Insights into Sonogashira Cross‐Coupling by High‐Throughput Kinetics and Descriptor Modeling

Abstract

A method is presented for the high-throughput monitoring of reaction kinetics in homogeneous catalysis, running up to 25 coupling reactions in a single reaction vessel. This method is demonstrated and validated on the Sonogashira reaction, analyzing the kinetics for almost 500 coupling reactions. First, one-pot reactions of phenylacetylene with a set of 20 different meta- and para-substituted aryl bromides were analyzed in the presence of 17 different Pd-phosphine complexes. In addition, the temperature-dependent Sonogashira reactions were examined for 21 different ArX (X=Cl, Br, I) substrates, and the corresponding activation enthalpies and entropies were determined by means of Eyring plots: ArI (DeltaH(not equal)=48-62 kJ mol(-1); DeltaS(not equal)=-71--39 J mol(-1) K; NO(2)-->OMe), ArBr (DeltaH(not equal)=54-82 kJ mol(-1), DeltaS(not equal)=-55-11 J mol(-1) K), and ArCl (DeltaH(not equal)=95-144 kJ mol(-1), DeltaS(not equal)=-6-100 J mol(-1) K). DFT calculations established a linear correlation of DeltaH( not equal) and the Kohn-Sham HOMO energies of ArX (X=Cl, Br, I) and confirmed their involvement in the rate-limiting step. However, despite different C--X bond energies, aryl iodides and electron-deficient aryl bromides showed similar activation parameters.

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

“…Those three ligands are electron-rich and sterically demanding phosphines, which is essential for the formation of high-activity Pd complexes. [73,74] This was done to demonstrate the superiority of highly polar Pd complexes over their mediumpolar and lipophilic counterparts. On treatment of 2-chloro-4-picoline with p-tolylboronic acid at 100 8C in the water/nbutanol (1:3) mixture, Pd complexes with the doubly sulfonated phosphine 4·3 H + showed significantly higher catalytic activity than their mono-and non-sulfonated relatives ( Table 2).…”

Bifunctional Mesoporous Silica Catalyst for C–C Bond Forming Tandem Reactions

“…As mentioned above, numerous methods have been used to immobilize palladium as well as amine groups on solid supports including mesoporous silicas. [11][12][13][14]16,20,27] Most importantly and in relevance to the work here, these two reactions, that is, the Sonogashira and the Henry reactions, are sometimes carried out one after another in order to generate various pharmaceutically and industrially valuable compounds. [37][38][39] However, catalyzing both reactions in one pot without isolating their intermediate products and at the same time controlling the selectivity of the reactions towards a particular product needs considerable effort.…”

“…These organopalladium complexes can also be supported on mesoporous materials by means of other ligands such as phosphanes and diamines. [11][12][13][14][15][16]20] The resulting materials can serve as active heterogeneous catalysts for various organic reactions. The use of such materials as heterogeneous catalysts in industrial processes results in more cost-effective catalysis, as they allow the rapid recovery and multiple uses of the relatively "expensive" active catalysts such as palladium complexes.…”

“…Consequently, mesoporous materials functionalized with palladium or other metal complexes hold great promise for use as efficient catalysts for various organic reactions. [9,[11][12][13][14][15][16][22][23][24][25][26][27] Similarly, numerous types of homogeneous and heterogeneous catalysts for the Henry reaction, which is another very important C-C bond forming reaction, have been reported. [28] Different types of amine groups that are tethered onto mesoporous silica support material have also been successfully used to catalyze the Henry reaction.…”

Time as a Dimension in High‐Throughput Homogeneous Catalysis

“…The need for HT kinetics data, including valid TOF and TON data, is now well recognized. [19,[28][29][30] Rothenberg and co-workers have succinctly described the issue as a "time-resolved chicken-and-egg problem": that is, while it is crucial to perform the "discovery measurement" at the correct time, the correct time is known only once the kinetic profile is established. [31] HT reaction profiles are essential for accurate representation of total productivity, induction periods and lifetime.…”