Computational Study of the Aminolysis of Esters. The Reaction of Methylformate with Ammonia

Ilieva, Sylvia; Galabov, Boris; Musaev, Djamaladdin G.; Morokuma, Keiji; Schaefer, Henry F.

doi:10.1021/jo0263723

Cited by 92 publications

(96 citation statements)

References 26 publications

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“…Experimental studies based on linear free-energy relationships 1 and isotope substitution effects 2 in solution support a stepwise mechanism with participation of different kinds of intermediates, ranging from anionic, cationic, neutral and zwitterionic species. Based on theoretical studies, [3][4][5] three different mechanisms have been proposed: (1) a concerted mechanism in which the nucleophilic attack on the amino group, the C-O bond cleavage and the proton transfer take place simultaneously; (2) a stepwise mechanism through a neutral intermediate; and (3) a stepwise mechanism through a zwitterionic intermediate. The latter mechanism has been the subject of controversy since even the presence of this intermediate has been questioned.…”

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confidence: 99%

Do zwitterionic species exist in the non-enzymatic peptide bond formation?

et al. 2012

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The use of proper computational methods and models has allowed answering the controversial question of whether zwitterionic species exist in the mechanism of peptide bond synthesis in aqueous solution. In fact, the different conformations of zwitterionic species open the door to different mechanistic paths.The peptide bond synthesis mechanism in ribosomes has attracted much attention in the past years. In order to get information on this problem, aminolysis of esters in aqueous solution has been the subject of many experimental and theoretical studies. The main reason for this interest comes from the hypothesis that similar mechanisms are involved in both media. Experimental studies based on linear free-energy relationships 1 and isotope substitution effects 2 in solution support a stepwise mechanism with participation of different kinds of intermediates, ranging from anionic, cationic, neutral and zwitterionic species. Based on theoretical studies, 3-5 three different mechanisms have been proposed: (1) a concerted mechanism in which the nucleophilic attack on the amino group, the C-O bond cleavage and the proton transfer take place simultaneously; (2) a stepwise mechanism through a neutral intermediate; and (3) a stepwise mechanism through a zwitterionic intermediate. The latter mechanism has been the subject of controversy since even the presence of this intermediate has been questioned. Nevertheless, theoretical studies using a reduced number of water molecules to describe the solvent, or by mixed explicit-polarizable continuum models (PCM), despite their limitations, 6 have supported the existence of this intermediate. [7][8][9] Warshel and coworkers located a zwitterionic intermediate in the catalyzed methanolysis of formamide (formally the reverse reaction of the one studied in the present manuscript) by combined ab initio/Langevin dipole calculations, 10 and more recently the solute electron density model (SMD) 11 has also been used to stabilize zwitterionic species. 12 The present communication is focused on the existence and relevance of the zwitterionic species in the aminolysis of esters in solution within a realistic molecular model similar to the natural substrate used by ribosomes, as shown in Scheme 1. The model of the substrate in our hybrid QM/MM calculations includes all the atoms involved in the different proposed mechanisms. It is important to point out that previous theoretical studies in solution have been performed with simpler molecular models ignoring, for instance, the constraint of the ribose ring that can govern the role of the hydroxyl group bound to C2 0 .The substrate has been treated by semiempirical AM1 13 hamiltonian and by means of the M06-2X functional developed by Truhlar's group 14 with the standard 6-31+G(d,p) basis set. The full molecule described quantum mechanically has been embedded in a cubic box of water molecules (100 Â 80 Â 80 Å 3 ) treated by the TIP3P 15 force field, as implemented in the fDYNAMO library. 16 Periodic boundary conditions were applied and a switched...

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Do zwitterionic species exist in the non-enzymatic peptide bond formation?

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“…6 As already mentioned, in a molecular modeling study Schaefer III and co-workers 5 suggest that the more stable pathway in the aminolysis of ethylformate by ammonia is a self catalyzed mechanism in which a …”

Section: Resultsmentioning

confidence: 96%

“…The transition state (TS) for this pathway was calculated to be from 7 to17 kcal mol -1 more stable than that for the uncatalyzed pathway. 5 The participation of a second molecule of base in the TS of the nucleophilic addition step is also suggested by the second order in amine observed in kinetic studies. 6 Based on these data, we expected that this reaction could be catalyzed by a strong base, as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).…”

Section: Introductionmentioning

confidence: 93%

“…3 Aminolysis of esters has also been employed to form amides and has been considered as a model reaction to form peptide bonds. 2,4 In a molecular modelling study Schaefer III and co-workers 5 showed that the more stable pathway in the aminolysis of ethylformate by ammonia is a self catalyzed Vol. 22, No.…”

Section: Introductionmentioning

confidence: 99%

“…5,7 Herein we report on the use of DBU as an efficient catalyst for the chemoselective aminolysis of methyl esters leading to amides, as tested by the reactions employing esters 1-4 and amines 5-7 ( Figure 1). …”

Section: Introductionmentioning

confidence: 99%

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DBU as a catalyst for the synthesis of amides via aminolysis of methyl esters

