HYDRAZONE LIGANDS FOR IRIDIUM CATALYZED C–H BORYLATIONS OF FLUOROARENES: STRATEGIES FOR ENHANCING RATES AND SELECTIVITIES By Christopher Daniel Peruzzi A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry – Doctor of Philosophy 2024 ABSTRACT Aryl boronic acids and esters are valuable intermediates for the broad chemistry community as building blocks for synthesis due to the wide variety of valuable transformations the C–B bond. The state-of-the-art methodology for generating these compounds is through iridium-catalyzed C–H activation borylation (CHB). Traditional systems activate the least sterically hinder C–H bond to activate, but many systems have been developed that can selectively activate ortho, meta, and para to several functional groups. To date, however, there are a limited number of systems using iridium that can selectively activate fluorinated aromatics due to its weak electrostatic interactions and small atomic size. The work described within detail a novel dipyridyl hydrazone ligand (dmadph) that can borylate fluoroarenes with increased selectivity for C–H activation meta to fluorine. This ligand also generates catalysts that are significantly more active than those generated using the most common ligand, 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy). Investigations into this novel ligand framework led to the discovery of an unusual effect of hydrogen pressure generated during CHB on the observed regioselectivity of the reaction, further increasing C–H activation meta to fluorine. The hydrogen pressure generated during CHB enabled an iridium-catalyzed transfer borylation, or isodesmic borylation, of arenes. These are the first examples reported that demonstrate these effects in iridium-catalyzed systems. Due to the activity of the catalysts generated with dmadph, the pre-assembled catalyst was synthesized and isolated and revealed an unusual coordination mode to iridium. Parallel conversion kinetic isotope effect experiments revealed a primary kinetic isotope effect for the C–H borylation. NMR experiments during catalysis, however, identified an Ir–fluoroaryl complex, suggesting it is a resting state for the transfer borylation process and thus operates separate to the canonical CHB mechanism. ACKNOWLEDGEMENTS This past nearly six years in graduate school I have grown substantially as both a person and a chemist. This journey was long, arduous, but totally worth it and I would not have made it without the support and guidance of the many people I have known and met along the way. I want to first and foremost thank my advisors, Professors Rob Maleczka and Mitch Smith, for their unwavering support, guidance, and freedom they gave me to explore my projects. The opportunity I have had to work within a collaborative project over the course of my graduate journey was one of the best experiences I could ask for. They taught me not only how to do chemistry, but most importantly how to think about the chemistry I am doing and to focus on the important findings. I am extremely thankful to have worked with both of them. To my group, Anshu, Arzoo, Pauline, Thomas, and previous group members thank you for the friendship, memories, and support over the years – I don’t think we would’ve made it without each other! To MSU’s awesome team of support specialists, Dan Holmes, Li Xie, Richard Staples, and Anna Osborn – you guys keep MSU running and without your help nobody could make it out. Last but certainly not least, thank you to my committee, Xuefei, Karen, and Jim for your guidance and support throughout my journey. To my parents, Luigi and Julie, I am forever grateful for your unconditional love and support throughout these years, I could not have done it without you both. To my sister, Lauren, and brothers, Mike and Kyle, having you guys always be there to support me and pick me up when I was looking down kept me going to make it to the end. And Mike, without your lead starting at Grand Valley, I would not be where I am today or even started my journey with chemistry. I can’t thank you enough for showing me what the chemistry world has to offer. To my grandparents, Luigi, Jeanne, Henry and Janet, I know I was always the one you were worried about – I am happy iii that finally you all can see I did it, I know you all are looking down at me and watching. I love and miss you all every day. Lastly, to Pauline Mansour, my rock and my partner – I couldn’t have done this journey without you being here. Whether that was you being in the lab and pushing me towards my next goals, or the brief vacations to Lake Michigan or the GRC in Rhode Island (I consider it a vacation as well as a learning experience, it was too beautiful there!) you were instrumental to my success. Through the good and the bad times starting even at GVSU, you have always been there for me and I wouldn’t want it any other way. I look forward to all the memories we will continue to make. iv TABLE OF CONTENTS LIST OF TABLES ...................................................................................................................... vii LIST OF SCHEMES ................................................................................................................. viii LIST OF FIGURES ..................................................................................................................... ix CHAPTER 1. INTRODUCTION ................................................................................................ 1 1.1. Synthetic Utility and Applications of Organoboronates .................................................. 1 1.2. Mechanism of C–H Borylation by IrIII ............................................................................. 2 1.3. Regioselectivity of Iridium-catalyzed C–H Borylations .................................................. 4 1.3.1. General Selectivity of Ir-catalyzed CHBs and Ortho-selective Methodologies ....... 4 1.3.2. Meta- and Para-selective CHBs Utilizing Non-covalent Interactions ...................... 6 1.4. Conclusions ...................................................................................................................... 9 REFERENCES .......................................................................................................................... 10 CHAPTER 2. A HYDRAZONE LIGAND FOR IRIDIUM-CATALYZED C–H BORYLATION: ENHANCED REACTIVITY AND SELECTIVITY FOR FLUORINATED ARENES ........................................................................................................ 14 2.1. Introduction ........................................................................................................................ 14 2.2. Results and Discussion ....................................................................................................... 17 2.2.1. Optimization of Reaction Conditions .......................................................................... 17 2.2.2. Meta-to-F CHBs of Fluoroarenes ................................................................................ 18 2.2.3. Investigation of the Catalytic Manifold ....................................................................... 22 2.3. Conclusions ........................................................................................................................ 24 2.4. Experimental ...................................................................................................................... 25 2.4.1. General Information .................................................................................................... 25 2.4.2. Preparation of dmadph Ligand .................................................................................... 26 2.4.3. Optimization of Reaction Conditions .......................................................................... 30 2.4.4. Catalyst Loading Studies ............................................................................................. 31 2.4.5. General Procedure for Borylation of Arenes and Hetero(arenes) ............................... 31 2.4.6. Characterization of Borylated Products ....................................................................... 32 2.4.7. Preparation of IrI hydrazido from dmadph and 6 ......................................................... 46 2.4.8. Borylation of fluorochlorobenzene with 6 and 7 ......................................................... 47 2.4.9. Preparation of dmadph-borane Adduct for X-ray Crystallography ............................. 48 2.4.10. NMR Tube Borylation of Pentafluorobenzene.......................................................... 49 2.4.11. Crystallographic Data for 6 ....................................................................................... 50 2.4.12. NMR Data ................................................................................................................. 52 REFERENCES ........................................................................................................................ 110 CHAPTER 3. HYDROGEN PRESSURE EFFECTS IN IRIDIUM-CATALYZED BORYLATIONS WITH A DI-PYRIDYL HYDRAZONE LIGAND: EVIDENCE OF TRANSFER BORYLATION AND EQUILIBRIUM ............................................................ 