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. 2021 Jul 12;11(39):24238–24246. doi: 10.1039/d1ra03019a

Insights into the nucleophilic substitution of pyridine at an unsaturated carbon center†

Pan Du 1,‡, Jiyang Zhao 2,‡,✉, Shanshan Liu 2, Zhen Yue 2
PMCID: PMC9036673  PMID: 35479030

Abstract

Bimolecular nucleophilic substitution (SN2) is a fundamental reaction that has been widely studied. So far, the nucleophiles are mainly anionic species in SN2 reactions. In this study, we use density functional theory calculations to assess the mechanisms of substitution of carbonyl, imidoyl, and vinyl compounds with a neutral nucleophile, pyridine. Charge decomposition analysis is performed to explore the main components of the transition state's LUMO. For reactions of imidoyl or carbonyl compounds with pyridine or Cl−, the LUMOs of the transition states are composed of mixed orbitals originating from the nucleophile and the substrate. Considering the unique mixed nature of the orbitals, the reaction mode is termed SNm (m means mix). Moreover, the main components of the transition state's LUMO are pure σ*C–Cl MO in the reactions of H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl with pyridine or Cl−. Computations were also performed for RY Created by potrace 1.16, written by Peter Selinger 2001-2019 CHX substrates with different X and Y groups (X= Cl−, Br−, or F−; Y = O, N, or C).

The nucleophilic substitution of carbonyl, imidoyl, and vinyl carbon centers with pyridine or halides is investigated in this paper.graphic file with name d1ra03019a-ga.jpg

Introduction

Bimolecular nucleophilic substitution (SN2) is a fundamental reaction that is implicated in different chemical and biological processes.1–10 This reaction is triggered by the attack of a nucleophile (Nu−) on a central atom (A), which results in the displacement of a leaving group (Y) (Scheme 1(a)). The nucleophilic attack can occur from the backside (SN2-b) or front side (SN2-f) of the reacting molecule. For most compounds, SN2-b is preferred to SN2-f, and the central atom at which substitution occurs is sp3 hybridized. However, in some cases, nucleophilic substitution may occur at sp2 hybridized olefinic sites, and the reaction is referred to as nucleophilic vinylic substitution (SNV) (Scheme 1(b)).11–14 SNV reactions proceed via perpendicular concerted π attack with retention (SNVπ) or via in-plane σ* attack with inversion (SNVσ).

Scheme 1. General reaction schemes and molecular orbital interactions of (a) SN2 and (b) SNV reactions. Nu− is the nucleophile, A is the central atom, and Y is the leaving group.

Scheme 1

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Although the mechanisms of nucleophilic substitution are well established for many substrates, the exact reactions steps for imidoyl and carbonyl compounds are controversial.15–21 According to Bach and Lee, the nucleophilic substitution of these compounds proceeds via the out-of-plane SNVπ mechanism (Scheme 1(b)).15,16 However, Lee and Yamabe show that X− + RCOY displacement reactions cannot follow the SNVπ mechanism since the σ*C–Y molecular orbital (MO) is the main component of the transition state's LUMO, and since the π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 X and σ*C–Y MOs are efficiently mixed.17–21

The nucleophiles involved in SN2 and SNV reactions are mainly anionic species, such as Cl−, Br−, I−, OH−, CN−, and SH−. Neutral nucleophiles are very rare, particularly the large ones.22,23 Recently, we had studied the electrophilic addition reactions of pyridine to acyl chlorides, chloroformates and chloro-oxime reagents (Scheme 2).24,25 These reactions can be described as SN2 reactions, where pyridine, a bulky neutral compound, is the nucleophile, and Cl− is the leaving group. Considering that pyridine and anionic species (ex. Cl−) exhibit significantly different electrostatic potential diagrams (Fig. 1), it is expected that their nucleophilic activity and mechanism will also be different. In this study, we investigate the SN2 reactions of pyridine with three kinds of substrates (RCOCl, RClCNR and RClCCR2, shown in Scheme 2).

Scheme 2. Electrophilic addition of pyridine to RCOCl, RClCNR and RClCCR2.

Scheme 2

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Fig. 1. Electrostatic potential diagrams of pyridine and Cl− (isosurface = 0.05 a.u.). Red and blue regions in the ESP map represent areas of negative and positive potential, respectively.

