Unraveling the Origin of the Regioselectivity of a Supramolecular Hydroformylation Catalyst

Supramolecular substrate preorganization using DIMPHos ligands, which are bisphosphine ligands equipped with a carboxylate binding site, allows for control over the regioselectivity in the hydroformylation reaction. In all reported examples, the aldehyde product in which the CO was inserted farthest from the directing group, was formed in excess (for terminal alkenes the linear aldehyde). We report here an in-depth DFT study to provide mechanistic insight into this selective transformation. These calculations show large energy differences between the different hydride migration steps of competing pathways that lead to either the linear or branched aldehyde product, in line with the experimentally found selectivity. Through the use of calculated model systems of the catalyst, it is shown that the substrate binding event itself plays an important role in determining these large energy differences. Following ditopic substrate binding, the product forming pathways that lead to the minor isomeric product is particularly disfavored by the steric repulsion between the ditopically bound substrate and the apical coordinated CO ligand

Supramolecular control of regioselectivity in the hydroformylation reaction: Substrate preorganization and second coordination sphere catalysis

In this thesis supramolecular strategies were investigated to obtain control over the regioselectivity in the hydroformylation reaction. In the hydroformylation reaction a double bond is reacted with syngas mixture (H2:CO) in the presence of a transition metal catalyst. Since the aldehyde can add on both sides of the double bond, this reaction has an inherent regioselectivity problem. Ligands can be coordinated to the catalytically active metal center to obtain control over the regioselectivity. This strategy is however not always successful and therefore supramolecular strategies were used in this thesis to obtain control over the regioselectivity for substrates that are difficult to control via traditional strategies in homogeneous catalysis. One strategy involves hydrogen bonding of the substrate to the catalyst to restrict the movement of the substrate during the reaction. Another strategy that is used involves the use of a supramolecular capsule around the metal center. For both strategies, the substrate movement is restricted and as a result the regioselectivity is controlled. Chapter 2 describes a computational investigation for why the hydrogen bonding based catalyst gives the regioisomeric outcome that is observed catalytically. Chapter 3 demonstrates first the regioselective conversion of natural fatty acids in the hydroformylation reaction with a tailor made ligand. Chapter 4 describes the a novel class of ligands for regioselective conversions via hydrogen bonding. Chapter 5 reports how the regioselectivity control of a catalyst varies when structural elements of substrates are varied. Chapter 6 investigates if descriptors of the substrate can be used to predict the regioselectivity of encapsulated and unencapsulated catalysts

A substrate descriptor based approach for the prediction and understanding of the regioselectivity in caged catalyzed hydroformylation

The use of data driven tools to predict the selectivity of homogeneous catalysts has received considerable attention in the past years. In these studies often the catalyst structure is varied, but the use of substrate descriptors to rationalize the catalytic outcome is relatively unexplored. To study whether this may be an effective tool, we investigated both an encapsulated and a non-encapsulated rhodium based catalyst in the hydroformylation reaction of 41 terminal alkenes. For the non-encapsulated catalyst, CAT2, the regioselectivity of the acquired substrate scope could be predicted with high accuracy using the Δ13C NMR shift of the alkene carbon atoms as a descriptor (R2 = 0.74) and when combined with a computed intensity of the C = C stretch vibration (IC C stretch) the accuracy increased further (R2 = 0.86). In contrast, a substrate descriptor approach with an encapsulated catalyst, CAT1, appeared more challenging indicating a confined space effect. We investigated Sterimol parameters of the substrates as well as computer-aided drug design descriptors of the substrates, but these parameters did not result in a predictive formula. The most accurate substrate descriptor based prediction was made with the Δ13C NMR shift and IC C stretch (R2 = 0.52), suggestive of the involvement of CH-π interactions. To further understand the confined space effect of CAT1, we focused on the subset of 21 allylbenzene derivatives to investigate predictive parameters unique for this subset. These results showed the inclusion of a charge parameter of the aryl ring improved the regioselectivity predictions, which is in agreement with our assessment that noncovalent interactions between the phenyl ring of the cage and the aryl ring of the substrate are relevant for the regioselectivity outcome. However, the correlation is still weak (R2 = 0.36) and as such we are investigating novel parameters that should improve the overall regioselectivity outcome.</p

Supramolecular Approaches To Control Activity and Selectivity in Hydroformylation Catalysis

The hydroformylation reaction is one of the most intensively explored reactions in the field of homogeneous transition metal catalysis, and many industrial applications are known. However, this atom economical reaction has not been used to its full potential, as many selectivity issues have not been solved. Traditionally, the selectivity is controlled by the ligand that is coordinated to the active metal center. Recently, supramolecular strategies have been demonstrated to provide powerful complementary tools to control activity and selectivity in hydroformylation reactions. In this review, we will highlight these supramolecular strategies. We have organized this paper in sections in which we describe the use of supramolecular bidentate ligands, substrate preorganization by interactions between the substrate and functional groups of the ligands, and hydroformylation catalysis in molecular cages

Nickel-Catalyzed Stereodivergent Synthesis of <i>E</i>- and <i>Z</i>-Alkenes by Hydrogenation of Alkynes

A convenient protocol for stereodivergent hydrogenation of alkynes to E- and Z-alkenes by using nickel catalysts was developed. Simple Ni(NO3)2.6 H2O as a catalyst precursor formed active nanoparticles, which were effective for the semihydrogenation of several alkynes with high selectivity for the Z-alkene (Z/E>99:1). Upon addition of specific multidentate ligands (triphos, tetraphos), the resulting molecular catalysts were highly selective for the E-alkene products (E/Z>99:1). Mechanistic studies revealed that the Z-alkene-selective catalyst was heterogeneous whereas the E-alkene-selective catalyst was homogeneous. In the latter case, the alkyne was first hydrogenated to a Z-alkene, which was subsequently isomerized to the E-alkene. This proposal was supported by density functional theory calculations. This synthetic methodology was shown to be generally applicable in >40 examples and scalable to multigram-scale experiments

Rational Redesign of a Regioselective Hydroformylation Catalyst for 3-Butenoic Acid by Supramolecular Substrate Orientation

Rational design of ligands for regioselective transformations is one of the long pursuing targets in the field of transition metal catalysis. In the current contribution, we report OrthoDIMphos ( L2 ), a ligand that was designed for regioselective hydroformylation of 3‐butenoic acid and its derivatives. The previously reported ParaDIMphos ( L1 ) based hydroformylation catalyst was very selectively producing the linear aldehyde when substrates were bound in its pocket via hydrogen bonding. However, the distance between the binding site and the rhodium center was too large to also address 3‐butenoic acid and its derivatives. We therefore designed OrthoDIMphos ( L2 ) as new ligand which has a shorter distance between the DIM‐receptor and the catalytic center. The OrthoDIMphos ( L2 ) based catalyst displays high regioselectivity in the hydroformylation of 3‐butenoic acid and challenging internal alkene analogue (l/b up to 84, TON up to 630), which cannot be achieved with the ParaDIMphos ( L1 ) catalyst. Detailed studies show that the OrthoDIMphos ( L2 ) based catalyst forms a dimeric structure, in which the two ligands coordinate to two different rhodium metals. Substrate binding to the DIM‐receptor is required to break up the dimeric structure, and as only the monomeric analogue is a selective catalyst, the outcome of the reaction is dependent on substrate concentration used in catalysis