Covalent drugs have garnered intense interest due to the unique ways in which they can modulate protein function. Over the past decade, several covalent drugs have been approved that target EGFR, BTK, KRASG12C, and the SARS-CoV-2 Mpro for oncology and antiviral indications. The success of these drugs has driven scientists to design strategies to discover and characterize electrophilic molecules, including specialized screening methods and selectivity-profiling techniques. These technologies have enabled the rapid discovery of covalent chemical probes that selectively modulate protein activity to facilitate study of protein function in different biological contexts. These covalent tool compounds have frequently been further optimized to yield enzymatic inhibitors that provide clinical benefit to patients. Electrophilic compounds have also proven exceptionally useful for inducing proximity between proteins using bifunctional molecules, specifically for targeted protein degradation (TPD). Bifunctional degraders, or proteolysis targeting chimeras (PROTACs), consist of an E3 ligase recruiter linked to a ligand for a target protein. While many degraders recruit the E3s CRBN and VHL to degrade target proteins, more than 600 E3 ligases exist in human cells which could be used for this purpose. To expand the scope of TPD, I discovered a novel covalent ligand for the E3 ligase FEM1B. This ligand, EN106, can be incorporated into bifunctional PROTACs that degrade BRD4 and BCR-ABL, demonstrating that FEM1B can be used to induce degradation of target proteins. While protein degradation is often desirable, there are many cases where protein stabilization could have a therapeutic benefit instead. Here, I describe a strategy for targeted protein stabilization enabled by bifunctional deubiquitinase targeting chimeras (DUBTACs) that induce proximity between a deubiquitinase (DUB) and a target protein. Discovery of a covalent, allosteric ligand for the DUB OTUB1 led to the discovery of DUBTACs that stabilize mutant cystic fibrosis transmembrane conductance regulator (CFTR), whose degradation is central to cystic fibrosis pathology, as well as the tumor suppressor kinase Wee1. This DUBTAC platform allows the modular design of molecules that induce stabilization, unlocking proteins whose gain-of-function would be therapeutically desirable as potential drug targets. Finally, I share the discovery and optimization of covalent inhibitors of the SARS-CoV-2 main protease (Mpro), as part of an effort to discover pan-coronavirus antiviral compounds. This thesis describes the discovery of covalent chemical probes and how they can be harnessed to modulate protein function in ways that highlight potential opportunities for future drug discovery.

While there is consensus that conceptual change is surprisingly difficult, many competing theories of conceptual change co-exist in the literature. This dissertation argues that this discord is partly the result of an inadequate account of the unwritten rules of human social interaction that underlie the field's preferred methodology--semi structured interviewing.

To better understand the contributions of interaction during explanations, I analyze eight undergraduate general chemistry students as they attempt to explain to various people, for various reasons, why phenomena involving chemical phase equilibrium occur. Using the methods of interaction analysis, I characterize the unwritten, but systematic, rules that these participants follow as they explain.

The result is a description of the contributions of interaction to explaining. Each step in each explanation is a jointly performed expression of a subject-predicate relation, an interactive accomplishment I call an information performance (in-form, for short). Unlike clauses, in-forms need not have a coherent grammatical structure. Unlike speaker turns, in-forms have the clear function of expressing information. Unlike both clauses and speaker turns, in-forms are a co-construction, jointly performed by both the primary speaker and the other interlocutor. The other interlocutor strongly affects the form and content of each explanation by giving or withholding feedback at the end of each in-form, moments I call feedback-relevant places.

While in-forms are the bricks out of which the explanation is constructed, they are secured by a series of inferential links I call an illative sequence. Illative sequences are forward-searching, starting with a remembered fact or observation and following a chain of inferences in the hope it leads to the target phenomenon. The participants treat an explanation as a success if the illative sequence generates an in-form that describes the phenomenon. If the illative sequence does not, it is partly or entirely scrubbed, a new in-form is introduced as a starting point, and the illative sequence begins anew.

