Mechanisms of the Knoevenagel hetero Diels-Alder sequence in multicomponent reactions to dihydropyrans: experimental and theoretical investigations into the role of water.

The role of water in a multicomponent domino reaction (MCR) involving styrene, 2,4-pentanedione, and formaldehyde was studied. Whereas anhydrous conditions produced no reaction, the MCR successfully proceeded in the presence of water, affording the targeted dihydropyran derivatives with good yield. The mechanism of this MCR (Knoevenagel hetero Diels-Alder sequence) was studied with and without explicit water molecules using the SMD continuum solvation model in combination with the B3LYP density functional and the 6-311++G** basis set to compute the water and acetone (aprotic organic solvent) solution Gibbs free energies. In the Knoevenagel step, we found that water acted as a proton relay to favor the formation of more flexible six-membered ring transition state structures both in concerted (direct H(2)O elimination) and stepwise (keto-enol tautomerization and dehydration) pathways. The inclusion of a water molecule in our model resulted in a significant decrease (-8.5 kcal mol(-1)ΔG(water)(‡)) of the direct water elimination activation barrier. Owing to the presence of water, all chemical steps involved in the MCR mechanism had activation free energies barriers lower than 39 kcal mol(-1) at 25 °C in aqueous solvent (<21 kcal mol(-1) ZPE corrected electronic energies barriers). Consequently, the MCR proceeded without the assistance of any catalyst.

[1]  J. Barrault,et al.  Catalyst-free aqueous multicomponent domino reactions from formaldehyde and 1,3-dicarbonyl derivatives , 2009 .

[2]  M. Raj,et al.  Organocatalytic reactions in water. , 2009, Chemical communications.

[3]  L. Tietze,et al.  Synthesis of the deoxyaminosugar (+)-D-forosamine via a novel domino-Knoevenagel-hetero-Diels-Alder reaction. , 2009, Organic letters.

[4]  C. Cramer,et al.  Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. , 2009, The journal of physical chemistry. B.

[5]  M. Botta,et al.  One-pot multicomponent synthesis of 2,3-dihydropyrans: new access to furanose–pyranose 1,3-C–C-linked-disaccharides , 2009 .

[6]  Yizhak Marcus,et al.  Effect of ions on the structure of water: structure making and breaking. , 2009, Chemical reviews.

[7]  Arani Chanda,et al.  Organic synthesis "on water". , 2009, Chemical reviews.

[8]  M. Pirrung,et al.  Hydrophobicity and mixing effects on select heterogeneous, water-accelerated synthetic reactions. , 2008, The Journal of organic chemistry.

[9]  F. J. Duarte,et al.  Mechanistic Study of Intramolecular Aldol Reactions of Dialdehydes , 2008 .

[10]  A. Armstrong,et al.  Clarification of the role of water in proline-mediated aldol reactions. , 2007, Journal of the American Chemical Society.

[11]  Yousung Jung,et al.  On the Theory of Organic Catalysis "on Water" , 2007 .

[12]  D. Tejedor,et al.  Chemo-differentiating ABB' multicomponent reactions. Privileged building blocks. , 2007, Chemical Society reviews.

[13]  K. Houk,et al.  Hydrogen bonding catalysis operates by charge stabilization in highly polar Diels-Alder reactions. , 2007, Organic letters.

[14]  Y. Hayashi.  In water or in the presence of water? , 2006, Angewandte Chemie.

[15]  K. Houk,et al.  Acid/base catalysis by pure water: the aldol reaction. , 2005, The Journal of organic chemistry.

[16]  M. Finn,et al.  "On water": unique reactivity of organic compounds in aqueous suspension. , 2005, Angewandte Chemie.

[17]  K. Janda,et al.  Nornicotine aqueous aldol reactions: synthetic and theoretical investigations into the origins of catalysis. , 2004, The Journal of organic chemistry.

[18]  V. Nair,et al.  Strategies for heterocyclic construction via novel multicomponent reactions based on isocyanides and nucleophilic carbenes. , 2003, Accounts of chemical research.

[19]  Giovanni Scalmani,et al.  Energies, structures, and electronic properties of molecules in solution with the C‐PCM solvation model , 2003, J. Comput. Chem..

[20]  V. Boucard.  Kinetic study of the Knoevenagel condensation applied to the synthesis of poly[bicarbazolylene-alt-phenylenebis(cyanovinylene)]s , 2001 .

[21]  I. Ugi,et al.  Multicomponent Reactions with Isocyanides. , 2000, Angewandte Chemie.

[22]  L. Yet.  Metal-mediated synthesis of medium-sized rings. , 2000, Chemical reviews.

[23]  V. Barone,et al.  Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model , 1998 .

[24]  M. Frisch,et al.  Using redundant internal coordinates to optimize equilibrium geometries and transition states , 1996, J. Comput. Chem..

[25]  Yves Queneau,et al.  Water-Promoted Organic Reactions , 1994 .

[26]  A. Becke.  Density-functional thermochemistry. III. The role of exact exchange , 1993 .

[27]  Ronald Breslow,et al.  Hydrophobic Effects on Simple Organic Reactions in Water , 1991 .

[28]  Parr,et al.  Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. , 1988, Physical review. B, Condensed matter.

[29]  M. Winbury,et al.  Influence of Antiarrhythmic Agents on Calcium‐Induced Cardiac Arrhythmias in the Rat , 1955, Circulation research.

[30]  C. Ghio,et al.  Keto‐enol tautomerism in linear and cyclic β‐diketones: A DFT study in vacuo and in solution , 2008 .

[31]  Alexander Dömling,et al.  Recent developments in isocyanide based multicomponent reactions in applied chemistry. , 2006, Chemical reviews.

[32]  H. Mikosch,et al.  DFT study of the gas phase proton transfer in guanine assisted by water, methanol, and hydrogen peroxide , 2006, Journal of molecular modeling.

[33]  H. Schlegel,et al.  Combining Synchronous Transit and Quasi-Newton Methods to Find Transition States , 1993 .

[34]  Y. Guggisberg,et al.  Monomeric Formaldehyde in Ethereal Solution , 1990 .

[35]  N. Yang,et al.  Anhydrous Molecular Formaldehyde Solution as a Synthetic Reagent , 1990 .