114 3.1. Introduction ...................................................................................................................... 114 3.2. Results and Discussion ..................................................................................................... 116 v 3.3. Investigating the Catalyst Structure ................................................................................. 120 3.4. Conclusions ...................................................................................................................... 126 3.5. Experimental .................................................................................................................... 126 3.5.1. General Information .................................................................................................. 126 3.5.2. Hydrogen Pressure Experiments ............................................................................... 128 3.3.3. NMR Tube Borylations ............................................................................................. 132 3.3.4. KIE Experiment ......................................................................................................... 135 3.3.5. Experiments Probing for Transfer Borylation ........................................................... 136 3.3.6. NMR Data ................................................................................................................. 139 REFERENCES ........................................................................................................................ 153 vi LIST OF TABLES Table 2.1. Meta-selective C–H Borylations of 1,3-Disubstituted Fluorinated and Cyanated Arenesa .......................................................................................................................................... 19 Table S2.1. Optimization of Reaction Conditions ........................................................................ 30 Table S2.2 Catalyst Loading Studies on Conversion and Selectivity ........................................... 31 vii LIST OF SCHEMES Scheme 1.1.1. Synthetic utility of C(sp2)- and C(sp3)-borylated Compounds ................................ 1 Scheme 1.2.1. First thermocatalytic C–H borylation catalyzed by Cp*IrIII(PMe3)(H)(Bpin) ........ 2 Scheme 1.3.1. Proposed mechanism for the activation and borylation of R–H bonds ................... 3 Scheme 1.4.1. Ligand field around IrIII active catalyst and consequences on regioselectivity ....... 4 Scheme 2.1. Challenges in selective fluoroarene C–H activations ............................................... 15 Scheme 2.2. Optimization of borylation conditionsa .................................................................... 18 Scheme 2.3. Investigations of other fluoroarenes ......................................................................... 20 Scheme 2.4. Stoichiometric studies of the reactivity of the hydrazone liganda ............................ 22 Scheme 2.5. Alkylation effects on activity and selectivity of CHB ............................................. 23 Scheme 2.6. Borylation of fluorochlorobenzene with isolated adduct and IrI hydrazidoa ............ 24 Scheme 3.2.1. Initial observation of selectivity difference ......................................................... 116 Scheme 3.2.2. Borylation of fluoroarenes in open and closed systemsa ..................................... 117 Scheme 3.2.3. Borylation of fluorobenzene over timea .............................................................. 119 Scheme 3.2.4. Probing for transfer borylationa........................................................................... 120 Scheme 3.3.2. Reaction of IrI hydrazido with pinacolborane ..................................................... 125 Scheme 3.3.3. KIE determination in a parallel conversion experiment of C6H6 and C6D6 ........ 125 viii LIST OF FIGURES Figure 1.4.1. Steric and chelate borylation catalysts and their ligands ........................................... 5 Figure 1.4.2. Strategies for meta-selective C–H activation and borylation .................................... 7 Figure 1.4.3. Strategies for para-selective C–H activation and borylation ..................................... 8 Figure 2.1. Selected examples of catalysts competent for high meta-to-F regioselectivity ......... 16 Figure S2.1. Representation of the solid-state structure of 6 at 50% probability ellipsoids. Co- crystallized H2O and CH3CN are shown. ..................................................................................... 50 Figure S2.2. The following hydrogen bonding interactions with a maximum D-D distance of 3.2 Å and a minimum angle of 110 ° are present in 6: N1–O1_1: 3.158 Å, C3–N4: 2.843 Å, C5– O2_2: 3.179 Å. .............................................................................................................................. 51 Figure 3.1.1. Known examples of transfer borylation chemistry ............................................... 115 Figure 3.3.1. 1H NMR (THF-d8) comparison of the aromatic region in pentafluorobenzene borylation .................................................................................................................................... 122 Figure 3.3.2. 1H NMR (THF/THF-d8) of the hydride region. Inset is a comparison of the 1H and {19F}1H of the hydride split into a ttd ......................................................................................... 123 Figure 3.3.3. Proposed structures of species observed during catalysis ..................................... 124 Figure S3.1. Ligand screen for the borylation of fluorobenzene according to general procedure C. Regioselectivities and conversions determined by 19F NMR. .................................................... 131 Figure S3.2. GC-MS trace of the crude reaction mixture at t = 6 h. ........................................... 135 ix LIST OF ABBREVIATIONS [M]+ µL bpy Bu CHB cod Cp Cy DCM DFT molecular ion peak microliters butyl C–H activation/borylation C–H activation/borylation 1,5-cyclooctadiene cyclopentadienyl cyclohexyl dichloromethane density functional theory dmadph 2,2'-(hydrazineylidenemethylene)bis(N,N-dimethylpyridin-4-amine) dmadpm 2,2'-methylenebis(N,N-dimethylpyridin-4-amine) dppe dtbpy eg EI 1,2-bis(diphenylphosphino)ethane 4,4’-di-tert-butyl-2,2’-bipyridine ethylene glycol electron ionization equiv equivalents FWHM full width at half maximum GC-MS Gas Chromatography-Mass Spectroscopy h J hours coupling constant KIE kinetic isotope effect x m Me MeCN MHz min mL mol mp NCI meta methyl acetonitrile megahertz minutes milliliters moles melting point non-covalent interaction NMR nuclear magnetic resonance o p Ph pin pKa ppm R RDS rt THF ortho para phenyl pinacolate acid dissociation constant at logarithmic scale parts per million remaining attachment to molecule rate determining step room temperature tetrahydrofuran tmphen 3,4,7,8-tetramethyl-1,10-phenanthroline TON turnover number xi CHAPTER 1. INTRODUCTION 1.1. Synthetic Utility and Applications of Organoboronates Organoboronates are desirable intermediates across many disciplines of chemistry due to their exceptional versatility as building blocks towards final molecules of interest. They are able to undergo a variety of transformations1,2 (Scheme 1.2.1) and can tolerate many reaction conditions depending on the oxo group attached to boron.3 Notably, the Nobel prize winning Suzuki-Miyaura cross-coupling,4,5 one of the most widely used reactions in medicinal chemistry,6 requires a boronic acid or ester precursor. While C–C bond formation is important, transformations of the C(sp2)–B bond via amination,7–9 halogenation,10 cyanation,11 and oxidation10,12 can also be performed. Transformations of C(sp3)–B bonds via 1,2-boronate rearrangements,1,13 heterocycle formation,14 and cross-coupling reactions14 are actively studied as ways to build complex molecules. Scheme 1.1.1. Synthetic utility of C(sp2)- and C(sp3)-borylated Compounds 1 With the obvious desire to generate organoboronic esters as tools for synthesis outlined in Scheme 1.2.1, first the C–B bond must be synthesized. The traditional methodologies to synthesize these compounds typically involved a Miyaura borylation,15 lithiation of an aryl halide or direct C–H lithiation followed by subsequent quenching with triisopropylborate. Early direct C–H activation routes both stoichiometric16 and catalytic17 required photochemical conditions to generate the products and a catalyst only requiring heat would offer substantial advantages. Scheme 1.2.1. First thermocatalytic C–H borylation catalyzed by Cp*IrIII(PMe3)(H)(Bpin) The first discovery of the thermocatalytic C–H borylation by a transition metal catalyst was made by Iverson and Smith in 1999.18 The catalyst, while not particularly active only achieving about three turnovers, inspired the community to further study the iridium-catalyzed systems. The system was greatly improved upon in 2002, when the Smith and Maleczka collaboration found that by employing a chelating, neutral phosphine donor, the turnover numbers (TON = 4500) greatly increased.19 Other seminal findings from this work were the proposal of an IrIII/IrV mechanism over an IrI/IrIII mechanism and the ability to telescope a borylation with a Suzuki- Miyaura cross-coupling in one pot, showing the Ir