Knowledge of these interactional contributions to the production of explanations could allow researchers to better characterize conceptual understanding, be in a stronger position to support particular theories of conceptual change over others, improve assessments of conceptual understanding, and improve interviewing practices.

Treatment of the Ni(II) chloride complexes, [LRNiIICl] (LR = {(2,6-iPr2C6H3)NC(R)}2CH, R = Me, tBu) with 1 equiv of KSCPh3 affords the Ni(II) triphenylmethylthiolate complexes, [LRNiII(SCPh3)], in good yields. The reaction of [LRNiII(SCPh3)] with 2 equiv of KC8 and L (L = 18-crown-6 or 2,2,2-cryptand) affords both [K(L)][LRNiII(S)] and [K(L)][CPh3] via reductive deprotection of the triphenylmethyl group. Treatment of [K(18-crown-6)][LtBuNiII(S)] with Ph2SiH2 affords a Ni(I) SH- complex, [K(18-crown-6)][LtBuNiI(SH)]. Treatment of [K(18-crown-6)][LtBuNiII(S)] with Me3SiOTf affords a Ni(II) trimethylsilanethiolato complex [LtBuNiII(SSiMe3)].

Treatment of [LtBuNiII(SCPh3)] with 2 equiv of decamethylcobaltocene (Cp*2Co) generates a transient NiII sulfide complex, [Cp*2Co][LtBuNiII(S)]. A subsequent deprotonation of [Cp*2Co]+ by [CPh3]- gives the CoI fulvenyl complex, [Cp*Co(C5Me4CH2)], which couples with the sulfide ligand in [Cp*2Co][LtBuNiII(S)] to form a Ni(I) cobaltocenium thiolate complex, [LtBuNiI(SCH2Me4C5)Co(Cp*)], concomitant with the reduction of the cobaltocenium cation.

Treatment of [K(18-crown-6)][LtBuNiII(S)] with CS2 yields the Ni(II) trithiocarbonate complex, [K(18-crown-6)][LtBuNiII(S,S:2-CS3)]. Treatment of [K(2,2,2-cryptand)][LtBuNiII(S)] with CS2 generates the double insertion product, a Ni(II) trithiocarbonate dithiocarboxylate complex, [K(2,2,2-cryptand)][(S,S:2-CS3)NiII{S,S:2-CS2(LtBu)}].

Treatment of [K(18-crown-6)][LtBuNiII(S)] with CO affords a Ni(II) carbonyl sulfide complex, [K(18-crown-6)][LtBuNiII(S,C:η2-SCO]. Treatment of [K(18-crown-6)][LtBuNiII(S)] with NO yields a nickel nitrosyl complex, [LtBuNi(NO)], and a perthionitrite salt, [K(18-crown-6)][SSNO].

Treatment of [K(18-crown-6)][LtBuNiII(S)] with N2O yields an unprecedented Ni(II) thiohyponitrite complex, [K(18-crown-6)][LtBuNiII(2-SNNO)]. Gentle thermolysis of [K(18-crown-6)][LtBuNiII(2-SNNO)] results in extrusion of N2 and formation of a thioperoxide complex, [K(18-crown-6)][LtBuNiII(2-SO)]. Treatment of [K(18-crown-6)][LtBuNiII(2-SO)] with CO, forms [K(18-crown-6)][LtBuNiII(S)] along with CO2, via O-atom abstraction. The Ni(II) sulfide then reacts with CO or CO2 to form [K(18-crown-6)][LtBuNiII(2-SCO)] and [K(18-crown-6)][LtBuNi(S,O:κ2-SCO2)], respectively. The thioperoxide complex, [K(18-crown-6)][LtBuNiII(2-SO)], can also react with the newly formed CO2 to form a putative monothiopercarbonate complex, [K(18-crown-6)][LtBuNiII(2-SOCO2)], which can then transfer an S atom to CO, forming COS and [K(18-crown-6)][LtBuNiII(2-CO3)].