The chemistry of conjugated nitrosoalkenes has been extensively studied for the synthesis and functionalization of a plethora of heterocyclic systems. These reactive intermediates act mainly as electron-deficient heterodienes in inverse electron-demand hetero-Diels-Alder reactions or as Michael-type acceptors in conjugated 1,4-addition reactions (Lopes et al., 2018a; Naumovich et al., 2019; Weinreb, 2019; Soares et al., 2022). In recent years, our research group has explored the reactivity and versatility of conjugated nitrosoalkenes as a synthetic tool to achieve heterocyclic structural diversity (Lopes et al., 2018a). Functionalization of five-membered heterocycles, such as pyrroles, dipyrromethanes, indoles and furans, was achieved by reaction with nitrosoalkenes, including the synthesis of 3-tetrazolyl and 3-triazolyl derivatives (Lopes et al., 2010; Lopes et al., 2011; Nunes et al., 2014; Lopes et al., 2015; Lopes et al., 2016; Alves et al., 2017; Jorda et al., 2017; Lopes et al., 2018b). One-pot methods have also been developed for the synthesis of dipyrromethanes (Pereira et al., 2014; Cardoso et al., 2021), bis(indolyl)methanes (Grosso et al., 2015; Grosso et al., 2017; Grosso et al., 2019), bis(pyrazol-1-yl)methanes (Grosso et al., 2014) and tetrapyrrolic compounds (Lopes and Pinho e Melo, 2020) via two consecutive hetero-Diels-Alder reactions (or conjugated additions) of in situ generated nitrosoalkenes with pyrroles, indoles, pyrazoles and dipyrromethanes, respectively. Moreover, tryptophan analogues have been obtained by reducing the oxime moiety of indoles C3-functionalized via hetero-Diels-Alder reactions with nitrosoalkenes. These tryptamine derivatives were used in the synthesis of 3-triazolyl- and 3-tetrazolyl-β-carbolines via Pictet–Spengler condensation followed by an oxidative step. ß-Carboline derivatives obtained by this strategy have shown interesting anticancer properties (Panice et al., 2019; Ribeiro et al., 2021; Ribeiro et al., 2022).

The reactivity of nitrosoalkenes with electron-rich heterocycles is strongly influenced not only by the nitrosoalkene substituents but also by the type of heterocycle (Nunes et al., 2014; Lopes et al., 2016). The pioneer work of Gilchrist and co-workers showed that the reaction of ethyl nitrosoacrylate (2, R = CO₂Et), generated from ethyl bromopyruvate oxime 1a by action of base, with pyrrole and indole afforded the open chain oximes 4 and 8, respectively, through hetero-Diels-Alder reactions (Scheme 1) (Gilchrist and Roberts, 1983; Gilchrist and Lemos, 1993). The outcome and mechanistic pathway of the reaction of nitrosoalkenes with pyrrole and pyrrole derivatives depends on the nitrosoalkene substituent, as shown by experimental and theoretical studies (Nunes et al., 2014). In fact, ethyl nitrosoacrylate (2, R = CO₂Et) reacts via hetero-Diels-Alder reaction, through the formation of the bicyclic 1,2-oxazine 3 followed by 1,2-oxazine ring-opening with concomitant rearomatization of the pyrrole unit, giving the open chain oxime 4, as a single isomer. However, aryl nitrosoalkenes 2 (R = Aryl) react with pyrrole by conjugated addition to give two isomeric oximes 5 and 6. On the other hand, the reaction of both nitrosoalkenes 2 with indole affords open chain oximes as single isomers via hetero-Diels-Alder reaction (Lopes et al., 2016). Furthermore, nitrosoalkenes 2 react with pyrrole to give 2-alkylated products, whereas indole undergoes alkylation at the 3-position, as would be expected from the opposite regioselectivity of the hetero-Diels-Alder reaction.

