PHENYLENEDIAMINE PYRIDYL LIGANDS AND BORYL SUPPORT LIGANDS FOR ORTHO-DIRECTED IRIDIUM CATALYZED C–H BORYLATION By Alex C. O’Connell A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry – Doctor of Philosophy 2022 ABSTRACT PHENYLENEDIAMINE PYRIDYL LIGANDS AND BORYL SUPPORT LIGANDS FOR ORTHO-DIRECTED IRIDIUM CATALYZED C–H BORYLATION By Alex C. O’Connell With organoboron compounds being useful components in the synthesis of pharmaceuticals, agrochemicals, and materials, it is imperative to find new catalytic strategies to design an effective system capable of borylating a broad range of (hetero)arene substrates in high yields and high selectivity. Traditional iridium-catalyzed systems borylate aromatic compounds and are directed by steric factors of the substrate. These steric-directed catalysts are hypothesized to have a singly open coordination site on the metal center where activation of the most accessible C–H bond can occur. In order to change regioselectivity from steric products to alternatives, new catalyst systems must be designed. A phenylenediamine pyridyl framework was implemented for chelate-directed C– H borylation, where an aromatic substrate undergoes borylation of the ortho C–H bond, relative to a directing group. This ligand type has been explored and shown to have three major components that influence the reactivity, selectivity, and coordination of the ligand. These parts that make up the ligand were examined using a ligand screen, NMR studies, and stoichiometric reactions. From the literature, it has been shown that double B,N-bidentate ligated catalysts work well for a broad substrate scope and produce borylated products whose substitution pattern is based on steric effects. Other variants of this system have used a single B,N- bidentate ligand to produce products borylated in the ortho-position relative to a directing group on the substrate. To improve upon these catalytic systems, experiments were performed to optimize ortho-selectivity of the originally steric-directed catalyst containing two B,N-bidentate ligands by reducing the loading of the dimer boryl ligand. In doing so, regioselectivities can be completely switched from steric products to chelate products. This modification of ligand to metal ratio greatly effects selectivity and is a unique feature to dimer boryl ligands. These phenylenediamine pyridyl ligands and boryl support ligands will be explored. Copyright by ALEX C. O’CONNELL 2022 Dedicated to my family– Thank you for everything you have done for me v ACKNOWLEDGMENTS Well, graduate school has been quite the experience. Lots of ups and downs but it was a journey worthwhile. As with every journey, you meet friend and foe along the way… Surviving graduate school would not have been possible without the love and support of my family. My mother and father (Cathy & Mike) and my brother (Zach) were the bedrock I could build my foundations on. Their encouragement and belief in me gave me the strength to keep going and push through. I thank them for their patience and understanding while I was away for so long. To my friends Kiyo, Ryan, Tim, Reza, and Mona–you have all been tremendously helpful and it was truly a pleasure to work, converse, and spend time with you while at Michigan State. You all are what made grad school fun and exciting. I probably learned more about chemistry discussing ideas and concepts with you than in any classroom. Lastly, I would like to acknowledge my advisor, committee members, and chemistry support staff for their aid in the graduation process, useful advice, and taking a part in my education. Thank you all. vi TABLE OF CONTENTS LIST OF TABLES ........................................................................................................... ix LIST OF FIGURES .......................................................................................................... x LIST OF SCHEMES ....................................................................................................... xi KEY TO ABBREVIATIONS ........................................................................................ xii Chapter 1. Introduction to C–H Borylation ................................................................... 1 1.1 C–H Activation and Functionalization ..................................................................... 1 1.2 Organoboron Compounds ......................................................................................... 1 1.3 Iridium Catalyzed C–H Borylation ........................................................................... 3 1.4 Selectivity and Mechanistic Insights into Ir-Catalyzed C–H Borylation.................. 5 1.5 Directed Iridium Catalyzed Borylations of Aromatic Compounds .......................... 7 1.6 ortho-Directed CHB.................................................................................................. 8 1.7 meta-Directed CHB ................................................................................................ 10 1.8 para-Directed CHB ................................................................................................. 10 1.9 Directed Iridium Catalyzed Borylations of Aliphatic Compounds......................... 12 1.10 Conclusions ........................................................................................................... 14 REFERENCES................................................................................................................ 15 Chapter 2. Readily-Accessible Phenylenediamine Pyridyl Ligands for Iridium Catalyzed Ortho-Directed C–H Borylation .................................................................. 21 2.1 Background to Nitrogen-Based Ligands for Iridium Catalyzed C–H Borylation .. 21 2.2 Other Ligand Types for Ortho-Directed C–H Borylation....................................... 22 2.3 Phenylenediamine Pyridyl Ligands Usage in C–H Borylations ............................. 23 2.4 Analysis and Scope of Phenylenediamine Pyridyl Ligands–Amine Type, NMR Studies, and Electronic Effects ..................................................................................... 24 2.5 Studies into the Catalyst System–Ligand Loading and Chloride Source ............... 33 2.6 Substrate Scope ....................................................................................................... 35 2.7 Conclusions ............................................................................................................. 37 REFERENCES................................................................................................................ 39 Chapter 3. Modification of a Steric- to a Chelate-Directed Iridium Catalyst for C–H Borylation with a Dimeric Boryl Support Ligand ....................................................... 43 3.1 The Catalyst Cycle for Iridium Catalyzed C–H Borylation.................................... 43 3.2 Boryl Ligands in Iridium Catalyzed C–H Borylation ............................................. 44 3.3 Modification of Boryl Support Ligand Systems ..................................................... 46 3.4 Complexes for Steric- and Chelate-Directed Catalysis .......................................... 50 3.5 Comparison of a Boron Dimer Ligand and Silicon-Boryl Ligand ......................... 50 3.6 Substrate Scope at Lower Ligand Loading Conditions .......................................... 52 3.7 Applications of Boryl Support Ligands .................................................................. 56 vii 3.8 Conclusions ............................................................................................................. 56 REFERENCES................................................................................................................ 58 Chapter 4. Experimental ................................................................................................ 61 4.1 Chapter 2 Experimental Procedures and Details .................................................... 61 4.2 Chapter 3 Experimental Procedures and Details .................................................... 91 4.3 Spectral Data ......................................................................................................... 125 REFERENCES.............................................................................................................. 192 viii LIST OF TABLES Table 2.1 Effects of ligand loading on the catalyst system. ............................................. 34 Table 2.2 Effects of a chloride source on the catalyst system.......................................... 35 Table 2.3 Substrate scope. ................................................................................................ 36 Table 3.1 Comparison of ligand loading and regioselectivity. ........................................ 48 Table 3.2 Comparison of precatalyst for CHB. ................................................................ 49 Table 3.3 Comparison of BB and SiB ligands for chelate-directed CHB. ....................... 52 Table 3.4 CHBs of arenes using conditions for chelate- and steric-directed catalysis. ... 53 Table 3.5 CHBs of a heteroarenes using conditions for chelate- and steric-directed catalysis. ............................................................................................................................ 55 ix LIST OF FIGURES Figure 1.1 An (a) isolated trisboryl iridium complex and (b) its proposed active form. ... 6 Figure 1.2 Ligands used for chelate-directed borylation--(a) monodentate phosphine ligand, (b) 'hemilabile' pyridyl hydrazone ligand, and (c) monoanionic quinoline silyl ligand................................................................................................................................... 9 Figure 1.3 Ion-pairing strategy for meta CHB. ................................................................ 10 Figure 1.4 Non-covalent strategy for para CHB. ............................................................ 12 Figure 2.1 Proposed active catalyst structures for (a) steric-directed catalyst using dtbpy and (b) chelate-directed catalyst using a hemilabile ligand. ............................................. 21 Figure 2.2 Ligand structures for Sawamura’s (a) Si-SMAP monodentate ligand and Li’s (b) silicon-boryl and (c) silicon-sulfur ligand. .................................................................. 22 Figure 2.3 Hydrogen-Bonding Effect Between L1 and Substrate. .................................. 28 Figure 2.4 Hydrogen-Bonding Effect Between L4 and Substrate. .................................. 29 Figure 2.5 Hydrogen-Bonding Effect Between L6 and Substrate. .................................. 30 Figure 2.6 Crystal structure of IrN complex with hydrogen atoms omitted for clarity. Ir (purple); N (blue); Cl (green); C (gray). ........................................................................... 32 Figure 3.1 Yamashita and Nozakis’ (a) pincer PBP ligand and Li’s bidentate (b) bidentate boryl ligand designs. ......................................................................................... 45 Figure 3.2 Crystal structure of complex IrBB’ with hydrogen atoms omitted for clarity. Ir (dark blue); N (blue); boron (yellow); Cl (green); C (gray). ............................................ 50 Figure 3.3 Boryl support ligands for CHB catalysis. ....................................................... 56 x LIST OF SCHEMES Scheme 1.1 Utility of aryl boronic acids/esters. ................................................................. 2 Scheme 1.2 Synthetic route to aryl boronic esters. ............................................................ 3 Scheme 1.3 Reaction of methane with catecholborane or ethylene glycol borane to form the organoboron product. Bond dissociation enthalpies (BDE) in (kcal/mol).................... 4 Scheme 1.4 First thermal CHB catalyst. ............................................................................ 4 Scheme 1.5 CHB reaction of a monosubstituted arene. ..................................................... 5 Scheme 1.6 Catalyst cycle for Ir-catalyzed CHBs. ............................................................ 7 Scheme 1.7 CHB reaction of a monosubstituted arene. ..................................................... 8 Scheme 1.8 Itami’s bulky bisphosphine ligand for para CHB. ........................................ 11 Scheme 1.9 Relay-directed route for sp3 CHBs. .............................................................. 12 Scheme 1.10 Heterogeneous catalyst with Si-SMAP for sp3 CHB. ................................. 13 Scheme 2.1 Ir-catalyzed C–H borylation of using nitrogen-based ligands. ..................... 24 Scheme 2.3 General reaction for ligand synthesis............................................................ 25 Scheme 2.2 Nitrogen-based ligand screen for ortho-directed CHB using tert-butyl benzoate as model substrate. ............................................................................................. 26 Scheme 2.4 Electronic effects of a modified L1. ............................................................. 33 Scheme 2.5 Mono- and bis-ligated iridium structures of Miyaura and Ishiyama’s catalysts where L = AsPh3 or tris[3,5-bis(trifluoromethyl)phenyl]phosphine. ............................... 34 Scheme 3.1 Catalyst cycle for Ir-catalyzed CHBs. .......................................................... 44 Scheme 3.2 Synthetic route to double B,N-bidentate complex (IrBB). ........................... 46 Scheme 3.3 Removal of boryl ligand by base additive. ................................................... 47 xi KEY TO ABBREVIATIONS Å Angstrom Ar Aryl BDE Bond dissociation enthalpy B2pin2 Bis(pinacolato)diboron Bz Benzyl °C Degrees Celsius CHB C–H borylation COD 1,5-Cyclooctadiene COE Cyclooctene Cp Cyclopentadiene DCM Dichloromethane DG Directing group dtbpy 4,4’-di-tert-butyl-2,2’dipyridyl EAS Electrophilic aromatic substitution equiv Equivalent h Hour HBpin Pinacolborane Ind Indenyl iPr isopropyl K Kelvin kcal kilocalorie xii KIE Kinetic isotope effect Me Methyl Mes Mesitylene mg Milligram mL Milliliter mol Mole mmol Millimole mp Melting point m/z Mass divided by charge of an ion NMR Nuclear magnetic resonance Ph Phenyl ppm Parts per million rt Room temperature SMAP Silica-supported monophosphine SMCC Suzuki-Miyaura Cross-Coupling THF Tetrahydrofuran tmphen 3,4,7,8-tetramethyl-1,10-phenanthroline t Bu tert-Butyl Xyl Xylene xiii Chapter 1. Introduction to C–H Borylation 1.1 C–H Activation and Functionalization C–H activation and functionalization is a key chemical transformation in building complex molecules. Organic compounds are the foundation of nature and comprise the structures within pharmaceuticals and biologically active molecules, agrochemicals, and materials. With such an abundance and prevalence of this chemical class, it is important to be able to selectively diversify it into more valuable end products. However, selectively activating and functionalizing hydrocarbons entails challenges owing to their relatively inert nature. This is due to C–H bonds being nonpolar and of low basicity/acidity, compared to other chemical groups. For functionalizing aromatic compounds, aromaticity usually needs to be temporarily broken in order to activate the C(sp2)–H and substitute a different functionality. Aromatic substitution reactions typically require stoichiometric amounts of metal for enhancement of the electrophile to be substituted on the ring and often use harsh basic or acidic conditions.1,2 These conditions may have a negative impact or increase the difficulty of synthesis when sensitive functional groups are present on the substrate. This becomes especially apparent for late-stage functionalization of complex molecules. Because of these matters, a more direct and mild method for functionalizing hydrocarbon bonds for further diversification is desirable.3 1.2 Organoboron Compounds Organoboron compounds are incredibly versatile in their ability to be easily transformed into other functionalities. The first prominent case of this was studied and disclosed by H. C. Brown who demonstrated organoboranes could be used as synthetic 1 intermediates to form alcohols.4,5 He was awarded the Nobel Prize in 1979 for his pioneering work on organoboranes. Another leading example, and Nobel winning work, highlighting organoboron’s proficiency as a chemical intermediate was the Suzuki-Miyaura cross-coupling (SMCC) reaction. In this palladium-catalyzed reaction, aryl carbon-carbon bonds are formed using boronic acid and organohalide starting reagents. In medicinal chemistry, the SMCC reaction has become the most employed method for carbon-carbon bond formation.5,6 Boronic acids and esters have found tremendous usage in further diversifying organic molecules. From a starting aryl-boronic ester, the C–B group can be transformed into alcohols,7 amines,8,9 halogens,10,11 cyano groups,12,13 aryl groups,14 and more (Scheme 1.1). Scheme 1.1 Utility of aryl boronic acids/esters. While organic boronic esters are valuable synthetic intermediates, their syntheses were not initially straightforward. Traditionally, the route to forming an aryl-boronic ester 2 was a three-step process (Scheme 1.2).15 Starting from an arene, one must first perform a halogenation reaction, form a Grignard reagent, and finally quench the Grignard reagent with a boronic ester. With each additional step in a reaction, yields will be lowered, and waste streams increased. Scheme 1.2 Synthetic route to aryl boronic esters. An alternative two-step route to these desired products is Miyaura borylation. By this method, an aryl halide is cross coupled with bis(pinacolato)diboron (B2pin2), forming the boronate.16 This reaction uses a palladium catalyst under basic conditions. 1.3 Iridium Catalyzed C–H Borylation Given that organoboron compounds are so versatile and important in chemistry, an efficient catalyst that has high functional group tolerance and could directly activate and functionalize a C–H bond into a C–B(OR)2 group would be highly valuable. In 1994, the Hartwig group published computational data revealing that the transformation from hydrocarbon to organoborane is thermoneutral (Scheme 1.3), showing that this overall process could be a feasible synthetic route.17 3 Scheme 1.3 Reaction of methane with catecholborane (HBcat) or ethylene glycol borane (HBeg) to form the organoboron product. Bond dissociation enthalpies (BDE) in (kcal/mol). The first thermal catalyst for direct CHB reactions was reported by Smith and Iverson in 1999.18 This landmark discovery presented an iridium catalyst borylating benzene using pinacolborane (HBpin) as the boron source, with H2 gas being the sole byproduct (Scheme 1.4). Scheme 1.4 First thermal CHB catalyst. In 2002, the Smith and Maleczka group made further developments of the iridium catalyst system and established the usage of bidentate neutral donor ligands. Their system using (1,5-cyclooctadiene)(η5-indenyl)iridium(I) precatalyst and bisphosphine ligand combination exhibited much higher turnover numbers (50-5000) and greater utility than the initial thermal catalyst. This new catalyst system was able to borylate a broad range of (hetero)arenes and the borylated products could be used in a one-pot synthesis for further functionalization via SMCC.15 Since the inception of iridium-based catalyst 4 systems, numerous other catalysts have been developed using additional transition metals like Co,19-21 Pd,22,23 Rh,24 and Fe.25,26 Even with these alternatives, the iridium and L2 ligand combination are still the most used and most studied catalysts due to their high efficacy, regio/chemoselectivities, and broad substrate scope. 