Fig. 1

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Computational details

Quantum chemistry calculations were conducted by the Gaussian16 program.26 The geometries of all stable species and transition states were optimized using the M06-2X functional with 6-311+G(d,p) basis set.27–30 All calculations were conducted in dichloromethane solution using the self-consistent reaction field (SCRF) method with the IEFPCM solvation model.31 The harmonic frequencies were calculated at the same level of theory in order to obtain the relevant thermodynamic energy corrections and to characterize the optimized stationary points as minima or saddle points. To ascertain the reasonability of our computational method, other functionals (QCISD, MP2, PBE1PBE, B3LYP, B3LYP-d3, w-b97xd) were also used to investigate the structures and energies of some important intermediates and transition states. The Gibbs free energies of all species were determined at T = 298.15 K and P = 1 atm. Intrinsic reaction coordinate (IRC) analysis was used to confirm important transition states and natural bond orbital analyses were carried out at the M062x/6-311+G** level.32–36 The 3D-optimized structures in this study were observed using the CYLview visualization program.37 As for the orbital interactions and orbital composition analysis, they were studied according to the charge decomposition analysis (CDA) method and Hirshfeld method implemented in the Multiwfn program.38–46 IBO (intrinsic bond orbital) analyses was performed to study the electronic structure changes in the reaction of pyridine with CH3COCl along the reaction pathway.47

Results and discussion

1. Nucleophilic substitution reactions of CH3COCl with pyridine or Cl−

The nucleophilic substitution reactions of acyl chloride CH3COCl with pyridine or Cl− are shown in Fig. 2. Considering that pyridine is not charged, it shows no minima related to the reactant complex, unlike the anionic nucleophile. However, the Cl− eliminated by the nucleophilic attack of pyridine leads to a potential well that is associated with product complex. The transition state (TS-pyridine, illustrated in Fig. 2) shows that when pyridine attacking the substrate, it induces the formation of a C–N bond and the simultaneous cleavage of the C–Cl bond. Fig. 3 shows that the IBOs transform continuously from the electronic structure of the starting material to that of the product along the intrinsic reaction coordinate. Two IBOs show a concerted transformation of one pyridine lone pair (top) into a Cl–C σ bond, while the C–Cl σ bond (down) breaks and transforms into a lone pair. Based on the calculated energy values, the free energy barrier of the reaction is only 13.8 kcal mol−1 (in dichloromethane), which indicates that pyridine is a strong nucleophile. The distance between the carbon center on acyl chloride and the nitrogen atom of pyridine is shortened from 2.81 Å in the reactants to 1.94 Å in the transition state, and to 1.51 Å in the product complex. Meanwhile, the C–Cl bond is elongated from 1.82 Å in CH3COCl to 1.96 Å in the transition state. Using the ωb97xd and B3LYP-d3 functionals, the related reaction barriers are 13.0 and 15.5 kcal mol−1, respectively, indicating that the results obtained using the two functionals and M062X functional are in good agreement. The structures of the transition states calculated by ωb97xd and B3LYP-d3 functionals are shown in Fig. S1 in the ESI.†

Fig. 2. The nucleophilic substitution reactions of acyl chloride CH3COCl with pyridine or Cl− (R: reactant, TS: transition state, P: product).

Fig. 2

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Fig. 3. IBOs of the two reactive orbitals in the reaction of pyridine with CH3COCl along the reaction pathway.

Fig. 3

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Although the reaction of nucleophilic substitution of acyl chloride with Cl− has been studied extensively, we chose to investigate it as well for the purpose of direct comparison.15–21 As shown in Fig. 2, the transition state in this reaction (TS-Cl) is characterized by a C–Cl bond length of 2.18 Å, which is longer than that calculated for TS-pyridine. Also, the dihedral angle Cl–O–C–C in TS-pyridine (139.4°) is greater than that in TS-Cl (126.9°), which suggests that Cl− induces more deformation of acyl chloride than pyridine due to its more negative charge and less hindrance.

