Chemistry & Biochemistry
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The Department of Chemistry and Biochemistry offers research-oriented programs culminating in the Doctor of Philosophy degree. The faculty in the department have expertise over a broad range of specialty areas including synthesis, structure, spectroscopy, and mechanism. In each of these fields, the strength of the department has been recognized at the international level.
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Item Oxidative Addition of (Hetero)aryl (Pseudo)halides at Palladium(0): Origin and Significance of Divergent Mechanisms(American Chemical Society, 2024-07) Kania, Matthew J.; Reyes, Albert; Neufeldt, Sharon R.Two limiting mechanisms are possible for oxidative addition of (hetero)aryl (pseudo)halides at Pd(0): a 3-centered concerted and a nucleophilic displacement mechanism. Until now, there has been little understanding about when each mechanism is relevant. Prior investigations to distinguish between these pathways were limited to a few specific combinations of the substrate and ligand. Here, we computationally evaluated over 180 transition structures for oxidative addition in order to determine mechanistic trends based on substrate, ligand(s), and coordination number. Natural abundance 13C kinetic isotope effects provide experimental results consistent with computational predictions. Key findings include that (1) differences in highest occupied molecular orbital (HOMO) symmetries dictate that, although 12e– PdL is strongly biased toward a 3-centered concerted mechanism, 14e– PdL2 often prefers a nucleophilic displacement mechanism; (2) ligand electronics and sterics, including ligand bite angle, influence the preferred mechanism of the reaction at PdL2; (3) phenyl triflate always reacts through a displacement mechanism regardless of the catalyst structure due to the stability of a triflate anion and the inability of oxygen to effectively donate electron density to Pd; and (4) the high reactivity of C–X bonds adjacent to nitrogen in pyridine substrates relates to stereoelectronic stabilization of a nucleophilic displacement transition state. This work has implications for controlling rate and selectivity in catalytic couplings, and we demonstrate application of the mechanistic insight toward chemodivergent cross-couplings of bromochloroheteroarenes.Item Nickel-Based Catalysts for the Selective Monoarylation of Dichloropyridines: Ligand Effects and Mechanistic Insights(American Chemical Society, 2024-04) Duran-Camacho, Geraldo; Bland, Douglas C.; Li, Fangzheng; Neufeldt, Sharon R.; Sanford, Melanie S.This report describes a detailed study of Ni phosphine catalysts for the Suzuki–Miyaura coupling of dichloropyridines with halogen-containing (hetero)aryl boronic acids. With most phosphine ligands, these transformations afford mixtures of mono- and diarylated cross-coupling products as well as competing oligomerization of the boronic acid. However, a ligand screen revealed that PPh2Me and PPh3 afford high yield and selectivity for monoarylation over diarylation as well as minimal competing oligomerization of the boronic acid. Several key observations were made regarding the selectivity of these reactions, including: (1) phosphine ligands that afford high selectivity for monoarylation fall within a narrow range of Tolman cone angles (between 136 and 157°); (2) more electron-rich trialkylphosphines afford predominantly diarylated products, while less electron-rich di- and triarylphosphines favor monoarylation; (3) diarylation proceeds via intramolecular oxidative addition; and (4) the solvent (MeCN) plays a crucial role in achieving high monoarylation selectivity. Experimental and density functional theory studies suggest that all of these data can be explained based on the reactivity of a key intermediate: a Ni0–π complex of the monoarylated product. With larger, more electron-rich trialkylphosphine ligands, this π complex undergoes intramolecular oxidative addition faster than ligand substitution by the MeCN solvent, leading to selective diarylation. In contrast, with relatively small di- and triarylphosphine ligands, associative ligand substitution by MeCN is competitive with oxidative addition, resulting in the selective formation of monoarylated products. The generality of this method is demonstrated with a variety of dichloropyridines and chloro-substituted aryl boronic acids. Furthermore, the optimal ligand (PPh2Me) and solvent (MeCN) are leveraged to achieve Ni-catalyzed monoarylation of a broader set of dichloroarene substrates.Item Solvent coordination to palladium can invert the selectivity of oxidative addition(Royal Society of Chemistry, 2022-01) Elias, Emily K; Rehbein, Steven M; Neufeldt, Sharon R.In the presence of the bulky monophosphine PtBu3, palladium usually prefers to react with Ar–Cl over Ar–OTf bonds. However, strongly coordinating solvents can bind to palladium, inducing a reversal of selectivity.Item Combined Experimental and Computational Mechanistic Investigation of the Palladium-Catalyzed Decarboxylative Cross-Coupling of Sodium Benzoates with Chloroarenes(American Chemical Society, 2021-08) Humke, Jenna N.; Daley, Ryan A.; Morrenzin, Aaron S.; Neufeldt, Sharon R.; Topczewski, Joseph J.Reported herein is a mechanistic investigation into the palladium catalyzed