catalysis was compatible with halogenated aromatics preferentially activating the C–H bond over the C–X bond. 1.2. Mechanism of C–H Borylation by IrIII Subsequently after the finding that a chelating neutral donor ligand was essential to generating highly active catalysts towards C–H activation and borylation, Hartwig and co-workers found that utilizing a bipyridine generated extraordinarily active catalysts.20 The ligand used in 2 their study, 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy), notably, is the state-of-the-art ligand used today and its analog, 2,2′-bipyridine has been used for extensive computational analysis.21 Importantly, this analysis from Sakaki and co-workers supported the initial proposal from Smith and Maleczka that the mechanism operates in an IrIII/IrV catalytic cycle. Scheme 1.3.1. Proposed mechanism for the activation and borylation of R–H bonds The mechanism was also empirically studied through careful kinetic analysis by the Hartwig group in 2005.22 They were able to isolate a resting state of the proposed active catalyst I with addition of an excess of cis-cyclooctene (COE) that they were able to crystallize and use for their kinetic analysis. They found that COE reversibly dissociates from the iridium center to generate the active 16 e– L2Ir(Bpin)3, which oxidatively adds a C–H bond to yield the somewhat unusual IrV intermediate II. This then goes on to reductively eliminate the borylated arene generating the bis(boryl)monohydride IV, which after oxidative addition of pinacolborane, yields intermediate VI. The catalyst is regenerated from reductive elimination of H2 from VI, closing the catalytic cycle. Importantly, this mechanism is distinct from the mechanism when a diphosphine ligand is used in place of a bipyridine. Careful examination and NMR analysis by the Smith and Maleczka 3 group23 identified several intermediates along the catalytic cycle where intermediates III and V are operating. The NMR analysis revealed that the agostic complexes are active and present during catalysis, and the mechanism is operating via σ-bond metathesis rather than oxidative addition and reductive elimination. Also revealed and described in this work was that intermediate IV and other hydridoiridium(boryls) are active for C–H borylation and not just complex I, though their exact competence has not been fully evaluated to date. 1.3. Regioselectivity of Iridium-catalyzed C–H Borylations 1.3.1. General Selectivity of Ir-catalyzed CHBs and Ortho-selective Methodologies Regioselectivity in iridium-catalyzed CHBs is generally governed by steric effects. 21,22,24 This means that for a given monosubstituted arene, when using a neutral chelating donor ligand, statistical ratio of 2:1 of the meta and para borylated products are generated.20,25 This is because, as shown in Scheme 1.4.1, with a chelating ligand, a 16 e– IrIII complex is generated, leaving available only one open coordination site for C–H activation. However, if a ligand system were created where a second coordination site could open, this would allow the possibility of a directing group (DG) to coordinate to the metal to direct C–H activation. Scheme 1.4.1. Ligand field around IrIII active catalyst and consequences on regioselectivity Towards this aim, several CHB systems have been created varying the ligand framework to allow the opening of a second coordination site. The “hemilabile” type ligands shown in Figure 1.4.1 have been pioneered by Lassaletta26 and Clark27 for chelate directed borylations. They 4 propose that one of the arms of the ligand is able to freely dissociate from the metal center during catalysis, allowing coordination of a directing group, i.e. benzylamines27, hydrazones29, and phenylpyridines.26 Figure 1.4.1. Steric and chelate borylation catalysts and their ligands The second type of ligands that can be used to generate 14 e– IrIII intermediates, are monoanionic LX ligand frameworks. Unlike the neutral ligands previously discussed, these ligands have an anionic arm of the ligand such as a hydrosilane31 or diboron30,31 which after oxidative addition yields the silyl and boryl iridium species respectively. Thus, to satisfy the oxidation state and coordination sphere of iridium, only two boryls (Bpin) can add to the iridium, yielding the chelate directed catalyst for borylation. Lastly, the third ligand set that has been utilized for directed ortho borylations are monodentate ligands. Simply, by controlling the stoichiometry a simple monodentate ligand will 5 allow the coordination of the DG to yield chelate directed borylations. Generally, however, these ligand systems suffer from poor activity, especially in the case of 2-methoxypyridine.32 The Si- SMAP ligand developed by Sawamura33 was proven to be extremely effective for the ortho borylation of esters and functional groups that are much more weakly coordinating like chlorides and methoxymethyl ethers. 1.3.2. Meta- and Para-selective CHBs Utilizing Non-covalent Interactions While directing effects can be powerful methods to achieve highly selective ortho borylations, strategies to selectively activate C–H bonds meta and para to functional groups is considerably more difficult. Directing groups covalently attach to the metal to direct catalysis in these methods, however, strategies involving non-covalent interactions (NCIs) are being developed as a way to address meta and para activation. Hydrogen bonding (Figure 1.4.2) is one such NCI that has been used by the Kanai group34 and Phipps group35 to enable meta borylations of aryl amides and benzylamines respectively. The Kanai group appended a bipyridine ligand with a urea which hydrogen bonds with the carbonyl of the substrate, directing C–H activation meta to the amide with exceptional selectivities (up to >99:1). Similarly, the sulfonate group on the ligand utilized by Phipps hydrogen bonds to protected benzyl, phenethyl, and phenylpropylamines with excellent selectivity (up to 20:1 meta:ortho). 6 Figure 1.4.2. Strategies for meta-selective C–H activation and borylation Another powerful non-covalent interaction used to direct CHBs meta is ion pairing effects. These effects can be due to full positive and negative charges, such as in Phipps36 work that uses the same sulfonated bipyridine used in H-bond directed CHB to ion pair with positively charged quaternary ammonium salts enabling meta direction. These can also be due to partial charges such as those found in the work from the Chattopadhyay group37 and Nakao group.38 The Chattopadhyay group utilized an electrostatic interaction from the electron poor phenanthroline ligand on iridium and the electron rich sulfamate or amide of the substrate directing meta CHBs. The Nakao group used a completely different approach by introducing a Lewis acid co-catalyst that attaches to the bipyridine ligand on iridium to direct the borylation. The amide in this work 7 interacts with the Lewis acid, aluminum, to direct borylation meta for amides and C3-directed borylations of pyridines. Figure 1.4.3. Strategies for para-selective C–H activation and borylation Non-covalent interactions have also been utilized for effective directed para borylations (Figure 1.4.3). The most commonly used NCI for these transformations has been in using ion pairing. One of the first examples for para selective borylations came from the Chattopadhyay group, where they modified their bipyridine ligand to have a deprotonated quinolinol where the metal countercation, potassium, can pair to the partial negative charge of the carbonyl on esters directing borylation para.39 A separate approach of this ion pairing directed catalysis from the Phipps40 and Smith and Maleczka groups41 concurrently. Phenols, anilines, benzylamines and 8 benzyl alcohols were converted to their respective sulfonates and paired with a bulky counteraction in tetrabutylammonium. This bulky countercation then sterically blocks the ortho and meta site, only enabling selective functionalization at the para position. The effect of the length of the alkyl chain of the cation further asserts this steric blocking, as shorter alkyl chains than butyl (propyl, ethyl…) erode the para selectivity. Notably, these methodologies can utilize the most commonly used ligands for borylation, 4,4′-disubstituted bipyridines, and only requires sulfonation of the substrates to direct the catalyst, which can easily be removed after borylation. The Liang group used a similar approach as seen in the meta selective borylations, ion pairing benzylammoniums with a sulfonate on a modified phenanthroline ligand to now direct the borylation to the para position.42 The final novel approach utilizing a NCI to enable para borylations of anilines, indoles, and quinolines was demonstrated by the Smith and Maleczka groups.43 Formal N-borylation of these arenes and (hetero)arenes enables a H-bond between the oxygen of the pinacolate and the ortho C–H bond, which in turn acts as a steric shield of the ortho and meta C–H sites. 