Pyrrolocarbazoles are tetracyclic ring systems containing a pyrrole ring fused to a carbazole unit. Depending on the position of the pyrrole/carbazole ring junction and the relative position of the pyrrole nitrogen to the carbazole moiety, several structural isomers can be found (Giraud et al., 2019). The best known are the pyrrolo[2,3-c]carbazoles (Zhang and Ready, 2017), mainly because their core structure is present in the marine natural product dictyodendrin A, and pyrrolo[2,3-a]carbazoles for the recognized kinase inhibitory activity of some derivatives (Akué-Gédu et al., 2009; Giraud et al., 2012) (Figure 1). Reports on the synthesis and reactivity of pyrrolo[3,2-c]carbazoles are scarce. Recently, however, a few reports describing the synthesis (Benzi et al., 2019), photophysical and biological activity, namely, antioxidant (Bingul et al., 2019), anticancer and antibacterial activity, have been disclosed (Sengul et al., 2016; Saglam et al., 2021; Sinicropi et al., 2021). Compound 9 is an example of a pyrrolo[3,2-c]carbazole with high cytotoxicity against human colon cancer HT29 cells (Sengul et al., 2016).

Compounds containing an oxime moiety have found a wide range of biological applications, displaying anti-inflammatory, antimicrobial, antioxidant and anticancer activity (Surowiak et al., 2020). In this context, and following our interest in the chemistry of nitrosoalkenes, we decided to explore the reactivity of nitrosoalkenes towards 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole (10) aiming at the synthesis of oxime-functionalized pyrrolo[3,2-c]carbazoles. The combination of these two structural elements in a single molecule would lead to new chemical entities with increased interest in terms of potential biological activity and with the possibility of further structural modulation.

Initially, the reaction of ethyl nitrosoacrylate (2a), generated in situ from ethyl bromopyruvate oxime (1a) by action of sodium carbonate, with pyrrolo[3,2-c]carbazole 10 was explored. The reaction, carried out in dichloromethane at room temperature, gave the 3- and 2-alkylated pyrrolo[3,2-c]carbazoles 11a and 12a, respectively, in 63% overall yield (Scheme 2). The same reactivity pattern was observed in the reaction of the less activated nitrosoalkene 2b with 10 affording the open chain oximes 11b and 12b in 37% and 8%, respectively (Scheme 2). In both cases, the regioisomeric open chain oximes were isolated as single stereoisomers, indicating that these were formed via hetero-Diels-Alder reaction followed by 1,2-oxazine ring-opening and concomitant rearomatization of the pyrrole unit.

The structural assignment of the two regioisomers was established by two-dimensional NMR spectroscopy. From the coupling observed in the COSY spectrum of compound 11a, it was possible to assign the signals corresponding to the protons H-2 (7.14 ppm), H-1 (10.49 ppm), H-4 (4.15 ppm) and the proton of the hydroxyimino moiety (11.35 ppm). The stereochemistry of the C,N-bond was established by the NOESY spectrum data, in which cross peaks were observed between the NOH proton and the H-4 protons, confirming the trans orientation of the OH and ester groups. The NOESY spectra of compounds 11b and 12b also showed a correlation between the proton of the oxime moiety and H-4 protons (see Supplementary Material), suggesting the trans orientation of the OH and ester groups.

Preliminary studies on the reactivity of the new 3-alkylated pyrrolo[3,2-c]carbazoles focused on the interconversion of the oxime-amine functional groups. However, the reduction reaction of pyrrolo[3,2-c]carbazole 11a, using zinc in acetic acid at room temperature, led to an unexpected but interesting result. One product was isolated whose ¹H NMR spectrum features, recorded using acetone-d ₆ as solvent, were not those expected for the desired amine 13. From the analysis of the ¹H NMR spectrum it was possible to confirm the presence of the pyrrolo[3,2-c]carbazole scaffold, signals corresponding to the ester group as well as to an ABX system, as it would be for amine 13. It was observed that when the product of the reduction reaction was treated with acetone for 1 h, a compound was isolated in 17% yield with a similar ¹H NMR spectrum but in which the presence of two methyl groups could be observed (Scheme 3).