1.4 Selectivity and Mechanistic Insights into Ir-Catalyzed C–H Borylation In traditional Ir-catalyzed systems, aromatic substrates are borylated with selectivity that is complimentary to electrophilic aromatic substitution (EAS) reactions. In EAS chemistry, arenes are activated/functionalized at the ortho/para or meta sites of the substrate based on the electronic effects of its substituents. For Ir-catalyzed CHBs, regioselectivity is based on the steric factors of the substrate.27 For example, borylating a monosubstituted arene will yield products with the boryl group in the meta and para positions in a 2:1 ratio. No (or trace) amounts of ortho borylated product will be present (Scheme 1.5). Scheme 1.5 CHB reaction of a monosubstituted arene. In 2002, Miyaura, Hartwig, and Ishiyama published on using [Ir(Cl)cod]2 and 4,4’- di-tert-butyl-2,2’-dipyridyl (dtbpy) as a reactive catalyst for CHB. Complex (a) of Figure 1.1 was synthesized and characterized by X-ray crystallography. The structure revealed a trisboryl species ligated with dtbpy and cyclooctene (COE). This trisboryl complex was very reactive for CHBs and could perform catalysis at room temperature, while reactions usually required heating. It was proposed that by dissociation of COE, that a singly vacant 5 coordination site is created for activation of the least sterically hindered C–H bond (Figure 1.1).28 Figure 1.1 An (a) isolated trisboryl iridium complex and (b) its proposed active form. Initial mechanistic studies of Ir-catalyzed CHB were done by Smith and Maleczka. They began by probing whether the catalytic cycle involved IrI/IrIII species versus IrIII/IrV. To probe this, they first performed borylations of benzene using either the Ir(I) complex, Ir(Bpin)(PMe3)4, and the Ir(III) complex, Ir(Bpin)3(PMe3)3. In this reaction, both Ir complexes were capable of producing the arylboronic ester product. Although, when the substrate was changed to iodobenzene, only the Ir(III) complex could carry out the CHB while the Ir(I) complex yielded no borylation. From this, Smith and Maleczka proposed an IrIII/IrV catalyst cycle.15 After these early insights, further investigative work was done by Hartwig and coworkers that provided more evidence of a IrIII/IrV cycle. With the trisboryl iridium complex they performed extensive kinetic studies using B2pin2 as the boron source and arene substrates. Through these studies, they found that the trisboryl species reacts with arenes after reversible dissociation of COE and via kinetic isotope experiments that oxidative addition is the rate limiting step.28 Computationally, Sasaki29 calculated 6 transition states for various possible catalyst structures and came to the same conclusions of an IrIII/IrV cycle and oxidative addition being the rate limiting step. The overall catalytic cycle based on the culmination of Smith and Maleczka’s, Hartwig and coworkers’, and computational data is presented in Scheme 1.6. Scheme 1.6 Catalyst cycle for Ir-catalyzed CHBs. In this cycle, the active catalyst is a trisboryl 16 e- species. The arene substrate undergoes oxidative addition and forms an Ir(V) species. Through reductive elimination, the organoboron product is expelled from the catalyst, returning it to the Ir(III) oxidation state. The boron source oxidatively adds to the metal, replenishing the lost boryl group creating an Ir(V) species. Lastly, HBpin or H2 gas reductively eliminates (depending upon the boron source used) as the byproduct and completes the cycle for further catalysis. 1.5 Directed Iridium Catalyzed Borylations of Aromatic Compounds In order to gain more regioselective control and greater options of which C–H bond is to be borylated, new catalyst designs were needed. For aromatic substrates, there are three main sites where CHB can be directed—ortho, meta, or para positions. Known strategies for each type are discussed below. 7 1.6 ortho-Directed CHB The first type of directed CHB using [Ir] was seen in 2008 by the Hartwig group.30 They showed that silyl groups could undergo metathesis with the boryl ligand on the metal. Once the silyl group is coordinated to the metal, the adjacent C–H bond is activated. Although this route had good selectivity, requiring substrates prefunctionalized with a silyl group was not ideal. To circumvent this, ‘chelate-directed’ catalysis was explored. In this design, the catalyst is proposed to have two vacant coordination sites rather than one. A directing group on the substrate coordinates to one of the vacant sites of iridium and positions the ortho C– H bond near the second vacant site for activation.31,32 Scheme 1.7 depicts a general reaction setup for the chelate-directed method. Scheme 1.7 CHB reaction of a monosubstituted arene. Chelate-directed catalysts are the most capable catalysts for ortho CHB and many ligand variations can be seen within the literature (Figure 1.2).31-33 8 Figure 1.2 Ligands used for chelate-directed borylations—(a) monodentate phosphine ligand, (b) ‘hemilabile’ pyridyl hydrazone ligand, and (c) monoanionic quinoline silyl ligand. Each of the ligands of Figure 1.2 are proposed to generate an active catalyst with two vacant coordination sites. Miyaura and Ishiyama’s phosphine ligand above, with its electron trifluoromethyl groups, can dissociate from the metal freeing up a coordination site.31 Lassaletta’s pyridyl hydrazone ligand is proposed to be hemilabile where the less donating imine portion of the ligand can freely dissociate from the metal center and free the second vacant site for ortho selectivity.32 Lastly, Smith and Maleczka’s monoanionic quinoline silyl ligand replaces one of the anionic boryl ligands while maintaining stability of the ligand through chelation.33 The previous two approaches to directed borylation rely on a functionality of the substrate to directly interact with the metal center. A different approach would be for an interaction between the ligand of the catalyst and the substrate. This approach is termed ‘outer-sphere’ directed. For outer-sphere directed borylations, the ligand acts as an acceptor for interaction of the substrate. Prominent examples of this have been seen with H-bonding for ortho borylation of phenols34 and anilines,35 and Lewis acid-base pairs for borylation of compounds with a sulfur directing group.36 9 1.7 meta-Directed CHB To perform meta-directed CHB, Kanai and coworkers designed a bipyridine ligand with a urea linked to it.37 They found that a hydrogen-bonding interaction between the urea N–H and the lone pairs of a directing group (ester, ketone, amide, phosphate) could poise the substrate for meta borylation. Phipps and coworkers also disclosed that ion-pairing interactions between an ammonium moiety of the substrate and a sulfate ion attached to a bipyridine ligand could direct CHBs for the meta site of aromatics (Figure 1.3).38-40 Figure 1.3 Ion-pairing strategy for meta CHB. 1.8 para-Directed CHB In 2015, Itami and coworkers devised a method for achieving para selectivity by taking advantage of steric interactions between the substrate and a bulky bisphosphine ligand with xylene (Xyl) substituents. The cumbersome ligand can effectively inhibit activation of ortho and meta C–H bonds due to steric crowding near the coordination site on iridium.41,42 Scheme 1.8 demonstrates this concept. 10 Scheme 1.8 Itami’s bulky bisphosphine ligand for para CHB. Aside from steric factors influencing selectivity, the Smith and Maleczka group and Phipps group concurrently showed that an ion-pairing method previously used for meta CHB, could also be implemented for para CHB. This was done by using an aryl sulfate as the substrate with an alkyl ammonium counterion to sterically shield the meta sites from CHB.43,44 Chattopadhyay group showed that para CHB could be achieved by noncovalent interactions. This method used an L-shaped ligand with a potassium ion substituent which acts as a Lewis acid. The attraction between the acidic ligand acceptor with the partially negative carbonyl oxygen of the phenyl ester substrate led to products that were borylated in the para position.45 This (C=O····K−O) interaction worked well for many phenyl esters with varying steric, electronic, and substitution patterns of the aryl substrate. The catalyst system showed to work well for heteroarenes donning an ester directing group as well. Figure 1.4 shows the proposed catalyst for these CHBs. 11 Figure 1.4 Non-covalent strategy for para CHB. In summary, there are many possible routes and iterations for achieving ortho, meta, and para regioselectivities of aromatic compounds. Iridium precatalysts paired with phosphine or nitrogen ligands create very reactive and tunable systems to yield the desired organoboron product. 1.9 Directed Iridium Catalyzed Borylations of Aliphatic Compounds Just like arylboronic esters, alkylboronic esters are an important class of compounds used as intermediates and are present in an array of useful pharmaceuticals like Ixazomib46 and Vaborbactam,47 which are used as anticancer and antibiotic therapeutics, respectively. Despite the great strides made for C(sp2)–H CHB of (hetero)arenes, Ir catalysts for C(sp3)–H borylation are not as well developed. The first use of an iridium catalyst for C(sp3)–H borylation was done by Hartwig using (η6-mesitylene)Ir(Bpin)3 and 3,4,7,8-tetramethyl-1,10-phenanthroline (tmphen) as precatalyst and ligand. This catalyst could borylate cyclic ethers and activation/functionalization occurred in the 3-position of the substrates (Scheme 1.9).48 12 Scheme 1.9 First iridium-catalyzed route for sp3 CHBs using (η6-mesitylene)Ir(Bpin)3 with tmphen on cyclic ethers. Another commonly used method for sp3 borylations is the relay-directed method that was similarly used for sp2 CHBs.49,50 Again, in this system, the starting material to be borylated needs to have a silyl group installed in order to successfully carry out the borylation. In this catalysis, the silyl group replaces a boryl ligand on the metal and positions the aliphatic C –H bond near the metal for activation. As mentioned previously for ortho-directed CHBs, chelate-directed catalysts are also capable of performing sp3 borylations. In these systems, ensuring that there is a second coordination site is imperative. A heterogeneous catalyst that is efficient for this type of borylation was developed by Sawamura51 and uses a monodentate silica-SMAP ligand (Scheme 1.10). Scheme 1.10 Heterogeneous catalyst with Si-SMAP for sp3 CHB. Other examples of catalysts exist in the literature for sp3 borylation, but these systems operate based on either using activated substrates, relay-direction, or chelate- direction methods. 13 1.10 Conclusions Organoboron compounds are incredibly versatile materials that have prominent use as intermediates for drug discovery in the pharmaceutical industry, late-stage functionalization of important complex molecules, and agrochemicals in the farming industry. C–H borylation reactions catalyzed by an iridium catalyst are the most atom economical way of producing organoboron reagents directly from hydrocarbon starting materials, cutting out the need of using prefunctionalized substrates. 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E., Jr; Chattopadhyay, B. Achieving High Ortho Selectivity in Aniline C-H Borylations by Modifying Boron Substituents. ACS Catal. 2018, 8, 6216–6223. 18 (36) Li, H. L.; Kuninobu, Y.; Kanai, M. Lewis Acid-Base Interaction-Controlled Ortho- Selective C-H Borylation of Aryl Sulfides. Angew. Chem. Int. Ed Engl. 2017, 56, 1495– 1499. (37) Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M. A Meta-Selective C–H Borylation Directed by a Secondary Interaction between Ligand and Substrate. Nat. Chem. 2015, 7, 712–717. (38) Davis, H. J.; Genov, G. R.; Phipps, R. J. Meta -Selective C−H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand. Angew. Chem. Int. Ed. 2017, 56, 13351–13355. (39) Mihai, M. T.; Davis, H. J.; Genov, G. R.; Phipps, R. J. Ion Pair-Directed C–H Activation on Flexible Ammonium Salts: Meta-Selective Borylation of Quaternized Phenethylamines and Phenylpropylamines. ACS Catal. 2018, 8, 3764–3769. (40) Davis, H. J.; Mihai, M. T.; Phipps, R. J. Ion Pair-Directed Regiocontrol in Transition- Metal Catalysis: A Meta-Selective C–H Borylation of Aromatic Quaternary Ammonium Salts. J. Am. Chem. Soc. 2016, 138, 12759–12762. (41) Saito, Y.; Segawa, Y.; Itami, K. Para-C–H Borylation of Benzene Derivatives by a Bulky Iridium Catalyst. J. Am. Chem. Soc. 2015, 137, 5193–5198. (42) Saito, Y.; Yamanoue, K.; Segawa, Y.; Itami, K. Selective Transformation of Strychnine and 1,2-Disubstituted Benzenes by C–H Borylation. Chem 2020, 6, 985–993. (43) Mihai, M. T.; Williams, B. D.; Phipps, R. J. Para-Selective C-H Borylation of Common Arene Building Blocks Enabled by Ion-Pairing with a Bulky Countercation. J. Am. Chem. Soc. 2019, 141, 15477–15482. (44) Montero Bastidas, J. R.; Oleskey, T. J.; Miller, S. L.; Smith, M. R., 3rd; Maleczka, R. E., Jr. Para-Selective, Iridium-Catalyzed C-H Borylations of Sulfated Phenols, Benzyl Alcohols, and Anilines Directed by Ion-Pair Electrostatic Interactions. J. Am. Chem. Soc. 2019, 141, 15483–15487. (45) Hoque, M. E.; Bisht, R.; Haldar, C.; Chattopadhyay, B. Noncovalent Interactions in Ir-Catalyzed C-H Activation: L-Shaped Ligand for Para-Selective Borylation of Aromatic Esters. J. Am. Chem. Soc. 2017, 139, 7745–7748. (46) Groll, M.; Berkers, C. R.; Ploegh, H. L.; Ovaa, H. Crystal Structure of the Boronic Acid-Based Proteasome Inhibitor Bortezomib in Complex with the Yeast 20S Proteasome. Structure 2006, 14, 451–456. (47) Gentile, M.; Offidani, M.; Vigna, E.; Corvatta, L.; Recchia, A. G.; Morabito, L.; Morabito, F.; Gentili, S. Expert Opin. Investig. Drugs 2015, 24, 1287. 19 (48) Liskey, C. W.; Hartwig, J. F. Iridium-Catalyzed Borylation of Secondary C-H Bonds in Cyclic Ethers. J. Am. Chem. Soc. 2012, 134, 12422–12425. (49) Cho, S. H.; Hartwig, J. F. Iridium-Catalyzed Diborylation of Benzylic C–H Bonds Directed by a Hydrosilyl Group: Synthesis of 1,1-Benzyldiboronate Esters. Chem. Sci. 2013, 5, 694–698. (50) Larsen, M. A.; Cho, S. H.; Hartwig, J. Iridium-Catalyzed, Hydrosilyl-Directed Borylation of Unactivated Alkyl C-H Bonds. J. Am. Chem. Soc. 2016, 138, 762–765. (51) Reyes, R. L.; Iwai, T.; Maeda, S.; Sawamura, M. Iridium-Catalyzed Asymmetric Borylation of Unactivated Methylene C(sp3)-H Bonds. J. Am. Chem. Soc. 2019, 141, 6817–6821. 20 Chapter 2. Readily-Accessible Phenylenediamine Pyridyl Ligands for Iridium Catalyzed Ortho-Directed C–H Borylation 2.1 Background to Nitrogen-Based Ligands for Iridium Catalyzed C–H Borylation For catalyzed CHBs, iridium precatalysts paired with nitrogen-based ligands have been at the forefront as the catalyst system of choice. The catalysts generated from this metal and ligand combination are known for their high performance, broad functional group tolerance, and versatility in ortho,1-5 meta,6-8 and para9-11 directed borylations of C(sp2)–H aromatic substrates. They are also well-known for their use in the borylation C(sp3)–H aliphatic substrates.12-15 Initial usage of bipyridines (bpy) and phenanthrolines (phen) have been employed in CHBs since 2002 and yield products from functionalization at the least sterically hindered C–H bond of aromatic substrates.16 These catalysts are proposed to have a single open coordination site where C–H bond functionalization occurs (Figure 2.1). Figure 2.1 Proposed active catalyst structures for (a) steric-directed catalyst using dtbpy and (b) chelate-directed catalyst using a hemilabile ligand. In the years following Miyaura, Hartwig, and Ishiyama’s initial use of bipyridyl ligands, pyridyl-hydrazone and benzylic amine pyridyl ligands by Lassaletta17-19 and Clark,20-22 respectively, had been designed to perform ortho CHBs relative to nitrogen- 21 based directing groups like hydrazone or amine groups of the substrate. Those ligands were proposed to be ‘hemilabile’ and thus create an active catalyst with two vacant coordination sites by the process of the weaker imine donor atom dissociating from the metal center (Figure 2.1). This type of directed borylation is called chelate-directed borylation since the substrate will interact with the metal center directly via a directing group and position the adjacent C–H bond close to the metal for activation to occur. However, a substrate scope limited to hydrazone, quinoline, or amine directing groups was observed. Functionalities such as esters and amides were not viable for these systems, and borylations of the substrates lead to low yields and selectivity. Not only that, but it is still unclear as to how this class of ‘hemilabile’ ligands work, which makes improvements upon their structures more elusive and challenging. 2.2 Other Ligand Types for Ortho-Directed C–H Borylation Other ligand types have been developed for chelate-directed CHBs, like Sawamura’s23,24 solid-supported monodentate phosphine silicon ligand (Si-SMAP) and Li’s25,26 Si,B- and Si,S-chelating ligands (Figure 2.2). These ligands have good ortho selectivity for various directing groups and produce products in moderate to high yields. Figure 2.2 Ligand structures for Sawamura’s (a) Si-SMAP monodentate ligand and Li’s (b) silicon-boryl and (c) silicon-sulfur ligand. 22 Although these ligands function well and are efficient for CHB chemistry, they involve nontrivial, multistep air-sensitive syntheses and/or require stoichiometric amounts of lithium reagents to produce, making their use less appealing. Sawamura’s Si-SMAP ligand requires an 11-step synthesis and involves multiple lithiations. Li’s ligands are also multistep and need stoichiometric amounts of lithium as well. Given these downsides, chelate-directed CHB is less appealing for syntheses since the ligands are either not readily accessible, have poor air-stability, or difficult for further modifications. 2.3 Phenylenediamine Pyridyl Ligands Usage in C–H Borylations In 2015, Li and coworkers developed a dimeric boryl ligand with a phenylenediamine backbone and pyridyl arm.27 This ligand operated as a steric-directed ligand for CHB catalysis using [Ir(OMe)cod]2, the same precatalyst used in the other systems. Based on the structures of previously designed ligands in Scheme 2.1, we wondered whether the pyridyl diamine precursor to Li’s diboron boryl ligand synthon might also work for CHB since pyridines are privileged ligands in Ir-catalyzed CHBs and a present feature of many ligand systems. Of the nitrogen-based ligands in Scheme 2.1, a limited substrate scope (Lassaletta’s ligand), lack of regioselectivity (Hartwig’s ligand), or air-sensitivity (Li’s ligand) are the main drawbacks. Because of these limitations and pitfalls, a ligand family that is both trivial to synthesize and tune, while imparting high regioselectivities in CHBs, would be valuable to chemists. The phenylenediamine pyridyl precursor of Li’s boryl dimer ligand is air and moisture stable, very tunable for both steric and electronic features, and its synthesis is trivial in that it can be synthesized in a single step starting with inexpensive starting materials with no need for stoichiometric amounts of metals. The precursor is also 23 easily purified by many means such as recrystallization, sublimation, flash column chromatography, or Soxhlet extraction. The design and investigation of these air-stable phenylenediamine pyridyls as CHB ligands is described. Scheme 2.1 Ir-catalyzed C–H borylation of using nitrogen-based ligands. 