Aminolysis of esters

Aminolysis of esters often exhibits general base catalysis in the form of reaction rate terms that are second order in the amine. The amine is believed to assist deprotonation of the zwitterionic tetrahedral intermediateDeprotonation of the nitrogen facilitates breakdown of the tetrahedral intermediate because the increased electron density at nitrogen favors expulsion of an alkoxide ion. 

Detailed mechanistic studies have been carried out on aminolysis of substituted aryl acetates and aryl carbonates. Aryl esters are considerably more reactive than alkyl esters because phenoxide ions are better leaving groups than alkoxide ions. The tetrahedral intermediate formed in aminolysis can exist in several forms that differ in the extent and the site of protonation. 

Addition, Condensation and Substitution Reactions of Carbonyl Compounds 

When the leaving group is better, breakdown can occur directly from TI+ . This is the case when R 0 is a phenolate anion. The mechanism also depends upon the pH and the presence of general acids and bases because the position of the equilibria among the tetrahedral intermediates and rates of breakdown are determined by these factors. 

Insight into the factors that govern breakdown of tetrahedral intermediates has been gained by studying the hydrolysis of amide acetals. If the amine is expelled, an ester is formed, whereas elimination of an alcohol gives an amide. 

The pH of the solution is of overwhelming importance in determining the course of these hydrolyses. In basic solution, oxygen elimination is dominant. This is because the unprotonated nitrogen substituent is a very poor leaving group and is also more effective at facilitating the alkoxide elimination by electron donation  

Aminolysis of esters often reveals general base catalysis and in particular a contribution to the reaction rate from terms that are second-order in the amine. The 

In acidic solution, nitrogen is protonated and becomes a better leaving group and also loses its ability to assist in the elimination of the alkoxide. Under these circumstances, nitrogen elimination is favored. 

In aprotic solvents other molecules which can assist proton removal by hydrogen bonding, such as amides, exhibit significant catalysis too.  

The preference for expulsion of one leaving group over another from a tetrahedral intermediate depends on several factors. Two of the most important are (a) basicity of the leaving group and (b) stabilization of the carbonyl bond in the product by the group which remains. 

The tetrahedral intermediate that is formed in aminolysis can exist in several different forms, depending upon the extent and site of protonation  

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The reaction (which is essentially the direct aminolysis of esters with benzylamine) proceeds readily when R is methyl or ethyl. Esters of higher alcohols should preferably be subjected to a preliminary methano-lysis by treatment with sodium methoxide in methanol ... 

The aminolysis of esters of pyrimidine occurs normally to yield amides. The reagent is commonly alcoholic ammonia or alcoholic amine, usually at room temperature for 20-24 hours, but occasionally under refiux aqueous amine or even undiluted amine are used sometimes. The process is exemplified in the conversion of methyl pyrimidine-5-carboxylate (193 R = Me) or its 4-isomer by methanolic ammonia at 25 °C into the amide (196) or pyrimidine-4-carboxamide, respectively (60MI21300), and in the butylaminolysis of butyl ttracil-6-carboxylate (butyl orotate) by ethanolic butylamine to give A-butyluracil-5-carboxamide (187) (60JOC1950). Hydrazides are made similarly from esters with ethanolic hydrazine hydrate. 

The second reaction that should be recalled is the aminolysis of esters (p. 479). This reaction leads to the formation of amides by N-acylation ... 

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... 

Although the aminolysis of esters to amides is auseful synthetic operation, usually it presents some disadvantages in terms of drastic reaction conditions, long reaction times or strong alkali metal as catalyst, which are usually not compatible with other functional groups in the molecule [6]. For this reason, enzymatic aminolysis of carboxylic acid derivatives offers a clean and ecological way for the preparation of different kind of amines and amides in a regio-, chemo-, and enantioselective manner. 

