Double-boron heterocyclic carbenes: a computational study of Diels–Alder reactions

Abstract

An aromatic boron-containing organic compound, C₂B₂H₂, with an unusual C=C bond was experimentally synthesized in 2017. Here we investigate the structure and bonding nature of C₂B₂H₂ and its derivatives C₂B₂R₂ using DFT and VB theory. Although the C=C bond in C₂B₂R₂ consists of a π bond and a charge-shift (CS) bond, C₂B₂F₂ has the lowest LUMO energy and its LUMO is similar to that of ethylene, suggesting that C₂B₂F₂ can be an ideal dienophile for the Diels–Alder reaction. Subsequently, the mechanism and stereoselectivity of the Diels–Alder reaction of C₂B₂F₂ with 5-substituted cyclopentadienes are studied. Computations demonstrate that these Diels–Alder reactions are feasible thermodynamically and kinetically. The stereoselectivity and distortion angles of C₂B₂R₂ exhibit linear correlations with the electronegativity difference between the two substituents bonded to the C(sp³) of cyclopentadiene, suggesting that the stereoselectivity of related Diels–Alder reaction products can be modulated by the substitution of cyclopentadiene. Considering the current interest in boron neutron capture therapy (BNCT), we design six BNCT drugs through the Diels–Alder reaction of C₂B₂F₂ with dienes containing peptide fragments. Thus, we demonstrate a new method for designing three-in-one BNCT drugs via the facile Diels–Alder reaction.

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Introduction

In 1928, Diels and his student Alder first synthesized an unsaturated six-membered ring from a dienophile and a diene and the reaction has been recognized as the Diels–Alder reaction or [4+2] cycloaddition.¹ The Diels–Alder reaction can efficiently and economically produce unsaturated six-membered rings under relatively simple reaction conditions, and has been widely applied in organic chemistry,^2,3 drug synthesis,^4–6 and materials science.^4,7,8 The simplest Diels–Alder reaction is the reaction of ethylene with butadiene to form cyclohexene. However, when a dienophile or diene with a complex structure exhibits stereo- and spatial selectivity, the accompanying Diels–Alder reaction can result in a diversity of products.^9–12 For example, reactions of cyclopentadiene with cyclopropene and substituted cyclopropenes can give endo- or exo-type products due to the stereoselectivity.¹⁰ To better understand the stereoselectivity of Diels–Alder reaction, Houk and co-workers identified hyperconjugative aromaticity or antiaromaticity as the main element of stereoselectivity,¹³ though electrostatic,^9,14 secondary orbital interaction^15,16 and steric effect^14,17 can also influence the stereoselectivity. In Diels–Alder reactions, the dienophile contains a classical double bond, such as C=C in olefin, C≡C in alkyne, and so on. In contrast to the classical dienophile, we theoretically found two types of novel dienophiles with an inverted C=C bond composed of a π bond and a charge-shift (CS) bond,¹⁸i.e., B-heterocyclic carbene (BHC)¹⁹ and (Si and B)-heterocyclic carbene (SiBHC)²⁰ as shown in Scheme 1a and b. Because the LUMOs of BHCs and SiBHCs are similar to that of ethylene, the Diels–Alder reactions of both BHCs and SiBHCs with diene can be expected.^19–21 These Diels–Alder reactions are favourable both thermodynamically and kinetically due to their low energy barriers and exergonic outcomes. However, neither BHC nor SiBHC has been isolated experimentally. Nevertheless, in 2017, the Zhou group reported a novel molecule C₂B₂H₂ which was experimentally obtained via the C–H bond activation reaction of acetylene by boron atoms, and confirmed that C₂B₂H₂ has a rhombus structure with D_2h symmetry as shown in Scheme 1c.²² Clearly, C₂B₂H₂ is structurally similar to BHC and SiBHC predicted in our previous computational work.

Scheme 1 Structures of (a) BHC, (b) SiBHC and (c) C₂B₂H₂.

