(112a) Mechanistic Study of the Carbonylation of Aryl Chlorides: CO Insertion and Nucleophilic Substitution

Introduction

The palladium-catalyzed carbonylation of aryl halides is a potentially important route to the efficient synthesis of pharmaceutical intermediates and fine chemicals. Both carbonylation and cross coupling are C-C bond forming reactions and start from aryl halides, however, the optimal catalyst systems differ. While monodentate phophine ligands greatly facilitate C-C cross coupling, [1,2] their excellent performance does not extend to carbonylation. Instead, flexible bidentate phosphine ligands such as dippp (1,3-bis(diisopropylphosphino)-propane) seem to provide a more successful catalyst system.[3,4] To better understand the ligand requirements for carbonylation, we performed a mechanistic study of the carbonylation of aryl halides, and focused on the steps where carbonylation differs from cross coupling: CO insertion and nucleophilic substitution (Figure 1).

Figure 1: Generalized catalytic cycle for the Pd-catalyzed carbonylation of aryl halides

Results and discussion

Various possible elementary steps were considered using B3LYP density functional theory with the LanL2DZ basis set for Pd and the 6-31G(d) basis for the other elements [5]. After oxidative addition of the aryl chloride, CO insertion takes place. In one possible mechanism, CO coordinates to Pd to form a 5-coordinate square pyramidal structure [6] (2 in Figure 2). This step passes via a 20 kJ/mol barrier. Since CO is a strong ligand, it can displace also one of the Pd-P bonds of the bidentate ligand (3). This step is thermodynamically favorable by -14 kJ/mol. Complete displacement of the chelating bidentate ligand by a second CO is however unfavorable by +9 kJ/mol. Strong π back donation to the CO ligand further reduces the electron density on the Pd(II) center, hence making the displacement of remaining phosphine ligand by second CO unfavorable. The barrier for CO insertion is also more favorable after partial dissociation of the bidentate ligand (3). After CO insertion, the second Pd-P bond reforms (5). The calculations hence indicate that the ability to break and restore one of the Pd-P bonds might be an important ligand requirement for the CO insertion step.

Figure 2:  CO insertion: effect of ligand dissociation (Energies in kJ/mol)

Next, the effect of base on the nucleophilic substitution step was investigated (Figure 3). Without an external base, the coordinated Cl accepts the proton from the ROH nucleophile. The barrier for this pathway is rather high at 59 kJ/mol. Interaction of a base significantly enhances the calculated electron density at the O-atom of the ROH nucleophile, and lowers the activation barrier to 31 kJ/mol for an amine-type base. The importance of base in the nucleophilic substitution step has also been observed experimentally. [7] After accepting the proton from the nucleophile, the calculations indicate that the base rotates and transfers the proton to the coordinated Cl, completing the carbonylation cycle.

Figure 3: Effect of base on the nucleophilic substitution. (Energies in kJ/mol)

Conclusions

A mechanistic study of the key steps in the carbonylation of aryl chlorides indicates that: (i) dissociation of one of the Pd-P bonds precedes the CO insertion step. Flexible bidentate ligands facilitate this dissociation; (ii) nucleophilic attack of the carbonyl group by ROH is significantly promoted by the presence of a base.

References

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