The structure of this new compound was unambiguously determined by X-ray crystallography as being hexahydropyrido [4′,3':4,5]pyrrolo[3,2-c]carbazole 14 (Scheme 3). This heterocyclic compound crystallized with an ethanol and water molecule as colourless plates in the triclinic crystal system within the P-1 space group, showing one molecule of 14⋅H₂O⋅C₂H₅OH per asymmetric unit. Its molecular structure consists of a five-fused ring system, in which a piperidine ring is fused to the 1,6-dihydropyrrolo[3,2-c]carbazole moiety. This six-membered heterocycle contains two methyl groups at C (19) and an ester substituent at C (18). Bond lengths and bond angles are normal. The 1,6-dihydropyrrolo[3,2-c]carbazole moiety is almost planar with the largest deviations from the least-squares plane shown by C (9) (0.091 (4)Å), C (7) (0.086 (3)Å) and C (5) (0.081 (3)Å). In the tetrahydropyridine moiety the atoms C (18) and N (3) show a statistical disorder with two different positions with site occupation factors refined to 0.671) (conformer A) and 0.331) (conformer B). Ring puckering analysis (Cremer and Pople, 1975) of the tetrahydropyridine ring shows the following parameters: conformer A: θ = 51.27°, φ = 32.08°, total puckering amplitudes (Q _T) 0.45 Å; conformer B: θ = 48.51°, φ = 32.65°, Q _T 0.57 Å, suggesting a half chair conformation for both the conformations. A network of intra- and intermolecular hydrogen bonding interactions involves the water and ethanol molecules. In particular, an intramolecular H-bond interaction involves O (1 Et)-H ^… O (1w) d H ^… O (1w) = 1.97 (1)Å and O (1w)-H ^… O (2) d H ^… O (2) = 2.76 (4)Å, and intermolecular H-bond interactions are N (1)-H ^… O (1w) (x-1, y+1, z) d H ^… O (1w) = 2.021) Å; N (2)-H ^… O (1et) (x-1,y,z) d H ^… O (1w) = 2.051) Å.

The formation of the pentaheterocyclic system 14 can be explained considering the initial reduction of the oxime moiety to give amine 13 followed by its Pictet-Spengler condensation with acetone to give the final product.

The condensation of tryptamines with aldehydes and ketones, known as the Pictet-Spengler reaction, has been extensively explored for the synthesis of ring-fused indole derivatives, including tetrahydro-β-carbolines a core structure of various indole alkaloids (Stöckigt et al., 2011; Maity et al., 2019; Panice et al., 2019; Ribeiro et al., 2022). The mechanism of this transformation has been a research topic of some controversy as two pathways can be considered: the formation of spiroindolenines via the attack of indole’s C3 to the initially formed imine followed by a 1,2-migration/elimination sequence to restore aromaticity, or the direct C2 attack. However, there are several experimental studies where the spiroindolenines, intermediates of Pictet−Spengler-type reactions, were captured (Williams and Unger, 1970; Stöckigt et al., 2011; Chambers et al., 2016; Zheng and You, 2020). Furthermore, in recent years the interrupted Pictet–Spengler reaction is being explored as a strategy for the dearomatisation of indoles (James et al., 2016). Several successful syntheses of spirocyclic indolenine are known resulting from methodologies designed to allow the initial spirocyclisation step but preventing further reaction. The reported synthesis of hexahydropyrido[4′,3':4,5]pyrrolo[3,2-c]carbazole 14 is a new entry to Pictet−Spengler-type reactions.

This interesting result justified the optimization of the synthetic procedure, as a one-pot two-step procedure. Thus, a solution of compound 11a in acetic acid and acetone was treated with zinc powder at room temperature for 48 h. After the neutralization of the reaction medium and purification, the target compound 14 was isolated in 85% yield (Scheme 3).

The reactivity of nitrosoalkenes towards 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole was studied leading to the synthesis of oxime-functionalized pyrrolo[3,2-c]carbazoles. The mechanistic pathway involves a hetero-Diels-Alder reaction leading to the construction of a 1,2-oxazine ring which undergoes a ring-opening reaction to give open-chain oximes. Calculations at the DFT level of theory were carried out to investigate the regioselectivity of the hetero-Diels-Alder reaction of ethyl nitrosoacrylate with 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole as well as with pyrrole and indole, allowing a comparison between these three types of heterocycles. The computational results allowed the rationalization of the regioselectivity observed in the cycloaddition reaction and the formation of the more stable open chain oximes as the final products. The relative energy values of the Frontier HOMO and LUMO molecular orbitals for the ethyl nitrosoacrylate and the studied heterocyclic dienophiles were also calculated, substantiating that the cycloadditions are LUMO_heterodiene-HOMO_dienophile controlled.