Earlier calculations showed that BHC, SiBHC and their derivatives can be used to design novel molecules with planar tetracoordinate carbon²³ or silicon²⁴ (ptC or ptSi) and porous organic molecules (POMs).²⁵ They can also react with dienes via the Diels–Alder reaction.^20,21,26 In this work, we intended to study the structures and bonding nature of C₂B₂H₂ and its derivatives C₂B₂R₂ where R is a substituent group. Interestingly, we found that C₂B₂F₂ is an ideal dienophile due to the similarity of its LUMO with that of ethylene and has the lowest LUMO energy level among the studied derivatives. Subsequently, the mechanism and stereoselectivity of the Diels–Alder reaction of C₂B₂F₂ with 5-substituted cyclopentadienes were investigated.

Recent studies in the literature have shown that boron neutron capture therapy (BNCT) drugs might have potential application in tumor treatment.^27,28 Because C₂B₂F₂ contains both key elements of boron and fluorine, a family of three-in-one BNCT drugs might be obtained by the Diels–Alder reaction of C₂B₂F₂ with dienes containing peptide fragments. Accordingly, the mechanism of such Diels–Alder reactions and the structural optimizations of the BNCT drugs were also computationally investigated.

Computational methods

Geometry optimizations and frequency calculations of C₂B₂H₂ and its derivatives C₂B₂R₂ (R = Me, SiH₃, NH₂, PH₂, OH, SH, F, Cl, Br, Ph, tBu, CN and NO₂) were carried out at the M06-2X/6-311++G** theoretical level.^29–34 Similarly, the structures of reactants, transition states and products of the Diels–Alder reaction of C₂B₂F₂ with substituted cyclopropenes were optimized and their vibrational frequencies were calculated at the same level of theory to confirm the true minima and transition states. The distortion/interaction model was used to describe the relationship between the activation energies vs. the distortion and interaction energies between dienes and dienophiles. Single-point solvation energies were computed using the solvation model based on density (SMD) for all species in the above Diels–Alder reactions, in which CH₂Cl₂ and water were used as the solvents. The Diels–Alder reaction mechanisms of C₂B₂F₂ with six dienes containing peptide fragments were investigated using same approach in aqueous solution. The convergence criteria in geometry optimizations were 10⁻⁸ for energy, 0.000450 for maximum force, 0.000300 for root-mean-square (RMS) force, 0.001800 for maximum displacement, and 0.001200 for RMS displacement with the grid of 75302. The Wiberg bond indices (WBIs) for bonds were calculated using natural bond orbital (NBO) analysis³⁵ to investigate the character of the inverted C=C bond in C₂B₂R₂.

To justify the reliability of the M06-2X/6-311++G** method, we used CBS-QB3³⁶ and DSD-PBEP86-D3(BJ)^37,38/6-311++G** methods to optimize the geometries and calculate the WBIs of both A1 and A8, two key molecules in this work. The bond lengths and WBIs are compiled in Fig. 1. Although the central C=C bond lengths were elongated in the order of M06-2X < CBS-QB3 < DSD-PBEP86-D3(BJ), all other bond lengths and the WBIs were consistent at all three theoretical levels. The Diels–Adler reaction of A8 with B10 was also investigated using the CBS-QB3 and DSD-PBEP86-D3(BJ) methods. The energy barriers and optimized geometries of the transition states are illustrated in Fig. S1 (ESI†). While there were insignificant differences for the optimal geometries of the transition states obtained at the three theoretical levels, the CBS-QB3 method generated the highest barriers and the DSD-PBEP86-D3(BJ) method the lowest barriers. Importantly, all three methods resulted in the same reaction mechanism, i.e., the Diels–Alder reaction prefers the anti-type product via the anti-type transition state. Considering that the M06-2X results were between the data from the CBS-QB3 and DSD-PBEP86-D3(BJ) methods, in the following we used the M06-2X results for discussion.