2.4 Analysis and Scope of Phenylenediamine Pyridyl Ligands–Amine Type, NMR Studies, and Electronic Effects Starting with the initial phenylenediamine pyridyl ligand, L1 (Scheme 2.2), and tert-butyl benzoate as the substrate, the borylation reaction exhibited high ortho selectivity. 24 While this ligand proved to be useful for ortho-directed CHB, the relevance of its structural features including the two amino groups substituted on the ligand was unclear. Ligands L2-L11 were designed to systematically investigate the structural features that contribute to the reactivity and selectivity of phenylenediamine pyridyl ligands. Their modular synthesis makes preparation of L2-L7 straightforward since each ligand can be synthesized by reacting halogenated pyridines with phenylenediamine starting materials under neat conditions as shown in Scheme 2.3. Scheme 2.3 General reaction for ligand synthesis. Pure ligands were easily obtained from the crude mixtures by sublimation (L1), recrystallization (L2), or flash column chromatography (L3 and L6). Synthesis of ligands L4 and L5 resulted in clean conversions that did not need further purification beyond workup and washing of the product. These ligands synthesized contained changes in the location, presence, and substitutions for the two amino groups. Ligands L7-L11 were also used to test various structural components and smaller fragments of L1. These are shown in Scheme 2.3 along with their ability to perform CHB chemistry. First, we tested the placement of the ortho substituted primary amine in the phenylenediamine L1. Ligands L2 and L3 were synthesized to place that amino group in the meta and para positions, respectively, of the phenyl ring. For both of these ligands, lower conversions were observed, however, there was no dramatic drop in selectivity. L4 25 lacks the primary amine group and borylations run under the same conditions of Scheme 2.2 show inferior conversion to product and a slight decrease in regioselectivity. Scheme 2.2 Nitrogen-based ligand screen for ortho-directed CHB using tert-butyl benzoate as model substrate. This suggests that the role of the primary amine group plays into the reactivity of the catalyst. Having shown that an ortho substituted amino group is beneficial for the ligand, we next tested the effects of N-substitution in the ortho-phenylenediamine fragment. The tertiary amine of L5 significantly hindered ortho CHBs. Comparing this to L1 and L4 suggests that the secondary amine has a major role in these reactions. Initially, since selectivity had plummeted when the secondary amino group had been changed to a tertiary amine, it was thought that a hydrogen-bonding effect was taking 26 place between the amino group and the directing group of the substrate. An 1H NMR study revealed that hydrogen-bonding interactions between the secondary amine of L1 and L4, and the carbonyl group of methyl benzoate was present. This was determined by collecting proton NMR of the ligand with methyl benzoate at varying concentrations. The extent of hydrogen bonding is affected by the solution concentration. A more concentrated sample will have more interaction between species and increase the amount of hydrogen bonding that occurs. This can be seen spectroscopically by the observance of the hydrogen that is involved in hydrogen bonding to be shifted more downfield due to it being deshielded. In this NMR experiment, concentration of the initial NMR sample was diluted by the addition of more solvent. Thus, as concentration decreases, the N–H bond of the secondary amine should be more upfield and show less of a hydrogen bonding effect. However, doing these same studies with L6 did not show any hydrogen bonding effect, yet the selectivity was still high. Thus, it was concluded that the added steric hindrance of the methyl group on the amine of L5 was the inhibitor for higher ortho selectivity. These spectra are displayed in Figures 2.3-2.5. 27 [0.08 M] [0.10 M] [0.13 M] [0.15 M] [0.17 M] [0.20 M] Figure 2.3 Hydrogen-Bonding Effect Between L1 and Substrate. 28 [0.10 M] [0.15 M] [0.20 M] Figure 2.4 Hydrogen-Bonding Effect Between L4 and Substrate. 29 [0.10 M] [0.15 M] [0.20 M] Figure 2.5 Hydrogen-Bonding Effect Between L6 and Substrate. Subjecting ligands L1-L6 to 1.2 equivalents of HBpin at room temperature had shown N–B bonding between the primary amine and boryl group, as evidenced by the 11B NMR showing a broadened peak at 24 ppm. No N–B bonding was seen for L6 or L4 indicating that the secondary amine is not responsible for the peak observed on NMR and that the interaction between the primary amine and boron source aids in catalysis. It has been proposed that the interaction between the ligand and boron source aids in preorganization of the ligand and better orients it to interact with the metal. 17 Also, the Smith and Maleczka groups have disclosed that the rigidity of the ligand can improve 30 coordination with the metal, evidenced by the more inflexible 3,4,7,8-tetramethyl-1,10- phenanthroline (tmphen) being a better ligand than 4,4’-di-tert-butyl-2,2’-bipyridyl (dtbpy).28 Perhaps the coordination of L1 with the boryl group also creates a similar effect. Ligand to metal connectivity was hypothesized to be occurring between the pyridyl nitrogen atom based on the previous literature. Ligand L7 was designed to test this hypothesis by replacing the pyridyl group with a phenyl group. When this ligand was used for CHB, it was shown to be unreactive. To confirm the ligand-metal connectivity, the reaction of [Ir(Cl)cod]2 (1 equiv) and L1 (2 equiv) was performed in hexanes at 65 °C for 3 hours. The proton NMR showed complete consumption of reagents and formation of a new compound. A crystal suitable for x-ray of the L1 ligated iridium complex (IrN) was obtained by recrystallization using DCM/pentane. This structure (Figure 2.6) revealed an iridium complex ligated with 1,5-cyclooctadiene (cod), chlorine, and L1 through the pyridyl nitrogen. The hydrogen of the secondary amine was measured to not be in close enough proximity to the metal center for hydrogen bonding to the metal or chlorine ligand. The IrN complex used for CHB reactions gave results consistent with the reactivity and selectivity of the catalyst generated in situ. For example, when using IrN to borylate methyl benzoate, a yield of 63% of product with an ortho selectivity of 80% was obtained. The in situ generated catalyst borylated methyl benzoate with a 65% yield with the same selectivity. 31 Figure 2.6 Crystal structure of IrN complex with hydrogen atoms omitted for clarity. Ir (purple); N (blue); Cl (green); C (gray). To verify that both the pyridyl and phenylenediamine components of L1 were crucial to the catalysis, ligands L8-L11 were used for CHBs. Of these ligands, none of the substituted pyridines or diaminobenzene groups that make up L1 had shown a high propensity for either selectivity or reactivity, indicating that both parts of the ligand are necessary for CHBs. Furthermore, when no ligand was used for catalysis, there was <5% conversion and selectivity was dominated by steric effects. If only L1 was used without a precatalyst, no reaction took place. Lastly, L12 and L13 were synthesized in similar fashion to Scheme 2.3 in a single step, demonstrating the ease of tuning the ligand with either electron donating or withdrawing substituents. Many combinations and locations are possible for modification; however, the 4-position of pyridine and backbone of the phenyl group are particularly attractive since these groups are in resonance with the pyridine sp2-N and could increase reactivity of the system. Following the reaction setup in Scheme 2.4, it was found that both ligands were viable for ortho CHB and showed a modest increase in reactivity. 32 Scheme 2.4 Electronic effects of a modified L1. From these reactions, it can be seen that this ligand framework is versatile and easily modified for different electronic groups. With further modifications available, different possibilities exist for changing the structure and capabilities of the ligand. 2.5 Studies into the Catalyst System–Ligand Loading and Chloride Source In order to glean information on the structure of the active catalyst, tests were performed to determine if multiple L1 ligands could be binding onto the metal during catalysis. This phenomenon of bis-ligation of monodentate ligands is hypothesized to occur in Miyaura and Ishiyama’s chelate-directing catalyst system. For this catalyst, monodentate, electron withdrawing ligands would dissociate from the metal center to free a second coordination site. However, it would be thermodynamically more favorable for the iridium center to be a pentacoordinate bis-ligated structure, which would decrease ortho selectivity, as shown in Scheme 2.5.29,30 33 Scheme 2.5 Mono- and bis-ligated iridium structures of Miyaura and Ishiyama’s catalysts where L = AsPh3 or tris[3,5-bis(trifluoromethyl)phenyl]phosphine. To test whether the active catalyst could be mono- or bis-ligated, similar conditions to Scheme 2.2 were performed using 2, 4, and 8 mol % ligand loadings of L1. Selectivity and reactivity dropped precipitously as more ligand was added (Table 2.1), suggesting that the catalyst has one L1 ligand bound to the iridium. Table 2.1 Effects of ligand loading on the catalyst system. Entry Ligand Loading Conversion o:(m+p) (mol %) (%) (%) 1 2 72 95:5 2 4 46 78:22 3 8 23 5:95 Reactions run on a 0.5 mmol scale of substrate, 0.5 mmol B2pin2, 1 mol % [Ir(OMe)cod]2, and 2 mol % L1 in 1.0 mL THF for 16 h. Selectivity determined by 1H NMR analysis of sample. Continuing with these studies, another test was run to determine whether the chlorine ligand remains on the metal during catalysis. Following the setup in Table 2.2, it was seen that concentrations of a chloride source (Et4N+Cl-) had an inverse relationship to both selectivity and conversion. Based on this, it can be reasoned that the chloride ligand is eliminated from the metal center before forming the active catalyst competent for CHB. The possibility of the chloride inhibiting catalysis is present as well. 34 Table 2.2 Effects of a chloride source on the catalyst system. Entry Et4N+Cl- Conversion o:(m+p) (mol %) (%) (%) 1 0 72 95:5 2 2 26 67:33 3 4 <1 --- Reactions run on a 0.5 mmol scale of substrate, 0.5 mmol B2pin2, 1 mol % [Ir(OMe)cod]2, and 2 mol % L1 in 1.0 mL THF for 16 h. Selectivity determined by 1H NMR analysis of sample. From these studies, it is proposed that the active catalyst for this ortho-directing system has one L1 ligand bound, no chloride ligand, and would likely be a trisboryl species based on what has already been disclosed about traditional Ir-catalyzed CHB systems. 2.6 Substrate Scope To demonstrate the effectiveness of this catalyst system, a substrate scope was carried out on several substrates with varying functionalities and directing groups. The substrates of Table 2.3 contain ester, amide, or hydrazone functionalities, which were all shown to be effective directing groups for ortho-directed CHB. For these substrates (1-7), high ortho regioselectivity could be achieved (80-97%) and in moderate to high yields (65- 82%). For monosubstituted substrate 1, more diborylation in the ortho position occurred (1a), but when the methyl ester directing group was bulkier like in the case for substrates 2, 6, and 7, there was no ortho diborylation seen. Likewise, for phenyl substrates substituted in the 3-position (3-5) no diborylation was observed. 35 Table 2.3 Substrate scope. Reactions run on a 0.5 mmol scale of substrate, 0.5 mmol B2pin2, 1 mol % [Ir(OMe)cod]2, and 2 mol % L1 in 1.0 mL THF for 16 h. Selectivity determined by 1H NMR analysis of sample. 36 For these same disubstituted arenes, both electron donating groups (methoxy and dimethyl amine) and electron withdrawing groups (trifluoromethyl) were shown to be borylated with high selectivity and moderate to high yields. High ortho selectivity was also observed with amide (6) and hydrazone (7) directing groups. Substrates with ketone (acetophenone) or aldehyde (benzaldehyde) functionalities were not viable as directing groups or CHB under the conditions of Table 2.3. These substrates had shown no conversion to borylated product by 1H NMR. Testing for other possible directing groups, it was found that chlorine, fluorine, and methoxy groups were non-directing and selectivity of the borylations were determined by steric factors. The heterocycle methyl 2-thiophenecarboxylate was tested as well to see if the catalyst could borylate ortho to the ester group. Full conversion was achieved within 4 hours, but the product was borylated in the 5-position. The quinoline silyl ligand designed by the Smith and Maleczka group could borylate this challenging heterocycle adjacent to the ester, but this ligand required air-free conditions and stoichiometric amounts of lithium to synthesize. 2.7 Conclusions In conclusion, phenylenediamine pyridyl ligands are capable of performing iridium catalyzed CHBs of arenes. Reactions yielded products borylated in the ortho position relative to an ester, amide, or hydrazone directing group of the substrate with various electron donating/withdrawing substituents. Ligand L1 works as a monodentate ligand, bonded through the pyridyl nitrogen. Based on the experiments mentioned, the primary amine coordinates to the boron source, which helps aid in the formation of the active catalyst, and the sterics of the secondary amine influence selectivity. The ligands 37 synthesized are air-stable and easily modified. The starting materials for the ligand are inexpensive, making these ligands very accessible to use in CHB catalysis. 38 REFERENCES 39 REFERENCES (1) Boebel, T. A.; Hartwig, J. F. Silyl-Directed, Iridium-Catalyzed Ortho-Borylation of Arenes. A One-Pot Ortho-Borylation of Phenols, Arylamines, and Alkylarenes. J. Am. Chem. Soc. 2008, 130, 7534–7535. (2) Li, H. L.; Kuninobu, Y.; Kanai, M. Lewis Acid-Base Interaction-Controlled Ortho- Selective C-H Borylation of Aryl Sulfides. Angew. Chem. Int. Ed Engl. 2017, 56, 1495– 1499. (3) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.; Maleczka, R. E., Jr; Smith, M. R., 3rd. Outer-Sphere Direction in Iridium C-H Borylation. J. Am. Chem. Soc. 2012, 134, 11350–11353. (4) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. Directed Ortho Borylation of Functionalized Arenes Catalyzed by a Silica-Supported Compact Phosphine- Iridium System. J. Am. Chem. Soc. 2009, 131, 5058–5089. (5) Ghaffari, B.; Preshlock, S. M.; Plattner, D. L.; Staples, R. J.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr; Smith, M. R., 3rd. Silyl Phosphorus and Nitrogen Donor Chelates for Homogeneous Ortho Borylation Catalysis. J. Am. Chem. Soc. 2014, 136, 14345–14348. (6) Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M. A Meta-Selective C–H Borylation Directed by a Secondary Interaction between Ligand and Substrate. Nat. Chem. 2015, 7, 712–717. (7) Davis, H. J.; Genov, G. R.; Phipps, R. J. Meta -Selective C−H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand. Angew. Chem. Int. Ed. 2017, 56, 13351–13355. (8) Mihai, M. T.; Davis, H. J.; Genov, G. R.; Phipps, R. J. Ion Pair-Directed C–H Activation on Flexible Ammonium Salts: Meta-Selective Borylation of Quaternized Phenethylamines and Phenylpropylamines. ACS Catal. 2018, 8, 3764–3769. (9) Saito, Y.; Segawa, Y.; Itami, K. Para-C–H Borylation of Benzene Derivatives by a Bulky Iridium Catalyst. J. Am. Chem. Soc. 2015, 137, 5193–5198. (10) Mihai, M. T.; Williams, B. D.; Phipps, R. J. Para-Selective C-H Borylation of Common Arene Building Blocks Enabled by Ion-Pairing with a Bulky Countercation. J. Am. Chem. Soc. 2019, 141, 15477–15482. (11) Montero Bastidas, J. R.; Oleskey, T. J.; Miller, S. L.; Smith, M. R., 3rd; Maleczka, R. E., Jr. Para-Selective, Iridium-Catalyzed C-H Borylations of Sulfated Phenols, Benzyl 40 Alcohols, and Anilines Directed by Ion-Pair Electrostatic Interactions. J. Am. Chem. Soc. 2019, 141, 15483–15487. (12) Miyamura, S.; Araki, M.; Suzuki, T.; Yamaguchi, J.; Itami, K. Stereodivergent Synthesis of Arylcyclopropylamines by Sequential C-H Borylation and Suzuki-Miyaura Coupling. Angew. Chem. Int. Ed Engl. 2015, 54, 846–851. (13) Ohmura, T.; Torigoe, T.; Suginome, M. Catalytic Functionalization of Methyl Group on Silicon: Iridium-Catalyzed C(sp3)-H Borylation of Methylchlorosilanes. J. Am. Chem. Soc. 2012, 134, 17416–17419. (14) Liskey, C. W.; Hartwig, J. F. Iridium-Catalyzed Borylation of Secondary C-H Bonds in Cyclic Ethers. J. Am. Chem. Soc. 2012, 134, 12422–12425. (15) Cho, S. H.; Hartwig, J. F. Iridium-Catalyzed Diborylation of Benzylic C–H Bonds Directed by a Hydrosilyl Group: Synthesis of 1,1-Benzyldiboronate Esters. Chem. Sci. 2013, 5, 694–698. (16) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. Mild Iridium-Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and Isolation of a Potential Intermediate. J. Am. Chem. Soc. 2002, 124, 390–391. (17) Ros, A.; Estepa, B.; López-Rodríguez, R.; Álvarez, E.; Fernández, R.; Lassaletta, J. M. Use of Hemilabile N,N Ligands in Nitrogen-Directed Iridium-Catalyzed Borylations of Arenes. Angew. Chem. Int. Ed Engl. 2011, 50, 11724–11728. (18) López-Rodríguez, R.; Ros, A.; Fernández, R.; Lassaletta, J. M. Pinacolborane as the Boron Source in Nitrogen-Directed Borylations of Aromatic N,N-Dimethylhydrazones. J. Org. Chem. 2012, 77, 9915–9920. (19) Ros, A.; López-Rodríguez, R.; Estepa, B.; Álvarez, E.; Fernández, R.; Lassaletta, J. M. Hydrazone as the Directing Group for Ir-Catalyzed Arene Diborylations and Sequential Functionalizations. J. Am. Chem. Soc. 2012, 134, 4573–4576. (20) Roering, A. J.; Hale, L. V. A.; Squier, P. A.; Ringgold, M. A.; Wiederspan, E. R.; Clark, T. B. Iridium-Catalyzed, Substrate-Directed C-H Borylation Reactions of Benzylic Amines. Org. Lett. 2012, 14, 3558–3561. (21) Crawford, K. M.; Ramseyer, T. R.; Daley, C. J. A.; Clark, T. B. Phosphine-Directed C–H Borylation Reactions: Facile and Selective Access to Ambiphilic Phosphine Boronate Esters. Angew. Chem. Int. Ed. 2014, 53, 7589–7593. (22) Hale, L. V. A.; McGarry, K. A.; Ringgold, M. A.; Clark, T. B. Role of Hemilabile Diamine Ligands in the Amine-Directed C–H Borylation of Arenes. Organometallics 2015, 34, 51–55. 41 (23) Sawamura, M. Air-Stable, Compact, Caged Trialkylphosphines (SMAPs): Synthesis, Properties and Applications to Homogeneous and Heterogeneous Catalysis. J. Synth. Org. Chem Jpn. 2009, 67, 1125–1135. (24) Kawamorita, S.; Ohmiya, H.; Sawamura, M. Ester-Directed Regioselective Borylation of Heteroarenes Catalyzed by a Silica-Supported Iridium Complex. J. Org. Chem. 2010, 75, 3855–3858. (25) Wang, G.; Liu, L.; Wang, H.; Ding, Y.