The construction of a new hexahydropyrido[4′,3':4,5]pyrrolo [3,2-c]carbazole system from one of the new 3-alkylated pyrrolo [3,2-c]carbazole was achieved in high yield via a one-pot two-step approach.

General Information: NMR spectra were recorded on a Bruker Avance III instrument operating at 400 MHz (¹H) or 100 MHz (¹³C). Chemical shifts are expressed in ppm relative to TMS and coupling constants (J) are in Hz. Infrared spectra (IR) were recorded in a Fourier Transform spectrometer. High-resolution mass spectra (HRMS) were obtained on a TOF VG Autospec M spectrometer with electrospray ionization (ESI). Melting points were recorded in open glass capillaries. Thin Layer Chromatography (TLC) was performed using precoated silica gel plates. Flash chromatography was performed using silica gel 60 as a stationary phase. Ethyl bromopyruvate oxime (1a) (Gilchrist and Roberts, 1983), 2-bromo-1-phenylethanone oxime (1b) (Masaki et al., 1967) and 8-methyl-1,6-dihydropyrrolo [3,2-c]carbazole (10) (Benzi et al., 2019) were prepared as described in the literature.

Sodium carbonate (0.75 mmol) was added to a solution of a-bromooxime 1 (0.15 mmol) and 8-methylpyrrolo[3,2-c]carbazole 10 (0.22 mmol) in dry dichloromethane (10 mL). The reaction mixture was stirred at room temperature for the time indicated in each case, monitored by TLC. Upon completion, the mixture was filtered through a Celite pad, which was washed with ethyl acetate (2 × 10 mL). The solvent was evaporated, and the products were purified by flash chromatography.

(E)-3-(2-Ethoxycarbonyl-2-hydroxyiminoethyl)-8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole (11a) and (E)-2-(2-Ethoxycarbonyl-2-hydroxyiminoethyl)-8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole (12a). Obtained from oxime 1a (31.5 mg, 0.15 mmol) and 8-methylpyrrolo[3,2-c]carbazole 10 (48.5 mg, 0.22 mmol) as described in general procedure (reaction time: 18 h). Purification of the crude product by flash chromatography [ethyl acetate/hexane (1:1)], gave, in order of elution, 12a obtained as a beige solid (11.0 mg, 21%) and 11a obtained as a beige solid (22.0 mg, 42%).

Data for compound 11a: mp 199.7°C-201.6°C (from ethyl acetate/hexane). IR (KBr) ν 796, 1020, 1136, 1196, 1389, 1429, 1643, 1714, 3261, 3419 and 3446 cm^-1. ¹H NMR (Acetone-d ₆ ) δ: 1.21 (t, J = 7.2 Hz, 3H), 2.49 (s, 3H), 4.15 (d, J = 0.8 Hz, 2H), 4.17 (q, J = 7.2 Hz, 2H), 7.02 (dd, J = 8.0 and 0.8 Hz, 1H), 7.14 (dd, J = 2.0 and 0.8 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 10.22 (br s, 1H), 10.50 (br s, 1H), 11.35 (s, 1H). ¹³C NMR (Acetone-d ₆ ) δ: 14.4, 21.1, 22.0, 61.5, 105.0, 108.3, 111.4, 111.6, 118.0, 120.5, 121.0, 121.3, 121.5, 121.8, 130.9, 134.2, 138.1, 140.3, 152.5, 164.9. HRMS (ESI): calcd. for C₂₀H₁₈N₃O₃, 348.1354 [M-H⁺]; found, 348.1352.