Fig. 1 Lengths (in angstroms) and WBI values of the C=C and C–B bonds in Ai (i = 1–14) at the M06-2X/6-311++G** level, with additional data for A1 and A8 at the CBS-QB3 (in italic) and DSD-PBEP86-D3(BJ)/6-311++G** (in bold) levels.

Nucleus independent chemical shifts NICS(0) and NICS(1) at the centers of the three-membered rings from two C atoms and one B atom of C₂B₂R₂ were calculated using the gauge-independent atomic orbital (GIAO) method.³⁹ All above calculations were performed using Gaussian09 and Gaussian16.^40,41 The valence bond (VB) analyses of the inverted C=C bond in C₂B₂H₂ and C₂B₂F₂ were conducted using the breathing orbital VB (BOVB) method and the 6-31G* basis set.^42,43 The BOVB calculations were carried out within the Xiamen valence bond (XMVB) package.⁴⁴

Results and discussion

Based on our previous studies of BHCs and SiBHCs, we designed thirteen derivatives of C₂B₂H₂, which were C₂B₂R₂ (R = Me, SiH₃, NH₂, PH₂, OH, SH, F, Cl, Br, Ph, tBu, CN and NO₂). Optimized geometries and WBIs are summarized in Fig. 1. For C₂B₂H₂ (A1), the C=C and C–B bond lengths are 1.484 and 1.476 Å, respectively, well consistent with the literature data.²² The lengths of C=C and C–B bonds of its derivatives (A2–A14) fluctuate in the ranges of 1.472–1.508 Å and 1.460–1.484 Å, respectively, indicating that the substituted group R bonded to the boron atoms influence their geometries slightly. The WBIs of C=C and C–B bonds are close to 1.40 and 1.05 respectively. Thus, the central C=C bonds are between single and double bonds, while C–B bonds are clearly single.

The occupied π-type and frontier molecular orbitals (MOs) of C₂B₂R₂ are displayed in Fig. S2 (ESI†) and Fig. 2, respectively. As seen from Fig. S2 (ESI†), each C₂B₂R₂ has an occupied π-type MO that extends the whole C₂B₂ unit, such as the HOMO−2 of C₂B₂H₂ (A1) and C₂B₂F₂ (A8). Thus, C₂B₂R₂ contains a delocalized Π²₄ bond. Fig. 2 shows the HOMOs of all substituted C₂B₂R₂ which are similar to those of BHCs or SiBHCs,^19,20 and C₂B₂R₂ can be similarly described in terms of resonance structures as shown in Scheme 2, where the covalent structure is weakly bonded with the characteristics of a singlet biradical. We were curious whether the inverted C=C bond in C₂B₂R₂ was a charge-shift (CS) bond. To answer this question, we calculated the contributions of both covalent (1) and ionic (2 and 3) resonance structures to the ground state, the bond energy, the resonance energy, and the ratio of the resonance energy to the bond energy for the inverted C=C bond in C₂B₂H₂ and C₂B₂F₂ at the BOVB/6-31G* level. The results are compiled in Table S1 (ESI†). The contributions of the covalent and ionic resonance structures of C₂B₂H₂ and C₂B₂F₂ are about 60% and 40%, respectively, while the ratios of the resonance energy to the C=C bond energy are 40% and 43%, respectively, meeting the definition of a CS bond.⁴⁵ Thus, the inverted C=C bond in C₂B₂R₂ contains a π bond and a charge-shift (CS) bond, and is unsurprisingly analogous to the C=C bonds in BHC and SiBHC.^19,20 Accordingly, C₂B₂H₂ and its derivatives C₂B₂R₂ can be labelled as double boron heterocyclic carbenes (DBHCs).

Fig. 2 The HOMOs and LUMOs of Ai (i = 1–14).

Scheme 2 One covalent structure (1) and two ionic resonance structures (2 and 3) arising from charge shifting over the inverted C=C bond in C₂B₂R₂.

