Theoretical Investigation on [2 + 2]/ [3 + 2] Cycloaddition from Biphosphole and Nitrone Yielding Phospholene Fused β‑Phosphinolactam or Isoxazolidine

The mechanism was explored for [2 + 2] and [3 + 2] cycloaddition of α-C2–bridged biphosphole 1 toward nitrone 2 affording phospholene fused β-phosphinolactam 3 and isoxazolidine 4 (Scheme 1). Illustrated by black arrow of Scheme 2, the dissociation of biphosphole 1 generates two molecules of 1-phosphafulvene A at first. Then the redox reaction between A and nitrone 2 provides 1-phosphafulvene oxide B and imine (red arrow). The reactivity of A is boosted via oxidation toward imine facilitating the next nucleophilic addition of imine to B affording intermediate C. A formal [2 + 2] cycloaddition of C produces phospholene fused β-phosphinolactam 3 as major product. Another competitive path also exists owing to slight antiaromaticity of phosphole oxide (blue arrow). The negative ion of C shifts to exocyclic carbon atom resulting in intermediate D, from which the intramolecular nucleophilic addition of carbanion to iminium ion gives another phosphole oxide E. The subsequent [3 + 2] cycloaddition between E and a second molecule of nitrone 2 leads to phospholene fused isoxazolidine 4 as by-product. Induced by antiaromaticity, the instability of phosphole oxide disfavors negative ion migration from C to D bringing about low yield of 4. The schematic structures of optimized TSs in Scheme 2 were listed by Figure 1. The activation energy was shown in Table 1 for all steps. Supplementary Table S1, Table S2 provided the relative energies of all stationary points. According to experiment, the Gibbs free energies in toluene solution phase are discussed here.

Table 1:The activation energy (in kcal mol−1) of all reactions in gas and solvent.

Table S1:Calculated relative energies (all in kcal mol-1, relative to isolated species) for the ZPE-corrected Gibbs free energies (ΔG_gas), Gibbs free energies for all species in solution phase (ΔG_sol) at 433 K by M06-2X/6-311++G(d,p)//M06-2X/6-31G(d) method and difference between absolute energy.

Table S2:The activation energy (local barrier) (in kcal mol⁻¹) of all reactions in the gas, solution phase calculated with M06-2X/6-311++G(d,p)//M06-2X/6-31G(d) method.

Biphosphole dissociation/redox/nucleophilic addition/ [2 + 2] cycloaddition

As convenient precursor, the α-C2-bridged biphosphole 1 undergoes dissociation via ts-1i1 in step 1 with the activation energy of 33.8 kcal mol⁻¹ endothermic by 13.9 kcal mol⁻¹ producing reactive complex i1 binding two molecules of 1-phosphafulvene A (black dash line of Figure 1). The transition vector includes simultaneous cleavage of P-P and C-C single bond (2.24, 2.36 Å). The typical structure A is also reactive from its relative energy (11.8 kcal mol⁻¹) compared with the half value of 1, which is ready for the process afterwards.

Then the participation of nitrone 2 with A forms i2 taken as new starting point of next three steps (red dash line of Figure 1). The redox reaction proceeds via ts-i2B in step 2 with activation energy of 30.8 kcal mol−1 exothermic by -16.9 kcal mol−1 generating stable 1-phosphafulvene oxide B and imine. The transition vector suggests breaking down of N1-O1 ionic bond and concerted bonding of P-O1 (1.72, 1.66 Å) (Figure S1a), which is strengthened to P=O1 double bond together with newly formed N1=C4 imine bond in resultant B.

Through oxidation of P, the reactivity of A is further boosted toward imine N1. Thus, the following nucleophilic addition occurs via ts-BC in step 3 with low activation energy of 6.0 kcal mol⁻¹ affording intermediate C exothermic by -19.8 kcal mol⁻¹. The transition vector is complicated containing a series of atomic motion. On one hand, the attack from N1 to P is noticable. On the other, the P-C1 and N1=C4 are slightly weakened (1.88, 1.73, 1.33 Å). As an explanation for experiment, the step from B to C is verified not only readily accessible from kinetics but favorable in thermodynamics [24].

Subsequently, a formal [2 + 2] cycloaddition of C takes place via ts-C3 in step 4 with activation energy of 12.7 kcal mo⁻¹ exothermic by -27.7 kcal mol⁻¹ delivering phospholene fused β-phosphinolactam 3 as major product. The transition vector corresponds to the approaching of carbanion C1 to C4 and continuous stretching of P-C1 and N1-C4 to single bond (2.51, 1.76, 1.37 Å) (Figure S1b). Once typical C1-C4 single bond is formed, the closure of stable quaternary ring is realized involving sp3 hybrid C1 and C4 as well as disappeared positive charge on imine N1. Comparatively, the redox of 1-phosphafulvene in step 2 forming its oxide and imine is determined to be rate-limiting for [2 + 2] cycloaddition.

Intramolecular nucleophilic addition/ [3 + 2] cycloaddition

Owing to the slight antiaromaticity of phosphole oxide, another competitive path is also possible (blue dash line of Figure 1). The negative charge on C1 of C shifts to exocyclic carbon C3 resulting in intermediate D. Hence the intramolecular nucleophilic addition of carbanion C3 to C4 happens via ts-DE in step 5 with activation energy of 28.1 kcal mol⁻¹ exothermic by -4.5 kcal mol⁻¹ giving another phosphole oxide E. The transition vector reveals detailed atomic motion about bonding from C3 to C4 and stretching of C2-C3, N1-C4 to single bond (2.31, 1.44, 1.41 Å) (Figure S1c). The positive charge on iminium ion is also dissolved in new five-membered ring of E. Although the relative energy of D is increased by 14.3 kcal mol⁻¹ from that of C, this path can’t be excluded considering the barrier completely capable to overcome under high temperature in experiment. The uphill energy from C to D agrees well with the case of disfavoring negative ion migration from C to D induced by antiaromaticity and instability of phosphole oxide [24].

Finally, with a second molecule of nitrone 2 and E, the intermediate i3 is located as starting point of last step 6 (magenta dash line of Figure 1). Via ts-i34, [3 + 2] cycloaddition proceeds with mediate activation energy of 16.1 kcal mol⁻¹ exothermic by -8.6 kcal mol⁻¹ yielding another five-membered heterocycle of phospholene fused isoxazolidine 4 as by-product. This process is illustrated according to the transition vector composed of stretching of C2-C5 from double bond to single, linkage of C2-C6 and C5-O2 in concerted mode (1.4, 2.28, 2.10 Å) (Figure S1d). There are also cooperated elongation of N2-O2 and N2-C6. The relative energy of 4 higher by 19.1 kcal mol⁻¹ than that of 3 is in accordance with fact of lower yield for compound 4 than 3 in experiment [24].

To highlight the idea of feasibility for changes in electron density and not molecular orbital interactions are responsible of the reactivity of organic molecules, quantum chemical tool Multiwfn was applied to analyze of electron density such as MBO results of bonding atoms and contribution of atomic orbital to HOMO of typical TSs (Table S3, Figure S2). These results all confirm the above analysis.

Table S3:Mayer bond order (MBO) of typical TSs.