1.4. Conclusions Overall, iridium catalyzed C–H activation borylation is a robust, well-established method for the functionalization of arenes. It has become the state-of-the-art method for complex molecule diversification and molecule building for the wide array of transformations that these organoboronates can undergo. Through the years, many methodologies have been developed to address regioselectivity and for a wide variety of substrates, selective activation of the ortho, meta, and para C–H bonds are achievable, often through the use of attractive non-covalent interactions. Selective activations of fluorinated arenes and (hetero)arenes remain a significant challenge and efforts in iridium-catalyzed methods for highly selective CHBs of these substrates will be discussed and explored in the following chapters. 9 REFERENCES (1) Thomas, S. P.; French, R. M.; Jheengut, V.; Aggarwal, V. K. 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Rev. 2010, 110 (2), 890–931. (25) Cho, J.-Y.; Iverson, C. N.; Smith, M. R., III. Steric and Chelate Directing Effects in Aromatic Borylation. J. Am. Chem. Soc. 2000, 122 (51), 12868–12869. (26) 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 (49), 11724–11728. 11 (27) 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 (13), 3558–3561. (28) 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 (21), 9915–9920. (29) Ghaffari, B.; Preshlock, S. M.; Plattner, D. L.; Staples, R. J.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr.; Smith, M. R., III. Silyl Phosphorus and Nitrogen Donor Chelates for Homogeneous Ortho Borylation Catalysis. J. Am. Chem. Soc. 2014, 136 (41), 14345–14348. (30) 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 (1), 91–94. (31) O’Connell, A. C.; Mansour, P. A.; Maleczka, R. E., Jr; Smith, M. R., III. Regiochemical Switching in Ir-Catalyzed C-H Borylation by Altering Ligand Loadings of N,B-Type Diboron Species. Org. Lett. 2023, 25 (45), 8057–8061. (32) Obligacion, J. V.; Bezdek, M. J.; Chirik, P. J. C(Sp2)-H Borylation of Fluorinated Arenes Using an Air-Stable Cobalt Precatalyst: Electronically Enhanced Site Selectivity Enables Synthetic Opportunities. J. Am. Chem. Soc. 2017, 139 (7), 2825–2832. (33) 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 (14), 5058–5089. (34) 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 (9), 712–717. (35) 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 Engl. 2017, 56 (43), 13351–13355. (36) 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 (39), 12759–12762. (37) Chaturvedi, J.; Haldar, C.; Bisht, R.; Pandey, G.; Chattopadhyay, B. Meta Selective C-H Borylation of Sterically Biased and Unbiased Substrates Directed by Electrostatic Interaction. J. Am. Chem. Soc. 2021, 143 (20), 7604–7611. (38) Yang, L.; Uemura, N.; Nakao, Y. Meta-Selective C-H Borylation of Benzamides and Pyridines by an Iridium-Lewis Acid Bifunctional Catalyst. J. Am. Chem. Soc. 2019, 141 (19), 7972– 7979. 12 (39) 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 (23), 7745–7748. (40) 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 (39), 15477–15482. (41) Montero Bastidas, J. R.; Oleskey, T. J.; Miller, S. L.; Smith, M. R., III; 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 (39), 15483–15487. (42) Lu, S.; Zheng, T.; Ma, J.; Deng, Z.; Qin, S.; Chen, Y.; Liang, Y. Para-Selective C-H Borylation of Aromatic Quaternary Ammonium and Phosphonium Salts. Angew. Chem. Int. Ed Engl. 2022. https://doi.org/10.1002/anie.202201285. (43) Montero Bastidas, J. R.; Chhabra, A.; Feng, Y.; Oleskey, T. J.; Smith, M. R., III; Maleczka, R. E. Steric Shielding Effects Induced by Intramolecular C–H···O Hydrogen Bonding: Remote Borylation Directed by Bpin Groups. ACS Catal. 2022, 12 (4), 2694–2705. 13 CHAPTER 2. A HYDRAZONE LIGAND FOR IRIDIUM-CATALYZED C–H BORYLATION: ENHANCED REACTIVITY AND SELECTIVITY FOR FLUORINATED ARENES 2.1. Introduction Ir-catalyzed C–H borylation (CHB) has become a ubiquitous, state of the art method for the direct formation of both alkyl and aryl boronic esters. There are few systems capable, however, of achieving high selectivity in direct borylations of fluoroarenes. The highly selective reactions are limited to cases where oxidative addition is reversible (“ortho fluorine effect”),1–3 directing groups are installed onto the substrate4,5, or borylation-deborylation strategies6 and the majority are ortho-selective.7–10 With the prominence of fluorine in pharmaceuticals11 and medicinal chemistry,12 developing C–H functionalizations with complementary selectivities to the existing methods is important. The major challenges with site selectivity arise from the intrinsic properties associated with fluorine. Fluorine is only 20% larger than hydrogen13 causing poor steric discrimination in the context of Ir-catalyzed CHBs,14–16 and is nonpolarizable13 preventing strong electrostatic interactions to guide selectivity. Furthermore, experimental work from Jones, Perutz, and co- workers2 (Scheme 2.1) and subsequent computational studies from Eisenstein demonstrated that across many transition metal–fluoroaryl complexes, the metal–carbon bond strength increases with increasing ortho fluorine substituents.1,17 Their findings suggest that, generally, regioselectivity for C–H activation is thermodynamically favored at sites proximal to F. Prior work from our group18,19 also has shown that, in agreement with increased metal–carbon bond strengths, the more acidic C–H bonds are more reactive. Thus an electronically enhanced selectivity for borylation ortho-to-F should be found. The clash of the electronic and thermodynamic preference for ortho- 14 to-F selectivity with the steric selectivity of CHBs often result in, poor regioselectivity for the CHB of fluoroarenes when utilizing Ir without the use of blocking groups20 or directing effects. Scheme 2.1. Challenges in selective fluoroarene C–H activations Thermodynamically, there is a small difference in the bond dissociation energies of the C– H bonds in fluorobenzene (<2.5 kcal·mol–1).1 To achieve kinetic control, the barrier that leads to the thermodynamic product must be at least 2.5 kcal·mol–1 (at 298K) higher than the barrier leading to the kinetic product. Moreover, the reaction must be run under conditions where equilibrium is not reached. Towards this aim, several CHB systems (Figure 2.1) have been developed for their selectivity in non-directed functionalizations of C–H bonds. Recent work by 15 the Chirik group (Figure 2.1a) demonstrated CHBs with an electron deficient Co catalyst bearing a terpyridine ligand enables slow C–H cleavage, affording up to 99:1 meta-to-F site selectivities.21 This is distinct from their [(iPrPNP)Co] system3 where high ortho-to-F selectivity is observed. The Driess group also reported a sterically encumbered Co catalyst generated from a pyridine bis- silylene ligand framework that provides high selectivities for meta functionalizations.22 Notably, these systems utilizing earth abundant cobalt are only amenable to activated, electron deficient arenes. Furthermore, the cobalt based systems do not tolerate heavier halogens due to more favorable C–X cleavage (X = Cl, Br, I). Figure 2.1. Selected examples of catalysts competent for high meta-to-F regioselectivity A well-known advantage of iridium catalysis is high functional group tolerance, but selective activation meta or para to fluorine via iridium catalysis is underdeveloped.6,23 Currently, high ortho-to-F selectivity can be achieved with an iridium-terpyridine catalyst that was developed 16 by Ilies.9 The only system with high meta-to-F selectivity was developed by our group, utilizing L2 (Figure 2.1b) as the ligand.23 However, catalysts generated from L2 are considerably less active than traditional bipyridines or phenanthrolines, requiring at least twice the reaction time for comparable conversions. Thus, we desired to generate a catalyst that achieved both high meta or para to fluorine selectivity and retained activity on the order of iridium catalysts generated from bipyridines such as dtbpy (L3). 2.2. Results and Discussion 2.2.1. Optimization of Reaction Conditions Inspired by prior demonstrations of hydrazone based ligands in Ir-catalyzed CHBs24,25 and our prior studies of L1-L2, L4 was designed to achieve this goal. Catalysts generated by L4 were much more reactive than the dipyridylmethane-type ligands (L1, L2) and on par with dtbpy (L3). Solvent choice proved to be vital to improving meta-to-F selectivity, as using a non-polar solvent (Scheme 2.2, entries 6-7) greatly diminishes selectivity. Additionally, there is an effect of temperature on the observed selectivity with lower temperatures improving the meta-to-F selectivity, consistent with kinetic control. This effect is distinct from Ir/bipyridine catalyzed CHBs, where temperature marginally impacts the regioselectivity.26 Though this effect was observed, 40 °C was the optimal temperature (Scheme 2, entry 8) for high activity while maintaining the improved selectivity. 17 Scheme 2.2. Optimization of borylation conditionsa aReaction conditions: fluoroarene (1.0 mmol), HBpin (2.0 mmol) or B2pin2 (1.0 mmol), [Ir(OMe)cod]2 (1.0 mol %), ligand (2.0 mol %), solvent (2.0 mL). bn-Hexane used as solvent. cCH2Cl2 used as solvent. dReaction run at 40 °C. Ratios of products were found with 19F NMR analysis. 