Since C₂B₂H₂ is an aromatic system,²² the values of NICS(0) and NICS(1) at the center of three-membered rings of C₂B₂R₂ were calculated and are listed in Table S2 (ESI†). With the values of NICS(0) and NICS(1) ranging from −23.90 to −12.81 ppm, it can be confirmed that C₂B₂R₂ are also aromatic and consistent with previous findings for C₂B₂H₂.²²

Fig. 2 shows that the LUMOs of A1–A3, A5, A7 and A9–A14 are the anti-bond MOs formed by the π orbitals of the two boron atoms; the LUMOs of A4 and A6 are a kind of σ orbital, but the LUMO of A8 is the anti-bond MO formed by the π orbitals of the two carbon atoms. Obviously, the LUMO of A8 is consistent with that of ethylene. In addition, the LUMO energy level of A8 is low (−0.85 eV). Following the frontier MO theory, A8 (C₂B₂F₂) thus would be the most suitable dienophile due to its low LUMO energy level. To confirm this hypothesis, we studied the reaction mechanism and stereoselectivity of the Diels–Alder reaction of C₂B₂F₂ with ten 5-substituted cyclopentadienes Bi (i = 1–10 as shown in Scheme 3), which can be sorted according to the order of van der Waals radius of the two substituent groups bonded to the C(sp³) atom. Between the two substituent groups R1 and R2, the van der Waals radius of R1 (top) is smaller than that of R2 (bottom). Because the two groups R1 and R2 are different, the Diels–Alder reaction of C₂B₂F₂ with these substituted cyclopentadienes undergoes anti- and syn-type transition states to produce isomers as shown in Scheme 4, where the anti- and syn-type structures of transition states and products are named in terms of the position of R1 relative to the substituted cyclopentadienes and the C=C bond. If the C=C bond and R1 are situated on the same side, the transition states and products are anti-type structures; otherwise, transition states and products are syn-type structures.

Scheme 3 5-substituted cyclopentadienes Bi (i = 1–10) with the electronegativity difference between the two substituent groups.

Scheme 4 The reactants (C₂B₂F₂ and Bi), transition states (TS-Bi-anti and TS-Bi-syn) and products (P-Bi-anti and P-Bi-syn) in the Diels–Alder reactions of C₂B₂F₂ with (Bi, i = 1–10).

The optimized geometries of the anti- and syn-type transition states of the Diels–Alder reactions of C₂B₂F₂ with substituted cyclopentadienes are displayed in Fig. 3 and labelled as TS-Bi-anti and TS-Bi-syn (i = 1–10), respectively, in which the optimal distances (d1 and d2) between the carbon atoms of C₂B₂F₂ and Bi are defined in Scheme 4. The structures of products undergoing TS-Bi-anti and TS-Bi-syn are P-Bi-anti and P-Bi-syn as shown in Fig. S3 (ESI†), respectively. The distances of d1 and d2 in TS-Bi-anti and TS-Bi-syn show no significant difference and are close to 2.26 Å, except for TS-B4-syn where d1 and d2 are 2.47 and 2.11 Å. These distances correspond well with those observed in the Diels–Alder reactions of BHCs with cyclopentadienes.²¹

Fig. 3 Optimized distances between C atoms in transition states (in Å), energy barriers ΔG_TS (in bold), and the reaction free energy ΔG_re (in italic). Energies are given in kcal mol⁻¹.