-S.; Zhou, J.; Mao, S.; Li, P. N,B-Bidentate Boryl Ligand-Supported Iridium Catalyst for Efficient Functional-Group-Directed C-H Borylation. J. Am. Chem. Soc. 2017, 139, 91–94. (26) Jiao, J.; Nie, W.; Song, P.; Li, P. A New Air-Stable Si,S-Chelating Ligand for Ir- Catalyzed Directed Ortho C-H Borylation. Org. Biomol. Chem. 2021, 19, 355–359. (27) Wang, G.; Xu, L.; Li, P. Double N,B-Type Bidentate Boryl Ligands Enabling a Highly Active Iridium Catalyst for C-H Borylation. J. Am. Chem. Soc. 2015, 137, 8058–8061. (28) Preshlock, S. M.; Ghaffari, B.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr; Smith, M. R., 3rd. High-Throughput Optimization of Ir-Catalyzed C-H Borylation: A Tutorial for Practical Applications. J. Am. Chem. Soc. 2013, 135, 7572–7582. (29) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. Ortho-C–H Borylation of Benzoate Esters with Bis(pinacolato)diboron Catalyzed by Iridium–phosphine Complexes. Chem. Commun. 2010, 46, 159–161. (30) Itoh, H.; Kikuchi, T.; Ishiyama, T.; Miyaura, N. Iridium-Catalyzed Ortho-C–H Borylation of Aryl Ketones with Bis(pinacolato)diboron. Chem. Lett. 2011, 40, 1007–1008. 42 Chapter 3. Modification of a Steric- to a Chelate-Directed Iridium Catalyst for C–H Borylation with a Dimeric Boryl Support Ligand 3.1 The Catalyst Cycle for Iridium Catalyzed C–H Borylation Iridium precatalysts supported by nitrogen-based ligands like 4,4’-di-tert-butyl- 2,2’-dipyridyl (dtbpy) or 3,4,7,8-tetramethyl-1,10-phenanthroline (tmphen) form active catalysts whose proposed active structure is an Ir(III) trisboryl complex.1,2 The catalytic cycle using iridium and an L2 ligand (bisphosphine) framework was first proposed by Smith and Maleczka as involving IrIII/V.3 Following this hypothesis, computational4 and experimental data2 were consistent with an IrIII/V cycle. The cycle begins with the Ir(III) trisboryl complex A and through oxidative addition of the substrate becomes an Ir(V) complex B. The organoboron product reductively eliminates leaving the catalyst as a monohydride, bisboryl Ir(III) complex C, which then undergoes a second oxidative addition of the boron source to replenish the lost boryl group, forming the Ir(V) complex D. Lastly, HBpin is expelled via reductive elimination to complete the cycle and return the iridium to the Ir(III) complex A (Scheme 3.1). 43 Scheme 3.1 Catalyst cycle for Ir-catalyzed CHBs. In this mechanism, the rate determining step is thought to be the initial oxidative addition of the C–H bond onto the metal. This is supported by the large primary kinetic isotope effect observed for the borylation of benzene versus benzene-d6. Because of this, it can be reasoned that a more electron-rich and donating ligand to the metal center would be valuable since it could promote faster cleavage of the C–H bond, thus creating a more reactive catalyst system. Since the initial Ir(III) complex only requires one boryl ligand to form the boronic ester product, the Li group designed a catalyst where the other two boryl ligands are preinstalled as support ligands, taking greater advantage of boron’s strong donor ability as a ligand.5 3.2 Boryl Ligands in Iridium Catalyzed C–H Borylation For iridium-catalyzed CHBs, boryl ligands (like HBpin or B2pin2) typically act as active ligands, coming on and off the metal center during catalysis. These ligands are usually the boron source, pinacolborane (HBpin) or B2pin2, which oxidatively add to the metal and reductively eliminate to form the organoboron product. Because these ligands 44 are monodentate, have empty (or less filled) p-orbitals, and are reactive, they are more susceptible to being removed from the metal during catalysis. In recent years, catalytic CHBs by Li and coworkers has shown that iridium catalysts with boron–nitrogen chelating ligands can operate well, like commonly employed bipyridine and phenanthroline ligated catalysts.6 Some of these applications include borylating electron rich (hetero)arenes and sterically hindered substrates, which is particularly impressive since sterics have been shown to be one of the greatest obstacles for CHB that are ortho to large substituents.7 The B,N-bidentate ligands were modeled after Yamashita and Nozaki’s tridentate PBP boryl pincer ligands8-10 and are sufficiently stable to maintain the boron-metal bond due to the chelate effect11 and reducing the Lewis acidity of the boron atom with π-donating nitrogen substituents. Because of this increased stability, the ligands were less susceptible to being removed from the catalyst and can operate as support ligands for catalysis. Designs of these ligands are shown below in Figure 3.1. Previous work by Yamashita and Nozaki has shown that tridentate boryl ligands are quite versatile and tunable. Their uses in catalysis have been explored for hydrogenation,12,13 cross-couplings,14,15 and now CHBs. (a) (b) Figure 3.1 Yamashita and Nozakis’ (a) pincer PBP ligand and Li’s bidentate (b) bidentate boryl ligand designs. As can be seen by structures (a) and (b) of Figure 3.1, stabilization of the typically reactive boryl ligand was achieved by chelation and having nitrogen atoms bonded to the 45 boron atom, which can donate into the empty orbital of boron and reduce its susceptibility of being removed from the metal since the Lewis acidity of the boron is reduced. From this stabilization, an electron-rich ligand that has a strong propensity for σ-donation to the metal center was created. 3.3 Modification of Boryl Support Ligand Systems The catalyst designed by Li that possesses two B,N-bidentate ligands (IrBB) works as a steric-directed catalyst whose synthesis is shown in Scheme 3.2. Based on IrBB’s structure, it was wondered whether this catalyst could be modified to yield chelate- directed products by removing one of the bidentate ligands. This would free a second coordination site and allow for ortho borylation of a substrate, relative to its directing group. Scheme 3.2 Synthetic route to double B,N-bidentate complex (IrBB). The method for changing the regioselectivity of IrBB for ortho CHB was initially attempted by using a base additive, like KO-t-Bu, that could interact with one of boron’s p orbitals and initiate cleavage of the bidentate ligand (Scheme 3.3). Similar reactions have precedent in the literature and our research group.3,16 46 Scheme 3.3 Removal of boryl ligand by base additive KO-t-Bu. This method was not successful in accomplishing the desired outcome, and in fact, inhibited borylation proportional to the amount of KO-t-Bu used based on both conversion and ortho selectivity. All reactions using KO-t-Bu suffered from low conversion and selectivity based on steric factors (see Chapter 4 for details). In order to have an iridium center possessing only one chelating ligand, an environment where there is only one bidentate ligand per iridium metal would be needed. In the original catalyst system, the B,N-bidentate compound (BB) was used in a 2:1 ratio to [Ir(OMe)cod]2, where there are two bidentate ligands per iridium metal, and yielded products borylated in positions predominantly based on steric effects. However, it was found that by reducing the ligand loading to a 1:1 ratio a new catalyst is formed. This was evidenced by the dramatic changes in selectivity between the original system and the new system using the reduced loading of ligand, which gave products borylated in the ortho position to a directing group. Results demonstrating the differences in selectivity and ligand loading are shown in Table 3.1. 47 Table 3.1 Comparison of ligand loading and regioselectivity. Entry Ligand Ligand Loading Conversion o:(m*+p) (mol %) (%) (%) 1 BB 2 99 1:99 2 BB 1 80 60:40 3 BB 0.75 74 90:10 4 BB 0.50 67 95:5 5 dtbpy 2 99 1:99 6 dtbpy 0.50 74 1:99 Reactions run on 0.5 mmol scale of substrate, 0.5 mmol B2pin2, 1 mol % [Ir(OMe)cod]2, and x mol % BB or dtbpy ligand in 1 mL THF. Conversions and selectivity determined by 1 H NMR analysis of sample. Meta selectivity (m*) includes dimeta-borylated products. The results of Table 1 demonstrated that using the BB ligand in lower loadings resulted in higher ortho selectivity. In fact, as the loading decreases, the chelate product is formed in much higher ratios to the steric product. These results did not follow typical CHBs using iridium catalysts. Stoichiometrically, traditional catalyst systems, like Hartwig’s [Ir(OMe)cod]2/dtbpy system, require a 2:1 ratio of ligand and precatalyst. Previous work done in the Smith and Maleczka group on ligand to precatalyst ratio had shown that optimal catalytic activity results when the ligand is in slight excess of the precatalyst. Attempts using a 1:1 ligand to precatalyst ratio have been performed before using dtbpy or tmphen and [Ir(OMe)cod]2, but resulted in lower catalyst activity.17 This is due to one chelating ligand being needed per iridium metal. With a less than 2:1 ratio of ligand:precatalyst, a lower concentration of competent catalyst is generated. Entries 5 and 6 of Table 3.1 demonstrate this concept using a standard L2 type bidentate ligand (dtbpy). Under the same conditions of Table 3.1, CHBs were attempted using solely BB or iridium precatalyst and yielded no borylated products, indicating the need for both to 48 provide successful borylation. Borylations were also run using the preassembled catalyst IrBB (2 mol %) with an additional (2 mol %) [Ir(Cl)cod]2 added to the reaction vessel. Interestingly, this setup gave products borylated in the ortho sites at similar conversions and selectivity as the conditions used in Table 3.1, entry 4. Other iridium complexes like [Ir(Cl)cod]2 and (Ind)Ir(cod) were also viable precatalyst options for ortho-directed CHBs. When using these precatalysts with lower ligand loading conditions, a high proclivity for the chelate-directed product was observed. Following the reaction conditions of Table 3.1, entry 4 with [Ir(Cl)cod]2 yielded borylated products in a ratio of 95:5 for (o:(m+p)) at 83% conversion. Under the same conditions but using (Ind)Ir(cod) gave products in a ratio of 45:55 for (o:(m+p)) at 66% conversion from starting material to borylated product. Using increased ligand loadings for these two precatalysts (2:1 BB:[Ir]) had shown an increase in steric-directed products. Table 3.2 outlines these results. Table 3.2 Comparison of iridium precatalyst and regioselectivity. Entry Precatalyst Conversion o:(m+p) (%) (%) 1 [Ir(OMe)cod]2 85 92:8 2 [Ir(Cl)cod]2 83 95:5 3 (Ind)Ir(cod) 66 45:55 Reactions run on 0.5 mmol scale of substrate, 0.5 mmol B2pin2, 1 mol % [Ir(X)cod]2 or 0.5 mol % (Ind)Ir(cod) and 0.5 mol % BB in 1 mL THF. Conversions and selectivity determined by 1H NMR analysis of sample. 49 3.4 Complexes for Steric- and Chelate-Directed Catalysis Crystals were grown of the catalyst used for chelate-directed CHB (Figure 3.2) to determine the cause of contrast between the steric and chelate conditions. This was done by heating [Ir(Cl)cod]2 and BB ligand in a 1:1 ratio in pentane at 70 °C for 3 hours. From the yellow solid that formed, crystals were grown via solvent displacement using DCM/hexanes. This iridium complex possessed the double B,N-bidentate ligands and was cationic, similar to IrBB. However, instead of having a chloride counter anion, IrBB’ had a dichloro cyclooctadiene iridium (I) species as the counter anion. Figure 3.2 Crystal structure of complex IrBB’ with hydrogen atoms omitted for clarity. Ir (dark blue); N (blue); boron (yellow); Cl (green); C (gray). The IrBB’ complex was used as catalyst for chelate-directed CHBs under standard reaction conditions, however, no borylated products were observed even after 24 h, which suggests that IrBB’ may not be representative of the active catalyst. The IrBB complex also required heating the system to 100 °C for meaningful reactivity to occur. At temperatures of 80 °C and below, the reaction was sluggish and gave minimum conversion to borylated products. 3.5 Comparison of a Boron Dimer Ligand and Silicon-Boryl Ligand Shortly after the initial publication of CHB using the BB ligand, an asymmetric analog of BB consisting of a boron-silicon ligand were designed for chelate-directed CHB. 50 Reaction of the ligand and [Ir(Cl)cod]2 precatalyst formed a complex with a single B,N- bidentate ligand and a silyl group that prevents the addition of another B,N group to the metal.19 A comparison between the reduced ligand loading conditions with BB and the standard conditions with SiB ligand are shown in Table 3.3. Based on the data presented, both BB and SiB ligands yield strikingly similar results in both conversion and selectivity. Although both can produce the chelate-directed products, the BB ligand at lower loadings would be more appealing to use for catalyzed CHBs. Its synthesis can be done in two steps starting from commercially available materials does not produce as large a waste stream as the SiB ligand, which uses an excess of lithium metal for its synthesis and is 4 steps to prepare. 51 Table 3.3 Comparison of BB and SiB ligands for chelate-directed CHB. Entry Substrate Ligand Conversion o:(m+p) (%) (%) 1 BB 78 93:7 SiB 77 90:10 2 BB 75 93:7 SiB 75 92:8 Reactions run on 0.5 mmol scale of substrate, 1 equiv B2pin2, and 1 mol % [Ir(Cl)cod]2. For BB ligand, 0.50 mol % was used and for SiB ligand, 2 mol % was used. Conversion and selectivity determined by 1H NMR. 3.6 Substrate Scope at Lower Ligand Loading Conditions Based on the promising results in Table 3.1, entry 4, a substrate scope was carried out using these lowered ligand loading conditions for achieving ortho regioselectivity. To fully show the effects of ligand loading in the catalysis of the system, reactions were run in parallel using the original 2:1 ligand to precatalyst ratio alongside the varied ligand loading system (Table 3.4). Results with [Ir(Cl)cod]2 are also shown in Chapter 4. 52 Table 3.4 CHBs of arenes using conditions for chelate- and steric-directed catalysis. Condition A (chelate conditions) yield Product A and Condition B (steric conditions) yield Product B. Reactions run on 0.5 mmol scale of substrate, 0.5 mmol B2pin2, 1 mol % [Ir(OMe)cod]2, and 0.50 mol % BB ligand for condition A or 2 mol % for condition B, in 1.0 mL THF for 4-16 h. Selectivity determined by 1H NMR analysis of sample. 53 From this scope, it was found that for most arenes tested, changing the ligand loading changes the regioselectivity. For substrates having an ester or amide functionality, particularly substrates 1-5 and 7, significant ortho-selectivity was noted, ranging from 60- 90%. Steric controlled conditions (Products B) gave almost exclusively the steric product (meta and para). To see the efficacy of the chelate-directed conditions, ortho borylation was attempted for substrate 6, which has only one ortho site to the ester directing group and a bulky substituent in the position meta to that directing group. Borylation of this substrate was in the steric position for both Conditions A and B. This result was expected however since the substrate has never been ortho borylated before and has a bulky halogen greatly hindering the ortho site. For 1,3-disubstituted arenes (2-5), Conditions A yielded the chelate product in good yields and selectivity, while Conditions B yielded almost exclusively 1,3,5 substituted product, also in good yields. CHB reactions for both Conditions A and B were effective for a variety of functional groups with both electron withdrawing or donating substituents. For heterocycles, Conditions A and B were run using 2-thiophenecarboxylate (entry 8) and 5-methyl-2-thiophenecarboxylate (entry 9) (Table 3.5). For entry 8, the thiophene was borylated in the more reactive 5-position of the substrate. By blocking the 5-position with a methyl group in entry 9, the heterocycle could be ortho borylated to an ester using Conditions A. Conditions B gave products borylated in the 4-position for the same substrate. 54 Table 3.5 CHBs of heteroarenes using conditions for chelate- and steric-directed catalysis. Conditions A (chelate conditions) yield Product A and Conditions B (steric conditions) yield Product B. Reactions run on 0.5 mmol scale of substrate, 0.5 mmol B2pin2, 1 mol % [Ir(OMe)cod]2, and 0.50 mol % BB ligand for condition A or 2 mol % for condition B, in 1.0 mL THF for 4-16 h. Selectivity determined by 1H NMR analysis of sample. Substrates of Entries 1-9 were also run using [Ir(Cl)cod]2 as the precatalyst for Condition A. Using this precatalyst would give higher chelate-directed products and a higher degree of regioselectivity than when [Ir(OMe)cod]2 was used. This difference in selectivity for chelate products was also observed in the SiB ligated systems as well although reason for this change is not known. For Condition B, using substrates 1-9, borylations gave higher yields and almost solely the steric product as expected from what has already been seen in the literature.5 Overall, from these studies, it was shown that for most substrates, regioselectivity could be flipped by altering the preligand loading of the BB dimeric boryl ligand. While usually a preligand can be used to change selectivity, this is the first case where selectivity can be changed without the need for a new preligand. 55 3.7 Applications of Boryl Support Ligands Given that spectator boryl ligands have become a powerful and versatile ligand for CHBs of both C(sp2)–H and C(sp3)–H bonds, the insights on derivatives of BB may be valuable due to their unique capabilities. Since the initial use of bidentate boryl ligands for homogeneous CHB catalysis, other boryl support ligands have appeared in the literature. These ligands are modeled after the asymmetric SiB ligand in that the boryl group is bonded to a silyl that can oxidatively add to the iridium precatalyst. Examples of these ligands and their capacity for CHB are shown below in Figure 3.3.6,19-22 Figure 3.3 Boryl support ligands for CHB catalysis. From the beginnings of Ir catalyzed CHBs,23 boron has typically been an actor ligand, but through new developments has shown to be a promising support ligand that can be tuned for different selectivities and capabilities. 3.8 Conclusions In conclusion, a catalyst system was modified from steric- to chelate-directed by changing the ligand loading so that there was a 1:2 ratio of bidentate ligand BB to iridium dimer precatalyst. This system works well for ortho CHB using esters and amides as directing groups and for (hetero)arenes. Although it is not fully understood what causes the 56 shift in regioselectivity, it was found that the iridium counteranion is necessary for the chelate-directed products to form since the chloride counteranion gave steric CHB products. More work on reaction mechanism and conditions with other boryl ligands are currently being carried out. 57 REFERENCES 58 REFERENCES (1) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. 