Proton transfer esters

This variation from the ester hydrolysis mechanism also reflects the poorer leaving ability of amide ions as compared to alkoxide ions. The evidence for the involvement of the dianion comes from kinetic studies and from solvent isotope effects, which suggest that a rate-limiting proton transfer is involved. The reaction is also higher than first-order in hydroxide ion under these circumstances, which is consistent with the dianion mechanism. 

Certain molecules that can permit concerted proton transfers are efficient catalysts for reactions at carbonyl centers. An example is the catalytic effect that 2-pyridone has on the aminolysis of esters. Although neither a strong base (pA aH+ = 0.75) nor a strong acid (pJsfa = 11.6), 2-pyridone is an effective catalyst of the reaction of -butylamine with 4-nitrophenyl acetate. The overall rate is more than 500 times greater when 2-pyridone acts... 

The dienol is unstable, and two separate processes have been identified for ketonization. These are a 1,5-sigmatropic shift of hydrogen leading back to the enone and a base-catalyzed proton transfer which leads to the / ,y-enone. The deconjugated enone is formed because of the kinetic preference for reprotonation of the dienolate at the a carbon. Photochemical deconjugation is a synthetically useful way of effecting isomerization of a,) -unsaturated ketones and esters to the j ,y-isomers. 

However, as can also be seen in Fig. 11, primary and secondary amines do not perform very effectively as primers, compared to tertiary amines, even though they also contain long alkyl chains. It has been demonstrated that, instead of directly initiating ECA polymerization, primary and secondary amines first form aminocyanopropionate esters, 12, because proton transfer occurs after formation of the initial zwitterionic species, as shown in Eq. 7 [8,9]. 

A catalyst is defined as a substance that influences the rate or the direction of a chemical reaction without being consumed. Homogeneous catalytic processes are where the catalyst is dissolved in a liquid reaction medium. The varieties of chemical species that may act as homogeneous catalysts include anions, cations, neutral species, enzymes, and association complexes. In acid-base catalysis, one step in the reaction mechanism consists of a proton transfer between the catalyst and the substrate. The protonated reactant species or intermediate further reacts with either another species in the solution or by a decomposition process. Table 1-1 shows typical reactions of an acid-base catalysis. An example of an acid-base catalysis in solution is hydrolysis of esters by acids. 

A system of this type is commonly said to possess a fast preequilibrium step. Proton transfers constitute a veiy important class of fast preequilibria, as illustrated by Scheme XVII for acid-catalyzed ester hydrolysis. 

Chemists have estabhshed that a Dieckmann condensation will not succeed unless the final keto-ester product is deprotonated by a base. In our example, this would be a reaction between EtO" and the keto-ester (it is necessary, therefore, to use excess EtO ). What reaction products are generated by this proton transfer Obtain the energies of the reactants and products, and calculate the energy for this final proton transfer. Is this reaction thermodynamically favorable or unfavorable Does this step make the overall condensation reaction favorable or unfavorable ... 

Volume 8 Volume 9 Volume 10 Volume 12 Volume 13 Proton Transfer Addition and Elimination Reactions of Aliphatic Compounds Ester Formation and Hydrolysis and Related Reactions Electrophilic Substitution at a Saturated Carbon Atom Reactions of Aromatic Compounds Section 5. POLYMERISATION REACTIONS (3 volumes)... 

Experimental observations and test calculations pointed out a special behaviour of the nitrate anion when faced with 6arbocations. Therefore a detailed investigation with the assistance of the MINDO/3 and the Huron-Claverie method was carried out122). It appeared that in addition to the ester formation and the proton transfer to the counterion, the formation of NO+ by oxygen transfer to the cation must be considered as well (see Fig. 11). 

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. 

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. ... 

As the final proton transfer cannot occur when a-substituted esters are used, such compounds do not condense under the normal reaction conditions, but this limitation... 

Two methods for converting carboxylic acids to esters fall into the mechanistic group under discussion the reaction of carboxylic acids with diazo compounds, especially diazomethane and alkylation of carboxylate anions by halides or sulfonates. The esterification of carboxylic acids with diazomethane is a very fast and clean reaction.41 The alkylating agent is the extremely reactive methyldiazonium ion, which is generated by proton transfer from the carboxylic acid to diazomethane. The collapse of the resulting ion pair with loss of nitrogen is extremely rapid. 