Data for compound 12a: mp 154.8°C-156.0°C (from carbon tetrachloride). IR (KBr) ν 804, 1020, 1132, 1261, 1382, 1464, 1614, 1722, 2924, 2977 and 3381 cm^-1. ¹H NMR (Acetone-d ₆ ) δ: 1.26 (t, J = 7.2 Hz, 3H), 2.49 (s, 3H), 4.22 (d, J = 1.2 Hz, 2H), 4.25 (q, J = 7.2 Hz, 2H), 6.32 (dd, J = 2.4 and 1.2 Hz, 1H), 7.03 (dd, J = 7.6 and 1.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 10.18 (br s, 1H), 10.26 (br s, 1H), 11.58 (br s, 1H). ¹³C NMR (Acetone-d ₆ ) δ: 14.4, 22.0, 24.3, 61.9, 102.0, 105.2, 111.6, 118.8, 120.4, 120.9, 121.2, 122.8, 124.4, 130.6, 131.3, 134.3, 137.8, 140.3, 150.7, 164.9. HRMS (ESI): calcd. for C₂₀H₂₀N₃O₃, 350.1499 [M + H⁺]; found, 350.1496.

(E)-3-(2-Phenyl-2-hydroxyiminoethyl)-8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole (11b) and (E)-2-(2-phenyl-2-hydroxyiminoethyl)-8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole (12b). Obtained from oxime 1b (32.1 mg, 0.15 mmol) and 8-methylpyrrolo[3,2-c]carbazole 10 (48.5 mg, 0.22 mmol) as described in general procedure (reaction time: 48 h). Purification of the crude product by flash chromatography [ethyl acetate/hexane, (1:2)], gave, in order of elution, 12b obtained as a beige solid (4.2 mg, 8%) and 11b obtained as a beige solid (19.6 mg, 37%).

Data for compound 11b: mp 179.8°C-181.7°C (from ethyl acetate/hexane). IR (KBr) ν 687, 761, 943, 1124, 1298, 1331, 1389, 1429, 1462, 1639, 2918, 3059 and 3392 cm^-1. ¹H NMR (Acetone-d ₆ ) δ: 2.48 (s, 3H), 4.39 (d, J = 1.2 Hz, 2H), 7.00 (dd, J = 8.0 and 1.2 Hz, 1H), 7.05 (dd, J = 2.4 and 1.2 Hz, 1H), 7.24-7.29 (m, 4H), 7.32 (br s, 1H), 7.75-7.77 (m, 3H), 8.21 (d, J = 8.0 Hz, 1H), 10.22 (br s, 1H), 10.41 (br s, 1H), 10.51 (s, 1H). ¹³C NMR (Acetone-d ₆ ) δ: 22.0, 22.1, 105.0, 109.6, 111.5, 112.4, 117.8, 120.5, 120.9, 121.1, 121.3, 121.8, 127.3, 128.9, 129.2, 131.0, 134.2, 137.7, 138.2, 140.3, 157.2. HRMS (ESI): calcd. for C₂₃H₂₀NO₃, 354.1601 [M + H⁺]; found, 354.1598.

Data for compound 12b: mp 118.0°C-119.5°C (from carbon tetrachloride). IR (KBr) ν 694, 760, 800, 1184, 1288, 1385, 1620, 1697, 2850, 2920 and 3398 cm^-1. ¹H NMR (Acetone-d ₆ ) δ: 2.49 (s, 3H), 4.45 (d, J = 0.8 Hz, 2H), 6.33 (dd, J = 2.0 and 0.8 Hz, 1H), 7.03 (dd, J = 8.0 and 1.6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.31-7.38 (m, 4H), 7.42 (d, J = 8.4 Hz, 1H), 7.57-7.61 (m, 1H), 7.82-7.85 (m, 1H), 8.15 (d, J = 8.0 Hz, 1H), 10.18 (br s, 1H), 10.33 (br s, 1H), 10.82 (s, 1H). ¹³C NMR (Acetone-d ₆ ) δ: 21.1, 24.6, 101.2, 104.2, 107.1, 110.7, 117.8, 120.0, 120.2, 124.9, 126.2, 127.3, 128.2, 128.5, 128.8, 129.8, 131.6, 133.4, 136.3, 136.9, 139.4, 154.9. HRMS (ESI): calcd. for C₂₃H₂₀NO₃, 354.1601 [M + H⁺]; found, 354.1598.