2.2.2. Meta-to-F CHBs of Fluoroarenes Catalysts generated by L4 afforded improved activity and selectivity for all 1,3- disubstituted arenes examined (Table 2.1). Borylations of electron poor substrates 4a-f were essentially complete within 2 h with kinetic selectivities of up to 18.0:1.0 and high yields. Notably, activated fluoroarenes containing heavier halogens (4e-f) are significantly less reactive when using dtbpy as the ancillary ligand. Electron rich substrates 4i-k still required longer reaction times, however, a nearly 3-fold improvement in both conversion to products and selectivities were found with L4. The borylation of fluorobenzene (4l) shows improved site selectivity without the influence of other functional groups. We also wanted to examine 5 as a non-fluorinated substrate that typically requires elevated temperatures, prolonged reaction times, and the more reactive borylating reagent (B2pin2)14,26 to achieve good conversion. Under much milder conditions, L4 18 Table 2.1. Meta-selective C–H Borylations of 1,3-Disubstituted Fluorinated and Cyanated Arenesa aReaction conditions: fluoroarene (3, 1.0 mmol), HBpin (2.0 mmol), [Ir(OMe)cod]2 (1.0 mol %), and ligand (2.0 mol %) in THF (2.5 mL), 40 °C, 0.5-24 h. Isolated yields are reported after column chromatography for dmadph and selectivities are from crude reaction mixtures. Percent conversions found from 19F NMR are reported for dtbpy. Numbers in parentheses correspond to the ratio of meta:ortho to F borylated isomers. bRatio of 5:2,5:4 borylated isomers given in parentheses. c5 equiv of fluorobenzene was used to suppress diborylation. Ratio of ortho:meta:para to F borylated isomers given in parentheses. dReaction ran at 65 °C. 19 achieves 72% conversion in 24 h whereas dtbpy only reaches 18% conversion demonstrating the superior activity of the catalysts generated. Catalyst loading studies were conducted (see section 2.4.4) to further demonstrate the superior activity of the hydrazone ligand. Excellent conversions were observed with only 0.1/0.2 mol% loadings of [Ir(OMe)cod]2/L4 respectively. These loadings could be lowered further to 0.01/0.02 mol% at the expense of longer reaction times, as 35% conversion was observed as compared to nearly full conversion at 0.1/0.2 mol%. Scheme 2.3. Investigations of other fluoroarenes Reaction conditions: fluoroarene (1.0 mmol), HBpin (2.0 mmol), [Ir(OMe)cod]2 (1.0 mol %), and dmadph (2.0 mol %) in THF (2.5 mL), 40 °C. Conversions are listed as determined by 19F NMR. Numbers in parentheses correspond to the ratios of the meta:ortho to F borylated isomers. aReaction run at rt. bSome reduction of the ester observed in the 1H NMR. cRatio of products given in parentheses is the meta:para:ortho-to-F borylated isomers. Other substrates beyond 1,3-disubstituted were also examined under the catalytic conditions in Scheme 2.4. The 1,2-disubstituted arenes 7a-7b bear –OH and –NH2 functional groups, which, first undergo O- and N-borylation with pinacolborane prior to C–H borylation.27– 29 This reactivity was leveraged to enable para-selective borylations of anilines27 through intramolecular C–H···O hydrogen bonding of the ortho hydrogen to the oxygen of the N–Bpin group. These conditions were not amenable to phenols, however, which provided no selectivity 20 (1:1 ratio of para:meta to –OH) for reactions using bipyridines or phenanthrolines as ligands. The meta-to-F selectivity (or para to the phenol) in the case of 7a was superior for dmadph than when the borylation was done under both conditions previously described by our group.27,30 Substrate 7b was not investigated in that work, however the meta-selectivity was moderate. Interestingly, the tri-substituted fluoroarene 7c showed diminished selectivity compared to 3- fluorochlorobenzene, suggesting an electronic contribution to the observed selectivity from the methoxy group. To determine if esters were tolerated, 7d was borylated under catalytic conditions and both poor selectivity and activity was observed. The 11B NMR of the crude reaction mixture revealed significant amounts of O–Bpin formation, suggesting reduction of the ester by pinacolborane to the corresponding alcohols. This could be responsible for the poor conversion, as previous work demonstrated lower conversion under the catalytic conditions with only one equivalent of pinacolborane. 21 Scheme 2.4. Stoichiometric studies of the reactivity of the hydrazone liganda aMolecular structure displayed with 50% probability ellipsoids and a partial labelling scheme (co-crystallized CH3CN and H2O omitted for clarity). N1–B1 = 1.520 Å, N3–B1 = 1.587 Å 2.2.3. Investigation of the Catalytic Manifold In trying to rationalize the greatly improved selectivity when using L4, we considered the ligand framework and potential structural changes or reactions that could occur during catalysis.31 As previously described, N–H and O–H sites are rapidly N- and O-borylated in CHB reactions catalyzed by Ir species with B2pin2 or pinacolborane.27–29 Shown in Scheme 2.4, the hydrazone is rapidly N-borylated in MeCN without Ir forming a hydrazone-boronate adduct (6). A sharp singlet was observed in the 11B NMR (2.96 ppm, ⍵1/2 = 49 Hz) evidencing the presence of a four- coordinate boron center. This is further validated by 1H NMR, as inequivalent methyl groups of the pinacolate are observed due to hindered rotation of the adduct. Single crystals suitable for Xray crystallography were obtained by crystallization in CH3CN at –34 °C, unequivocally confirming 22 the structure. It is noteworthy that with the precatalyst, this reaction occurs on the order of seconds rather than hours. Scheme 2.5. Alkylation effects on activity and selectivity of CHB We originally hypothesized that the hydrazone-boronate adduct (6) formed in-situ during borylation and introduced an increased steric demand to the metal that improved selectivities. In practice, the stoichiometric reactions of both L4 and 6 with [Ir(OMe)cod]2 in pentane leads to exclusive formation of the IrI hydrazido 7 (Scheme 2.4) and methanol or MeO–Bpin, respectively. While catalytic amounts of material are difficult to characterize, the judicious choice of substrate can allow some analysis of the species generated during the reaction. Thus, the CHB of pentafluorobenzene was monitored via a NMR tube reaction (see section 2.2.10 for details), and 11B NMR evidenced the formation of a new N–B bond during the reaction. Based on this evidence, both hydrogens in the amino hydrazone, L4, may be important for the reactivity and selectivity observed. To explore this, we synthesized substituted analogs of L4 (Scheme 2.5). Alkylation of the free amine of the hydrazone in L5-L6 proved deleterious to both regioselectivity and activity. These results implicate the importance of the amine in hydrazone L4. We hypothesize that the hydrazone amine forms both the Ir–hydrazido and the N–Bpin in the active catalyst. Furthermore, we wanted to determine if the isolated hydrazido 7 and boronate adduct 6 lead to active catalyst formation by comparison with in-situ generation in Table 1. When both 23 were used for a borylation of fluorochlorobenzene (Scheme 2.5), nearly identical selectivities to those found when generating the catalyst in-situ were observed. With these results in mind, a bis(boryl)IrIII is likely operating in a canonical IrIII/IrV catalytic cycle. Scheme 2.6. Borylation of fluorochlorobenzene with isolated adduct and IrI hydrazidoa 2.3. Conclusions In summary, a new dipyridyl hydrazone ligand, dmadph, has been used in Ir-catalyzed C– H borylations of fluorinated arenes to afford significantly greater kinetic products than with dtbpy. We have shown dmadph generates catalysts that are both more active and selective than those generated from dtbpy. Additionally, HBpin is utilized to increase meta selectivity, an effect that we previously observed with the dipyridylmethane type ligands.23 This unusual increase in regioselectivity using HBpin with both L2 and L4 warrants further mechanistic evaluation and investigations are ongoing. 24 2.4. Experimental 2.4.1. General Information Pinacolborane (HBpin) (97% stabilized with 1% triethylamine) was purchased commercially and used as received without further purification. The iridium catalyst, bis(η4-1,5- cyclooctadiene)-di-µ-methoxy-diiridium (I), [Ir(OMe)(cod)]2, was prepared by a literature procedure.32 All substrates were obtained commercially and used as received unless otherwise noted. All reactions were prepared in 3.0 mL Wheaton microreactor vials equipped with stir bars and pressure caps in a glovebox under a nitrogen atmosphere and then transferred to a preheated aluminum block outside of the glovebox. THF and n-hexane were obtained from wet stills refluxing over sodium and benzophenone. Methylene chloride and acetonitrile were obtained from dry stills according to the literature procedure.33 Reactions were monitored by 19F NMR, and crude reaction ratios were verified by 1H NMR or 19F NMR for fluorine containing substrates. NMR spectra were recorded on a Varian 500 MHz DD2 Spectrometer equipped with a 1H-19F/15N-31P 5mm Pulsed Field Gradient (PFG) Probe. Spectra were taken in deuterated solvents referenced to residual solvent signals in 1H NMR and 13C{1H} NMR. 13C{1H} NMR resonances for the boron-bearing carbon atom were not observed due to quadrupolar relaxation. NMR spectra were processed for display using the MNova software with only phasing and baseline corrections applied. For all NMR spectra, no peaks were manually corrected, suppressed or altered in any form, and unprocessed fids are available upon request. Single crystal analyses were performed by Michigan State University Center for Crystallographic Research on a Charge Coupled Device (CCD diffractometer). 