a base to deprotonate the -OH group of serine, with the negatively charged carboxylate of aspartic acid stabilizing the nearby histidine cation that results. Serine then adds to the carbonyl group of the triacylglycerol, yielding a tetrahedral intermediate. 

The mechanism for the lipase-catalyzed reaction of an acid derivative with a nucleophile (alcohol, amine, or thiol) is known as a serine hydrolase mechanism (Scheme 7.2). The active site of the enzyme is constituted by a catalytic triad (serine, aspartic, and histidine residues). The serine residue accepts the acyl group of the ester, leading to an acyl-enzyme activated intermediate. This acyl-enzyme intermediate reacts with the nucleophile, an amine or ammonia in this case, to yield the final amide product and leading to the free biocatalyst, which can enter again into the catalytic cycle. A histidine residue, activated by an aspartate side chain, is responsible for the proton transference necessary for the catalysis. Another important factor is that the oxyanion hole, formed by different residues, is able to stabilize the negatively charged oxygen present in both the transition state and the tetrahedral intermediate. 

Such an intermediate ean also stabilize itself by combining with a positive species. When it does, the reaction is nucleophilic addition to a C=C double bond (see Chapter 15). It is not surprising that with vinylie substrates addition and substitution often compete. For chloroquinones, where the charge is spread by resonance, tetrahedral intermediates have been isolated ... 

There are some special cases where tetrahedral intermediates are unusually stable there are three phenomena which lead to this stability enhancement. The first is an unusually reactive carbonyl (or imine) compound which is very prone to addition. An example of such a compound is trichoroacetaldehyde or chloral, for which the covalent hydrate can be isolated. A simple way to recognize such compounds is to think of the carbonyl group as a (very) stabilized carbocation, bearing an substituent. 

Aminolysis of simple esters is snrprisingly difficnlt, despite the greater thermodynamic stability of amides than esters the problem is that the initial tetrahedral intermediate preferentially reverts to starting material (not only is the amine the better leaving gronp, bnt loss of alkoxide would lead to an A-protonated amide), and only trapping of this intermediate by proton transfer allows the reaction to proceed. ... 

Tetrahedral intermediates vary enormonsly in stability relative to the corresponding carbonyl componnds, from extremes like hexaflnoroacetone hydrate where it is difflcnlt to remove the nncleophile from the addnct, to amide hydrates where the obligatory intermediate in acyl transfer is present at nndetectably low concentrations. Linear free-energy relations provide a route to calculating the eqnilibrinm constant... 

V-Methyl-A-methoxyamides are also useful starting materials for preparation of ketones Again, the reaction depends upon the stability of the tetrahedral intermediate against elimination and a second addition step. In this case chelation with the IV-methoxy substituent is responsible. 

Tetrahedral intermediates, derived from carboxylic acids, spectroscopic detection and the investigation of their properties, 21, 37 Topochemical phenomena in solid-state chemistry, 15, 63 Transition state structure, crystallographic approaches to, 29, 87 Transition state structure, in solution, effective charge and, 27, 1 Transition state structure, secondary deuterium isotope effects and, 31, 143 Transition states, structure in solution, cross-interaction constants and, 27, 57 Transition states, the stabilization of by cyclodextrins and other catalysts, 29, 1 Transition states, theory revisited, 28, 139... 

Scheme 3 A simplified process for 9 Zn2+ (pOCH3) or La2 + ( OCH3)2-promoted meth-anolysis of a carboxylate ester demonstrating the reversible formation of a metal-ion stabilized tetrahedral intermediate.

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