Lima¹,

Souza²,

Soares³

et al. 2011

J. Braz. Chem. Soc.

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Benzoato de metila e p-clorofenil acetato de metila reagem com benzilamina e pirrolidina levando às correspondentes amidas. Estas reações são mais rápidas na presença de 20 mol% de DBU, fornecendo os produtos com rendimentos levemente superiores. Quando um diéster derivado do ácido L-aspártico foi usado como substrato, a reação com benzilamina e pirrolidina foi quimiosseletiva para o éster metílico, levando às correspondentes amidas em bons rendimentos. Reação do monoéster metílico do ácido aspártico com estas aminas conduziu a amidas com um grupo ácido livre em C1. Anilina, menos básica e menos nucleofílica, não formou os produtos esperados tanto na ausência quanto na presença de DBU. Através do monitoramento da reação por ESI-MS, foi possível interceptar os intermediários-chave catiônicos formados nas reações entre o benzoato de metila e o p-clorofenil acetato de metila com a benzilamina, os quais foram caracterizados por ESI-MS/MS.Methyl benzoate and methyl p-chlorophenyl acetate react with neat benzylamine and pyrrolidine to form the corresponding amides. These reactions are faster in the presence of 20 mol% of DBU providing slight better yields. When a diester derived from L-aspartic acid was used as substrate, the reaction with benzylamine and pyrrolidine in the presence of DBU was chemoselective and led to the corresponding amides in good yields. Reaction of aspartic acid monomethyl ester with these amines led to amides having a free carboxy group (at C1). Less nucleophilic and less basic aniline failed to form the expected products in both absence and presence of DBU. By monitoring the course of reaction by ESI-MS, key charged intermediates formed by the reactions of methyl benzoate and methyl p-chlorophenyl acetate with benzylamine were intercepted and further characterized by ESI-MS/MS. Keywords: DBU, catalysis, aminolysis, esters, amides, ESI-MS IntroductionThe amide is one of the most important functional groups in organic molecules. Life depends on this group and its properties since proteins and peptides are essentially polyamides. Many natural and synthetic bioactive molecules are also amides of low molecular weight.1 The preparation of amides from amines and carboxylic acids or its derivatives is therefore one of the most important and commonly employed reactions in organic synthesis. 1,2 Amides are usually prepared by transforming carboxylic acids into the corresponding acyl chlorides or by in situ activation of the carboxyl group followed by reaction of the resulting intermediates with amines.3 Aminolysis of esters has also been employed to form amides and has been considered as a model reaction to form peptide bonds. 2,4 In a molecular modelling study Schaefer III and co-workers 5 showed that the more stable pathway in the aminolysis of ethylformate by ammonia is a self catalyzed Lima et al. 2187 Vol. 22, No. 11, 2011 mechanism in which a second molecule of ammonia is involved in the transition state, facilitating the proton transfer process. The transition state (TS) for this pathway wa...

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Catalytic Aminolysis (Amide Formation) from Esters and Carboxylic Acids: Mechanism, Enhanced Ionic Liquid Effect, and its Origin

et al. 2011

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This paper describes the use of imidazolium‐based ionic liquids {1‐n‐butyl‐3‐methylimidazolium tetrafluoroborate [BMI‐BF4], 1‐n‐butyl‐3‐methylimidazolium hexafluorophosphate [BMI‐PF6], and 1‐n‐butyl‐3‐methylimidazolium bis(trifluoromethylsulfonyl)imide [BMI‐NTf2]} as efficient supports for Lewis and Brønsted acids ,which are promoters of the aminolysis of some esters, fatty acids, and fatty acid esters (among others) to form amide derivatives. Some esters and carboxylic acids were tested to demonstrate the generality of the methodology, and the corresponding amides were obtained in high yields. Recycling reactions (at least eight reuses) without a notable loss in activity could be performed by using CdO and SnCl2 as catalysts in BMI‐NTf2 as the ionic medium. Brønsted acids, such as H2SO4 and HCl, were also tested with impressive results; however, it was not possible to perform recycling reactions because of catalyst leaching. The same was true when using BF3⋅OEt2 as the catalyst. Mechanistic insights and the ionic‐liquid effect were investigated by using 13C{1H} NMR spectroscopy, which showed that there is a strong interaction of the imidazolium cation with the CO and CC bonds of methyl oleate, most likely through CH⋅⋅⋅π interactions, π‐stacking interactions, and ion‐pair formation in the presence of a metal catalyst. Electrospray ionization–quadrupole time‐of‐flight experiments allowed a better understanding of the reaction mechanism. The results could explain the enhanced ionic‐liquid effect on the stabilization of the formed intermediates, which facilitated the amide bond formation.

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Computational Study of the Aminolysis of Esters. The Reaction of Methylformate with Ammonia

Cited by 92 publications

References 26 publications

Do zwitterionic species exist in the non-enzymatic peptide bond formation?

Do zwitterionic species exist in the non-enzymatic peptide bond formation?

DBU as a catalyst for the synthesis of amides via aminolysis of methyl esters

Catalytic Aminolysis (Amide Formation) from Esters and Carboxylic Acids: Mechanism, Enhanced Ionic Liquid Effect, and its Origin

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