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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Can an Alcohol Act As an Acid/Base Catalyst in Water Solution? An Experimental and Theoretical Study of Imidazole Catalysis of the Aqueous Morita-Baylis--Hillman Reaction

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Raich, Lluis [1, 2] ; Santos, Hugo [3, 1] ; Gomes, Juliana C. [3] ; Rodrigues, Jr., Manoel T. [3] ; Galaverna, Renan [4] ; Eberlin, Marcos N. [4] ; Coelho, Fernando [3] ; Rovira, Carme [1, 2, 5] ; Moyano, Albert [1]
Total Authors: 9
[1] Univ Barcelona, Fac Quim, Dept Quim Inorgan & Organ, Seccio Quim Organ, Marti i Franques 1-11, E-08028 Barcelona, Catalonia - Spain
[2] Univ Barcelona, Fac Quim, Inst Quim Teor & Computac IQTCUB, Marti i Franques 1-11, E-08028 Barcelona, Catalonia - Spain
[3] Univ Estadual Campinas, UNICAMP, Inst Chem, Lab Synth Nat Prod & Drugs, POB 6154, BR-13083970 Campinas, SP - Brazil
[4] Univ Estadual Campinas, UNICAMP, ThoMSon Mass Spectrometry Lab, Inst Chem, POB 6154, BR-13083970 Campinas, SP - Brazil
[5] ICREA, Passeig Lluis Co 23, Barcelona 08018, Catalonia - Spain
Total Affiliations: 5
Document type: Journal article
Source: ACS CATALYSIS; v. 8, n. 3, p. 1703-1714, MAR 2018.
Web of Science Citations: 5

The formation of carbon carbon sigma bonds by the organocatalyzed Morita-Baylis-Hillman (MBH) reaction constitutes a convenient method for the synthesis of valuable, highly functionalized molecules. Its large-scale implementation is however hampered both by its poor performance with substrates such as alpha,beta-unsaturated ketones and by the reduction of the nucleophilicity of the catalyst when using water as a solvent. Recent work from our laboratories has shown that a bicyclic imidazolyl alcohol (BIA) overcomes these limitations and is a much more efficient catalyst than imidazole for the aqueous MBH reactions of cyclic enones. The role of the hydroxyl group in the former catalyst is not easy to Low energy understand, however, since these reactions take place in water solution. We have studied the mechanism of the aqueous MBH reaction between 2-cyclohexenone and isatin, catalyzed either by imidazole or by the BIA catalyst, using a combined experimental and computational approach. The data allowed us to propose mechanistic free-energy profiles for the two catalysts. An intramolecular proton transfer step, facilitated by the hydroxyl group of the catalyst even if the reaction takes place in water, accounts for the higher catalytic efficiency of BIA in comparison to imidazole, which requires assistance by an external base (either hydroxide ion or another imidazole molecule) for this catalytic step. The computed activation energies are in good agreement with the experimentally observed trends in reaction rates. The crucial role of the BIA hydroxyl has been confirmed by NMR study of the reaction kinetics, and in situ ESI-MS/MS monitoring experiments have detected and characterized all the relevant reaction intermediates, validating the computational model. This study provides clear evidence for the intramolecular participation of a bifunctional catalyst in the proton transfer step of an MBH reaction. The fact that the introduction of a suitable functional group favors the intramolecular proton transfer over solvent-mediated pathways, just in the spirit of enzymatic catalysis, provides a basis for the rational design of future efficient catalysts for aqueous reactions. (AU)

FAPESP's process: 15/09205-0 - New frontiers of the Morita-Baylis-Hillman reaction: 1) New applications of a bifunctional catalyst derived from imidazole. 2) Studies on the asymmetric synthesis of a natural high-potency sweetener
Grantee:Hugo dos Santos
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 13/10449-5 - Morita-Baylis-Hillman adducts as efficient building blocks for the synthesis of molecules of biological interest
Grantee:Fernando Antonio Santos Coelho
Support Opportunities: Regular Research Grants
FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
Grantee:Glaucius Oliva
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC