The carbon nanotube (CNT)-confined chloride exchange SN2 reaction for methyl chloride has been examined using either a full quantum mechanical (QM) DFT approach based on the M06-2X functional or a hybrid approach where a (6,6) CNT is satisfactorily described by the molecular mechanics (MM) UFF force field and the substrate by the M06-2X functional (M06-2X/UFF approach). We found that inside the CNT the reaction is disfavored with respect to the gas phase, the intrinsic reaction barrier E a (difference between the preliminary complex I and transition state TS) being 17.9 kcal mol–1 (13.2 kcal mol–1 in the gas phase). The augmented barrier, with respect to the gas phase, can be ascribed to a complex interplay between Cl···π and C–H···π interactions (i.e., interactions of the two Cl atoms and the C–H bonds of the substrate with the carbon electron cloud of the tube wall). While the Cl···π interactions behave like a molecular glue which sticks the two Cl atoms to the tube wall and remain approximately constant in I and TS, the importance of the stabilizing C–H···π interactions is significantly lower in TS with a consequent increase of the barrier. The barrier increases with the increase of the tube length to reach the asymptotic value of 19.9 kcal mol–1 for tube length larger than 24.4 Å. This value is the minimum length of a (6,6) CNT model system that can emulate the CNT-confined SN2 reaction and provides useful suggestions to build reliable model systems for other SN2 reactions and, in general, different chemical processes. Furthermore, the activation barrier E a is strongly affected by the tube radius. Because of the reduced volume inside the tube causing a strong structural distortion in TS, E a is very large for small tube radii (34.4 kcal mol–1 in the (4,4) case). When the volume increases enough (tube (5,5)) to avoid the distortion, the barrier suddenly decreases and remains approximately constant (about 20 kcal mol–1) for tubes in the range (5,5) to (8,8). The activation barrier grows for a (9.9) tube, and the value again remains approximately constant (about 22 kcal mol–1) for larger tubes.

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.

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.

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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.

We carried out a computational investigation on the mechanism of the bromination reaction of N-phenylacetamide inside CNTs, in water, and in an aprotic solvent (ethylbenzene). A full QM and a QM/MM approach was used. In the aprotic solvent, a Wheland intermediate (ion pair formed by arenium ion and chloride) exists only for the attack in the ortho position, while the para attack proceeds in a concerted manner (concerted direct substitution). The reaction is catalyzed by the HCl byproduct, which lowers significantly the activation barriers. The ortho product is favored, in contrast to the common belief based on simple steric effects. In water solution a Wheland intermediate was located for both ortho and para attacks (the ion pair is stabilized by the polar protic solvent). The formation of the para product is favored with respect to the ortho product: 9.0 and 9.9 kcal mol–1 are the corresponding activation barriers. Inside CNTs, as found in aprotic solvent, the Wheland-type arenium ion exists only along the ortho pathway. The initial production of the HCl byproduct activates rapidly the catalyzed mechanism that proceeds almost exclusively along the para pathway (para and ortho activation barriers are 6.1 and 17.0 kcal mol–1, respectively). The almost exclusive para regioselectivity for the CNT-confined reaction and its acceleration with respect to water (in agreement with the experimental evidence) are due to noncovalent (van der Waals) interactions between the endohedral system and the electron cloud of the surrounding CNT. The effect of these interactions was estimated quantitatively within the UFF scheme used in our QM/MM computations, and we found that they are particularly stabilizing for the para-catalyzed process.

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.

LAC (hydroxylactone (1R,5S)-1-hydroxy-3,6-dioxabicyclo[3.2.1]octan-2-one) is one of the most interesting products of the pyrolysis of cellulose and represents a useful chiral building block in organic synthesis. A computational investigation at the DFT level on the mechanism of formation of LAC shows that this species can be obtained following two reaction paths, path A and path B, starting from a well-known pyrolysis product (ascopyrone P). A series of internal rearrangements involving in all cases a proton transfer leads directly to LAC (path B). An alternative path (path A) can be also followed. From this path, via a "gate" connecting the two reaction channels, it is possible to reach path B and form LAC. In both cases, the rate-determining step of the process is the initial keto-enol isomerization. We found that water, which is present in the reaction mixture, "catalyzes" the reaction by assisting the proton transfers present in all the steps of the process. In particular, water lowers the barrier of the rate-determining step that becomes 40.9 kcal mol (79.4 kcal mol in the absence of water). The corresponding computed rate constant is 4.3×10 s at 500 °C, a value which is consistent with the presence of LAC in the absence of metal catalysts. The results of this study on the non-catalyzed process underpin the important role played by water in the formation of pyrolysis products of cellulose where proton transfer is a key mechanistic step.