The reaction barriers and Gibbs free energies of the ten Diels–Alder reactions are given in Fig. 3. The barriers of the reactions via anti-transition states are mostly lower than those of syn-transition states, except for B9 and B10. In detail, the barriers undergoing anti-transition states range from 20.4 to 31.7 kcal mol⁻¹ for Bi (i = 1–8), while for B9 and B10, the barriers via syn-transition states TS-Bi-syn (i = 9 and 10) are 24.72 and 18.40 kcal mol⁻¹, respectively. The Diels–Alder reaction with the lowest barrier occurs between C₂B₂F₂ and C₅H₅F (B10). All these ten Diels–Alder reactions are exergonic. Thus, these Diels–Alder reactions are both thermodynamically and kinetically feasible. As seen from Scheme 4, the products can be considered as derivatives of [1.2.2]-propellane. The lengths and WBIs of the inverted C–C bond in P-Bi-anti and P-Bi-syn are summarized in Table S2 (ESI†). For the inverted C–C bond, its distances and WBIs are close to 1.710 Å and 0.74 in all products, indicating that the inverted C–C bond is weak. Similar findings have been shown in the products of the Diels–Alder reactions of BHCs.²⁶

To understand the different energy barriers in the Diels–Alder reactions via syn- and anti-type transition states, we examined the electronegativity difference (Δχ = χ_R2 − χ_R1) between the two substituent groups (R1 and R2) bonded to the C(sp³) of cyclopentadiene as shown in Scheme 4. We used Δχ to compare with the difference of the energy barriers via syn- and anti-type transition states (ΔΔG_TS(s–a) = ΔG_TSs − ΔG_TSa). Fig. 4a shows the linear correlation between Δχ and ΔΔG_TS(s–a) with the correlation coefficient of 0.94. Thus, the stereoselectivity of the Diels–Alder reaction of C₂B₂F₂ with substituted cyclopentadienes can be modulated by the electronegativity difference between the two substituted groups bonded to the C(sp³) of cyclopentadiene.

Fig. 4 Correlations of the electronegativity difference with (a) reaction barriers (ΔΔG_TS(s-a) = −5.62Δχ + 2.92, r² = 0.94); (b) distortion angles of the ground-state 5-substituted cyclopentadienes (θ_dis = −0.31Δχ − 0.18, r² = 0.93).

Unlike cyclopentadiene whose five-membered ring is planar, the inequivalent substituent groups R1 and R2 drive the C(sp³) atom in substituted cyclopentadienes out of the planarity. We calculated the distortion angles (θ_dis) of substituted cyclopentadienes as defined in Fig. S4 (ESI†) to quantify such deviation. Interestingly, there is also a good linear correlation between Δχ and θ_dis as shown in Fig. 4b. Thus, the stereoselectivity of the Diels–Alder reactions of C₂B₂F₂ with substituted cyclopentadienes is expected to correlate with the distortion angles of substituted cyclopentadienes. To elucidate such a correlation, the variations between the distortion angles of substituted cyclopentadienes from their isolated optimal states to their respective syn- and anti-transition states were calculated and are displayed in Fig. S5 (ESI†). Fig. S5 (ESI†) shows that a smaller variation of the distortion angle would result in a lower energy barrier. For example, the changes in the distortion angles of TS-B1-anti and TS-B1-syn are 24.4° and −33.0°, respectively. Accordingly, the energy barrier of TS-B1-anti is lower than that of TS-B1-syn. Thus, the selectivity of Diels–Alder reactions of C₂B₂F₂ with substituted cyclopentadienes is largely ruled by the electronegativity difference between the two substituents, with the more electronegative substituent leading to a smaller distortion from the planar structure of cyclopentadiene and a lower reaction barrier.

In contrast to classical dienes, C₂B₂F₂ contains two electron-deficient boron atoms which might exhibit interactions with substituted groups R1 or R2 in substituted cyclopentadienes. Therefore, we used the distortion/interaction model proposed by the Houk group to investigate the distortion energies (E_dis-A8 and E_dis-Bi) of C₂B₂F₂ and substituted cyclopentadienes, as well as the activation energy (E_act) and the interaction energies (E_int) in their reactions. Calculated distortion, interaction, and activation energies of the anti- and syn-type transition states (TS-Bi-anti and TS-Bi-syn) are depicted in Fig. 5 which shows that E_act can be decomposed into three components, including E_dis-Bi, E_dis-A8 and E_int. All these three components may make significant contributions to the reaction barrier. For the example of TS-B1-anti, E_dis-Bi, E_dis-A8 and E_int are 12.60, 8.84 and −14.91 kcal mol⁻¹, respectively, leading to the reaction barrier of 6.53 kcal mol⁻¹.

