Density Functional Study of Proline‐Catalyzed Intramolecular Baylis–Hillman Reactions

Abstract

The mechanisms of proline-catalyzed and imidazole-co-catalyzed intramolecular Baylis-Hillman reactions have been studied by using density functional theory methods at the B3LYP/6-31G(d,p) level of theory. A polarizable continuum model (PCM B3LYP/6-31++G(d,p)//B3LYP/6-31G(d,p)) was used to describe solvent effects. Different reaction pathways were investigated, which indicated that water is an important catalyst in the imine/enamine conversion step in the absence of imidazole. When imidazole is used as a co-catalyst, water is still important in the imidazole addition step, but is not present in the Baylis-Hillman cyclization step. The computational data has allowed us to rationalize the experimental outcome of the intramolecular Baylis-Hillman reaction, validating some of the mechanistic steps proposed in the literature, as well as to propose new ones that considerably change and improve our understanding of the full reaction path.

Computational investigations of the stereoselectivities of proline-related catalysts for aldol reactions☆

“…Catalysis of the aldol reaction by proline analogs, including bicyclic prolines,5 heteroatom-substituted prolines,4c prolinamides,6 prolinol ethers7, and amine-, ammonium-, and tetrazole-functionalized pyrrolidines8 (Figure 1), have also been studied computationally. Computational investigations of the Mannich,9 Michael addition,6e, 7b, 10 and Morita-Baylis Hillman11 reactions by proline catalysts have also been reported.…”

Accurateab InitioSpin Densities

“…Hence, the application of DFT became instrumental in theoretical studies of mechanisms in metalmediated catalysis. [6][7][8][9][10][11][12][13][14] Yet, the treatment of open-shell systems 16,18,19 and (near-)degenerate states remains a challenge for DFT. 15 Failures of approximate exchange-correlation density functionals in predicting properties of open-shell systems have been traced to the delocalization error and static correlation error 17,20 which are rooted in an inappropriate behavior of the energy with respect to fractional charges and fractional spins.…”

Enantioselective, Organocatalytic Morita-Baylis-Hillman and Aza-Morita-Baylis-Hillman Reactions: Stereochemical Issues

“…Subtle details of this mechanism have come to light as a consequence of an extensive density functional analysis at the B3LYP/6-31-G(d,p) level which included the use of the polarized continuum model (PCM B3LYP/6-31++G(d,p)//B3LYP/6-31G(d,p)) to describe solvent effects, the most important being the role played by water to give rise to the required syn and anti , ( E,Z )-dienamine key intermediates in equilibrium, as the theoretical calculations demonstrated that ( E,E )-enamines could not undergo cyclization [ 150 ]. According to these PCM calculations, the cyclization of the anti , E,Z -dienamine is biased towards the formation of the ( S )-configured product, as illustrated in Scheme 14 which displays, in a simplified manner, the modifications introduced by the computational work by Gil Santos et al ., in close analogy with the model proposed and by List and coworkers [ 151 ].…”

“…), have recently been added to the above armoury of bifunctional organocatalysts [ 69 , 70 , 71 , 72 ]. Obviously, from a mechanistic viewpoint these α-amino acid-organocatalyzed MBH reactions differ completely to those categorized as standard MBH and aza-MBH reactions which involve tertiary amine or phosphine catalysts [ 73 , 74 , 75 ].…”