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Solvents used came from wet stills and commercially available chemicals were used as received unless otherwise noted. Proton NMR spectra were recorded on a Varian 500 MHz instrument. Carbon NMR and Boron NMR were recorded on 126 MHz and 160 MHz instruments, respectively. Borylation reactions were conducted using stock solutions of the ligand and precatalyst in a nitrogen-filled glovebox. High-resolution mass spectra (HRMS) were obtained at the Michigan State University Mass Spectrometry Service Center using electrospray ionization (ESI+ or ESI-) on quadrupole time-of-flight (Q-TOF) instruments. Melting points were measured in a capillary melting point apparatus and are uncorrected. Synthesis of N1-(pyridin-2-yl)benzene-1,2-diamine (L1) 1,2-Diaminobenzene (1.0 g, 9.26 mmol, 2.0 equiv) along with 2-chloropyridine (0.42 mL, 4.63 mmol, 1.0 equiv) were added to a 100 mL round bottom flask containing a magnetic stir bar. A condenser was attached, the system was purged with N2, and the contents were heated at 160 °C for 16 hours while under nitrogen. The black solid that formed was cooled to room temperature, after which the reaction flask was opened to air. Water and acetone were then added in equal amounts to the solid until it completely dissolved. The pH of the solution was adjusted to 10 by adding a saturated Na2CO3 solution. 61 Brine was then added, and the crude product was extracted with ethyl acetate. Organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was washed with hexanes (3 x 10 mL) on a filter frit. The solids were then transferred to a Soxhlet thimble, and a Soxhlet extraction was performed with DCM for 20 hours. Solvent was removed from the filtrate by rotary evaporation, yielding the product as a pale violet solid (528 mg, 62%). 1H NMR (500 MHz, CDCl3) δ 8.16 (ddd, J = 5.1, 1.9, 0.9 Hz, 1H), 7.44 (ddd, J = 8.6, 7.2, 1.9 Hz, 1H), 7.20 (dd, J = 7.8, 1.5 Hz, 1H), 7.10 (td, J = 7.7, 1.5 Hz, 1H), 6.83 (dd, J = 8.0, 1.4 Hz, 1H), 6.78 (td, J = 7.6, 1.4 Hz, 1H), 6.69 (ddd, J = 7.1, 5.0, 0.9 Hz, 1H), 6.42 (dt, J = 8.4, 0.9 Hz, 1H), 6.27 – 6.12 (s, 1H), 3.88 (s, 2H); 13 C NMR (126 MHz, CDCl3) δ 157.7, 148.3, 143.0, 137.9, 127.2, 127.0, 125.8, 118.9, 116.2, 114.4, 107.2.1 Synthesis of N1-(pyridin-2-yl)benzene-1,3-diamine (L2) 1,3-Diaminobenzene (1.0 g, 9.26 mmol, 2.0 equiv) along with 2-chloropyridine (0.42 mL, 4.63 mmol, 1.0 equiv) were added to a 100 mL round bottom flask containing a magnetic stir bar in open air. A condenser was attached, the system was purged with N2, and the contents were heated at 160 °C for 16 hours while under nitrogen. The black solid that formed was cooled to room temperature, after which the reaction flask was opened to air. Water and acetone were added in equal amounts to the solid until it completely dissolved. The pH of the solution was adjusted to 10 by adding a saturated Na2CO3 solution. Brine was then added, and the crude product was extracted with ethyl acetate. Organic layers were combined, dried over Na2SO4, filtered, and concentrated under 62 reduced pressure. The residue was purified via hexanes wash (3 x 10 mL) followed by flash column chromatography with 100% EtOAc to give the product as a tan solid (357 mg, 43%), m.p. = 127-130 °C. 1H NMR (500 MHz, CDCl3) δ 8.19 (ddd, J = 5.0, 2.0, 0.9 Hz, 1H), 7.47 (ddd, J = 8.8, 7.2, 2.0 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 6.91 (dd, J = 8.4, 0.9 Hz, 1H), 6.79 (s, 1H), 6.75 – 6.68 (m, 2H), 6.66 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H), 6.38 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H), 3.70 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 156.0, 148.4, 147.4, 141.5, 137.6, 130.0, 114.9, 110.5, 109.8, 108.5, 106.7. HRMS (ESI) (m+1)/z calc for C11H11N3 186.0952, found 186.1017.2 Synthesis of N1-(pyridin-2-yl)benzene-1,4-diamine (L3) 1,4-Diaminobenzene (1.0 g, 9.26 mmol, 2.0 equiv) along with 2-chloropyridine (0.42 mL, 4.63 mmol, 1.0 equiv) were added to a 100 mL round bottom flask containing a magnetic stir bar in open air. A condenser was attached, the system was purged with N2, and the contents were heated at 160 °C for 16 hours while under nitrogen. The black solid that formed was cooled to room temperature, after which the reaction flask was opened to air. Water and acetone were added in equal amounts to the solid until it completely dissolved. The pH of the solution was adjusted to 10 by adding a saturated Na2CO3 solution. Brine was then added, and the crude product was extracted with ethyl acetate. Organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via hexanes wash (3 x 10 mL) followed by flash chromatography using 100% EtOAc to give the product as an off-white solid (611 mg, 63 74%), m.p. = 118-120 °C. 1H NMR (500 MHz, CDCl3) δ 8.12 (dd, J = 5.4, 2.0 Hz, 1H), 7.40 (td, J = 8.5, 2.0 Hz, 1H), 7.10 (d, J = 8.20, 2H), 6.70 (d, J = 8.20, 2H), 6.64 (m, 2H), 6.58 (bs, 1H) 3.65 (bs, 2H); 13C NMR (126 MHz, C6D6) δ 158.3, 148.5, 143.4, 136.8, 131.1, 124.6, 115.1, 113.3, 106.6. HRMS (ESI) (m+1)/z calc for C11H11N3 185.0952, found 185.1068.3 Synthesis of N-phenylpyridin-2-amine (L4) Aniline (1.4 g, 15.0 mmol, 1.0 equiv) along with 2-chloropyridine (1.42 mL, 15.0 mmol, 1.0 equiv) were added to a 100 mL round bottom flask containing a magnetic stir bar in open air. A condenser was attached, the system was purged with N2, and the contents were heated at 160 °C for 16 hours while under nitrogen. The black solid that formed was cooled to room temperature, after which the reaction flask was opened to air. Water and acetone were added in equal amounts to the solid until it completely dissolved. The pH of the solution was adjusted to 10 by adding a saturated Na2CO3 solution. Brine was then added, and the crude product was extracted with ethyl acetate. Organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was washed with hexanes (3 x 10 mL) and dried under reduced pressure to give the product as a deep purple solid (2.248 g, 81%), m.p. = 100-102 °C. 1H NMR (500 MHz, CDCl3) δ 8.22 (ddd, J = 5.01, 1.95, 0.93 Hz, 1H), 7.50 (ddd, J = 8.35, 7.17, 1.94 Hz, 1H), 7.34 (m, 4H), 7.05 (ddd, J = 8.7, 5.0, 3.7 Hz, 1H), 6.89 (dd, J = 8.3, 1.0 Hz, 1H), 6.86 (s, 1H), 6.73 (ddd, J = 7.1, 5.0, 0.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 156.0, 148.4, 64 140.5, 137.7, 129.3, 122.8, 120.3, 115.0, 108.1. HRMS (ESI) (m+1)/z calc for C11H10N2 171.0843, found 171.0912.4 Synthesis of N-methyl-N-phenylpyridin-2-amine (L5) N-Methylaniline (1.76 g, 16.4 mmol, 1.0 equiv) along with 2-chloropyridine (1.55 mL, 16.4 mmol, 1.0 equiv) were added to a 100 mL round bottom flask containing a magnetic stir bar in open air. A condenser was attached, the system was purged with N2, and the contents were heated at 160 °C for 16 hours while under nitrogen. The black solid that formed was cooled to room temperature, after which the reaction flask was opened to air. Water and acetone were added in equal amounts to the solid until it completely dissolved. The pH of the solution was adjusted to 10 by adding a saturated Na2CO3 solution. Brine was then added, and the crude product was extracted with ethyl acetate. Organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was washed with hexanes (3 x 10 mL) and dried under reduced pressure to give the product as a white crystalline solid (871 mg, 29%), m.p. = 187-190 °C. 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 5.0 Hz, 1H), 7.64 (ddd, J = 9.00, 6.98, 1.80 Hz, 1H), 7.54 (t, J = 2.0 Hz, 2H), 7.49 – 7.42 (m, 1H), 7.26 – 7.21 (m, 2H), 6.87 (ddd, J = 7.11, 6.34, 1.02 Hz, 1H), 6.54 (dt, J = 9.19, 0.92 Hz, 1H), 3.86 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 152.5, 142.5, 142.3, 137.7, 131.1, 129.2, 126.6, 112.9, 112.6, 42.3. HRMS (ESI) (m+1)/z calc for C12H12N2 185.1000, found 185.1068.5 65 Synthesis of N1-N1-dimethyl-N2-(pyridin-2-yl)benzene-1,2-diamine (L6) Method A: 1,2-Diaminobenzene (0.0216 g, 0.2 mmol, 2.0 equiv) along with 2- bromopyridine (0.0158 g, 0.1 mmol, 1.0 equiv) were added to a 100 mL round bottom flask containing a magnetic stir bar in open air. A condenser was attached, the system was purged with N2, and the contents were heated at 160 °C for 16 hours while under nitrogen. The black solid that formed was cooled to room temperature, after which the reaction flask was opened to air. Water and acetone were added in equal amounts to the solid until it completely dissolved. The pH of the solution was adjusted to 10 by adding a saturated Na2CO3 solution. Brine was then added, and the crude product was extracted with ethyl acetate. Organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via hexanes wash (3 x 10 mL) followed by flash chromatography using 100% ACN to give the product as tan solid (4.8 mg, 23%). 1H NMR (500 MHz, CDCl3) δ 8.25 (ddd, J = 5.1, 2.0, 0.9 Hz, 1H), 8.00 (dd, J = 8.1, 1.5 Hz, 1H), 7.51 (ddd, J = 8.4, 7.2, 2.0 Hz, 2H), 7.14 (dd, J = 7.8, 1.5 Hz, 1H), 7.08 (td, J = 7.7, 1.6 Hz, 1H), 6.95 (td, J = 7.6, 1.5 Hz, 1H), 6.91 (dt, J = 8.3, 0.9 Hz, 1H), 6.73 (ddd, J = 7.1, 5.0, 0.9 Hz, 1H), 2.67 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 155.7, 148.3, 143.1, 137.4, 135.6, 124.3, 121.4, 119.7, 117.6, 114.8, 109.6, 44.4. HRMS (ESI) (m+1)/z calc for C13H15N3 213.1265, found 213.1755. Method B6: In a 25 mL three-neck flask equipped with a stir bar, 2- aminopyridine(0.4887 g, 4 mmol, 2.0 equiv), sodium tert-butoxide (0.3844 g, 4 mmol, 2 equiv), (dibenzylideneacetone)dipalladium(0) (0.03 mmol, 3 mol % Pd), and BINAP (0.06 66 mmol, 6 mol %) were added under a stream of nitrogen. The flask was sealed and dry toluene (10 mL) was added to the flask via syringe. A water condenser was added to the flask while under nitrogen. The contents were allowed to stir for ten minutes at rt before adding 2-bromo-N,N-aniline (0.29 mL, 2 mmol, 1 equiv) to the flask. The flask stirred at 80 °C for 20 h and before being cooled to rt. The solution was then taken up in ethyl acetate, filtered, and concentrated. Crude residue was purified via hexanes wash (3 x 10 mL) followed by flash chromatography using 100% ACN to give the product as an off-white solid (123 mg, 58%). Synthesis of N1-(4-(trifluoromethyl)pyridin-2-yl)benzene-1,2-diamine (L12) 1,2-Diaminobenzene (1.0 g, 9.26 mmol, 2.0 equiv) along with 2-chloro-4- (trifluoromethyl)pyridine (0.60 mL, 4.63 mmol, 1.0 equiv) were added to a 100 mL round bottom flask containing a magnetic stir bar in open air. A condenser was attached, the system was purged with N2, and the contents were heated at 160 °C for 16 hours while under nitrogen. The black solid that formed was cooled to room temperature, after which the reaction flask was opened to air. Water and acetone were added in equal amounts to the solid until it completely dissolved. The pH of the solution was adjusted to 10 by adding a saturated Na2CO3 solution. Brine was then added, and the crude product was extracted with ethyl acetate. Organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via hexanes wash (3 x 10 mL) followed by flash chromatography using 100% EtOAc to give the product as an off- white solid (862 mg, 73%), m.p. = 135-137 °C. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 67 5.22 Hz, 1H), 7.19 (dd, J = 7.84, 1.41 Hz, 1H), 7.15 (td, J = 7.70, 1.47 Hz, 1H), 6.87 (m, 2H), 6.82 (td, J = 7.55, 1.42 Hz, 1H), 6.60 (d, J = 1.6 Hz, 1H), 6.43 (bs, 1H), 3.85 (bs, 2H); 13 C NMR (126 MHz, CDCl3) δ 158.4, 149.5, 143.0, 140.2, 127.8, 127.1, 124.5, 121.8, 119.1, 116.4, 109.6, 102.9. HRMS (ESI) (m+1)/z calc for C12H10N3F3 254.0826, found 254.0894. Synthesis of N1-(4-(dimethylamino)pyridin-2-yl)benzene-1,2-diamine (L13) Method A: 1,2-Diaminobenzene (0.4320 g, 0.004 mol, 2.0 equiv) along with 2- bromo-4-(dimethylamino)pyridine (0.4021 g, 0.002 mol, 0.1 equiv) were added to a 100 mL round bottom flask containing a magnetic stir bar in open air. A condenser was attached, the system was purged with N2, and the contents were heated at 160 °C for 16 hours while under nitrogen. The black solid that formed was cooled to room temperature, after which the reaction flask was opened to air. Water and acetone were added in equal amounts to the solid until it completely dissolved. The pH of the solution was adjusted to 10 by adding a saturated Na2CO3 solution. Brine was then added, and the crude product was extracted with ethyl acetate. Organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified via hexanes wash (3 x 10 mL) followed by flash chromatography using 100% ACN to give the product as an off-white solid (251 mg, 51%). 1H NMR (500 MHz, CDCl3) 7.85 (d, J = 6.1 Hz, 1H), 7.20 (dd, J = 7.8, 1.5 Hz, 1H), 7.05 (ddd, J = 7.9, 7.3, 1.5 Hz, 1H), 6.80 (dd, J = 7.9, 1.4 Hz, 1H), 6.75 (td, J = 7.5, 1.5 Hz, 1H), 6.07 (dd, J = 6.1, 2.3 Hz, 1H), 5.60 (d, J = 2.3 Hz, 1H), 3.89 (s, 2H), 2.88 (s, 7H); 13C NMR (126 MHz, CDCl3) δ 158.4, 156.2, 148.3, 142.9, 126.8, 126.6, 126.5, 118.8, 68 116.0, 100.0, 88.1, 39.1. HRMS (ESI) (m+1)/z calc for C13H16N4 229.1374, found 229.1430. Method B: In a 25 mL three-neck flask equipped with a stir bar, 1,2- diaminobenzene (0.4320 g, 0.004 mol, 2.0 equiv), sodium tert-butoxide (0.3844 g, 0.004 mol, 2 equiv), (dibenzylideneacetone)dipalladium(0) (0.03 mmol, 1.5 mol % Pd), and BINAP (0.06 mmol, 3 mol %) were added under a stream of nitrogen. The flask was sealed and dry toluene (10 mL) was added to the flask via syringe. A water condenser was added to the flask while under nitrogen. The contents were allowed to stir for ten minutes at rt before adding 2-bromo-4-(dimethylamino)pyridine (0.4021 g, 0.002 mol, 0.1 equiv) to the flask. The flask stirred at 80 °C for 20 h and before being cooled to rt. The solution was then taken up in ethyl acetate, filtered, and concentrated. Crude residue was purified via hexanes wash (3 x 10 mL) followed by flash chromatography using 100% ACN to give the product as an off-white solid (301 mg, 66 %).6 Synthesis of IrN Complex In a 10 mL Schlenk flask equipped with stir bar, [Ir(Cl)cod]2 (26.8 mg, 0.04 mmol, 1 equiv) was added. L1 (14.8 mg, 0.08 mmol, 2 equiv) and n-hexane (2.0 mL) were added. The flask was sealed and the mixture stirred at 70 °C for 3 hours, producing a yellow solution. The contents of the flask were cooled to room temperature, and volatiles were removed under reduced pressure, leaving a yellow solid (41.6 mg, quantitative yield). 1H 69 NMR (500 MHz, C6D6) δ 8.29 (s, 1H), 7.70 (d, J = 5.00 Hz, 1H), 7.01 (dd, J = 7.75, 1.48 Hz, 1H), 6.94 (td, J = 7.74, 1.55 Hz, 1H), 6.58 (td, J = 7.58, 1.48 Hz, 1H), 6.53 (t, J = 5.00 Hz, 1H), 6.31 (dd, J = 8.03, 1.40 Hz, 1H), 5.94 (t, J = 5.00 Hz, 1H), 4.81 (s, 2H), 4.18 (s, 2H), 3.24 (s, 2H), 2.06 (s, 4H), 1.52 – 1.27 (m, 4H). 13C NMR spectrum was not obtainable. Single Crystal X-ray Diffraction Data for IrN Complex Crystals suitable for x-ray analysis were developed via solvent diffusion of DCM and pentane. IrN complex was dissolved in minimal DCM inside a test tube. The test tube was then placed in a larger vessel containing pentane and sealed in a nitrogen-filled glovebox. Golden crystals formed after 1 week. The crystal structure of IrN (with hydrogen atoms omitted for clarity) had a square planar Ir complex ligated with L1 through the pyridyl nitrogen, bidentate cod, and chlorine atom. Ir (purple); N (blue); Cl (green); C (gray). No hydrogen-bonding between either of the primary and secondary amine protons with iridium was observed based on H–Ir distance. Crystal data and structure refinement for AlexOIrN1prime. Identification code AlexOIrN1prime Empirical formula C19H23ClIrN3 Formula weight 521.05 Temperature/K 173(2) Crystal system monoclinic 70 Space group P21/c a/Å 11.0305(2) b/Å 7.76740(10) c/Å 20.9114(3) α/° 90 β/° 98.9910(10) γ/° 90 Volume/Å3 1769.64(5) Z 4 ρcalcg/cm3 1.956 μ/mm‑1 16.022 F(000) 1008.0 Crystal size/mm3 0.262 × 0.184 × 0.114 Radiation CuKα (λ = 1.54178) 2Θ range for data collection/° 8.114 to 144.384 Index ranges -13 ≤ h ≤ 13, -9 ≤ k ≤ 9, -25 ≤ l ≤ 24 Reflections collected 33562 Independent reflections 3502 [Rint = 0.0450, Rsigma = 0.0236] Data/restraints/parameters 3502/0/218 Goodness-of-fit on F2 1.074 Final R indexes [I>=2σ (I)] R1 = 0.0202, wR2 = 0.0480 Final R indexes [all data] R1 = 0.0215, wR2 = 0.0487 Largest diff. peak/hole / e Å-3 0.69/-0.66 71 Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for AlexOIrN1prime. Ueq is defined as 1/3 of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) Ir01 2825.1(2) 1644.0(2) 6898.0(2) 18.82(6) Cl02 1741.4(9) -397.7(11) 6199.8(4) 38.1(2) N003 3886(2) 2115(3) 6165.4(12) 20.6(5) N004 1087(3) 1652(3) 4629.7(15) 30.8(6) C005 4111(3) 2791(4) 7622.3(13) 20.9(6) C006 3293(3) 4064(4) 7314.6(14) 22.5(6) N007 2360(2) 3813(4) 5591.8(13) 25.1(5) C008 1467(3) 1776(4) 7519.0(15) 22.8(6) C009 1706(3) 6282(4) 4909.5(17) 27.0(7) C00A 2271(3) 405(4) 7709.0(14) 23.3(6) C00B 4998(3) 1326(4) 6211.5(15) 24.5(6) C00C 5255(3) 2270(4) 5165.0(16) 27.2(7) C00D 1706(3) 4524(4) 5005.7(14) 21.5(6) C00E 1046(3) 3432(4) 4543.8(15) 21.6(6) C00F 3308(3) 433(4) 8275.4(14) 25.2(6) C00G 3456(3) 2998(4) 5619.2(14) 21.1(6) C00H 4143(3) 3081(4) 5109.1(15) 25.2(6) C00I 1478(3) 3482(4) 7883.5(16) 27.2(7) C00J 395(3) 4178(4) 3983.3(15) 26.4(7) 72 C00K 5704(3) 1364(4) 5732.5(17) 27.5(7) C00L 2242(3) 4845(4) 7594.9(15) 27.0(6) C00M 422(3) 5920(5) 3886.4(17) 30.0(7) C00N 1068(3) 7004(4) 4345.4(19) 31.7(7) C00O 4069(3) 2083(4) 8299.1(14) 24.7(6) Anisotropic Displacement Parameters (Å2×103) for AlexOIrN1prime. The Anisotropic displacement factor exponent takes the form: - 2π2[h2a*2U11+2hka*b*U12+…]. Atom U11 U22 U33 U23 U13 U12 Ir01 21.29(8) 19.73(8) 14.33(8) -0.33(4) -0.64(5) -4.96(4) Cl02 48.8(5) 35.4(4) 27.4(4) -7.7(3) -2.1(3) -20.5(4) N003 21.1(12) 22.9(12) 16.8(11) -0.4(10) -0.1(9) -2.8(10) N004 36.4(16) 23.5(14) 30.3(15) 0.3(11) -1.0(12) -0.4(11) C005 22.2(14) 26.4(15) 12.5(13) -3.5(11) -2.7(10) -6.2(12) C006 29.4(16) 17.7(14) 19.1(14) -2.3(11) -0.5(12) -8.8(12) N007 23.1(13) 34.2(14) 17.8(12) 1.7(11) 2.4(10) 4.2(11) C008 20.2(14) 26.3(15) 22.3(14) 3.1(12) 4.7(11) -5.9(11) C009 23.6(16) 26.6(15) 31.6(17) -7.6(13) 6.4(13) -2.7(12) C00A 30.0(16) 20.9(14) 19.7(14) 3.1(11) 6.2(12) -4.6(12) C00B 25.1(16) 22.4(14) 24.1(15) 1.1(12) -2.2(12) 1.3(12) C00C 24.0(16) 32.1(16) 26.3(16) 1.3(13) 6.1(12) 0.7(13) C00D 19.8(14) 27.8(15) 17.0(13) 1.0(12) 3.4(11) 4.5(11) C00E 21.4(15) 25.3(15) 19.6(14) -0.9(11) 7.6(12) 3.0(11) 73 C00F 32.3(17) 24.5(15) 18.6(14) 5.9(12) 3.1(12) 3.9(12) C00G 22.4(14) 20.8(13) 19.1(14) -1.4(12) 0.3(11) -1.4(12) C00H 25.5(16) 30.2(16) 19.9(14) 4.6(12) 3.4(12) 1.4(12) C00I 27.2(16) 26.5(16) 27.9(16) 2.3(13) 4.6(13) 5.7(12) C00J 21.9(15) 33.9(17) 22.5(15) -2.4(13) 0.5(12) 4.2(13) C00K 22.9(16) 28.6(16) 29.9(17) 0.6(13) 0.9(13) 4.1(12) C00L 33.6(17) 20.8(14) 24.3(15) -0.4(12) -2.3(12) -1.1(13) C00M 26.0(16) 37.0(18) 27.6(16) 10.6(14) 6.0(13) 9.9(14) C00N 31.3(17) 21.8(15) 44(2) 6.9(14) 12.6(15) 6.9(13) C00O 26.8(16) 29.7(16) 16.3(14) -0.2(12) -1.1(11) 2.6(13) Bond Lengths for AlexOIrN1prime. Atom Atom Length/Å Atom Atom Length/Å Ir01 Cl02 2.3517(8) C008 C00I 1.528(4) Ir01 N003 2.100(2) C009 C00D 1.381(5) Ir01 C005 2.104(3) C009 C00N 1.393(5) Ir01 C006 2.102(3) C00A C00F 1.512(4) Ir01 C008 2.133(3) C00B C00K 1.362(5) Ir01 C00A 2.121(3) C00C C00H 1.368(5) N003 C00B 1.361(4) C00C C00K 1.402(5) N003 C00G 1.353(4) C00D C00E 1.400(4) N004 C00E 1.394(4) C00E C00J 1.401(4) C005 C006 1.423(4) C00F C00O 1.529(5) C005 C00O 1.526(4) C00G C00H 1.403(4) 74 C006 C00L 1.506(5) C00I