25 High-resolution mass spectra were obtained at the Michigan State University Mass Spectrometry Core using electron spray ionization (ESI+). Low resolution GC-MS was obtained on a Shimadzu GCMS-QP2010SE. Silica used for purification of crude material was standard laboratory grade 230 - 400 mesh designed for flash chromatography applications. Purification of crude materials on a 1 mmol scale was achieved by standard flash chromatography methods employing 2-3 g silica gel plugs in small chromatography columns of dimension approximately 2 x 30 cm. The concentrated crude materials were dissolved in a minimum amount of solvent, applied to the silica gel with a Pasteur pipette and eluted into test tubes. Compounds that eluted were visualized by spotting on TLC plates and irradiating with 254 nm UV light 2.4.2. Preparation of dmadph Ligand Synthesis of 4-(dimethylamino)picolinic acid hydrogen chloride34 To a 350 mL pressure tube equipped with a stir bar, 4-chloropicolinic acid (18.0 g, 0.114 mol, 1 equiv) was added. Next, dimethylamine (40% in H2O, 80.0 mL, 0.632 mol, 5.5 equiv) was added directly to the pressure tube. The pressure tube was then sealed and heated at 100 °C for 48 h. After cooling the pressure tube, the pH was adjusted to 11 using 10 M NaOH. The solvent was removed under vacuum, and the resulting solid was extracted with ethyl acetate (3 x 150mL). The solvent was removed on a rotary evaporator to yield the crude 4-(dimethylamino)picolinate. The solid was then recrystallized using a minimal amount of hot HCl (pH = 3) and allowing it to cool 26 at -10 °C overnight. The resulting pale-yellow needles were filtered and washed with a 50/50 mixture of EtOH/Et2O until the washings were colorless. The solid was then further dried to yield 4-(dimethylamino)picolinic acid hydrogen chloride (15.6 g, 83%) as white crystals (mp 236.0- 239.8 °C dec). The NMR data matches with those previously reported.34 1H NMR (500 MHz, D2O) δ 7.78 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 2.9 Hz, 1H), 6.68 (dd, J = 7.3, 3.0 Hz, 1H), 3.00 (s, 6H). 13C{1H} NMR (126 MHz, D2O) δ 162.9, 157.9, 139.4, 138.4, 108.0, 107.6, 39.7, 39.5. Synthesis of ethyl-4-(dimethylamino)picolinate The title compound was synthesized according to a known literature procedure34 for the analogous methyl ester, with a slight modification to the work up procedure. A 250 mL 3-neck round bottom flask was equipped with a Dimroth condenser, pressure equalized addition funnel, and a stir bar. 4-(Dimethylamino)picolinic acid hydrogen chloride (5.127 g, 25.3 mmol, 1 equiv) was weighed into the flask followed by 65 mL of ethanol. Thionyl chloride (22.0 mL, 303.3 mmol, 12 equiv) was added to the addition funnel and the flask was then cooled to 0 °C. Thionyl chloride was added dropwise over a period of 25 minutes while keeping the solution close to 0 °C. When the addition was complete, the solution was brought to reflux for 16 hours. Upon cooling, the solution was quenched using sat. aq. NaHCO3 until pH = 7. The pH was balanced to approximately pH = 10 using 10 M NaOH and the resulting solution was extracted with CH2Cl2 (3 x 60 mL). The combined CH2Cl2 layers were passed through a plug of basic 27 alumina and dried over MgSO4. The drying agent was then gravity filtered and the solvent removed under vacuum to yield ethyl-4-(dimethylamino)picolinate (5.134 g, 88%) as an orange oil. 1H NMR (500 MHz, CDCl3) δ 8.33 (d, J = 5.9 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H), 6.59 (dd, J = 5.9, 2.8 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 3.05 (s, 6H), 1.43 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 166.4, 154.8, 149.8, 148.4, 108.7, 108.1, 61.7, 39.2, 14.4. Synthesis of bis(4-(dimethylamino)pyridin-2-yl)methanone To an oven-dried, 250 mL round bottom flask equipped with a stir bar, 4-(dimethylamino)pyridine (0.7436 g, 6.0 mmol, 1.0 equiv) was added along with 90 mL of dry THF. The clear solution was sparged with N2 for 30 minutes. After this, BF3·OEt2 (0.890 mL, 7.2 mmol, 1.2 equiv) was added dropwise to the DMAP solution causing it to briefly warm up and turn the clear, colorless solution to a slightly cloudy and yellow solution and stirred for 1 h at room temperature. Afterwards, the mixture was cooled to –78 °C and the temperature was carefully monitored with a thermocouple probe inserted through a septum into the mixture. Next, n-BuLi (2.5 M in hexanes, 2.60 mL, 1.1 equiv) was added dropwise via syringe over 20 minutes, ensuring that the temperature did not rise above –70 °C. The solution was stirred cold at –78 °C for 1.5 h. Separately, ethyl-4- (dimethylamino)picolinate was added to a 300 mL, 3-neck round bottom flask equipped with a stir bar. Under nitrogen, 50 mL of THF was added and the solution was cooled to to –78 °C. After 1.5 h of stirring, the lithiated 4-(dimethylamino)pyridine was cannula transferred dropwise to the cooled solution of ethyl-4-(dimethylamino)picolinate, causing the light-yellow solution to become 28 a deep, golden yellow-orange. The mixture was stirred cold for 1.5 h and then quenched with 1.0 mL of anhydrous EtOH and allowed to come to rt overnight. The solvent was removed on a rotary evaporator and the solid dissolved in CH2Cl2 (80 mL) and washed with a 1M KOH/1% ethylene glycol solution (3x30mL). After drying under Na2SO4, the solvent was again removed on a rotary evaporator to yield a yellow-white solid which was dissolved in CH2Cl2 and washed with EtOAc (3x20 mL). The CH2Cl2 was dried again and evaporated to yield a white powder of bis(4- (dimethylamino)pyridin-2-yl)methanone (0.5232 g, 32% yield). The spectral data matched with previously reported literature values.23 Synthesis of 2,2'-(hydrazineylidenemethylene)bis(N,N-dimethylpyridin-4-amine) (L4) To a 25 mL, heavy walled Schlenk flask equipped with a stir bar, bis(DMAP)methanone (0.523 g, 1.9 mmol, 1 equiv) was added and dissolved in 15 mL of anhydrous ethanol with stirring. At room temperature, acetic acid (0.177 mL, 3.1 mmol, 1.6 equiv) was added via syringe with vigorous stirring, and the color of the solution turned to a pale yellow. Then, hydrazine hydrate (65%, 0.462 mL, 6.2 mmol, 3.3 equiv) was added via a syringe to the solution, which caused it to become an orange color. The reaction was stirred at 70 °C for 4 h and allowed to cool back down to rt. The solvent was then carefully removed under vacuum until a white precipitate formed. The resulting white solid was collected by filtration and washed with several portions of 2-3 mLs of ice-cold isopropanol. The mother liquor was subsequently concentrated to yield a second crop of the white solid, which was also washed with isopropanol. The combined white solids were then 29 recrystallized in a minimal amount of iPrOH to yield dmadph (0.511 g, 91%) as white needles (mp 149.0-152.0 °C dec.) 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 6.0 Hz, 1H), 8.20 (d, J = 5.9 Hz, 1H), 7.46 (s, 2H), 7.04 (d, J = 2.7 Hz, 1H), 6.54 (d, J = 2.7 Hz, 1H), 6.47 (dd, J = 6.0, 2.7 Hz, 1H), 6.44 (dd, J = 5.9, 2.7 Hz, 1H), 3.03 (s, 6H), 2.94 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 157.3, 154.8, 153.0, 148.7, 148.5, 145.2, 108.1, 106.1, 105.7, 105.0, 39.2, 39.1. 2.4.3. Optimization of Reaction Conditions Table S2.1. Optimization of Reaction Conditions Optimized conditions chosen are highlighted in yellow. Ratios of products were determined by 19F NMR analysis of the crude reaction mixtures. 30 2.4.4. Catalyst Loading Studies Table S2.2 Catalyst Loading Studies on Conversion and Selectivity Ratios of products were determined by19F NMR analysis of the crude reaction mixtures. 2.4.5. General Procedure for Borylation of Arenes and Hetero(arenes) In a nitrogen-filled glovebox, a 3.0 mL Wheaton pressure vial equipped with a stir bar was charged with a 1.0 mL THF solution of [Ir(OMe)cod]2 (6.6 mg, 0.01 equiv). To this solution, pinacolborane (0.290 mL, 2 mmol, 2.0 equiv) was added with a syringe while stirring, turning the light-yellow solution into a golden orange. Then, in a small test tube, a 1.0 mL THF solution of dmadph (5.6 mg, 0.02 equiv) or dtbpy (5.4 mg, 0.02 equiv) was made and added to the iridium solution with a syringe and the solution immediately turned dark red in color. Last, the substrate 31 was added to this solution and capped. The reaction was heated at 40 °C and stirred in an aluminum heating block on top of a stir plate. Reactions were monitored by 19F and 1H NMR spectroscopies. When reactions were completed, the volatiles were evaporated, and the crude reaction mixtures purified by silica gel chromatography in 100% CH2Cl2. The borylated products were isolated as the regioisomeric mixtures. 2.4.6. Characterization of Borylated Products Borylation of 2-chloro-6-fluoropyridine (4a) Isolated as a white, crystalline solid (88%, >20:1.0 m:o selectivity) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be >99% at 30 min. The spectral data agree with previously reported literature values.23 (mp 77.8-80.1 °C) Selectivity found via 19F NMR of the crude material was >20:1.0 4a:4a′. The selectivity found via 19F NMR for dtbpy was 5.8:1.0 4a:4a′. 