Ethyl 1,1,9-trimethyl-1,2,3,4,7,12-hexahydropyrido[4′,3':4,5]pyrrolo[3,2-c]carbazole-3-carboxylate (14): Zinc powder (80 mg, 1.22 mmol) was added portion-wise to a solution of 3-alkylated pyrrolo [3,2-c]carbazole 11a (35.6 mg; 0.102 mmol) in acetic acid (1.5 mL) and acetone (0.1 mL). The resulting mixture was stirred at room temperature for 24 h. After this time, zinc powder (80 mg, 1.22 mmol) was added and the resulting mixture stirred at room temperature for more 24 h. Upon completion, the zinc salts were removed by filtration through a Celite pad, which was washed with ethyl acetate (3 × 10 mL). The filtrate was neutralized with aqueous NaOH 5% to pH 7 and then extracted with ethyl acetate (3 × 20 mL). The organic extracts were dried over Na₂SO₄ and the solvent evaporated off. Compound 14 was purified by flash chromatography [ethyl acetate/hexane, (1:1)] and obtained as a beige solid (32.5 mg, 85%). mp 114.0°C-115.8°C (from ethyl acetate/hexane). IR (KBr) ν 808, 1030, 1192, 1265, 1469, 1620, 1705, 2921, 2962 and 3392 cm^-1. ¹H NMR (CDCl₃) δ: 1.37 (t, J = 7.2 Hz, 3H), 1.58 (s, 3H), 1.66 (s, 3H), 2.55 (s, 3H), 2.84 (dd, J = 15.2 and 11.2 Hz, 1H), 3.20 (dd, J = 15.2 and 4.2 Hz, 1H), 4.00 (dd, J = 11.2 and 4.2 Hz, 1H), 4.28-4.36 (m, 2H), 7.13 (dd, J = 8.0 and 1.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 8.11 (s, 1H). ¹³C NMR (CDCl₃) δ: 14.4, 22.2, 27.0, 28.9, 30.1, 51.1, 53.1, 61.3, 104.4, 107.4, 107.8, 111.0, 116.5, 119.6, 120.3, 120.7, 120.9, 129.9, 134.6, 137.0, 137.3, 139.2, 174.0. HRMS (ESI): calcd. for C₂₃H₂₆N₂O₃, 376.2019 [M⁺]; found, 376.2015.

Crystallographic data for Ethyl 1,1,9-trimethyl-1,2,3,4,7,12-hexahydropyrido[4′,3':4,5]pyrrolo[3,2-c]carbazole-3-carboxylate (14): A single crystal of compound 14 ^. H₂O^.C₂H₅OH was submitted to X-ray data collection on a Bruker APEX-II CCD diffractometer with a graphite monochromated Cu-Kα radiation (λ = 1.54178 Å) at 100 K. The structure was solved by direct methods implemented in SHELXS-97 program (Sheldrick, 2008). The refinement was carried out by full-matrix anisotropic least-squares on F² for all reflections for non-H atoms by means of the SHELXL (version 2019/2) program (Sheldrick, 2015). The structure crystallizes with a water and an ethanol molecule in the Triclinic crystal system, space group P-1 with one molecule in the asymmetric unit. Crystallographic data for this structure has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 2222762. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; (fax: +44 0) 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk).

Calculations were performed with Gaussian 09 (Frisch et al., 2009) and Gamess (Schmidt et al., 1993) program packages. All structures were fully optimized at the DFT level of theory, using the B3LYP hybrid functional (Becke, 1988; Lee et al., 1988; Becke, 1993) and the standard 6-31G (d,p) basis set.

Vibrational frequencies were calculated at the same level of theory to evaluate the zero-point vibrational energy, ZPE, and to confirm the nature of the stationary points, that in the case of the transition states were characterized by having only one imaginary frequency. Inspection of the corresponding imaginary frequency allowed to confirm that the transition states connect the reactants with the expected products. The geometrical counterpoise correction was added to all transition state structures. Frontier molecular orbitals were calculated on DFT-optimized structures at the HF level of theory with the 6-31G(d) basis set. The orbital coefficients were calculated using the NBO module of Gaussian. Graphical representations were obtained with Gaussview.