C00L 1.534(5) N007 C00D 1.432(4) C00J C00M 1.369(5) N007 C00G 1.358(4) C00M C00N 1.387(5) C008 C00A 1.403(4) Bond Angles for AlexOIrN1prime. Atom Atom Atom Angle/˚ Atom Atom Atom Angle/˚ N003 Ir01 Cl02 87.23(7) C00A C008 C00I 124.2(3) N003 Ir01 C005 93.53(11) C00I C008 Ir01 113.2(2) N003 Ir01 C006 91.01(11) C00D C009 C00N 120.7(3) N003 Ir01 C008 163.78(11) C008 C00A Ir01 71.19(17) N003 Ir01 C00A 157.70(11) C008 C00A C00F 125.3(3) C005 Ir01 Cl02 162.26(9) C00F C00A Ir01 110.0(2) C005 Ir01 C008 90.00(12) N003 C00B C00K 123.4(3) C005 Ir01 C00A 82.10(12) C00H C00C C00K 119.8(3) C006 Ir01 Cl02 158.20(9) C009 C00D N007 119.6(3) C006 Ir01 C005 39.54(12) C009 C00D C00E 120.7(3) C006 Ir01 C008 81.67(12) C00E C00D N007 119.7(3) C006 Ir01 C00A 99.06(12) N004 C00E C00D 120.6(3) C008 Ir01 Cl02 94.20(9) N004 C00E C00J 121.3(3) C00A Ir01 Cl02 90.48(9) C00D C00E C00J 118.0(3) C00A Ir01 C008 38.52(12) C00A C00F C00O 112.4(2) C00B N003 Ir01 117.9(2) N003 C00G N007 117.7(3) C00G N003 Ir01 122.8(2) N003 C00G C00H 120.4(3) 75 C00G N003 C00B 118.8(3) N007 C00G C00H 122.0(3) C006 C005 Ir01 70.16(16) C00C C00H C00G 119.8(3) C006 C005 C00O 124.1(3) C008 C00I C00L 111.4(3) C00O C005 Ir01 113.6(2) C00M C00J C00E 120.8(3) C005 C006 Ir01 70.30(16) C00B C00K C00C 117.8(3) C005 C006 C00L 125.2(3) C006 C00L C00I 112.3(3) C00L C006 Ir01 111.5(2) C00J C00M C00N 121.2(3) C00G N007 C00D 122.8(3) C00M C00N C009 118.6(3) C00A C008 Ir01 70.29(17) C005 C00O C00F 111.6(2) Torsion Angles for AlexOIrN1prime. A B C D Angle/˚ A B C D Angle/˚ Ir01 N003 C00B C00K 172.0(3) C00A C008 C00I C00L 95.1(4) Ir01 N003 C00G N007 9.6(4) C00A C00F C00O C005 -31.5(4) Ir01 N003 C00G C00H -171.6(2) C00B N003 C00G N007 -178.3(3) Ir01 C005 C006 C00L 103.0(3) C00B N003 C00G C00H 0.5(4) Ir01 C005 C00O C00F 12.8(3) C00D N007 C00G N003 -168.5(3) Ir01 C006 C00L C00I 34.7(3) C00D N007 C00G C00H 12.7(5) Ir01 C008 C00A C00F 101.7(3) C00D C009 C00N C00M 0.7(5) Ir01 C008 C00I C00L 13.9(3) C00D C00E C00J C00M 1.1(5) Ir01 C00A C00F C00O 35.1(3) C00E C00J C00M C00N -1.6(5) N003 C00B C00K C00C 0.2(5) C00G N003 C00B C00K -0.5(5) N003 C00G C00H C00C -0.2(5) C00G N007 C00D C009 -104.2(4) N004 C00E C00J C00M -176.0(3) C00G N007 C00D C00E 77.5(4) 76 C005 C006 C00L C00I -45.8(4) C00H C00C C00K C00B 0.2(5) C006 C005 C00O C00F 94.1(4) C00I C008 C00A Ir01 -105.2(3) N007 C00D C00E N004 -4.3(4) C00I C008 C00A C00F -3.6(5) N007 C00D C00E C00J 178.6(3) C00J C00M C00N C009 0.7(5) N007 C00G C00H C00C 178.5(3) C00K C00C C00H C00G -0.2(5) C008 C00A C00F C00O -45.6(4) C00N C009 C00D N007 -179.5(3) C008 C00I C00L C006 -31.5(4) C00N C009 C00D C00E -1.2(5) C009 C00D C00E N004 177.4(3) C00O C005 C006 Ir01 -105.7(3) C009 C00D C00E C00J 0.3(4) C00O C005 C006 C00L -2.7(5) Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for AlexOIrN1prime. Atom x y z U(eq) H00A 1205.33 1411.16 5045.96 37 H00B 388.16 1198.48 4444.91 37 H005 4957.55 2863.35 7509.6 25 H006 3675.29 4862.75 7028.04 27 H007 2037.63 3908.85 5949.56 30 H008 631.17 1405.54 7308.19 27 H009 2144.88 7006.89 5231.16 32 H00C 1899.67 -758.83 7611.8 28 H00D 5297.02 717.47 6598.04 29 H00E 5721.61 2321.35 4820.17 33 H00F 3849.6 -569.81 8244.19 30 77 H00G 2962.48 323.21 8682.93 30 H00H 3836.03 3699.32 4725.89 30 H00I 1823.75 3296.89 8344.34 33 H00J 625.72 3903.23 7862.99 33 H00K -71.19 3466.68 3666.36 32 H00L 6475.73 794.45 5781.28 33 H00M 1705.52 5482.76 7250.94 32 H00N 2569.87 5678.36 7936.8 32 H00O -9.06 6395.12 3497.66 36 H00P 1075.69 8212.75 4276.66 38 H00Q 3710.35 2961 8557.39 30 H00R 4915.56 1842.98 8516.26 30 Crystal structure determination of [AlexOIrN1prime] Crystal Data for C19H23ClIrN3 (M =521.05 g/mol): monoclinic, space group P21/c (no. 14), a = 11.0305(2) Å, b = 7.76740(10) Å, c = 20.9114(3) Å, β = 98.9910(10)°, V = 1769.64(5) Å3, Z = 4, T = 173(2) K, μ(CuKα) = 16.022 mm-1, Dcalc = 1.956 g/cm3, 33562 reflections measured (8.114° ≤ 2Θ ≤ 144.384°), 3502 unique (Rint = 0.0450, Rsigma = 0.0236) which were used in all calculations. The final R1 was 0.0202 (I > 2σ(I)) and wR2 was 0.0487 (all data). 78 Hydrogen-Bonding Effect Between L1 and Substrate [0.08 M] [0.10 M] [0.13 M] [0.15 M] [0.17 M] [0.20 M] Inside a nitrogen-filled glovebox, a 0.20 M solution of L1 (19.0 mg, 0.103 mmol) in benzene-d6 (0.60 mL) was made inside a J-Young NMR tube. To this NMR tube, methyl benzoate (6.4 uL, 0.05 mmol) was added. The tube was sealed and 1H NMR was acquired. Following the initial NMR taken, five subsequent additions of benzene-d6 were added via syringe to this same NMR tube producing 0.20 M, 0.17 M, 0.15 M, 0.13 M, 0.10 M, and 0.08 M concentrations of the L1 solution. The spectra above show the proton spectrum acquired from lower to higher concentrations of L1 solution (from top to bottom). As seen 79 from the spectra, there is hydrogen-bonding between the secondary amine of L1 and methyl benzoate substrate. The secondary amine of L1 was unaffected by changes in concentration and showed little to no hydrogen-bonding with the substrate. Hydrogen-Bonding Effect Between L4 and Substrate [0.10 M] [0.15 M] [0.20 M] Inside a nitrogen-filled glovebox, a 0.20 M solution of L4 (17.5 mg, 0.103 mmol) in benzene-d6 (0.60 mL) was made inside a J-Young NMR tube. To this NMR tube, methyl benzoate (6.4 uL, 0.05 mmol) was added. The tube was sealed and 1H NMR was acquired. Following the initial NMR taken, five subsequent additions of benzene-d6 were added via syringe to this same NMR tube producing 0.10 M, 0.15 M, and 0.20 M concentrations of 80 the L4 solution. The spectra above show the proton spectrum acquired from lower to higher concentrations of L4 solution (from top to bottom). As seen from the spectra, there is hydrogen-bonding between the secondary amine of L4 and methyl benzoate substrate. Hydrogen-Bonding Effect Between L6 and Substrate [0.20 M] [0.15 M] [0.10 M] Inside a nitrogen-filled glovebox, a 0.20 M solution of L6 (22.0 mg, 0.103 mmol) in benzene-d6 (0.60 mL) was made inside a J-Young NMR tube. To this NMR tube, methyl benzoate (6.4 uL, 0.05 mmol) was added. The tube was sealed and 1H NMR was acquired. Following the initial NMR taken, five subsequent additions of benzene-d6 were added via syringe to this same NMR tube producing 0.10 M, 0.15 M, and 0.20 M concentrations of 81 the L6 solution. The spectra above show the proton spectrum acquired from lower to higher concentrations of L6 solution (from top to bottom). As seen from the spectra, there is hydrogen-bonding between the secondary amine of L6 and methyl benzoate substrate. The secondary amine of L6 was unaffected by changes in concentration and showed no hydrogen-bonding with the substrate. Effects of Ligand Loading on ortho-Directed C–H Borylations Entry Ligand Loading Conversion o:(m+p) (mol %) (%) (%) 1 2 72 95:5 2 4 46 78:22 3 8 23 5:95 Inside a nitrogen-filled glove box, B2pin2 (127 mg, 0.500 mmol, 1 equiv) and 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol) were added to 2.5 mL reaction vial equipped with stir bar in THF (0.50 mL). Following these additions, either a 1, 2, 4, or 8 mol % stock solution of L1 were added, bringing the total volume of THF solvent to 1 mL. Arene substrate (0.500 mmol, 1 equiv) was then added to the vial and sealed with a screw valve cap. The contents of the vial stirred at 80 °C for 16 hours. Conversion and selectivity were determined by proton NMR. 82 Effects of an Added Chloride Source on ortho-Directed C–H Borylations Entry Et4N+Cl- Conversion o:(m+p) (mol %) (%) (%) 1 0 72 95:5 2 2 26 67:33 3 4 <1 --- Inside a nitrogen-filled glove box, B2pin2 (127 mg, 0.500 mmol, 1 equiv) and 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to 2.5 mL reaction vial equipped with stir bar in THF (1 mL). Following these additions, either 0, 2, or 4 mol% loading of Et4N+Cl- was added. Arene substrate (0.500 mmol, 1 equiv) was then added to the vial and sealed with a screw valve cap. The contents of the vial stirred at 80 °C for 16 hours. Conversion and selectivity were determined by 1H NMR. Effect of Precatalysts on ortho-Directed C–H Borylations Entry Precatalyst Conversion o:(m+p) (%) (%) 1 [Ir(OMe)cod]2 54 90:10 2 [Ir(Cl)cod]2 48 91:9 Inside a nitrogen-filled glove box, B2pin2 (0.1270 g, 0.500 mmol, 1 equiv) and 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol); (X = OMe or Cl), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to 2.5 mL reaction vial equipped with stir bar in THF (1 mL). Arene substrate (0.500 mmol, 1 equiv) was then added to the vial and sealed with a screw 83 cap. The contents of the vial stirred at 80 °C for 8 hours. Conversion and selectivity were determined by 1H NMR. Evidence for N–B Bonding Between Ligands and Boron Source (HBpin) To a J-Young NMR tube, L1 (0.0092 g, 0.05 mmol, 1 equiv) and HBpin (0.0128 g, 11 0.10 mmol, 2 equiv) was added in benzene-d6 (0.60 mL). The tube was sealed and B NMR was taken. This same protocol was followed for L2-L5, using the same equivalents of ligand and boron source. The spectra for L1-L3 had shown a broad singlet at 24.3 which is indicative of N–B bonding. HBpin as a sharp singlet (28.5 ppm) and a borates peak (21.8 ppm) were present as well. No N–B bonding appeared to be present for L4 or L5. The stacked spectra below start at the top from L1 and go sequentially to L5 spectrum on the bottom. 84 Borylation of Aromatic Substrates with L1 General conditions for ortho-directed C–H borylation: Inside a nitrogen-filled glove box, B2pin2 (0.1270 g, 0.500 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to a 2.5 mL reaction vial equipped with stir bar and dissolved in THF (1 mL). Arene substrate (0.500 mmol, 1 equiv) was added to the vial which was then sealed with a screw valve cap. The contents of the vial were stirred at 80 °C for 16 hours. Contents were cooled to room temperature and volatiles were removed by rotary evaporation. The crude compound was then run through a small plug of silica gel with DCM as eluent. Collected material was dried under vacuum. Methyl 2-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (1a) Following the general procedure, B2pin2 (0.1270 g, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to a reaction vial equipped with a magnetic stir bar in THF (1 mL). Methyl benzoate (63 µL, 68 mg, 0.50 mmol) was added and the vial was sealed with a screw cap. The reaction mixture was stirred at 80 °C for 16 h. Starting material converted to 70% borylated products in the ratio of o:(m+p):di-o = 80:8:12 borylated products. Crude material was passed through a short plug of silica using DCM as eluent and dried to give 1a as a colorless oil (0.085 g, 65%). 1H NMR (500 MHz, CDCl3) δ 7.95 (dt, J = 7.8, 0.9 Hz, 1H), 7.54 – 7.50 (ddd, J = 7.8, 6.2, 2.6 Hz, 1H), 7.44 – 7.40 (m, 1H), 3.92 (s, 3H), 1.43 (s, 12H). 11B NMR (160 MHz, CDCl3) δ 31.5 (s). Spectral data were in accordance with literature.7 85 tert-Butyl 2-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (2a) Following the general procedure, B2pin2 (0.1270 g, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to a reaction vial equipped with a magnetic stir bar in THF (1 mL). tert-Butyl benzoate (89 µL, 89 mg, 0.50 mmol) was added and the vial was sealed with a screw cap. The reaction mixture was stirred at 80 °C for 16 h. Starting material converted to 80% borylated products in the ratio of o:(m+p):di-o = 91:9:0 borylated products. Crude material was passed through a short plug of silica using DCM as eluent and dried to give 2a as a white solid (0.122 g, 77%). 1H NMR (500 MHz, CDCl3) δ 7.82 (dt, J = 7.7, 0.9 Hz, 1H), 7.49 – 7.45 (m, 2H), 7.39 – 7.34 (ddd, J = 7.7, 6.0, 2.8 Hz, 1H), 1.59 (s, 3H), 1.42 (s, 12H). 11B NMR (160 MHz, CDCl3) δ 31.2 (s). Spectral data were in accordance with literature.8 Methyl 3-methoxy-6-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (3a) Following the general procedure, B2pin2 (0.1270 g, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to a reaction vial equipped with a magnetic stir bar in THF (1 mL). Methyl 3- methoxybenzoate (73 µL, 83 mg, 0.50 mmol) was added and the vial was sealed with a screw cap. The reaction mixture was stirred at 80 °C for 16 h. Starting material converted to 63% borylated products in the ratio of (6 position:5 position) = 92:8 borylated products. Crude material was passed through a short plug of silica using DCM as eluent and dried to 86 give 3a as a colorless oil (0.082 g, 56%). 1H NMR (500 MHz, CDCl3) δ 7.43 (s, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.03 (dd, J = 8.1, 2.6 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 1.40 (s, 12H). 11 B NMR (160 MHz, CDCl3) δ 30.9 (s). Spectral data were in accordance with literature.8 Methyl 3-dimethylamino-6-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (4a) Following the general procedure, B2pin2 (0.1270 g, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to a reaction vial equipped with a magnetic stir bar in THF (1 mL). Methyl 3- (dimethylamino)benzoate (81 µL, 90 mg, 0.50 mmol) was added and the vial was sealed with a screw cap. The reaction mixture was stirred at 80 °C for 16 h. Starting material converted to 54% borylated products in the ratio of (6 position:5 position) = 97:3 borylated products. Crude material was passed through a short plug of silica using DCM as eluent and dried to give 4a as a colorless oil (0.082 g, 54%). 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 8.3, 2.6 Hz, 1H), 3.87 (s, 3H), 2.97 (s, 6H), 1.36 (s, 12H). 11B NMR (160 MHz, CDCl3) δ 31.8 (s). Spectral data were in accordance to literature.9 Methyl 3-trifluoromethyl-6-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (5a) 87 Following the general procedure, B2pin2 (0.1270 g, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to a reaction vial equipped with a magnetic stir bar in THF (1 mL). Methyl 3- (trifluoromethyl)benzoate (79 µL, 102 mg, 0.50 mmol) was added and the vial was sealed with a screw cap. The reaction mixture was stirred at 80 °C for 16 h. Starting material converted to 89% borylated products in the ratio of (6 position:5 position) = 83:17 borylated products. Crude material was passed through a short plug of silica using DCM as eluent and dried to give 5a as a white solid (0.135 g, 82%). 1H NMR (500 MHz, CDCl3) δ 8.21 (dt, J = 1.6, 0.8 Hz, 1H), 7.77 (dtd, J = 7.70, 1.42, 0.69 Hz, 1H), 7.63 (dt, J = 7.72, 0.75 HZ, 1H), 3.96 (s, 3H), 1.44 (s, 12H). 11 B NMR (160 MHz, CDCl3) δ 31.3 (s). Spectral data were in accordance to literature.8 N,N-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (6a) Following the general procedure, B2pin2 (0.1270 g, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to a reaction vial equipped with a magnetic stir bar in THF (1 mL). N,N- Dimethylbenzamide (74 mg, 0.50 mmol) was added and the vial was sealed with a screw cap. The reaction mixture was stirred at 80 °C for 16 h. Starting material converted to 92% borylated products in the ratio of o:(m+p):di-o = 95:5:0 borylated products. Crude material was passed through a short plug of silica using DCM as eluent and dried to give 6a as a white solid (0.113 g, 82%). 1H NMR (500 MHz, CDCl3) δ 7.81 (ddd, J = 7.5, 1.4, 0.6 Hz, 1H), 7.46 (td, J = 7.5, 1.4 Hz, 1H), 7.37 (td, J = 7.5, 1.2 Hz, 1H), 7.30 (ddd, J = 7.6, 1.3, 88 0.7 Hz, 1H), 3.06 (s, 3H), 2.89 (s, 3H), 1.30 (s, 12H). 11B NMR (160 MHz, CDCl3) δ 29.4 (s). Spectral data were in accordance to literature.8 1,1-dimethyl-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene) hydrazine (7a) Following the general procedure, B2pin2 (0.1270 g, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to a reaction vial equipped with a magnetic stir bar in THF (1 mL). 2-Benzylidene-1,1- dimethylhydrazine (75 µL, 74 mg, 0.50 mmol) was added and the vial was sealed with a screw cap. The reaction mixture was stirred at 80 °C for 16 h. Starting material converted to 92% borylated products in the ratio of o:(m+p):di-o = borylated products. Crude material was passed through a short plug of silica using DCM as eluent and dried to give 7a as a (0.102 g, 74%). 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 7.77 (dd, J = 7.5, 1.5 Hz, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.20 (td, J = 7.4, 1.4 Hz, 1H), 2.98 (s, 6H), 1.36 (s, 12H). 11 B NMR (160 MHz, CDCl3) δ 31.1 (s). Spectral data were in accordance to literature.10 2-(3-chloro-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8a) Following the general procedure, B2pin2 (0.1270 g, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to a reaction vial equipped with a magnetic stir bar in THF (1 mL). 1-chloro-3- 89 fluorobenzene (54 µL, 65 mg, 0.50 mmol) was added and the vial was sealed with a screw cap. The reaction mixture was stirred at 80 °C for 16 h. Starting material converted to 32% borylated products in the ratio of o:m (relative to F) = 52:48 borylated products. Crude material was passed through a short plug of silica using DCM as eluent and dried to give 8a as a clear oil (0.019 g, 29%). 1H NMR (500 MHz, CDCl3) δ 7.64 (dd, J = 8.0, 6.8 Hz, 1H), 7.14 (dd, J = 7.9, 1.7 Hz, 1H), 7.05 (dd, J = 7.9, 1.7 Hz, 1H), 1.34 (s, 12H). 11B NMR (160 MHz, CDCl3) δ 30.6 (s). Spectral data were in accordance to literature.11 Methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (9a) Following the general procedure, B2pin2 (0.1270 g, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol), and 2 mol % L1 (1.8 mg, 0.010 mmol) were added to a reaction vial equipped with a magnetic stir bar in THF (1 mL). 2-thiophenecarboxylate (75 µL, 71 mg, 0.50 mmol) was added and the vial was sealed with a screw cap. The reaction mixture was stirred at 80 °C for 16 h. Starting material converted to 99% borylated products in the ratio of 3:5 = 0:100 borylated products. Crude material was passed through a short plug of silica using DCM as eluent and dried to give 9a as a white solid (0.121 g, 90%). 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 3.7 Hz, 1H), 7.55 (d, J = 3.7 Hz, 1H), 3.88 (s, 3H), 1.34 (s, 12H). 11B NMR (160 MHz, CDCl3) δ 28.9 (bs). Spectral data were in accordance to literature.12 90 4.2 Chapter 3 Experimental Procedures and Details General Information All reactions were carried out in oven-dried glassware under an inert atmosphere. Solvents used came from wet stills and commercially available chemicals were used as received unless otherwise noted. Proton NMR spectra were recorded on a Varian 500 MHz instrument. Carbon NMR and Boron NMR were recorded on 126 MHz and 160 MHz instruments, respectively. Borylation reactions were conducted using stock solutions of the ligand and precatalyst in a nitrogen-filled glovebox. High-resolution mass spectra (HRMS) were obtained at the Michigan State University Mass Spectrometry Service Center using electrospray ionization (ESI+ or ESI-) on quadrupole time-of-flight (Q-TOF) instruments. Melting points were measured in a capillary melting point apparatus and are uncorrected. Synthesis of N1-(pyridin-2-yl)benzene-1,2-diamine (L1) 1,2-Diaminobenzene (1.0 g, 9.26 mmol, 2.0 equiv) along with 2-chloropyridine (0.42 mL, 4.63 mmol, 1.0 equiv) were added to a 100 mL round bottom flask containing a magnetic stir bar. A condenser was attached, the system was purged with N2, and the contents were heated at 160 °C for 16 hours while under nitrogen. After the allotted time, the black solid formed was cooled to room temperature, after which the reaction flask was opened to air. Water and acetone were then added in equal amounts to the solid until it completely dissolved. The pH of the solution was adjusted to 10 by adding a saturated Na2CO3 solution. Brine was then added, and the crude product was extracted with ethyl 91 acetate. Organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was washed with hexanes (3 x 10 mL) on a filter frit. The solids were then transferred to a Soxhlet thimble, and a Soxhlet extraction was performed with DCM for 20 hours. Solvent was removed from the filtrate by rotary evaporation, yielding the product as a pale violet solid (528 mg, 62%). 