When pyridine approaches the central carbon of CH3COCl, an electron migrates from the electron-rich HOMO of the nucleophile to the LUMO of the substrate, which result in the deformation of the latter.17,18 Considering that the energy gap between the π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 O and σ*C–Cl molecular orbitals of CH3COCl is small (1.3 eV), electron migration from pyridine induces sufficient mixing of these two MOs.15,17–19,21 Based on the results of charge decomposition analysis (CDA)38–42 illustrated in Fig. 4, the LUMO (orbital 44) of the reactant complex (Int 1) is primarily composed of acyl chloride's orbital 21 (π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 O, LUMO). However, as pyridine approaches, orbitals 21 and 24 of pyridine gradually mix into the LUMO of the complex (orbital 44), along with orbital 21 of CH3COCl. In the transition state, the LUMO is formed by mixing the orbitals 21 and 24 of pyridine with orbitals 21 and 22 of CH3COCl. Based on the orbital composition analysis (Fig. 3(TS)), atom orbitals of chloride and carbonyl oxygen have 17.3% and 8.3% contributions to MO 44 in the transition state, respectively, indicating that the σ*C–Cl MO becomes the main component of the transition state's LUMO. Therefore, it may be concluded that the nucleophilic substitution reaction is initiated by the attack of pyridine's np orbital on the π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 O MO of CH3COCl. Knowing that after charge transfer, σ*C–Cl is mixed into the LUMO of CH3COCl, eventually it becomes the major component. Considering the transition state's LUMO is a mixed orbital, the attack mode is labeled SNm (m means mix).

Fig. 4. Molecular orbital interaction diagrams of the intermediates and transition states implicated in the reaction of pyridine and acyl chloride (isosurface = 0.05 a.u.). The diagrams are constructed using fragments of pyridine (Frag 1) and acyl chloride (Frag 2).

Fig. 4

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CDA was also performed on the reaction of Cl− and CH3COCl. The results shown in Fig. 5 demonstrate that the transition state's LUMO consists of orbital 7 (np) of Cl− and orbitals 21 and 22 of CH3COCl. The contributions of chloride atom orbital and carbonyl oxygen atom orbital to MO 30 in the transition state are 12.8% and 12.7%, respectively, indicating that the σ*C–Cl and π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 O MOs are nearly identical in the transition state's LUMO. The energy level of orbital 22 (σ*) of CH3COCl in TSCl reduced by 0.89 eV from free CH3COCl, which is larger than that in TSpyridine (0.25 eV). Therefore, more π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 O MO mix into orbital 22 in TSCl compared to TSpyridine (as shown in Fig. 3 and 4). As a result, π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 O MO remains comparable contributions to σ*C–Cl in the transition state. This reaction mode is different from that observed in earlier studies, wherein the σ*C–Cl MO was shown to be the main component of the LUMO of the transition state in the reaction of X− (X = Cl, F) with CH3COCl.17–21

Fig. 5. Schematic molecular orbital interaction diagram showing the transition state of the reaction of Cl− and acyl chloride (isosurface = 0.05 a.u.). Frag 1and Frag 2 are fragments of Cl− and acyl chloride, respectively.

Fig. 5

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An alternative mechanism of the nucleophilic substitution of CH3COCl with pyridine is the in-plane σ attack with inversion (SNσ-pyridine, Fig. 2).15,16,21 The free energy barrier of this reaction is 29.5 kcal mol−1 in dichloromethane, which is much higher than that of the SNm path (13.8 kcal mol−1). The C–N and C–Cl bonds lengths in the SNσ transition state are 2.51 and 2.91 Å, respectively. Both bonds are longer than those observed in the SNm transition state, resulting in a larger free energy barrier of the SNσ reaction. However, the C–Cl bond lengths of the SNm and SNσ transition states corresponding to the reaction of CH3COCl with Cl− are 2.18 and 2.90 Å, respectively. The smaller difference between these two values compared to that determined for the reaction of CH3COCl and pyridine indicates that the deformation energies of the two mechanisms (SNm and SNσ) are close. Therefore, the related free energy barriers of the SNm and SNσ pathways of CH3COCl + Cl− are close (16.1 and 20.1 kcal mol−1, respectively).

Chloroformates were also assessed. The energy values listed in Table 1 indicate that the reactions of these substrates (s2–s6; Scheme 2) with pyridine are similar to that of s1. Overall, the calculated energies suggested that the investigated chloroformates can easy react with pyridine under very low reaction temperature, which is consistent with previous experimental observations (−20 °C).24,25 The very small energy gaps between the π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 O and σ*C–Cl MOs of all substrates (0.3 to 0.9 eV) indicates that these MOs are efficiently mixed in the transition states.17–19 Moreover, the main component of the LUMO of each transition state is the σ*C–Cl MO of the chloroformates. The optimized geometries of the transition states and the structures of the mixed orbitals are presented in Fig. S2–S3 of ESI.†

