Pietro Giacinto

Gold(I)‐Catalyzed Dearomative [2+2]‐Cycloaddition of Indoles with Activated Allenes: A Combined Experimental–Computational Study

The gold-catalyzed synthesis of methylidene 2,3-cyclobutane-indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is presented to its full extent. In particular, the scope of the reaction encompasses both aryloxyallenes and allenamides as electrophilic partners providing high yields and excellent stereochemical controls in the desired cycloadducts. The computational (DFT) investigation has fully elucidated the reaction mechanism providing clear evidence for a two-step reaction. Two parallel reaction pathways explain the regioisomeric products obtained under kinetic and thermodynamic conditions. In both cases, the dearomative CC bond-forming event turned out to be the rate-determining step.

Gold(I)‐Assisted α‐Allylation of Enals and Enones with Alcohols

The intermolecular α-allylation of enals and enones occurs by the condensation of variously substituted allenamides with allylic alcohols. Cooperative catalysis by [Au(ItBu)NTf2] and AgNTf2 enables the synthesis of a range of densely functionalized α-allylated enals, enones, and acyl silanes in good yield under mild reaction conditions. DFT calculations support the role of an α-gold(I) enal/enone as the active nucleophilic species.

DFT Mechanistic Investigation of the Gold(I)-Catalyzed Synthesis of Azepino[1,2-a]indoles

We describe a computational DFT investigation on the mechanism of the one‐pot synthesis of azepino‐indoles catalyzed by [Au(IPr)Cl]/AgOTf (IPr=1,3‐bis(2,6‐diisopropylphenyl‐imidazol‐2‐ylidene) by the simultaneous construction of the pyrrolyl and seven‐membered rings. The mechanism of the final ring‐closing event is elucidated, which reveals the counterion‐assisted nucleophilic trapping of the carbonyl moiety by the alkenyl‐gold species formed in situ. The computational evidence supports the labeling control experiments and highlights the presence of a cyclopropyl‐gold‐carbenoid intermediate in the final intramolecular 1,3‐hydrogen‐shift/skeleton‐rearrangement sequence.

CNT-Confinement Effects on the Menshutkin SN2 Reaction: The Role of Nonbonded Interactions

We investigated the effects of CNT confinement ((6,6) tube) on the model Menshutkin reaction H3N + H3CCl = H3NCH3((+)) + Cl((-)), which is representative of chemical processes involving developing of charge separation along the reaction pathway. We used either a full QM approach or a hybrid QM/MM approach. We found that the CNT significantly lowers the activation barrier with respect to the hypothetical gas-phase reaction: The activation barrier Ea varies from 34.6 to 25.7 kcal mol(-1) (a value similar to that found in a nonpolar solvent) and the endothermicity ΔE from 31.2 to 13.5 kcal mol(-1). A complex interplay between C-H···π, N-H···π, and Cl···π nonbonded interactions of the endohedral system with the CNT wall explains the lower barrier and lower endothermicity. The hybrid QM/MM approach (MM = UFF force field) does not reproduce satisfactorily the QM energy ΔE (18.1 vs 13.5 kcal mol(-1)), while optimum agreement is found in the barrier Ea (25.8 vs 25.7 kcal mol(-1)). These results suggest that the simple Qeq formalism (included in the MM potential) does not describe properly the effect of CNT polarization in the presence of the net charge separation featuring the final product. A more accurate estimate of the tube polarization was obtained with single-point QM/MM computations including PCM corrections (using the benzene dielectric constant) on the QM/MM optimized structures. After PCM corrections, Ea changes slightly (from 25.8 to 24.5 kcal mol(-1)), but a more significant variation is observed for ΔE that becomes 13.1 kcal mol(-1), in rather good agreement with the full QM. This level of theory (QM/MM with PCM correction, MM = UFF) represents a more general approach suitable for describing CNT-confined chemical processes involving significant charge separation. QM/MM computations were extended to CNTs of different radii: (4,4), (5,5), (7,7), (8,8), (9,9), (10,10), (12,12), (14,14) CNTs and, as a limit case, a graphene sheet. The lack of space available in the small tube (4,4) causes a strong structural distortion and a consequent increase in Ea and ΔE (40.8 and 44.0 kcal mol(-1), respectively). These quantities suddenly decrease with the augmented volume inside the (5,5) tube. For larger tubes, different structural arrangements of the endohedral system are possible, and Ea and ΔE remain almost constant until the limiting case of graphene.

Covalent or Non-Covalent? A Mechanistic Insight into the Enantioselective Brønsted Acid Catalyzed Dearomatization of Indoles with Allenamides

The reaction mechanism of the enantioselective Brønsted acid catalyzed dearomatization of C(2),C(3)‐disubstituted indoles with allenamides is investigated by means of density functional theory (DFT) calculations and ESI‐MS analysis. The first step of the process (rate‐determining step) is the formation of a covalent adduct between allenamide and the chiral organo‐promoter. The resulting chiral α‐amino allylic phosphate undergoes dearomative condensation with indoles. In the first step, the indole moiety remains bonded to the catalyst through strong hydrogen contacts. It can take on two different orientations that make the Re or Si prochiral face available to the subsequent electrophilic attack of allenamide. The attack on the indole faces originates two reaction paths leading to different stereoisomeric products, which differ in the configuration of the new stereocenter at the C3‐indole position.