decarboxylative cross-coupling of sodium benzoates and chloroarenes. The reaction was found to be first order in Pd. A minimal substituent effect was observed with respect to the chloroarene and the reaction was zero order with respect to chloroarene. Palladium mediated decarboxylation was assigned as the turn-over limiting step based on an Eyring plot and DFT computations. Catalyst performance was found to vary based on the electrophile, which is best explained by catalyst decomposition at Pd(0). The COD ligand contained in the precatalyst CODPd(CH2TMS)2 (Pd1) was shown to be a beneficial additive. The bench stable Buchwald complex XPhos-PdG2 could be used with exogenous COD and XPhos instead of complex Pd1. Adding exogenous XPhos significantly increased the catalyst TON and enhanced reproducibility.Item Experimental and Computational Evaluation of Tantalocene Hydrides for C–H Activation of Arenes(American Chemical Society, 2021-08) Rehbein, Steven M.; Kania, Matthew J.; Neufeldt, Sharon R.Half a century ago, tantalocene hydrides (especially Cp2TaH3, where Cp = η5-C5H5) were reported to catalyze H/D exchange with arenes. However, there has been very little follow-up to the seminal reports, and numerous questions about this chemistry remain unanswered. In an effort to better evaluate the potential of tantalocene hydrides for processes involving C–H activation, we have conducted a series of experimental and computational studies on these complexes. Density functional theory (DFT) calculations support a mechanism for arene C–H activation involving oxidative addition at transient TaIII, rather than a σ-bond metathesis mechanism at TaV. Comparisons were made between thermal and photochemical conditions for the reaction of Cp2TaH3 with benzene-d6, and H/D exchange was found to be moderately faster under thermal conditions. In a reaction with toluene, Cp2TaH3 activates the aromatic C(sp2)–H bonds but not the benzylic bonds. DFT calculations suggest that benzylic C–H activation at TaIII has a barrier similar to aromatic C–H activation, but that formation of a π-complex with Cp2TaH directs preferential aromatic C–H activation. Analogous complexes containing the less labile permethylated ligand Cp* (Cp* = η5-C5Me5) were also evaluated for their ability to catalyze H/D exchange with benzene-d6, but these complexes are less active than Cp2TaH3. DFT calculations indicate that the methyl groups of Cp* disfavor π-coordination of an arene to the TaIII intermediate.Item Mechanistic Investigation into the Gold-Catalyzed Decarboxylative Cross-Coupling of Iodoarenes(American Chemical Society, 2021-07) Daley, Ryan A.; Morrenzin, Aaron S.; Neufeldt, Sharon R.; Topczewski, Joseph J.While many gold catalyzed reactions have been thoroughly developed, most are not thought to involve redox events at gold. In contrast, recent advances have demonstrated the feasibility of redox gold catalysis. This report describes a detailed mechanistic investigation of the gold catalyzed decarboxylative cross-coupling, which likely proceeds via a high valent Au(I/III) pathway. This investigation includes a kinetic analysis, stoichiometric experiments with Au(III) complexes, and DFT calculations. These data support a turnover limiting oxidative addition to form an Au(III) aryl complex, with an off cycle resting state. The dominant pathway appears to proceed through a silver mediated decarboxylation with a subsequent Ag(I) to Au(III) transmetalation. These data provide some rationale for the significant counterion effects between SbF6– and NTf2– and may explain why MeDalphos is not a superior ligand for the catalytic reaction.Item C–O-Selective Cross-Coupling of Chlorinated Phenol Derivatives(Georg Thieme Verlag KG, 2021-05) Neufeldt, Sharon R.; Russell, John E. A.Chemoselective cross-coupling of phenol derivatives is valuable for generating products that retain halides. Here we discuss recent developments in selective cross-couplings of chloroaryl phenol derivatives, with a particular focus on reactions of chloroaryl tosylates. The first example of a C–O-selective Ni-catalyzed Suzuki–Miyaura coupling of chloroaryl tosylates is discussed in detail.1 Introduction2 Density Functional Theory Studies on Oxidative Addition at Nickel(0)3 Stoichiometric Oxidative Addition Studies4 Development of a Tosylate-Selective Suzuki Coupling5 Conclusion and OutlookItem Chemodivergence between Electrophiles in Cross‐Coupling Reactions(Wiley, 2021-04) Reeves, Emily K.; Entz, Emily D.; Neufeldt, Sharon R.Chemodivergent cross-couplings are those in which either one of two (or more) potentially reactive functional groups can be made to react based on choice of conditions. In particular, this review focuses on cross-couplings involving two different (pseudo)halides that can compete for the role of the electrophilic coupling partner. The discussion is primarily organized by pairs of electrophiles including chloride vs. triflate, bromide vs. triflate, chloride vs. tosylate, and halide vs. halide. Some common themes emerge regarding the origin of selectivity control. These include catalyst ligation state and solvent polarity or coordinating ability. However, in many cases, further systematic studies will be necessary to deconvolute the influences of metal identity, ligand, solvent, additives, nucleophilic coupling partner, and other factors on chemoselectivity.