Free energy barriers of the bimolecular nucleophilic substitution (SN2) reactions of chloroformates with pyridine (kcal mol−1), and the energy gaps between σ*C–Cl and π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 O of all substrates (eV).

s2 s3 s4 s5 s6
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ΔG≠ 15.4 15.8 16.8 13.4 15.1
Energy gap 0.8 0.6 0.3 0.9 0.7
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The transition state of the reaction of acyl bromide with pyridine (Fig. 6(a)) is similar to that of the acyl chloride. However, when the leaving group is F−, no transition state is formed. Instead, the reaction of acyl fluoride with pyridine leads to a tetrahedral intermediate (Fig. 6(b)) that lies at 3.4 kcal mol−1 above the reactants (M06-2X level). The absence of a transition state for this reaction may be attributed to the greater strength of the C–F bond compared to the C–Cl bond.19 A tetrahedron intermediate is also detected for the reaction of acyl fluoride with NH3 (Fig. 6(c)). Based on M06-2X calculations, this intermediate lies at 5.4 kcal mol−1 above the reactants. The tetrahedral structure of the intermediate was verified using other theoretical methods including QCISD, MP2, PBE1PBE, B3LYP, B3LYP-d3, ωb97xd. The structures of these tetrahedral structures are illustrated in Fig. S1 in the ESI.† As for the reaction of CH3COF with Cl−, it shows only a product complex (CH3COCl…F−), with no transition state or tetrahedral intermediate. The CH3COCl…F− complex is similar to that reported previously by Yamabe et al. for the reaction of CH3COF with Cl−.17,18

Fig. 6. (a) Transition state of the nucleophilic substitution reaction of acyl bromide with pyridine. Tetrahedron intermediates formed by reacting acyl fluoride with (b) pyridine and (c) NH3.

Fig. 6

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Fig. S4 in ESI† depicts the potential energy diagrams representing the reaction of acyl fluoride with different nucleophiles (pyridine, NH3, and Cl−). These diagrams clearly show stable intermediates for the reactions of acyl fluoride with pyridine and NH3, but not with Cl−. According to previous studies, the formation of tetrahedron intermediate in nucleophilic substitution reactions of acyl chlorides is controlled by the leaving ability of the nucleofuge and by the energy gap between the π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 O and σ*C–Cl MOs.18–20 In the case of acyl fluoride, the energy of newly formed bond in the product is also related to the formation of an intermediate. Based on our calculations, the bond energies of the newly formed C–N (pyridine), C–N (NH3), and C–Cl in the products of the reactions of acyl fluoride with pyridine, NH3, and Cl− are 79.1, 67.7 and 65.5 kcal mol−1, respectively. With the least strong bond, the CH3COCl…F− adduct is the least stable, and so, its formation is not favored. The greater strength of the C–N bond compared to the C–Cl bond also explains why the reaction barrier of nucleophilic substitution of CH3COCl with pyridine is lower than that of substitution with Cl−.

2. Nucleophilic substitution reactions of CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf with pyridine or Cl−

Pyridine may also be used as a nucleophile in substitution reactions of imidoyl substrates (C Created by potrace 1.16, written by Peter Selinger 2001-2019 N moiety, Scheme 2).24,25 Based on our theoretical analyses, the nucleophilic substitution reaction of CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf (s7) with pyridine proceed via two possible mechanisms, SNm and SNσ (Fig. 7(a) and (b)), which are characterized by free energy barriers of 22.8 and 49.3 kcal mol−1, respectively. The energy values indicate that the SNm pathway is relatively feasible, but the SNσ pathway is improbable under moderate reaction conditions. We recalculate the SNm reactions of substrate s7 using the ωb97xd and B3LYP-d3 functionals. Related reaction barriers of SNm mechanism are 23.4 and 24.6 kcal mol−1, respectively, in agreement with the values obtained using the M062X functional. The structures of transition states calculated by ωb97xd and B3LYP-d3 functionals are shown in Fig. S1 in the SI.† As for reaction of CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf with Cl−, it may occur via SNm and SNσ mechanisms (Fig. 7(c) and (d)), with free energy barriers of 26.5 and 40.0 kcal mol−1, respectively. Overall, the calculated energy values suggest that the nucleophilic substitution of CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf (s7) with pyridine is more facile than that of Cl−.