Proton transfer reactions are often the first step in many reactions that alcohols, ethers, aldehydes, ketones, esters, amides, and carboxylic acids undergo. 

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

Further studies on 1,3-dipolar addition reactions of diazophosphonates have been recorded,122 and work on 2-diazo-l-hydroxyalkylphosphonates also continues.123 The ester (155 R = H) reacts with esters of acetylenedicarboxylic acid without liberation of nitrogen to give stereoisomeric C-phosphorylated pyrazolines, which can be decomposed with both phosphorus-carbon and carbon-carbon bond fission, affording mixtures containing dimethyl acetylphosphonate, dimethyl hydrogen phosphonate, and tri(alkoxycarbonyl)pyrazolines. In the reaction between the same diazophosphonate and diazomethane, the latter conceivably acts as a basic catalyst for proton transfer in a series of steps which includes phosphonate-phosphate isomerization. The importance of a labile proton is demonstrated by the fact that the ester (155 R = Me) does not react in the manner described above. 

Direct coupling of carbon nucleophiles with 1,3-dinitrobenzene is promoted by ultraviolet irradiation in the presence of quaternary ammonium fluorides, which can act not only as the base to generate the carbon nucleophile, but also as a proton transfer agent in the rearomatization step [83], The dinitrobenzene acts as the electron acceptor in the photochemical step. No reaction occurs in the absence of the fluoride and, surprisingly, although simple ketones, nitriles, esters and fl-kcto esters react, pentan-2,4-dione does not. 

Mechanism of esterification of carboxylic acids The esterification of carboxylic acids with alcohols is a kind of nncleophilic acyl snbstitntion. Protonation of the carbonyl ojq gen activates the carbonyl gronp towards nncleophilic addition of the alcohol. Proton transfer in the tetrahedral intermediate converts the hydrojq l group into - 0H2 group, which, being a better leaving group, is eliminated as neutml water molecule. The protonated ester so formed finally loses a proton to give the ester. 

In the third transition state (TS3), the neutral catalyst is recovered by transferring the proton back from the catalyst to the substrate. In other words, the (former) azlactone ether oxygen atom deprotonates the tertiary ammonium ion. For proton transfer, again an LBHB is formed (N-0 distance 2.479 A, <(0,H,N)=166.2°). In the product complex, the catayst is neutral and the A-acylamino acid ester is bound in its iminol form to the catalyst (Product(iininol)). Finally, an additional 66.6 kJ moF are gained by the subsequent iminol-amide tautomerization (Product(ainide)) (Fig. 1). 

The mechanistic hypothesis was tested with experiments involving a pair of substrates differing only in olefin geometry abont the a,[3-unsatnrated ester. If the assumption that proton transfer occnrs faster than the bond rotation of converting C to D is valid then the ( )- and (Z)-isomers are expected to prodnce opposite diastereomers. In the event, ( )-99 provides 42 1 dr while (Z)-99 provides 1 6 dr favoring the opposite diastereomer (Scheme 14). 

The proposed catalytic cycle for this reaction begins with the initial attack of the in situ generated thiazolylidene carbene on the epoxyaldehyde followed by intramolecular proton transfer (Scheme 28, XXXII-XXXIII). Isomerization occurs to open the epoxide forming XXXIV which undergoes a second proton transfer forming XXXV. Diastereoselective protonation provides activated carboxylate intermediate XXXVI. Nucleophilic attack of the activated carboxylate regenerates the catalyst and provides the desired P-hydroxy ester. 

The final step drives the reaction to completion. Ethyl acetoacetate is more acidic than any of the other species present, and it is converted to its conjugate base in the final step. A full equivalent of base is needed to bring the reaction to completion. The /i-kctocstcr product is obtained after neutralization and workup. As a practical matter, the alkoxide used as the base must be the same as the alcohol portion of the ester to prevent product mixtures resulting from ester interchange. Because the final proton transfer cannot occur when a-substituted esters are used, such compounds do not condense under the normal reaction conditions. This limitation can be overcome by use of a very strong base that converts the reactant ester completely to its enolate. Entry 2 of Scheme 2.13 illustrates the use of triphenylmethylsodium for this purpose. 

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