1H NMR (500 MHz, CDCl3) δ 8.16 (ddd, J = 5.1, 1.9, 0.9 Hz, 1H), 7.44 (ddd, J = 8.6, 7.2, 1.9 Hz, 1H), 7.20 (dd, J = 7.8, 1.5 Hz, 1H), 7.10 (td, J = 7.7, 1.5 Hz, 1H), 6.83 (dd, J = 8.0, 1.4 Hz, 1H), 6.78 (td, J = 7.6, 1.4 Hz, 1H), 6.69 (ddd, J = 7.1, 5.0, 0.9 Hz, 1H), 6.42 (dt, J = 8.4, 0.9 Hz, 1H), 6.27 – 6.12 (s, 1H), 3.88 (s, 2H); 13 C NMR (126 MHz, CDCl3) δ 157.7, 148.3, 143.0, 137.9, 127.2, 125.8, 118.9, 116.2, 114.4, 107.2.1 Synthesis 1,1'-Di(Pyridin-2-yl)-1,1',3,3'-tetrahydro-2,2'-bibenzo[d][1,3,2]diazaborole (BB) Inside a glovebox, L1 (0.3700 g, 2 mmol, 1 equiv) was added to a 10 mL Schlenk flask equipped with a magnetic stir bar. Tetrakis(dimethylamino)diboron (0.24 mL, 1.2 mmol, 0.6 equiv) was added, along with 5 mL of toluene via syringes. The flask was then sealed and taken outside of the glovebox. Next, under a positive flow of nitrogen, a water condenser was attached to the flask. Contents were stirred and heated at 128 °C for 48 hours while under nitrogen. After 48 hours, volatiles were removed, and a light tan solid was obtained (0.390 g, 99%). 1H NMR (500 MHz, CDCl3) δ 8.53 (d, J = 4.9 Hz, 1H), 7.64 92 – 7.56 (m, 2H), 7.50 (bs, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 7.5, 1.5 Hz, 1H), 7.10 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H), 7.03 (dtd, J = 22.0, 7.4, 1.3 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 155.1, 148.7, 137.9, 137.3, 135.8, 120.6, 120.3, 119.5, 118.6, 111.5; 11B NMR (160 MHz, CDCl3) δ 29.1 (bs).1 Synthesis of Double B,N-Bidenate Catalyst (IrBB) In a 10 mL Schlenk flask with stir bar, [Ir(Cl)cod]2 (26.8 mg, 0.04 mmol, 1 equiv) was added. BB (31.2 mg, 0.08 mmol, 2 equiv) and n-hexane (1.0 mL) were added. The flask stirred at 70 °C for 12 hours, producing a yellow mixture. Once the contents cooled to room temperature, volatiles were removed via reduced pressure, leaving a light-yellow solid that was catalyst IrBB (0.023 g, 80%). 1H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.44 (d, J = 5.6 Hz, 1H), 8.34 (t, J = 5.6 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 4.2 Hz, 1H), 8.05 (s, 1H), 7.90 (t, J = 8.7 Hz, 1H), 7.86 (t, J = 8.0 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.56 (t, J = 6.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.92 – 6.82 (m, 3H), 4.84 – 4.78 (m, 1H), 4.74 – 4.68 (m, 1H), 4.29 (t, J = 8.6 Hz, 1H), 3.40 (t, J = 8.5 Hz, 1H), 3.00 (q, J = 11.6 Hz, 1H), 2.55 – 2.35 (m, 3H), 2.26 – 1.99 (m, 1H), 2.09 – 1.99 (m, 1H). Spectra were in accordance with the literature.1 93 Synthesis of B,N-Double Bidentate Iridium Complex (IrBB’) [Ir(Cl)cod]2 (0.0375 g, 0.056 mmol, 1 equiv) and BB (0.0205 g, 0.053 mmol, 1 equiv) were added to a Schlenk flask containing a magnetic stir bar. The contents were dissolved in pentane. Contents were stirred at 36 °C for 3 hours, then the reaction was allowed to cool to room temperature before removing solvent by reduced pressure. A bright yellow solid was obtained (mass recovery 58 mg) that was catalyst (IrBB’). 1H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.44 (d, J = 5.6 Hz, 1H), 8.34 (t, J = 5.6 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 4.2 Hz, 1H), 8.05 (s, 1H), 7.90 (t, J = 8.7 Hz, 1H), 7.86 (t, J = 8.0 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.56 (t, J = 6.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.92 – 6.82 (m, 3H), 4.84 – 4.78 (m, 1H), 4.74 – 4.68 (m, 1H), 4.29 (t, J = 8.6 Hz, 1H), 3.97 (S, 4H), 3.40 (t, J = 8.5 Hz, 1H), 3.00 (q, J = 11.6 Hz, 1H), 2.55 – 2.35 (m, 3H), 2.26 – 1.99 (m, 1H), 2.16 (m, 4H), 2.09 – 1.99 (m, 1H), 1.57 (m, 4H). 94 Single Crystal X-ray Diffraction Data for Complex 2 Crystals suitable for x-ray analysis were made via solvent diffusion. Complex 2 was dissolved in minimal DCM inside a 20 mL vial. The vial was then placed in a larger vessel containing pentane and sealed in a nitrogen-filled glovebox. Golden sheet-like crystals formed from this method. Crystal data and structure refinement for IrBB’. Identification code IrBB’ Empirical formula C19H21BClIrN3 Formula weight 529.85 Temperature/K 173.15 Crystal system monoclinic Space group P21/n a/Å 16.7801(14) b/Å 15.1131(12) c/Å 17.9229(15) α/° 90 β/° 112.8850(10) γ/° 90 95 Volume/Å3 4187.5(6) Z 8 ρcalcg/cm3 1.681 μ/mm‑1 6.510 F(000) 2040.0 Crystal size/mm3 0.22 × 0.16 × 0.085 Radiation MoKα (λ = 0.71073) 2Θ range for data collection/° 3.654 to 50.844 Index ranges -20 ≤ h ≤ 20, -18 ≤ k ≤ 18, -21 ≤ l ≤ 21 Reflections collected 33637 Independent reflections 7716 [Rint = 0.1098, Rsigma = 0.0967] Data/restraints/parameters 7716/0/451 Goodness-of-fit on F2 0.944 Final R indexes [I>=2σ (I)] R1 = 0.0487, wR2 = 0.1049 Final R indexes [all data] R1 = 0.0817, wR2 = 0.1178 Largest diff. peak/hole / e Å-3 2.40/-1.35 Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for AlexOBN. Ueq is defined as 1/3 of the trace of the orthogonalized UIJ tensor. Atom x y z U(eq) Ir01 7236.2(2) 4353.3(2) 7400.9(2) 23.04(12) Ir02 7449.5(3) 1692.4(3) 4318.2(2) 29.32(13) Cl1 6366.7(18) 1446.9(18) 4833.8(17) 41.7(7) 96 Cl2 8411.8(18) 2135.4(18) 5632.1(16) 44.2(7) N007 6358(5) 5418(5) 6967(4) 20.6(17) N008 6394(5) 5064(5) 5747(4) 22.4(18) N009 6723(5) 4211(5) 8369(5) 26.2(19) N00A 5822(5) 3226(5) 7472(5) 24.1(18) N00B 6004(5) 2741(5) 6333(4) 27.1(19) N00C 7262(5) 3969(5) 5599(5) 28.1(19) C00D 5343(6) 2237(6) 6429(5) 23(2) C00E 6051(6) 5606(6) 6161(6) 27(2) C00F 6322(5) 5060(6) 4926(5) 22(2) C00G 8116(6) 3332(6) 8082(5) 23(2) C00H 6021(6) 3666(6) 8201(6) 24(2) C00I 6798(6) 921(7) 3288(6) 35(3) C00J 8495(7) 1457(7) 3987(7) 35(3) C00K 5230(6) 2533(6) 7124(6) 28(2) C00L 8337(6) 5349(6) 7512(6) 28(2) C00M 5480(6) 6584(6) 7134(6) 30(2) B00N 7040(6) 4394(6) 6199(7) 21(2) C00O 9052(6) 3927(6) 7336(6) 27(2) C00P 5428(6) 6258(6) 5814(6) 33(2) C00Q 8996(6) 4642(6) 8903(5) 29(2) C00R 8345(6) 5221(6) 8271(6) 26(2) C00S 8939(6) 4929(6) 7185(5) 31(2) 97 C00T 5846(6) 5571(6) 4242(6) 34(3) C00U 4596(6) 2129(6) 7336(6) 30(2) C00V 4849(6) 1566(6) 5960(6) 33(3) C00W 4249(7) 1173(6) 6157(6) 37(3) C00X 8249(6) 3449(6) 7371(6) 27(2) C00Y 6857(6) 4380(6) 4860(6) 24(2) C00Z 6087(6) 5927(6) 7427(6) 28(2) C010 5585(7) 3593(7) 8710(6) 33(2) C011 6936(6) 4217(7) 4137(5) 33(3) B012 6308(7) 3391(7) 6963(7) 24(2) C013 8177(7) 2302(7) 3769(7) 43(3) C014 6503(7) 1799(7) 3150(7) 42(3) C015 8712(6) 3667(6) 8905(6) 30(2) C016 5141(6) 6740(6) 6315(6) 31(2) C017 6458(7) 4727(6) 3484(6) 37(3) C018 5926(7) 5398(7) 3540(6) 38(3) C019 4104(7) 1439(7) 6832(7) 38(3) C01A 6602(7) 4586(7) 9627(6) 39(3) C01B 7000(7) 4654(7) 9088(6) 33(2) C01C 6724(8) 2451(8) 2635(7) 57(4) C01D 8338(8) 698(7) 3389(7) 51(3) C01E 5876(7) 4047(7) 9426(7) 44(3) C01F 7683(8) 2598(8) 2890(7) 47(3) 98 C01G 7382(7) 540(8) 2882(8) 58(4) Anisotropic Displacement Parameters (Å2×103) for AlexOBN. The Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+…]. Atom U11 U22 U33 U23 U13 U12 Ir01 20.0(2) 24.7(2) 18.7(2) 0.33(17) 1.34(15) 0.24(16) Ir02 31.5(2) 31.3(2) 24.8(2) 1.21(18) 10.61(18) 3.82(18) Cl1 44.5(17) 46.8(16) 41.1(16) 14.2(13) 24.8(14) 11.9(13) Cl2 46.9(17) 47.0(16) 26.8(14) -6.0(13) 1.3(13) 15.7(14) N007 23(4) 20(4) 18(4) 6(3) 7(4) 5(3) N008 18(4) 21(4) 22(4) -2(3) 2(3) -1(3) N009 23(4) 23(4) 33(5) -5(4) 11(4) -1(4) N00A 22(4) 26(4) 21(4) -3(3) 4(4) 1(4) N00B 26(5) 34(5) 18(4) -1(4) 5(4) -8(4) N00C 26(5) 28(4) 30(5) 6(4) 10(4) 15(4) C00D 16(5) 24(5) 24(5) 4(4) 3(4) 2(4) C00E 13(5) 33(6) 36(6) 0(5) 10(4) -8(4) C00F 13(5) 24(5) 24(5) 7(4) 1(4) 0(4) C00G 26(5) 19(5) 21(5) 0(4) 6(4) 5(4) C00H 18(5) 21(5) 24(5) 1(4) -3(4) 5(4) C00I 27(6) 45(6) 28(6) -3(5) 6(5) 3(5) C00J 27(6) 44(7) 43(7) -5(5) 25(5) 6(5) C00K 13(5) 24(5) 33(6) -2(4) -5(4) 4(4) C00L 28(6) 29(5) 22(5) -7(4) 3(5) -2(5) 99 C00M 32(6) 29(6) 34(6) -4(5) 17(5) 6(5) B00N 12(5) 15(5) 29(6) 10(5) 2(5) -3(4) C00O 21(5) 45(6) 22(5) -2(5) 14(4) 2(5) C00P 27(6) 33(6) 29(6) 4(5) 1(5) 5(5) C00Q 10(5) 51(6) 14(5) -3(5) -7(4) 1(4) C00R 15(5) 28(5) 28(6) 3(4) 2(4) 0(4) C00S 36(6) 42(6) 12(5) -6(4) 6(4) -5(5) C00T 29(6) 36(6) 25(6) 0(5) -2(5) 15(5) C00U 33(6) 31(6) 21(5) -11(4) 4(5) 5(5) C00V 32(6) 33(6) 27(6) 14(5) 3(5) 8(5) C00W 33(6) 29(6) 33(6) -10(5) -3(5) -10(5) C00X 29(6) 21(5) 30(6) -2(4) 10(5) 12(4) C00Y 20(5) 25(5) 24(5) 1(4) 3(4) 2(4) C00Z 22(5) 38(6) 22(5) 5(5) 6(4) -6(5) C010 31(6) 43(6) 30(6) -9(5) 18(5) -12(5) C011 16(5) 64(7) 14(5) 0(5) -1(4) 0(5) B012 21(6) 28(6) 26(6) -3(5) 13(5) 8(5) C013 40(7) 50(7) 35(7) 0(6) 11(5) -2(6) C014 30(6) 54(7) 37(7) -1(6) 9(5) -8(5) C015 25(6) 30(5) 26(6) 2(4) 0(5) -1(4) C016 30(6) 31(6) 30(6) 7(5) 7(5) 2(5) C017 44(7) 34(6) 28(6) 1(5) 8(5) 10(5) C018 38(7) 40(6) 26(6) 13(5) 1(5) 9(5) 100 C019 26(6) 40(6) 46(7) -2(5) 13(5) -7(5) C01A 49(7) 47(7) 23(6) -12(5) 15(5) -12(6) C01B 36(6) 39(6) 17(5) -1(5) 2(5) 0(5) C01C 72(9) 52(8) 37(7) 0(6) 10(7) -20(7) C01D 60(8) 52(7) 43(7) -7(6) 24(6) 18(6) C01E 40(7) 58(7) 36(7) -5(6) 17(6) -4(6) C01F 60(8) 45(7) 40(7) -7(6) 24(6) -6(6) C01G 46(8) 61(8) 58(9) -29(7) 12(7) -8(6) Bond Lengths for AlexOBN. Atom Atom Length/Å Atom Atom Length/Å Ir01 N007 2.115(7) C00F C00Y 1.400(12) Ir01 N009 2.226(8) C00G C00X 1.388(13) Ir01 C00G 2.156(8) C00G C015 1.512(12) Ir01 C00L 2.330(9) C00H C010 1.378(13) Ir01 B00N 2.050(11) C00I C014 1.405(14) Ir01 C00R 2.314(9) C00I C01G 1.540(15) Ir01 C00X 2.198(9) C00J C013 1.380(14) Ir01 B012 2.051(11) C00J C01D 1.522(14) Ir02 Cl1 2.366(3) C00K C00U 1.402(13) Ir02 Cl2 2.376(3) C00L C00R 1.368(13) Ir02 C00I 2.097(10) C00L C00S 1.493(13) Ir02 C00J 2.090(9) C00M C00Z 1.372(13) Ir02 C013 2.060(11) C00M C016 1.372(13) 101 Ir02 C014 2.085(11) C00O C00S 1.538(13) N007 C00E 1.361(12) C00O C00X 1.551(13) N007 C00Z 1.330(12) C00P C016 1.383(14) N008 C00E 1.373(11) C00Q C00R 1.509(12) N008 C00F 1.429(11) C00Q C015 1.550(13) N008 B00N 1.474(12) C00T C018 1.344(14) N009 C00H 1.372(11) C00U C019 1.416(13) N009 C01B 1.364(12) C00V C00W 1.330(14) N00A C00H 1.386(11) C00W C019 1.383(14) N00A C00K 1.410(11) C00Y C011 1.375(13) N00A B012 1.461(13) C010 C01E 1.367(14) N00B C00D 1.410(11) C011 C017 1.370(13) N00B B012 1.432(12) C013 C01F 1.535(15) N00C B00N 1.421(13) C014 C01C 1.492(15) N00C C00Y 1.379(11) C017 C018 1.380(13) C00D C00K 1.404(13) C01A C01B 1.375(14) C00D C00V 1.370(13) C01A C01E 1.392(14) C00E C00P 1.395(13) C01C C01F 1.509(16) C00F C00T 1.405(12) C01D C01G 1.524(16) Bond Angles for AlexOBN. Atom Atom Atom Angle/˚ Atom Atom Atom Angle/˚ N007 Ir01 N009 86.3(3) C00Y C00F C00T 119.8(9) N007 Ir01 C00G 168.1(3) C00X C00G Ir01 73.1(5) 102 N007 Ir01 C00L 87.5(3) C00X C00G C015 124.9(9) N007 Ir01 C00R 94.6(3) C015 C00G Ir01 111.1(6) N007 Ir01 C00X 154.0(3) N009 C00H N00A 111.5(8) N009 Ir01 C00L 122.0(3) N009 C00H C010 122.3(9) N009 Ir01 C00R 89.0(3) C010 C00H N00A 126.2(9) C00G Ir01 N009 82.9(3) C014 C00I Ir02 69.9(6) C00G Ir01 C00L 93.9(3) C014 C00I C01G 121.0(10) C00G Ir01 C00R 80.2(3) C01G C00I Ir02 114.5(7) C00G Ir01 C00X 37.1(3) C013 C00J Ir02 69.4(6) B00N Ir01 N007 77.7(3) C013 C00J C01D 123.9(10) B00N Ir01 N009 150.4(3) C01D C00J Ir02 113.2(7) B00N Ir01 C00G 114.3(4) C00D C00K N00A 108.3(8) B00N Ir01 C00L 82.4(4) C00U C00K N00A 133.0(9) B00N Ir01 C00R 116.7(4) C00U C00K C00D 118.7(8) B00N Ir01 C00X 78.6(4) C00R C00L Ir01 72.2(6) B00N Ir01 B012 80.3(4) C00R C00L C00S 125.7(9) C00R Ir01 C00L 34.3(3) C00S C00L Ir01 109.0(6) C00X Ir01 N009 119.7(3) C016 C00M C00Z 118.1(9) C00X Ir01 C00L 79.0(3) N008 B00N Ir01 112.4(7) C00X Ir01 C00R 86.7(3) N00C B00N Ir01 143.1(7) B012 Ir01 N007 94.7(4) N00C B00N N008 104.3(8) B012 Ir01 N009 76.3(4) C00S C00O C00X 114.5(8) B012 Ir01 C00G 87.7(4) C016 C00P C00E 118.2(9) 103 B012 Ir01 C00L 161.7(4) C00R C00Q C015 114.8(7) B012 Ir01 C00R 162.1(4) C00L C00R Ir01 73.5(5) B012 Ir01 C00X 91.7(4) C00L C00R C00Q 123.5(9) Cl1 Ir02 Cl2 89.21(10) C00Q C00R Ir01 109.6(6) C00I Ir02 Cl1 92.3(3) C00L C00S C00O 114.0(8) C00I Ir02 Cl2 161.9(3) C018 C00T C00F 118.6(9) C00J Ir02 Cl1 160.3(3) C00K C00U C019 117.6(9) C00J Ir02 Cl2 90.4(3) C00W C00V C00D 120.5(10) C00J Ir02 C00I 82.1(4) C00V C00W C019 120.7(10) C013 Ir02 Cl1 160.8(3) C00G C00X Ir01 69.8(5) C013 Ir02 Cl2 92.7(3) C00G C00X C00O 123.2(9) C013 Ir02 C00I 91.7(4) C00O C00X Ir01 113.8(6) C013 Ir02 C00J 38.8(4) N00C C00Y C00F 110.0(8) C013 Ir02 C014 81.2(4) C011 C00Y N00C 129.2(9) C014 Ir02 Cl1 90.2(3) C011 C00Y C00F 120.7(9) C014 Ir02 Cl2 158.8(3) N007 C00Z C00M 124.3(9) C014 Ir02 C00I 39.3(4) C01E C010 C00H 119.6(10) C014 Ir02 C00J 97.1(4) C017 C011 C00Y 117.7(10) C00E N007 Ir01 118.1(6) N00A B012 Ir01 114.0(7) C00Z N007 Ir01 124.7(6) N00B B012 Ir01 140.6(8) C00Z N007 C00E 117.2(8) N00B B012 N00A 105.1(8) C00E N008 C00F 132.4(8) C00J C013 Ir02 71.8(6) C00E N008 B00N 119.0(8) C00J C013 C01F 123.7(10) 104 C00F N008 B00N 108.2(7) C01F C013 Ir02 116.0(8) C00H N009 Ir01 116.5(6) C00I C014 Ir02 70.8(6) C01B N009 Ir01 126.6(6) C00I C014 C01C 125.2(11) C01B N009 C00H 116.7(8) C01C C014 Ir02 113.4(7) C00H N00A C00K 130.0(8) C00G C015 C00Q 113.7(8) C00H N00A B012 121.2(8) C00M C016 C00P 120.0(9) C00K N00A B012 108.6(8) C011 C017 C018 122.1(10) C00D N00B B012 109.3(8) C00T C018 C017 121.1(9) C00Y N00C B00N 110.3(7) C00W C019 C00U 121.0(10) C00K C00D N00B 108.6(8) C01B C01A C01E 118.5(10) C00V C00D N00B 129.9(9) N009 C01B C01A 123.2(10) C00V C00D C00K 121.5(9) C014 C01C C01F 113.8(10) N007 C00E N008 112.6(8) C00J C01D C01G 113.0(9) N007 C00E C00P 122.0(9) C010 C01E C01A 119.6(10) N008 C00E C00P 125.3(9) C01C C01F C013 110.7(9) C00T C00F N008 133.4(8) C01D C01G C00I 112.1(9) C00Y C00F N008 106.8(7) Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for AlexOBN. Atom x y z U(eq) H00B 5862 2960 5843 33 H00C 7608 3509 5686 34 H00G 7824 2762 8102 27 105 H00J 6374 490 3347 42 H00K 9068 1434 4453 42 H00L 8125 5947 7280 34 H00M 5300 6921 7488 36 H00A 9550 3826 7855 33 H00D 9195 3656 6901 33 H00P 5208 6367 5247 39 H00E 9116 4901 9443 35 H00F 9543 4651 8815 35 H00R 8146 5743 8496 31 H00H 9512 5217 7434 37 H00I 8718 5038 6594 37 H00T 5474 6030 4276 41 H00U 4500 2311 7801 36 H00V 4936 1381 5491 40 H00W 3915 705 5830 44 H00X 8029 2952 6975 33 H00Z 6329 5829 7995 34 H010 5086 3229 8564 39 H011 7309 3766 4092 40 H013 8569 2771 4114 51 H014 5906 1877 3137 50 H01A 9235 3288 9110 36 106 H01B 8416 3609 9284 36 H016 4709 7180 6094 38 H017 6494 4615 2976 45 H018 5613 5742 3074 46 H019 3668 1154 6959 45 H01C 6819 4900 10126 47 H01D 7492 5027 9223 40 H01F 6445 3023 2653 68 H01G 6481 2240 2067 68 H01H 8592 150 3692 61 H01I 8639 826 3023 61 H01E 5583 3996 9784 53 H01J 7795 3234 2837 56 H01K 7893 2261 2528 56 H01L 7276 -103 2799 69 H01M 7229 819 2344 69 Crystal structure determination of [AlexOBN] Crystal Data for C19H21BClIrN3 (M =529.85 g/mol): monoclinic, space group P21/n (no. 14), a = 16.7801(14) Å, b = 15.1131(12) Å, c = 17.9229(15) Å, β = 112.8850(10)°, V = 4187.5(6) Å3, Z = 8, T = 173.15 K, μ(MoKα) = 6.510 mm-1, Dcalc = 1.681 g/cm3, 33637 reflections measured (3.654° ≤ 2Θ ≤ 50.844°), 7716 unique (Rint = 0.1098, Rsigma = 0.0967) which were used in all calculations. The final R1 was 0.0487 (I > 2σ(I)) and wR2 was 0.1178 (all data). 107 Synthesis of 2-(dimethyl(phenyl)silyl)-1-(pyridin-2-yl)-2,3-dihydro-1H- benzo[d][1,3,2]diazaborole (SiB) a) Synthesis of Chlorobis(diisopropylamino)borane (BClN2) In a 250 mL three-neck flask with magnetic stir bar and condenser, diisopropylamine (9.1 g, 12.6 mL, 90 mmol, 4.5 equiv) and toluene (20 mL) were added under nitrogen flow. 1.0 M solution of boron trichloride in heptane (20 mL, 20 mmol, 1 equiv) was added dropwise over 5 minutes at room temperature via syringe. Once the boron reagent was added, the temperature was kept at 40 °C for 7 hours. After this, the reaction was cooled to room temperature and solids were filtered off and rinsed with cyclohexane (2 x 20 mL). The filtrate was concentrated, and the resulting crude oil was distilled (33 °C, 0.008 mmHg) to yield 1.82 g (37%) as a milky white oil. 1H NMR (500 MHz, CDCl3) δ 3.47 (septet, J = 6.8 Hz, 2H), 1.21 (d, J = 1.2 Hz, 12H); 11B NMR (160 MHz, CDCl3) δ 30.2 (s).13 108 b) Synthesis of Dimethylphenylsilyllithium Solution (LiSi) In a 50 mL Schlenk flask equipped with a magnetic stir bar, granular lithium (1.11 g, 160 mmol, 10 equiv) was added under a flow of argon gas. Under continuous argon flow, THF (17.6 mL) was added followed by chloro(dimethyl)phenylsilane (2.72 g, 16 mmol, 1 equiv) dropwise via syringe. The contents were allowed to stir for 16 hours at room temperature yielding a dark brown silyl-lithium solution (0.8 M in THF, 20 mL).13 c) Synthesis of Dimethylphenylsilylbis(diisopropylamino)borane Preligand (SiBP) To a 50 mL Schlenk flask with stir bar, BClN2 (2.96 g, 12 mmol, 1 equiv) was added via syringe under a flow of argon gas. 12 mL of n-hexane was added to this same flask followed by LiSi solution (15 mL, 12 mmol, 1 equiv) dropwise. The solution was stirred at room temperature until the contents went from dark brown to a light tan color. The solid precipitate that formed was filtered off and THF (3 x 5 mL) was passed through the same filter. The oil that resulted was concentrated and distilled (115 °C, 0.007 mmHg) to give a colorless oil (2.25 g, 54%). 1H NMR (500 MHz, CDCl3) δ 7.54 (m, 2H), 7.30 (m, 3H), 3.82 (m, 4H), 1.18 (dd, J = 26.7, 6.9 Hz, 24H), 0.34 (d, J = 0.32 Hz, 6H); 11B NMR (160 MHz, CDCl3) δ 41.5 (s).13 109 d) Synthesis of (SiB) In a 10 mL Schlenk flask equipped with a magnetic stir bar, with L1 (0.185 g, 1 mmol, 1 equiv) was added along with SiBP (0.450 g, 1.3 mmol, 1.3 equiv). Next, 2 mL of toluene was added to the flask. The flask was sealed and stirred at 125 °C for 36 hours. After this time, volatiles were removed, and the crude solid was washed with cyclohexane (3 x 5 mL). A pale lavender solid was obtained (0.253 g, 77%). 1H NMR (500 MHz, CDCl3) δ 8.52 (ddd, J = 4.9, 2.0, 0.9 Hz, 1H), 7.72 – 7.68 (ddd, J = 8.0, 7.4, 2.0 Hz, 1H), 7.54 – 7.51 (m, 2H), 7.47 (dd, J = 7.5, 1.6 Hz, 1H), 7.34 – 7.30 (m, 4H), 7.29 (t, J = 0.9Hz, 1H), 7.16 (ddd, J = 7.4, 4.9, 1.0 Hz, 1H), 7.13 – 7.10 (m, 1H), 7.05 – 6.98 (m, 2H) 6.93 (bs, 1H), 0.34 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 154.8, 148.9, 140.4, 137.9, 137.1, 136.0, 134.0, 128.4, 127.8, 120.6, 119.8, 118.5, 111.5, 111.3, -2.47; 11B NMR (160 MHz, CDCl3) δ 31.1 (bs).13 110 Optimization Screen for ortho C—H Borylation—potassium tert-butoxide additive. Entry KOtBu Loading Conversion o:(m+p) (mol %) (%) (%) 1 1 80 1:99 2 2 65 1:99 3 5 16 1:99 4 10 --- --- Reactions run on 0.5 mmol scale of substrate, 0.5 mmol B2pin2, 1 mol % [Ir(OMe)cod]2, and 2 mol % BB ligand in 1 mL THF. Conversions and selectivity determined by 1H NMR analysis of sample. Optimization Screen for ortho C—H Borylation Entry Ligand Loading Conversion o:(m*+p) (mol %) (%) (%) 1 2 99 1:99 2 1 80 60:40 3 0.75 74 90:10 4 0.50 67 95:5 Reactions run on 0.5 mmol scale of substrate, 0.5 mmol B2pin2, 1 mol % [Ir(OMe)cod]2, and x mol % BB ligand in 1 mL THF. Conversions and selectivity determined by 1H NMR analysis of sample. Meta selectivity (m*) includes dimeta-borylated products. 