Fig. 7. The nucleophilic substitution reactions of CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf (s7) with pyridine or Cl−. Reaction of pyridine with CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf by (a) SNm and (b) SNσ mechanisms, and reaction of Cl− with CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf by (c) SNm and (d) SNσ mechanisms.

Fig. 7

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The energy gap between the π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 N and σ*C–Cl MOs of CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf is only 1.1 eV. Therefore, electron migration induces sufficient mixing of these two orbitals when pyridine reacts with CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf. The CDA presented in Fig. 8(a) shows that the LUMO (orbital 68) of the transition state consists of mixed np (orbital 21, pyridine), orbitals 45 and 46 of CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf, with σ* orbital being the main component because of the large composition of chloride (26.4%). For the reaction of Cl− with CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf, the CDA results of the transition state are similar to that observed in the reaction of pyridine with CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf (Fig. 8(b)). These reaction modes are similar to that observed in earlier studies.17–21

Fig. 8. Molecular orbital interaction diagrams showing the transition states of the reaction of (a) pyridine with CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf, (b) Cl− with CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf (isosurface = 0.05 a.u.). The diagrams are constructed using fragments of the pyridine or Cl− (Frag 1) and CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf (Frag 2).

Fig. 8

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The reactions of the imidoyl substrates s8–s13 with pyridine are similar to that of CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf (s7). As shown in Table 2, these reactions exhibit free energy barriers in the narrow range of 23.4–26.3 kcal mol−1, which is higher than the energy barriers corresponding to the reaction of acyl chloride with pyridine. The free energy barriers of these reactions indicate that these reactions can occur under the condition of proper heating. In experiments, these reactions were carried out at 80 °C. Therefore, theoretical calculation results are reliable. Moreover, considering that the energy gaps between π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 N and σ*C–Cl MOs of the imidoyl substrates are low (0.5 and 2.4 eV), it may be concluded that these orbitals are efficiently mixed. Like CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf, the main component of the transition state LUMOs of substrates (s8–s13) is the σ*C–Cl MO. The transition state and mixing orbitals of the imidoyl substrates are shown in Fig. S5 and S6 of ESI.†

Free energy barriers of the bimolecular nucleophilic substitution (SN2) reactions of chloro-oxime reagents with pyridine (kcal mol−1). The energy gaps between σ*C–Cl and π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 N MOs of all substrates (eV).

s8 s9 s10 s11 s12 s13
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ΔG≠ 24.0 23.7 23.4 26.3 23.6 23.9
Energy gap 0.5 1.7 1.1 2.2 2.2 2.4
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The relationship between the free energy barrier and the product yield of the substrate (s7–s11) reaction with pyridine is shown in Fig. 9. As can be seen from Fig. 9, there is a good linear relationship between the yields of these reactions and the free energy barriers. The lower the free energy barrier, the higher the yields. The theoretical calculation results are in good agreement with experimental observations. Thus, theoretical calculation results are reliable.

Fig. 9. The relationship between the free energy barrier and the product yield of the substrate (s7–s11) reaction with pyridine.

Fig. 9

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The reaction of CH3FC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf with pyridine leads to the formation of a tetrahedral intermediate (Fig. 10, 19.9 kcal mol−1 above the reactants at the M06-2X level), which is characterized by C–N and C–F bond lengths of 1.61 and 1.42 Å, respectively. When Cl− is used as nucleophile, no stable adduct or transition state are evident, just like in the case of the reaction between Cl− and CH3COF. The profile scans of nucleophile approach to CH3FC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf (Fig. S7 in ESI†) confirm that a tetrahedral intermediate is formed with pyridine but not with Cl−.

Fig. 10. Tetrahedral intermediate formed by reacting pyridine with CH3FC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf.

Fig. 10

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In summary, the reaction of pyridine with CH3XC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf proceeds via a transition state when X is Cl− or forms a stable adduct when X is F−. Similarly, a transition state is discerned for the substitution of CH3ClC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf with Cl−; however, the CH3FC Created by potrace 1.16, written by Peter Selinger 2001-2019 NOTf substrate shows neither a transition state nor a stable adduct when reacting with chloride.