1H NMR of 4a (500 MHz, CDCl3) δ 7.56 (d, J = 1.7 Hz, 1H), 7.20 (d, J = 2.6 Hz, 1H), 1.35 (s, 12H) 1H NMR of 4a′ (500 MHz, CDCl3) δ 8.11 (t, J = 8.1 Hz, 1H), 7.22 (dd, J = 7.5 Hz, 1.6 Hz, 1H), 1.35 (s, 12H) 13C{1H} NMR of 4a (126 MHz, CDCl3) δ 162.3 (d, J = 247.6 Hz), 148.7 (d, J = 12.8 Hz), 126.6 (d, J = 4.8 Hz), 112.9 (d, J = 33.0 Hz), 85.3, 25.0. 19F NMR of 4a (470 MHz, CDCl3) δ -67.38 19F NMR of 4a′ (470 MHz, CDCl3) δ -55.95 32 11B NMR (160 MHz, CDCl3) δ 29.69 (br s) Borylation of isophthalonitrile (4b) Isolated as a white, crystalline solid (85%, 14.3:1.0 m:o selectivity) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be >99% at 30 min. The spectral data agree with previously reported literature values.23 Selectivity found via 19F NMR of the crude material was 12.5:1.0 4b:4b′. The selectivity found via 1H NMR analysis for dtbpy was 4.4:1.0 4b:4b′. 1H NMR of 4b (500 MHz, CDCl3) δ 8.26 (d, J = 1.6 Hz, 2H), 7.98 (t, J = 1.6 Hz, 1H), 1.35 (s, 12H). 1H NMR of 4b′ (500 MHz, CDCl3) δ 8.01 (d, J = 7.9 Hz, 1H), 7.96-7.95 (m, 1H), 7.83 (dd, J = 7.8, 1.5 Hz, 1H) 1.38 (s, 12H). 13C{1H} NMR of 4b (126 MHz, CDCl3) δ 141.8, 137.1, 116.7, 113.6, 85.3, 24.8. 13C{1H} NMR of 4b′ (126 MHz, CDCl3) δ 136.7, 136.1, 136. 0, 134.4, 118.7, 116.9, 116.7, 115.4, 85.6, 24.8. 11B NMR (160 MHz, CDCl3) δ 29.73 (br s) Borylation of 3-(trifluoromethoxy)fluorobenzene (4c) 33 Isolated as a colorless, clear liquid (96%, 8.0:1.0 m:o selectivity) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be >99% at 2 h. Selectivity found via 19F NMR of the crude material was 8.0:1.0 4c:4c′. The selectivity found via 19F NMR for dtbpy was 4.1:1.0 4c:4c′. 1H NMR of 4c (500 MHz, CDCl3) δ 7.44-7.42 (m, 2H), 7.03 (ddd, J = 9.0, 2.5, 1.5 Hz, 1H), 1.35 (s, 12H). 1H NMR of 4c′ (500 MHz, CDCl3) δ 7.78 (dd, J = 8.5, 1.5 Hz, 1H), 6.99 – 7.02* (m, 1H), 6.92 (dq, J = 9.5, 0.9 Hz, 1H), 1.36 (s, 12H). 13C{1H} NMR of 4c (126 MHz, CDCl3) δ 162.4 (d, J = 250.1 Hz), 138.0 (d, J = 9.7 Hz), 122.3 (d, J = 3.1 Hz), 119.5 (d, J = 19.3 Hz), 111.6 (d, J = 25.0 Hz), 84.5, 24.7. 13C{1H} NMR of 4c′ (126 MHz, CDCl3) δ 167.4 (d, J = 254.0 Hz), 149.4 (d, J = 9.9 Hz), 121.4, 115.1 (d, J = 3.8 Hz), 108.2 (d, J = 28.3 Hz), 84.1, 24.7. 19F NMR of 4c (470 MHz, CDCl3) δ -57.92 (3F), -110.87 (1F) 19F NMR of 4c′ (470 MHz, CDCl3) δ -57.81 (3F), -98.93 (1F) 11B NMR (160 MHz, CDCl3) δ 30.06 (br s) *apparent doublet of quartets with matching coupling constants to the resonance at 6.92 ppm, one of the quartets is buried under the major isomer, however. Borylation of 3-(trifluoromethyl)fluorobenzene (4d) 34 Isolated as a colorless, clear liquid (87%, 4.4:1.0 m:o selectivity) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be >99% at 2 h. The spectral data agree with previously reported literature values.7,22 Selectivity found via 19F NMR of the crude material was 4.4:1.0 4d:4d′. The selectivity found via 19F NMR for dtbpy was 1.8:1.0 4d:4d′.. 1H NMR of 4d (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.65 (dd, J = 8.5, 2.5 Hz, 1H), 7.40-7.37 (m, 1H), 1.36 (s, 12H). 1H NMR of 4d′* (500 MHz, CDCl3) δ 7.86 (t, J = 7.0 Hz, 1H), 7.40 (m, 1H), 7.29 (d, J = 8.9 Hz, 1H), 1.37 (s, 12H). 13C{1H} NMR of 4d (126 MHz, CDCl3) δ 162.1 (d, J = 249.5 Hz), 132.0 (dd, J = 33.2, 7.0 Hz), 127.0 (p, J = 3.8 Hz), 124.6 (d, J = 19.5 Hz), 115.3 (dq, J = 24.5, 3.7 Hz), 84.6, 24.8. 13C{1H} NMR of 4d′ (126 MHz, CDCl3) δ 166.7 (d, J = 253.2 Hz), 137.6 (d, J = 8.3 Hz), 120.4 – 120.1 (m), 112.8 – 112.2 (m), 84.4, 24.8. 19F NMR of 4d (470 MHz, CDCl3) δ -62.69 (3F), -111.94 (1F). 19F NMR of 4d′ (470 MHz, CDCl3) δ -100.52 11B NMR (160 MHz, CDCl3) δ 30.15 (br s) *Resonance at 7.86 buried under major isomer, assumed triplet from previously reported literature values. Resonance at 7.40 completely buried under major isomer, but visible, matching the chemical shift from previously reported values.7 Borylation of 3-fluorochlorobenzene (4e) 35 Isolated as a colorless, clear liquid (82%, 6.1:1.0 m:o selectivity) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be 98% at 1 h. The spectral data agree with previously reported literature values.23 Selectivity found via 19F NMR of the crude material was 6.4:1.0 4e:4e′. The selectivity found via 19F NMR for dtbpy was 2.5:1.0 4e:4e′.. 1H NMR of 4e (500 MHz, CDCl3) δ 7.56 (d, J = 1.1 Hz, 1H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.16 (dt, J = 8.6, 2.3 Hz, 1H), 1.34 (s, 12H). 1H NMR of 4e′ (500 MHz, CDCl3) δ 7.67 (dd, J = 7.8, 6.7 Hz, 1H), 7.14 (dd, J = 8.3, 2.0 Hz, 1H), 7.07 (dd, J = 9.0, 1.7 Hz, 1H), 1.34 (s, 12H). 13C{1H} NMR of 4e (126 MHz, CDCl3) δ 162.3 (d, J = 250.5 Hz), 134.7 (d, J = 8.82 Hz), 130.3 (d, J = 3.0 Hz), 119.3 (d, J = 19.3 Hz), 118.7 (d, J = 24.6 Hz), 84.4, 24.8. 13C{1H} NMR of 4e′ (126 MHz, CDCl3) δ 167.1 (d, J = 254.7 Hz), 138.4 (d, J = 10.6 Hz), 137.6 (d, J = 9.2 Hz), 124.1 (d, J = 3.4 Hz), 116.1 (d, J = 27.6 Hz), 84.0, 24.8. 19F NMR of 4e (470 MHz, CDCl3) δ -111.94 19F NMR of 4e′ (470 MHz, CDCl3) δ -100.52 11B NMR (160 MHz, CDCl3) δ 30.15 (br s) Borylation of 3-fluorobromobenzene (4f) Isolated as a colorless, clear liquid (93%, 7.2:1.0 m:o selectivity) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be 97% at 2 h. The spectral data agree with previously reported literature values.9 36 Selectivity found via 19F NMR of the crude material was 7.1:1.0 4f:4f′. The selectivity found via 19F NMR for dtbpy was 2.9:1.0 4f:4f′. 1H NMR of 4f (500 MHz, CDCl3) δ 7.71 (dd, J = 1.75, 0.70 Hz, 1H), 7.41 (ddd, J = 8.5, 2.5, 0.6 Hz, 1H), 7.32 (ddd, J = 8.3, 2.5, 0.60 Hz, 1H), 1.34 (s, 12H). 1H NMR of 4f′ (500 MHz, CDCl3) δ 7.60 (dd, J = 8.0, 6.5 Hz, 1H), 7.29 (dd, J = 8.0, 1.7 Hz, 1H), 7.23 (dd, J = 8.6, 1.7 Hz, 1H), 1.35 (s, 12H). 13C{1H} NMR of 4f (126 MHz, CDCl3) δ 162.3 (d, J = 251.6 Hz), 133.3 (d, J = 3.1 Hz), 121.6 (d, J = 24.4 Hz), 119.7 (d, J = 19.3 Hz), 84.4, 24.8. 13C{1H} NMR of 4f′ (126 MHz, CDCl3) δ 166.9 (d, J = 255.7 Hz), 137.8 (d, J = 8.8 Hz), 127.1 (d, J = 3.4 Hz), 126.4 (d, J = 10.0 Hz), 119.0 (d, J = 27.4 Hz), 84.1, 24.8. 19F NMR of 4f (470 MHz, CDCl3) δ -111.56 19F NMR of 4f′ (470 MHz, CDCl3) δ -100.30 11B NMR (160 MHz, CDCl3) δ 30.11 (br s) Borylation of 1,3-difluorobenzene (4g) Isolated as a white solid (88%, 4.3:1.0:0.9 5:4:2,5-diborylated selectivity) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be >99% at 8 h. The spectral data agree with previously reported literature values for the 4- and 5-borylated isomers.18 The resonances at δ -94.1 (corresponding to the 4,6-diborylated isomer) and -100.6 (corresponding to the 2-borylated isomer) represent 2% of the regioisomeric mixture. Selectivity found via 19F NMR of the crude material was 4.6:1.0:0.9 4g:4g′:4g′′. 37 The selectivity found via 19F NMR for dtbpy was 3.3:2.7:1.0 of 4g:4g′:4g′′. 1H NMR of 4g (500 MHz, CDCl3) δ 7.27 (dt, J = 6.1, 2.2 Hz, 2H), 6.86 (tt, J = 8.9, 2.4 Hz, 1H), 1.33 (s, 12H). 1H NMR of 4g′ (500 MHz, CDCl3) δ 7.74 – 7.70 (m, 1H), 6.88 – 6.83* (m, 1H), 6.75 (td, J = 9.5, 2.3 Hz, 1H), 1.37 (s, 12H). 1H NMR of 4g′′ (500 MHz, CDCl3) δ 7.23 – 7.25 (m, 2H), 1.34 (s, 12H). 13C{1H} NMR of 4g (126 MHz, CDCl3) δ 162.7 (dd, J = 249.7, 11.0 Hz), 116.8 (dd, J = 17.7, 5.0 Hz), 106.4 (t, J = 25.1 Hz), 84.4, 24.8. 13C{1H} NMR of 4g′ (126 MHz, CDCl3) δ 165.7 (dd, J = 289.7, 12.2 Hz), 116.7 – 115.9 (m), 111.1 (dd, J = 20.2, 3.6 Hz), 103.6 (dd, J = 27.9, 24.3 Hz), 83.9, 24.7. 19F NMR of 4g (470 MHz, CDCl3) δ -110.79 19F NMR of 4g′ (470 MHz, CDCl3) δ -98.63, -105.13 19F NMR of 4g′′ (470 MHz, CDCl3) δ -101.80 11B NMR (160 MHz, CDCl3) δ 30.02 (br s) *Resonance is completely buried underneath the major isomer. An irregular peak shape for the major isomer provides evidence of the resonance and is in agreement with previous reported values. Borylation of 3-fluorobenzonitrile (4h) 38 Isolated as a colorless, clear liquid (93%, 3.5:1.0 m:o selectivity) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be >99% at 2 h. Selectivity found via 19F NMR of the crude material was 3.4:1.0 4h:4h′. The selectivity found via 19F NMR for dtbpy was 1.1:1.0 4h:4h′.. 1H NMR of 4h (500 MHz, CDCl3) δ 7.88 (s, 1H), 7.70 (dd, J = 8.5, 0.6 Hz, 1H), 7.41 (ddd, J = 8.1, 2.6, 1.4 Hz, 1H), 1.35 (s, 12H). 1H NMR of 4h′ (500 MHz, CDCl3) δ 7.62 (t, J = 6.7 Hz, 1H), 6.95* (m, 1H), 6.86 (d, J = 10.4 Hz, 1H), 1.36 (s, 12H). 13C{1H} NMR of 4h (126 MHz, CDCl3) δ 161.7 (d, J = 251.0 Hz), 137.8 (d, J = 8.7 Hz), 134.2 (d, J = 3.3 Hz), 125.8 (d, J = 19.4 Hz), 121.1 (d, J = 24.7 Hz), 84.8, 24.7. 13C{1H} NMR of 4h′ (126 MHz, CDCl3) δ 166.2 (d, J = 254.7 Hz), 127.2 (d, J = 3.7 Hz), 118.7 (d, J = 27.6 Hz), 117.4 (d, J = 3.0 Hz), 113.5 (d, J = 8.5 Hz), 84.6, 24.7. 19F NMR of 4h (470 MHz, CDCl3) δ -111.07 19F NMR of 4h′ (470 MHz, CDCl3) δ -99.87 11B NMR (160 MHz, CDCl3) δ 29.96 (br s) *Resonance at 6.95 is completely buried under major isomer. Borylation of 3-fluorotoluene (4i) Isolated as a colorless, clear liquid (72%, 4.2:1.0 m:o selectivity) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be >99% at 24 h. The spectral data agree with previously reported literature values.7 39 Selectivity found via 19F NMR of the crude material was 4.0:1.0 4i:4i′. The selectivity found via 19F NMR for dtbpy was 1.4:1.0 4i:4i′.. 1H NMR of 4i (500 MHz, CDCl3) δ 7.40 (s, 1H), 7.28 (dd, J = 8.9, 2.0 Hz, 1H), 6.98-6.95 (m, 1H), 2.36 (s, 3H), 1.35 (s, 12H). 