Fig. 5 Energy analysis of the barriers (E_act, in red) in the Diels–Alder reactions of C₂B₂F₂ with substituted cyclopentadienes based on the distortion/interaction model.

The variation of the energy barriers of the Diels–Alder reactions of C₂B₂F₂ with substituted cyclopentadienes in solvents including water and dichloromethane was further investigated, and the calculated results are illustrated in Fig. 6. Computations showed that the energy barriers slightly decrease by 0.03–1.86 kcal mol⁻¹ in water, while they slightly increase by 0.09–1.42 kcal mol⁻¹ in dichloromethane. Thus, such Diels–Alder reactions are more favourable to occur in water. Moreover, Fig. 6 demonstrates that the trends of the changes of barriers via anti- and syn-type transition states in solvents are consistent with that in gas, indicating that solvation effect has limited influence on the stereoselectivity of such Diels–Alder reactions.

Fig. 6 The energy barrier in gas and solvents (H₂O and CH₂Cl₂).

Boron neutron capture therapy (BNCT) is a radiation treatment designed to improve tumour control while reducing damage to surrounding tissues. The key to BNCT is the use of boronated compounds. Yan's group obtained a type of three-in-one BNCT drugs by photocatalytic B–C coupling via a carboranyl cage radical in 2022.⁴⁶ Additionally, five classes of boron-containing drugs, bortezomib,⁴⁷ ixazomib,⁴⁸ vaborbactam,⁴⁹ tavaborole⁵⁰ and crisaborole,⁵¹ have been marketed during the past thirty years, while many boron-containing drugs, such as Dutogliptin⁵² and Acoziborole⁵³ are in clinical trials. Based on the feasibility of the Diels–Alder reactions of C₂B₂F₂ with 5-substituted cyclopentadienes, as well as the fact that C₂B₂F₂ involves boron and fluorine atoms, we propose the synthesis of a family of three-in-one BNCT drugs through the Diels–Alder reactions of C₂B₂F₂ with dienes containing peptide fragments. Here we computationally designed six dienes (Ci, i = 1–6) with peptide fragments as shown in Scheme 5 by modifying the unit bound to B(OH)₂ of boron-containing drugs with a diene structure. The optimized geometries of Ci (i = 1–6) are displayed in Fig. S6 (ESI†), and their HOMOs and LUMOs are illustrated in Fig. S7 (ESI†). It should be noted that their HOMOs are all located at the modified diene unit. Due to the unsymmetrical groups bound to the diene unit in these dienes Ci (i = 1–6), C₂B₂F₂ can attack them via both anti- and syn-forms. Accordingly, the subsequent Diels–Alder reactions can go through anti- and syn-type transition states (TS-Ci-anti, TS-Ci-syn, i = 1–6) and generate the corresponding products (P-Ci-anti and P-Ci-syn, i = 1–6). Optimized geometries of the transition states and products are shown in Fig. S8 and S9 (ESI†), respectively. The optimal distances (d1 and d2) between the carbon atoms of C₂B₂F₂ and Ci in TS-Ci-anti and TS-Ci-syn for i = 1–3 are close in the range of 2.18–2.36 Å with a gap less than 0.17 Å, and consistent with those of TS-Bi-anti and TS-Bi-syn shown in Fig. 3. But for i = 4–6, the distances of d1 and d2 in TS-Ci-anti and TS-Ci-syn (i = 2, 4–6) are quite different with a gap between 0.23 and 0.59 Å, consistent with those of the Diels–Alder reactions of BHCs with butadiene.²⁶

Scheme 5 Six dienes (Ci, i = 1–6) with peptide fragments by modifying the unit bound to B(OH)₂ of boron-containing drugs.