Surprisingly, the 7t-system geometry in a substrate has a notable influence in the enzymatic aminolysis of esters. The reaction of diethyl fumarate with different amines or ammonia in the presence of CALB led to the corresponding trans-amidoesters with good isolated yields, but in the absence of enzyme, a high percentage of the corresponding Michael adduct is obtained (Scheme 7.9). Enzymatic aminolysis of diethyl maleate led to the recovery of the same a, P-unsaturated amidoester, diethyl fumarate, and diethyl maleate. The explanation of these results can be rationalized via a previous Michael/retro-Michael type isomerization of diethyl maleate to fumarate, before the enzymatic reaction takes place. In conclusion, diethylmaleate is not an adequate substrate for this enzymatic aminolysis reaction [23]. 

Intramolecular general base catalysed reactions (Section II, Tables E-G) present less difficulty. A classification similar to that of Table I is used, but since the electrophilic centre of interest is always a proton substantial differences between different general bases are not expected. This section (unlike Section I, which contains exclusively unimolecular reactions) contains mostly bimolecular reactions (e.g. the hydrolysis of aspirin [4]). Where these are hydrolysis reactions, calculation of the EM still involves comparison of a first order with a second order rate constant, because the order with respect to solvent is not measurable. The intermolecular processes involved are in fact termolecular reactions (e.g. [5]), and in those cases where solvent is not involved directly in the reaction, as in the general base catalysed aminolysis of esters, the calculation of the EM requires the comparison of second and third order rate constants. 

JH Jones, GT Young. Anchimeric acceleration of aminolysis of esters and its application to peptide synthesis. Chem Commun 35, 1967. 

Aminolysis of esters.2 Reaction of esters with dialkylamines proceeds slowly if at all, but can be catalyzed effectively by A1C13 or ZrCl4. The reaction of a-chloro carboxylic esters proceeds with only slight racemization (equation I). 

Studies of the ability of the lipase B from Candida antarctica (CAL-B) to catalyse the enantioselective aminolysis of esters by cis- and firms-2-phenylcycloalkanamines (54 n = 1, 3, 4) have been followed up by molecular modelling approaches in order to probe the lipase-catalysed aminolysis mechanism. CAL-B possesses a typical serine-dependent triad, so it was possible, with access to an X-ray crystal structure of CAL-B, to model a series of phosphonamidates (55 n = 1, 3, 4) as analogues of the tetrahedral intermediate (TI) resulting from attack of the amine on the carbonyl of the acyl-enzyme. The results suggested as the most plausible intermediate for the CAL-B-catalysed aminolysis a zwitterionic TI resulting from the direct His-assisted attack of the amine on to a C=0 group of the acyl-enzyme.80... 

Note This partial aminolysis of esters has been used extensively. 

In the aminolysis of esters 6, 8a, 8b, and 9a-9d with the amine 5a, no evidence was obtained for mieelle or complex formation (Bruice el al., 1968). The rate of disappearanee of the esters obeyed pseudo-first order kinetics at [5a] > [ester] and eonstant pH and could be expressed... 

The aminolysis of esters 8a, 8b, and 9a-9e by the amine 5b did not obey the simple kinetic expression, equation (28), but provided evidence for distribution of the esters between the bulk phase and micelles of the... 

Fischer carbenes readily undergo nucleophilic attack at the carbene carbon, as shown in equation (15). The attack of amines can give the zwitterionic intermediate shown, or by loss of methanol, the aminocarbene. Mentally replacing the (CO)sCr group by an oxygen atom, shows the relation of this reaction to the aminolysis of esters to give amides. 

Lewis acid, This organoaluminum reagent (MeA10) , a partial hydrolysis product of trimethylaluminum, is more efficient than conventional Lewis acids such as MCjAl, as catalyst for inducing Diels-Alder reactions and aminolysis of esters. 

A very straightforward approach as compared with the existing one (Fig. 3) would have been the direct enzyme-catalyzed peptide formation (cf. Chen et al. [30]) by enantioselective aminolysis of ester 2 with histidine methylester 4 or even racemic histidine ester, as it would resolve the objectives of resolution and coupling in one step. Orientating experiments in which 20 proteases adsorbed on porous glass beads (SIKUG 041/02/120/A, Schott) were in contact with EtOH solutions of 2 and 4 with various water contents, however, did not reveal any reaction. 

Figure 5.6. -Elimination on fluorenyl linker. Figure 5.7. Aminolysis of ester linker.

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