Wacker Process - Mechanism Summary

Mechanism Summary

Early mechanistic studies from the 1960s elucidated much of the oxidation process. Several interesting key points were found, and these observations are generally not considered controversial:

1. There is no H/D exchange seen in this reaction. Experiments using C₂D₄ in water generate CD₃CDO, and runs with C₂H₄ in D₂O generate CH₃CHO. Thus, keto-enol tautomerization is not a possible mechanistic step.
2. There is a negligible kinetic isotope effect with fully deuterated reactants (k _H/k _D=1.07). Hence, it is inferred that hydride transfer is not a rate-determining step.
3. A significant competitive isotope effect with C₂H₂D₂, (k _H/k _D= ~1.9), suggests that the rate determining step should be prior to oxidized product formation.
4. Running the reaction under higher concentrations of chloride and copper(II) chloride result in the formation of a new product, chlorohydrin.

Based on these observations, it is generally accepted the rate-determining step occurs before a series of hydride rearrangements. Many experimental and theoretical investigations have sought to identify the rate determining step, but a unifying interpretation of these experiments has been difficult to attain.

Most mechanistic studies on the Wacker process have focused on identifying whether nucleophilic attack occurred via an external (anti-addition) pathway or via an internal (syn-addition) pathway. Using arguments supported by kinetics experiments, Henry inferred the mechanism for nucleophilic attack would be by an internal (syn-) pathway. Later, stereochemical studies by Stille and coworkers yielded chemical products that indicated the Wacker process proceeds via anti-addition; however, since these experiments were run under conditions significantly different from industrial Wacker process conditions, the conclusions were disputed. Contemporary stereochemical studies using normal industrial Wacker conditions (except with high chloride and high copper chloride concentrations) also yielded products that inferred nucleophilic attack was an anti-addition reaction. The published results of these two independent stereochemical studies were accepted by the chemistry community as proof that the standard reaction process occurs via an anti-addition step, and many reference texts have not renewed their presentation of the Wacker process mechanism since this point.

Later kinetic studies by Henry and coworkers used isotopically substituted allyl alcohols at standard industrial conditions (with low-chloride concentrations) to probe the reaction mechanisms. Those results showed nucleophilic attack is a slow process, while the proposed mechanisms explaining the earlier stereochemical studies assumed nucleophilic attack to be a fast process.

Subsequent stereochemical studies by Patrick M. Henry and coworkers observed different stereoisomers of products that indicated that both pathways occur and are dependent on chloride concentrations. However, these studies too are disputed since allyl-alcohols may be sensitive to isomerization reactions, and different stereoisomers may be formed from those reactions and not from the standard Wacker process.

In summary, experimental evidence seems to support that syn-addition occurs under low-chloride reaction concentrations (< 1 mol/L, industrial process conditions), while anti-addition occurs under high-chloride (> 3mol/L) reaction concentrations, probably due to chloride ions saturating the catalyst and inhibiting the inner-sphere mechanism. However, the exact pathway and the reason for this switching of pathways is still unknown.

Further complicating the Wacker process mechanism is questions about the role of copper chloride in the mechanism. Most mechanistic theories so far presented have invoked Occam's razor, and assumed copper does not play a role in the olefin oxidation mechanisms. Yet, experiments by Stangl and Jira found chlorohydrin formation was dependent on copper chloride concentrations. Work by Hosokawa and coworkers yielded a crystallized product containing copper chloride, indicating it may have a non-innocent role in olefin oxidation. Finally, an ab initio studio by Comas-Vives, et al. concluded that the anti-addition was the preferred one under low chloride and copper co-catalyst concentrations. This was afterwards confirmed by experiments by Anderson and Sigman which yielded a different kinetic rate law for olefin oxidation without copper than reactions using industrial conditions. While these works complicate the picture of the Wacker process mechanism, one should probably infer that this and related chemistry can be sensitive to reaction conditions, and multiple different reaction pathways may be in play.

Another key step in the Wacker process is the migration of the hydrogen from oxygen to chlorine and formation of the C-O double bond. This step is often regarded to proceed through a so-called β-hydride elimination with a four-membered cyclic transition state:

In silico studies argue that the transition state for this reaction step is unfavorable and an alternative reductive elimination reaction mechanism is in play. The proposed reaction steps are likely assisted by water molecule in solution acting as a catalyst.