Theoretical Investigations On Synthesis Of β-lactone Via NHC-catalyzed [2+2] Cycloaddition Of Ketene With C=O

β-lactones are one kind of the important small organic molecules, which can beapplied as a versatile starting material in complex molecule and biodegradablepolymer synthesis, as well as being the core structure in a range of natural productswith notable pharmacological properties. β-lactones, which are synthesized in largequantities experimentally, serve as useful intermediates in an array of fields, includingmaterial science and synthetic organic chemistry. Generally, β-lactones can beobtained by ketene and C=O [2+2] cycloaddition reactions. Due to the specialreactivity of the ketene and C=O [2+2] cycloadditions in organic chemistry, more andmore attention has also been attracted in both experiment and theory.In this paper, the possible reaction mechanisms and stereoselectivities on formal[2+2] cycloaddition of aryl(alkyl)ketenes and electron-deficient benzaldehydescatalyzed by N-heterocyclic carbenes (NHCs) have been explored. The reactionmechanisms were studied using density functional theory, all the reactants, reactionprecursors, intermediates, and products optimizations were carried out at theM06-2X[36-39]/6-31G(d, p) level in toluene solvent, using the integral equationformalism polarizable continuum model (IEF-PCM), then the correspondingvibrational frequencies were calculated at the same level to take account of thezero-point vibrational energy (ZPVE) and to identify the transition states. Based onthe optimized structures, the single-point energies were further refined using the6-311+G(d, p) basis set in toluene solvent. All discussions in this paper are based onthe single-point energies plus ZPVEs.Two possible mechanisms (mechanisms A and B) have been investigated. Ourcalculated results indicate that the favorable mechanism (mechanism A) includesthreeprocesses: the first step is the nucleophilic attack on the arylalkylketenes by NHCcatalyst to form an intermediate, the second step is the [2+2] cycloaddition of theintermediate and benzaldehydes for the formation of β-lactones, and the last step isthe dissociation of NHC catalyst and the β-lactones. Notably, the [2+2] cycloaddition, in which the two chiral centers associated with four configurations (SS,RR,SR&RS)are formed, is demonstrated to be both the rate-and stereoselectivity-determiningsteps, the energy barriers of15.88,19.68,13.58and17.07kcal/mol are correspondingto the stereoisomer transition states (SS,RR,SR&RS), respectively. And the reactionpathway associated with the SR configuration is the most favorable pathway andleads to the main product, which is in good agreement with the experimental results.Similarly, there are also three steps involved in mechanism B: the first step is thenucleophilic attack on the carbonyl carbon of benzaldehydes by NHC to form acomplexation intermediate, the second step is reaction between the intermediate andaryl(alkyl)ketenes, and the last step is SN2nucleophilic substitution to dissociateNHC and product. The calculated energy barrier via transition states is32.23/29.69/28.45/27.06kcal/mol, which is far higher than those of first and secondsteps in mechanism B, therefore, we think the third step should be therate-determining step. Noteworthy, the energy barrier of rate-determining step inmechanism B is much higher than those in mechanism A, indicating that mechanismB should be not favorable in the competition with mechanism A and cannot reallyoccur in the experiment. Furthermore, the analysis of global reactivity indexes hasbeen performed to explain the role of catalyst NHC in the [2+2] cycloadditionreaction. This study would be some worth on the rational design of the more efficientcatalysts for the kind of cycloadditions.In addition, we also investigated the possible reaction mechanisms andstereoselectivities on formal [2+2] cycloaddition of aryl(alkyl)ketenes and2-and4-Pyridinecarboxaldehydes catalyzed by N-heterocyclic carbenes (NHCs). Thecalculated results reveal that the energetic favorability of the SS configurationstereoisomer should be the dominant product, which is in good agreement with theexperiment. As concerned as above, the substituents have a great influence on thestereoselectivity of the title reaction. In summary, this study helps us to understandthe role of NHC catalyst and thus provides valuable insights for rational design of thecatalysts in this kind of [2+2] cycloadditions.