3. Nucleophilic substitution reactions of H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl with pyridine or Cl−

The energy gap between the π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 C and σ*C–Cl molecular orbitals of H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl (s14) is only 0.6 eV, so electron migration from pyridine or Cl− induces sufficient mixing of these two MOs. As shown in Fig. 11(a) – 10(d), the main components of each transition state's LUMO of the nucleophilic substitution reaction of H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl with pyridine or Cl− is the σ*C–Cl MO of H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl. The mechanism is different from earlier studies, wherein the SNV reactions proceed via concerted π attack (SNVπ) or via in-plane σ* attack (SNVσ).11–14 There are two ways nucleophile attack H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl. One way is for nucleophile to attack the reactive molecule vertically (the mode is labeled SNV-σv, Fig. 10(a) and (c)), and the other way is to attack it from backside (the mode is labeled SNV-σb, Fig. 11(b) and (d)).

Fig. 11. The geometries and LUMO of transition states in the nucleophilic substitution reactions of H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl with pyridine or Cl−. Reaction of pyridine with H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl by (a) SNV-σv and (b) SNV-σb mechanisms, and reaction of Cl− with H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl by (c) SNV-σv and (d) SNV-σb mechanisms.

Fig. 11

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The free energy barriers of the reaction of pyridine with H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl (s14) via the SNV-σv and SNV-σb mechanisms are 42.4 and 47.5 kcal mol−1, respectively. Similarly, the related free energy barriers for the reaction of H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl with Cl−via two modes are 47.9 kcal mol−1 and 42.3 kcal mol−1, respectively. The calculated barriers are consistent with that reported by the group of Radom.48 It can be concluded that SNV-σv is more facile than SNV-σb. CH3HC Created by potrace 1.16, written by Peter Selinger 2001-2019 CCH3Cl (s15) and Cl2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CCl2 (s16) are also tested as substrates, and the free energy barriers of their nucleophilic substitution reactions with pyridine are 46.0 and 38.2 kcal mol−1, respectively (SNV-σv mode).

Conclusion

The mechanisms of nucleophilic substitution of carbonyl, imidoyl, and vinyl carbon centers with pyridine or halides are investigated using detailed density functional theory calculations. The main conclusions are summarized below.

(1) The transition state LUMOs of the reactions of RCOCl with pyridine, RClCNR with pyridine and RClCNR with Cl− are composed of mixed orbitals (part from pyridine or Cl− and part from substrate), with the σ* MO of the substrate being the main component. However, for the reaction of Cl− and CH3COCl, the σ*C–Cl and π*C Created by potrace 1.16, written by Peter Selinger 2001-2019 O MOs are nearly identical in the transition state's LUMO. This type of transition state has not been reported previously for nucleophilic substitution reactions of acyl chlorides. In fact, earlier studies show that the transition state LUMOs corresponding to the reaction of CH3COCl with halides are composed primarily of the σ*C–Cl MO. The newly discovered reaction mode is called SNm (m means mix).

(2) For the reactions of H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl with pyridine and Cl−, the main components of each transition state's LUMO is the σ*C–Cl MO. The mechanism is different from earlier studies, wherein the SNV reactions proceed via concerted π attack (SNVπ) or via in-plane σ* attack (SNVσ). According to the way of attack, there are two ways nucleophile attack H2C Created by potrace 1.16, written by Peter Selinger 2001-2019 CHCl (SNV-σv and SNV-σb).

(3) The reactions of pyridine with RCOX and RXCNR proceed via transition states when X is Cl−; however, when X is F−, a tetrahedral intermediate is formed instead. Similarly, transition states are observed for the reactions of RCOCl and RClCNR with Cl−, but no transition states or intermediate are detected for the RCOF and RFCNR substrates. Our results suggest that adduct formation is favored by stronger C–X bonds (X = pyridine, NH3, or Cl−).

SNV reactions are involved in several biological processes, and we believe that our proposed mechanism can provide inspiration for the study of these biological processes. In the future, we would like to investigate other neutral nucleophiles so as to discover new bimolecular nucleophilic substitution reactions.

Conflicts of interest

There are no conflicts to declare.

Supplementary Material

RA-011-D1RA03019A-s001

Acknowledgments

This work was supported by The Natural Science Foundation of the Jiangsu Higher Education Institutions of China (grant no. 18KJB150010, 19KJB150034).

†

Electronic supplementary information (ESI) available: The transition states and mixing orbitals of the carbonyl and imidoyl substrates, the profile scans of nucleophile (pyridine or Cl−) approach to substrates, corrected free energies, imaginary frequency and Cartesian coordinates are included in the ESI. See DOI: 10.1039/d1ra03019a

Notes and references

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