The energy barriers and reaction free energies in water for the six Diels–Alder reactions were shown in Fig. 7. Fig. 7a shows that the energy barriers viaTS-Ci-anti (i = 1, 4–6) are lower than those of TS-Ci-syn, while the barriers viaTS-Ci-syn (i = 2 and 3) are lower than those of TS-Ci-anti. The barriers undergoing TS-Ci-anti (i = 1, 4–6) and TS-Ci-syn (i = 2 and 3) range from 18.71 to 26.30 kcal mol⁻¹, indicating these Diels–Alder reactions are feasible kinetically. In particular, the barrier in the reaction of C₂B₂F₂ with C4viaTS-C4-anti is the lowest. The reaction free energies (in Fig. 7b) are all negative, suggesting that these Diels–Alder reactions are also thermodynamically feasible. Furthermore, the lower the energy barrier of formation of P-Ci-anti or P-Ci-syn, the more negative the reaction free energy. Thus, a new method for designing BNCT drugs by the simple Diels–Alder reaction was anticipated. Moreover, such BNCT drugs contain boron, fluorine, and peptide fragments, i.e., three-in-one BNCT. If C₂B₂F₂ were synthesized, it could be used to synthesize such BNCT drugs. These BNCT drugs might have potential applications in tumor treatment because of their special structures.

Fig. 7 (a) The energy barriers (energy changes from reactants to the transition states); (b) reaction free energies (energy changes from reactants to products) of the Diels–Alder reactions of C₂B₂F₂ with Ci (i = 1–6) in water.

Conclusions

Using density-functional theory (DFT) and valence bond theory (VBT), the structure, stability, and bonding of the rhombus molecule C₂B₂H₂ with D_2h symmetry and its derivatives (C₂B₂R₂) have been investigated in this work. We also explored the mechanism and stereoselectivity of the Diels–Alder reactions of C₂B₂F₂ with ten kinds of 5-substituted cyclopentadienes at the M06-2X/6-311++G** level. Besides, six BNCT drugs were designed and it was demonstrated that they can be produced via Diels–Alder reactions of C₂B₂F₂ with six dienes containing peptide fragments.

Although our VBT computations confirmed that the inverted C=C bond in the derivatives of C₂B₂H₂ similarly contains a π bond and a charge-shift (CS) bond, C₂B₂F₂ stands out as a preferable dienophile to proceed the Diels–Alder reaction due to its low LUMO energy level and the similarity of its LUMO to that of ethylene. DFT computations showed that the Diels–Alder reactions of C₂B₂F₂ with 5-substituted cyclopentadienes are feasible both thermodynamically and kinetically, and the stereoselectivity of products is controlled by the substituent groups bonded to C(sp³) of cyclopentadiene. Finally, we demonstrated a new method for designing BNCT drugs by the Diels–Alder reactions of C₂B₂F₂ with dienes containing peptide fragments. We anticipate the experimental synthesis of C₂B₂F₂ and expect its promising potential for application in organic chemistry and in the pharmaceutical industry.

Author contributions

Changyu Cao: performing DFT computations and drafting the initial version of the manuscript. Junjing Gu: performing VBT calculations and summarizing the results. Congjie Zhang: initializing and supervising the project and writing the final version of the manuscript. Yirong Mo: supervising the project and editing the final version of the manuscript.

Data availability

All data related to this work including structural information and energies are available in the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors thank the National Natural Science Foundation of China for financial support (No. 21373133). This work was performed in part at the Joint School of Nanoscience and Nanoengineering, a member of the Southeastern Nanotechnology Infrastructure Corridor (SENIC) and National Nanotechnology Coordinated Infrastructure (NNCI), which is supported by the National Science Foundation (Grant ECCS-2025462).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4cp03615h

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