111 Compound Characterizations for Steric- and Chelate-Directed Products Condition A (for ortho borylation): Inside a nitrogen-filled glove box, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(X)cod]2 (0.005 mmol) (X = OMe or Cl), 0.50 mol % BB ligand (0.0025 mmol), in 1 mL THF to a reaction vial equipped with a stir bar. (Hetero)Arene substrate (0.5 mmol, 1 equiv) was added and the vial was sealed with a screw cap. Heat the vial while stirring for 4-16 hours. Allow contents to cool to room temperature, remove volatiles, run compound through a small plug of silica gel with DCM as eluent. Concentrate collected material and dry under vacuum. Condition B (for steric borylation): Inside a nitrogen-filled glove box, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 2 mol % BB ligand (0.010 mmol), in 1 mL THF to a reaction vial equipped with a stir bar. (Hetero)Arene substrate (0.5 mmol, 1 equiv) was added and the vial was sealed with a screw cap. Heat the vial while stirring for 4-8 hours. Allow contents to cool to room temperature, remove volatiles, run compound through a small plug of silica gel with DCM as eluent. Concentrate collected material and dry under vacuum. 112 Methyl 2-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (1a) Following general procedure A, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(Cl)cod]2 (0.005 mmol), 0.50 mol % BB ligand (0.0025 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl benzoate (63 µL, 68 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 16 h. Starting material converted to 80% (o:(m+p):di-o) = 76:6:2:14) borylated products. 1a was obtained as a colorless oil (96 mg, 73%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 7.95 (dt, J = 7.8, 0.9 Hz, 1H), 7.54 – 7.50 (m, 2H), 7.44 – 7.40 (ddd, J = 7.8, 6.2, 2.6 Hz, 1H), 3.92 (s, 3H), 1.43 (s, 12H); 11B NMR (160 MHz, CDCl3) δ 31.6 (s). Using [Ir(Cl)cod]2 as the precatalyst yielded 111 mg (85%) borylated products in the ratio (o:(m+p):di-o) = 76:6:2:14). Spectral data were in accordance to literature.7 Methyl 3,5-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (1b) Following general procedure B, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 2 mol % BB ligand (0.010 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl benzoate (63 µL, 68 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 8 h. Starting material converted to 99% (o:(m+di-m):p) = (0:70:30) 113 borylated products. 1b was obtained as a colorless oil (124 mg, 95%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J = 1.3 Hz, 1H), 8.44 (t, J = 1.3 Hz, 1H), 4.00 – 3.81 (m, 3H), 1.36 (d, J = 4.2 Hz, 12H); 11 B NMR (160 MHz, CDCl3) δ 31.4 (s). Spectral data were in accordance to literature.15 tert-Butyl 2-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (2a) Following general procedure A, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 0.50 mol % BB ligand (0.0025 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. tert-Butyl benzoate (89 µL, 89 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 16 h. Starting material converted to 67% (o:(m+p) = 95:5) borylated products. 2a was obtained as a white solid (99 mg, 63%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 7.82 (dt, J = 7.7, 0.9 Hz, 1H), 7.49 – 7.45 (m, 2H), 7.39 – 7.34 (ddd, J = 7.7, 6.0, 2.8 Hz, 1H), 1.59 (s, 3H), 1.42 (s, 12H); 11B NMR (160 MHz, CDCl3) δ 31.4 (s). Using [Ir(Cl)cod]2 as the precatalyst yielded 126 mg (83%) borylated products in the ratio (o:(m+p) = 96:4). Spectral data were in accordance to literature.8 tert-Butyl 3,5-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (2b) 114 Following general procedure B, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 2 mol % BB ligand (0.010 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. tert-Butyl benzoate (89 µL, 89 mg, 0.5 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 8 h. Starting material converted to 90% (o:(m+di-m):p = 0:65:35) products. 2b was obtained as a colorless oil (225 mg, 66%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 8.40 (dt, J = 2.8, 1.5 Hz, 1H), 8.31 (dt, J = 7.8, 1.6 Hz, 1H), (d, J = 1.4 Hz, 9H), 1.18 (d, J = 2.6 Hz, 12H); 11 B NMR (160 MHz, CDCl3) δ 30.2 (bs). Spectral data were in accordance to literature.13 Methyl 3-methoxy-6-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (3a) Following general procedure A, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 0.50 mol % BB ligand (0.0025 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 3-methoxybenzoate (73 µL, 83 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 16 h. Starting material converted to 65% (6 position:5 position = 92:8) borylated products. 3a was obtained as a colorless oil (83 mg, 62%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 7.43 (s, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.03 (dd, J = 8.1, 2.6 Hz, 1H), 3.91 (d, J = 1.3 Hz, 4H), 3.84 (s, 3H), 1.41 (s, 12H).; 11B NMR (160 MHz, CDCl3) δ 31.1 (bs). Using 115 [Ir(Cl)cod]2 as the precatalyst yielded 104 mg (78%) borylated products in the ratio (6 position:5 position = 93:7). Spectral data were in accordance to literature.8 Methyl 3-methoxy-5-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (3b) Following general procedure B, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 2 mol % BB ligand (0.010 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 3-methoxybenzoate (73 µL, 83 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 8 h. Starting material converted to 85% (6 position:5 position = 5:95) borylated products. 3b was obtained as a colorless oil (112 mg, 76%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 8.07 (dd, J = 1.5, 0.9 Hz, 1H), 7.66 (dd, J = 2.7, 1.5 Hz, 1H), 7.52 (dd, J = 2.8, 0.9 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 1.36 (s, 12H); 11B NMR (160 MHz, CDCl3) δ 30.8 (s). Spectral data were in accordance to literature.16 Methyl 3-dimethylamino-6-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (4a) Following general procedure A, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 0.50 mol % BB ligand (0.0025 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 3-(dimethylamino)benzoate (81 116 µL, 90 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 16 h. Starting material converted to 76% (6 position:5 position = 84:16) products. 4a was obtained as a colorless oil (90 mg, 62%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 2.6 Hz, 1H), 6.81 (dd, J = 8.3, 2.6 Hz, 1H), 3.89 (s, 3H), 2.99 (s, 6H), 1.38 (s, 12H). 11B NMR (160 MHz, CDCl3) δ 31.9 (bs). Using [Ir(Cl)cod]2 as the precatalyst yielded 110 mg (72%) borylated products in the ratio (6 position:5 position = 91:9). Spectral data were in accordance to literature.9 Methyl 3-dimethylamino-5-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (4b) Following general procedure B, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 2 mol % BB ligand (0.010 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 3-(dimethylamino)benzoate (81 µL, 90 mg, 0.50 mmol) was added, and the vial was sealed with a screw valve cap. The reaction mixture was stirred at 100 °C for 8 h. Starting material converted to 94% (6 position:5 position = 1:99) products. 4b was obtained as a colorless oil (122 mg, 80%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 7.82 (dd, J = 1.5, 0.9 Hz, 1H), 7.49 (dd, J = 2.9, 1.5 Hz, 1H), 7.34 (dd, J = 2.9, 0.9 Hz, 1H), 3.89 (s, 3H), 3.01 (s, 6H), 1.35 (s, 12H); ); 11B NMR (160 MHz, CDCl3) δ 31.1 (bs). Spectral data were in accordance to literature.4 117 Methyl 3-bromo-6-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (5a) Following general procedure A, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 0.50 mol % BB ligand (0.0025 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 3-bromobenzoate (108 mg, 0.5 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 16 h. Starting material converted to 80% (6 position:5 position = 80:20) products. 5a was obtained as a colorless oil (132 mg, 77%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 8.09 (dd, J = 2.0, 0.5 Hz, 1H), 7.62 (dd, J = 7.9, 1.9 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 3.93 (s, 3H), 1.42 (s, 12H); 11 B NMR (160 MHz, CDCl3) δ 30.9 (bs). Using [Ir(Cl)cod]2 as the precatalyst yielded 138 mg (96%) borylated products in the ratio (6 position:5 position = 77:33). Spectral data were in accordance to literature.4 Methyl 3-bromo-5-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (5b) Following general procedure B, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 2 mol % BB ligand (0.010 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 3-bromobenzoate (108 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 8 h. Starting material converted to 98% (6 position:5 position = 1:99) 118 products. 5b was obtained as a colorless oil (159 mg, 93%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 8.37 (t, J = 1.3 Hz, 1H), 8.25 (t, J = 1.9 Hz, 1H), 8.10 (dd, J = 2.1, 1.0 Hz, 1H), 3.92 (s 3H), 1.35 (s, 12H); 11 B NMR (160 MHz, CDCl3) δ 30.4 (bs). Spectral data were in accordance to literature.17 Methyl 3-trifluoromethyl-6-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (6a) Following general procedure A, B2pin2 (127 mg, 0.500 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 0.50 mol % BB ligand (0.0025 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 3-(trifluoromethyl)benzoate (79 µL, 102 mg, 0.50 mmol) was added and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 16 h. Starting material converted to 85% (6 position:5 position = 73:27) products. 6a was obtained as a colorless oil (117 mg, 72%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 8.21 (dt, J = 1.6, 0.8 Hz, 1H), 7.77 (ddt, J = 7.8, 1.8, 0.8 Hz, 1H), 7.63 (dt, J = 7.7, 0.7 Hz, 1H), 3.94 (s, 3H), 1.41 (s, 12H); 11 B NMR (160 MHz, CDCl3) δ 29.6 (bs). Using [Ir(Cl)cod]2 as the precatalyst yielded 134 mg (82%) borylated products in the ratio (6 position:5 position = 83:17). Spectral data were in accordance to literature.8 119 Methyl 3-trifluoromethyl-5-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)benzoate (6b) Following general procedure B, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 0.50 mol % BB ligand (0.010 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 3-(trifluoromethyl)benzoate (79 µL, 102 mg, 0.50 mmol) was added and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 8 h. Starting material converted to 93% (6 position:5 position = 1:99) products. 6b was obtained as a colorless oil (145 mg, 88%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 8.62 (ddd, J = 1.7, 1.2, 0.6 Hz, 1H), 8.37 (tq, J = 1.2, 0.6 Hz, 1H), 8.23 (dq, J = 1.9, 0.9 Hz, 1H)., 3.95 (s, 3H), 1.36 (s, 12H); 11B NMR (160 MHz, CDCl3) δ 30.5 (bs). Spectral data were in accordance to literature.16 Methyl 5-bromo-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (7a) Following general procedure A, B2pin2 (127 mg, 0.500 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 0.50 mol % BB ligand (0.0025 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 5-bromo-2-fluorobenzoate (116 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture 120 was stirred at 100 °C for 16 h. Starting material converted to 94% (3 position = 100) products. 7a was obtained as a colorless oil (116 mg, 65%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 8.12 (dd, J = 6.2, 2.7, 1H), 7.99 (dd, J = 4.4, 2.8 Hz, 1H), 3.91 (s, 3H), 1.35 (s, 12H); 11B NMR (160 MHz, CDCl3) δ 28.2 (bs). Using [Ir(Cl)cod]2 as the precatalyst yielded 153 mg (90%) borylated products in the ratio (3 position = 1:99). Spectral data were in accordance to literature.4 Methyl 5-bromo-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (7b) Following general procedure B, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 2 mol % BB ligand (0.010 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 5-bromo-2-fluorobenzoate (116 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 8 h. Starting material converted to 98% (3 position = 1:99) products. 7b was obtained as a colorless oil (167 mg, 93%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 8.12 (dd, J = 6.2, 2.7, 1H), 7.99 (dd, J = 4.4, 2.8 Hz, 1H), 3.91 (s, 3H), 1.35 (s, 12H). 11B NMR (160 MHz, CDCl3) δ 29.9 (bs). Spectral data were in accordance to literature.4 121 N,N-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (9a) Following general procedure A, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 0.50 mol % BB ligand (0.0025 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. N,N-Dimethylbenzamide (74 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 16 h. Starting material converted to 95% (o:(m+p) = 95:5) products. 9a was obtained as a colorless oil (114 mg, 83%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 7.81 (ddd, J = 7.5, 1.4, 0.6 Hz, 1H), 7.46 (td, J = 7.5, 1.4 Hz, 1H), 7.37 (td, J = 7.5, 1.2 Hz, 1H), 7.30 (ddd, J 11 = 7.6, 1.3, 0.7 Hz, 1H), 3.06 (s, 3H), 2.89 (s, 3H), 1.30 (s, 12H); B NMR (160 MHz, CDCl3) δ 29.4 (bs). Using [Ir(Cl)cod]2 as the precatalyst yielded 123 mg (89%) borylated products in the ratio (o:(m+p) = 96:4). Spectral data were in accordance to literature.8 N,N-dimethyl-3,5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (9b) Following general procedure B, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 2 mol % BB ligand (0.010 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. N,N-Dimethylbenzamide (75 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 8 h. Starting material converted to 99% (o:(m+di-m):p = 1:77:22) 122 products. 9b was obtained as a colorless oil (119 mg, 91%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 8.29 (d, 11 J = 1.5 Hz, 1H), 7.93 (d, J = 1.2 Hz, 2H), 3.10 (s, 3H), 2.95 (s, 3H), 1.34 (s, 24H); B NMR (160 MHz, CDCl3) δ 29.0 (bs). Spectral data were in accordance to literature.18 Methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (11a) Following general procedure A, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 0.50 mol % BB ligand (0.0025 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl thiophene-2-carboxylate (58 µL, 71 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 16 h. Starting material converted to 99% (3:5 = 1:99) products. 11a was obtained as a colorless oil (118 mg, 90%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 Hz, CDCl3) δ 7.80 (d, J = 3.7 Hz, 1H), 7.55 (d, J = 3.7 Hz, 1H), 3.88 (s, 3H), 1.34 (s, 12H). 11B NMR (160 MHz, CDCl3) δ 28.9 (bs). Using [Ir(Cl)cod]2 as the precatalyst yielded 124 mg (85%) borylated products in the ratio (3:5 = 1:99).13 Methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (11b) Following general procedure B, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 2 mol % BB ligand (0.010 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl thiophene-2-carboxylate (58 µL, 71 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction 123 mixture was stirred at 100 °C for 4 h. Starting material converted to 99% (3-position:5- position = 1:99) products. 11b was obtained as a colorless oil (156 mg, 99%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 3.8 Hz, 1H), 7.56 (d, J = 3.7 Hz, 1H), 3.90 (s, 3H), 1.36 (s, 12H); 11B NMR (160 MHz, CDCl3) δ 28.9 (bs). Spectral data were in accordance to literature.13 Methyl-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2- carboxylate (12a) Following general procedure A, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 0.50 mol % BB ligand (0.0025 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 5-methylthiophene-2-carboxylate (66 µL, 78 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 4 h. Starting material converted to 88% (3:4 = 80:20) products. 12a was obtained as a colorless oil (78 mg, 55%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 6.86 (q, J = 1.0 Hz, 1H), 3.93 (s, 3H), 2.53 (d, J = 1.0 Hz, 3H), 1.40 (s, 12H); 11B NMR (160 MHz, CDCl3) δ 28.8 (bs). Using [Ir(Cl)cod]2 as the precatalyst yielded 120 mg (85%) borylated products in the ratio (3:4 = 86:14).14 Methyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2- carboxylate (12b) 124 Following general procedure B, B2pin2 (127 mg, 0.50 mmol, 1 equiv), 1 mol % [Ir(OMe)cod]2 (0.005 mmol), 2 mol % BB ligand (0.010 mmol), and THF (1 mL) were added to a reaction vial equipped with a stir bar. Methyl 5-methylthiophene-2-carboxylate (66 µL, 78 mg, 0.50 mmol) was added, and the vial was sealed with a screw cap. The reaction mixture was stirred at 100 °C for 4 h. Starting material converted to 99% (3:4 = 1:99) products. 12b was obtained as a colorless oil (131 mg, 93%) after passing crude material through a short plug of silica using DCM as eluent. 1H NMR (500 MHz, CDCl3) δ 7.93 (s, 1H), 3.83 (s, 3H), 2.69 (s, 3H), 1.30 (s, 12H); 11 B NMR (160 MHz, CDCl3) δ 31.0 (bs).14 4.3 Spectral Data Proton NMR spectra were recorded on a Varian 500 MHz instrument. Carbon NMR and Boron NMR were recorded on 126 MHz and 160 MHz instruments, respectively. The following pages show the spectral data for chapters 2 and 3. 125 1H NMR (500 MHz, CDCl3) 126 13C NMR (126 MHz, CDCl3) 127 1H NMR (500 MHz, CDCl3) 128 13C NMR (126 MHz, CDCl3) 129 1H NMR (500 MHz, CDCl3) 130 13C NMR (126 MHz, CDCl3) 131 1H NMR (500 MHz, CDCl3) 132 13C NMR (126 MHz, CDCl3) 133 1H NMR (500 MHz, CDCl3) 134 13C NMR (126 MHz, CDCl3) 135 1H NMR (500 MHz, CDCl3) 136 13C NMR (126 MHz, CDCl3) 137 1H NMR (500 MHz, CDCl3) 138 13C NMR (126 MHz, CDCl3) 139 1H NMR (500 MHz, CDCl3) 140 13C NMR (126 MHz, CDCl3) 141 1H NMR (500 MHz, CDCl3) 142 13C NMR (126 MHz, CDCl3) 143 1H NMR (500 MHz, CDCl3) 144 1H NMR (500 MHz, CDCl3) 145 13C NMR (126 MHz, CDCl3) 146 1H NMR (500 MHz, CDCl3) 147 13C NMR (126 MHz, CDCl3) 148 11B NMR (160 MHz, CDCl3) 149 1H NMR (500 MHz, DMSO-d6) 150 1H NMR (500 MHz, DMSO-d6) 151 1H NMR (500 MHz, CDCl3) 152 11B NMR (160 MHz, CDCl3) 153 1H NMR (500 MHz, CDCl3) 154 11B NMR (160 MHz, CDCl3) 155 1H NMR (500 MHz, CDCl3) 156 13C NMR (126 MHz, CDCl3) 157 11B NMR (160 MHz, CDCl3) 158 1H NMR (500 MHz, CDCl3) 159 11B NMR (160 MHz, CDCl3) 160 1H NMR (500 MHz, CDCl3) 161 1H NMR (500 MHz, CDCl3) 162 11B NMR (160 MHz, CDCl3) 163 1H NMR (500 MHz, CDCl3) 164 11B NMR (160 MHz, CDCl3) 165 1H NMR (500 MHz, CDCl3) 166 11B NMR (60 MHz, CDCl3) 167 1H NMR (500 MHz, CDCl3) 168 11B NMR (160 MHz, CDCl3) 169 1H NMR (500 MHz, CDCl3) 170 11B NMR (60 MHz, CDCl3) 171 1H NMR (500 MHz, CDCl3) 172 11B NMR (160 MHz, CDCl3) 173 1H NMR (500 MHz, CDCl3) 174 11B NMR (60 MHz, CDCl3) 175 1H NMR (500 MHz, CDCl3) 176 11B NMR (160 MHz, CDCl3) 177 1H NMR (500 MHz, CDCl3) 178 11B NMR (60 MHz, CDCl3) 179 1H NMR (500 MHz, CDCl3) 180 11B NMR (60 MHz, CDCl3) 181 1H NMR (500 MHz, CDCl3) 182 11B NMR (160 MHz, CDCl3) 183 1H NMR (500 MHz, CDCl3) 184 11B NMR (60 MHz, CDCl3) 185 1H NMR (500 MHz, CDCl3) 186 11B NMR (60 MHz, CDCl3) 187 1H NMR (500 MHz, CDCl3) 188 11B NMR (160 MHz, CDCl3) 189 1H NMR (500 MHz, CDCl3) 190 11B NMR (160 MHz, CDCl3) 191 REFERENCES 192 REFERENCES (1) Wang, G.; Xu, L.; Li, P. 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