1H NMR of 4i′ (500 MHz, CDCl3) δ 7.40 (s, 1H), 7.28 (dd, J = 8.9, 2.0 Hz, 1H), 6.98-6.95 (m, 1H), 2.36 (s, 3H), 1.35 (s, 12H). 13C{1H} NMR of 4i (126 MHz, CDCl3) δ 162.5 (d, J = 246.4 Hz), 139.8 (d, J = 7.0 Hz), 136.6 (d, J = 8.7 Hz), 131.0 (d, J = 2.5 Hz), 118.8 (d, J = 20.9 Hz), 117.9 (d, J = 19.3 Hz), 84.0, 24.8, 21.1. 13C{1H} NMR of 4i′ (126 MHz, CDCl3) δ 144.3 (d, J = 8.7 Hz), 136.6 (d, J = 8.7 Hz), 124.5 (d, J = 2.8 Hz), 115.8 (d, J = 23.9 Hz), 83.7, 24.8, 21.0. 19F NMR of 4i (470 MHz, CDCl3) δ -115.35 19F NMR of 4i′ (470 MHz, CDCl3) δ -103.84 11B NMR (160 MHz, CDCl3) δ 30.53 (br s) Borylation of 3-fluoroanisole (4j) Isolated as a colorless, clear liquid (80%, 5.8:1.0 m:o selectivity) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be 88% at 24 h. The spectral data agree with previously reported literature values.7 Selectivity found via 19F NMR of the crude material was 6.0:1.0 4j:4j′. The selectivity found via 19F NMR for dtbpy was 2.2:1.0 4j:4j′. 40 1H NMR 4j (500 MHz, CDCl3) δ 7.10 (d, J = 5.0 Hz, 1H), 7.09 (dd, J = 8.5, 2.4 Hz, 1H), 6.70 (dt, J = 10, 5.0 Hz, 1H), 3.82 (s, 3H), 1.34 (s, 12H). 1H NMR 4j′ (500 MHz, CDCl3) δ 7.65 (dd, J = 8.3, 7.2 Hz, 1H), 6.68* (dd, J = 2.5 Hz, 1H), 6.57 (dd, J = 11.3, 2.3 Hz, 1H), 3.81 (s, 3H), 1.35 (s, 12H). 13C{1H} NMR of 4j (126 MHz, CDCl3) δ 163.2 (d, J = 246.3 Hz), 160.5 (d, J = 10.3 Hz), 114.7 (d, J = 2.5 Hz), 113.3 (d, J = 19.7 Hz), 105.1 (d, J = 24.7 Hz), 84.1, 55.6, 24.8. 13C{1H} NMR of 4j′ (126 MHz, CDCl3) δ 168.5 (d, J = 250.9 Hz), 137.7 (d, J = 10.5 Hz), 109.9 (d, J = 2.7 Hz), 101.1 (d, J = 28.0 Hz), 83.6, 55.5, 24.8. 19F NMR of 4j (470 MHz, CDCl3) δ -57.92 (3F), -110.87 (1F) 19F NMR of 4j′ (470 MHz, CDCl3) δ -57.81 (3F), -98.93 (1F) 11B NMR (160 MHz, CDCl3) δ 30.45 (br s) *Agrees with previous reported literature values7, the only coupling constant visible is given, and the other half of the resonance is buried under the major isomer. Borylation of 3-fluoro-N,N-dimethylaniline (4k) Isolated as a white solid (93%, 3.1:1.0 m:o selectivity) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be 71% at 24 h. The spectral data agree with previously reported literature values.7 Selectivity found via 19F NMR of the crude material was 3.3:1.0 4k:4k′. The selectivity found via 19F NMR for dtbpy was 1.9:1.0 4k:4k′.. 41 1H NMR 4k (500 MHz, CDCl3) δ 6.94 (d, J = 2.3 Hz, 1H), 6.84 (dd, J = 8.5, 2.3 Hz, 1H), 6.49 (dt, J = 12.6, 2.3 Hz, 1H), 2.97 (s, 6H), 1.35 (s, 12H). 1H NMR 4k′ (500 MHz, CDCl3) δ 7.59 (t, J = 7.9 Hz, 1H), 6.44 (dd, J = 8.5, 2.2 Hz, 1H), 6.31 (dd, J = 13.4, 2.2 Hz, 1H), 2.98 (s, 6H), 1.35 (s, 12H). 19F NMR of 4k (470 MHz, CDCl3) δ -113.79. 19F NMR of 4k′ (470 MHz, CDCl3) δ -101.65. 13C{1H} NMR of 4k (126 MHz, CDCl3) δ 163.7 (d, J = 242.9 Hz), 151.9 (d, J = 9.8 Hz), 114.1 (d, J = 1.9 Hz), 108.4 (d, J = 19.8 Hz), 102.1 (d, J = 25.9 Hz), 83.9, 40.5, 24.8. 13C{1H} NMR of 4k′ (126 MHz, CDCl3) δ 163.7 (d, J = 242.9 Hz), 151.9 (d, J = 9.8 Hz), 114.1 (d, J = 1.9 Hz), 108.4 (d, J = 19.8 Hz), 102.1 (d, J = 25.9 Hz), 83.8 (m), 40.5, 24.8. 11B NMR (160 MHz, CDCl3) δ 30.59 (br s). Borylation of fluorobenzene (4l) Reaction run with 5-fold excess of substrate. Isolated as a colorless, clear liquid (99%, 1.4 : 5.5 : 1.0 o:m:p, <5% diborylated isomers) after column chromatography in 100% CH2Cl2. Conversion was determined from 19F NMR to be 98% at 3 h. The NMR spectral data agree with previously reported literature.22,35 The 1H NMR resonances of the 2-monoborylated isomer and 4- monoborylated isomer were not assigned due to significant overlap with each other and the major isomer. Selectivity found via 19F NMR of the crude material was 1.3:5.4:1.0 4l:4l′:4l′′. The selectivity found via 19F NMR for dtbpy was 3.4:5.2:1.0 4l:4l′:4l′′. 42 1H NMR of 4l′ (500 MHz, CDCl3) δ 7.56 (dd, J = 7.2, 0.5 Hz, 1H), 7.47 (dd, J = 9.2, 2.6 Hz, 1H), 7.33 (ddd, J = 13.3, 5.5, 2.6 Hz, 1H), 7.13 (m, 1H), 1.34 (s, 12H). 13C{1H} NMR of 4l (126 MHz, CDCl3) δ 167.2 (d, J = 250.9 Hz), 136.8 (d, J = 7.9 Hz), 133.3 (d, J = 8.8 Hz), 123.6 (d, J = 3.2 Hz), 115.2 (d, J = 23.9 Hz), 83.9, 24.8. 13C{1H} NMR of 4l′ (126 MHz, CDCl3) δ 162.5 (d, J = 246.4 Hz), 130.3 (d, J = 3.0 Hz), 129.5 (d, J = 7.1 Hz), 120.9 (d, J = 19.3 Hz), 118.2 (d, J = 21.0 Hz), 84.1, 24.8. 13C{1H} NMR of 4l′′ (126 MHz, CDCl3) δ 165.1 (d, J = 250.2 Hz), 137.0 (d, J = 8.2 Hz), 114.8 (d, J = 20.2 Hz), 83.9, 24.8. 19F NMR of 4l (470 MHz, CDCl3) δ -102.66 19F NMR of 4l′ (470 MHz, CDCl3) δ -114.22 19F NMR of 4l′′ (470 MHz, CDCl3) δ -108.45 11B NMR (160 MHz, CDCl3) δ 30.54 (br s) Borylation of dimethyl resorcinol (5) Reaction run at 65 °C, and the conversion at 24 h was determined to be 72% by 1H NMR. Product is known36 and was not isolated but assigned spectroscopically as the known product. Borylation of 2-fluorophenol (7a) 43 Reaction run according to the general procedure. After stirring for 24 h, the reaction conversion was determined to be 60% by 19F NMR The products were not isolated as this was a scouting reaction to gauge selectivity. The NMR data match previously reported literature values.30 1H NMR of 7a* (500 MHz, CDCl3) δ 7.51 – 7.48 (m, 2H), 6.98 (t, J = 8.3 Hz, 1 H), 5.38 (br s, 1H), 1.33 (s, 12H) 19F NMR of 7a (470 MHz, CDCl3) δ -142.5 19F NMR of 7a′ (470 MHz, CDCl3) δ -132.5 19F NMR of 7a′′ (470 MHz, CDCl3) δ -136.4 11B NMR (160 MHz, CDCl3) δ 29.7 (br s) *Due to significant overlap in the 1H NMR, products 7a′ and 7a′′ were not assigned. Borylation of 2-fluoroaniline (7b) Reaction run according to the general procedure. The products were not isolated as this was a scouting reaction to gauge selectivity. After stirring for 24 h, the reaction conversion was determined to be 96% by 19F NMR. The NMR data match previously reported literature values.30 1H NMR of 7b (500 MHz, CDCl3) δ 7.41 – 7.38 (m, 2H), 6.75 (t, J = 8.0 Hz), 3.01 (br s, 2H), 1.32 (s, 12 H). 1H NMR of 7b′ (500 MHz, CDCl3) δ 7.09 (ddd, J = 7.1, 5.1, 1.7 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.88 (ddd, J = 9.0, 7.8, 1.8 Hz, 1H), 3.70 (br s, 2H), 1.36 (s, 12H). 19F NMR of 7b (470 MHz, CDCl3) δ -137.3 19F NMR of 7b′ (470 MHz, CDCl3) δ -125.6 44 11B NMR (160 MHz, CDCl3) δ 30.3 (br s) Borylation of 1-chloro-3-fluoro-2-methoxybenzene (7c) Reaction run according to the general procedure at room temperature. After stirring for 24 h, the reaction conversion was determined to be 98% by 19F NMR. The products were not isolated as this was a scouting reaction to gauge selectivity. Product 7c′ was known and matched previously reported literature values.37 1H NMR of 7c (500 MHz, CDCl3) δ 7.59 (s, 1H), 7.42 (d, J = 11.1 Hz), 4.00 (s, 3H), 1.33 (s, 12H). 1H NMR of 7c′ (500 MHz, CDCl3) δ 7.35 (dd, J = 8.1, 5.7 Hz, 1H) 7.15 (dd, J = 8.2, 1.2 Hz, 1H), 3.96 (s, 3H), 1.36 (s, 12H). 19F NMR of 7c (470 MHz, CDCl3) δ -129.1 19F NMR of 7c′ (470 MHz, CDCl3) δ -118.1 11B NMR (160 MHz, CDCl3) δ 29.7 (br s) Borylation of methyl 3-fluorobenzoate (7d) 45 Reaction run according to the general procedure. After stirring for 24 h, the reaction conversion was determined to be 34% by 19F NMR. The products were not isolated as this was a scouting reaction to gauge selectivity and functional group tolerance. 1H NMR of 7d (500 MHz, CDCl3)* δ 8.20 (s, 1H), 7.76 – 7.75 (m, 1H), 7.62 – 7.60 (m, 1H), 3.88 (s, 3H), 1.22 (s, 12H). 19F NMR of 7d (470 MHz, CDCl3) δ -113.7 19F NMR of 7d′ (470 MHz, CDCl3) δ -102.4 11B NMR (160 MHz, CDCl3) δ 30.1 (br s) *Due to significant overlap with 7d and starting material, product 7d′ was not assigned via 1H NMR. 2.4.7. Preparation of IrI hydrazido from dmadph and 6 In a N2 filled glovebox, a 20 mL scintillation vial was charged with [Ir(OMe)cod]2 (0.033 g, 0.05 mmol) and a stir bar. In a small test tube, dmadph (0.028 g, 0.1 mmol) was weighed and suspended in 3.0 mL of pentane. Then, 2.0 mL of pentane was added to the scintillation vial with strong stirring yielding a light-yellow solution. The suspension of dmadph was then added with a pipette, changing the color immediately to a dark red-brown with significant precipitate. The mixture was allowed to stir for 4 hours at room temperature and placed in a freezer at -35 °C overnight. The resulting suspension was filtered over a glass frit funnel (F porosity) and washed with 3x5 mL portions of pentane and dried, yielding a dark maroon solid (0.030 g, 99% yield) of the IrI hydrazido 7. 46 In a N2 filled glovebox, a 20 mL scintillation vial was charged with [Ir(OMe)cod]2 (0.033 g, 0.05 mmol) and a stir bar. In a small test tube, 6 (0.040 g, 0.1 mmol) was weighed and suspended in 3.0 mL of pentane. Then, 2.0 mL of pentane was added to the scintillation vial with strong stirring yielding a light-yellow solution. The suspension of 6 was then added with a pipette, changing the color immediately to a dark red-brown. The mixture was allowed to stir for 1 hour at room temperature and placed in a freezer at -35 °C overnight. The resulting suspension was filtered over a glass frit funnel (F porosity) and washed with 3x5 mL portions of pentane and dried, yielding a dark maroon solid (0.028 g, 93% yield) of the IrI hydrazido 7. 1H NMR (500 MHz, THF-d8) δ 9.23 (s, 1H), 8.12 (d, J = 5.7 Hz, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.49 (d, J = 3.1 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 6.45 (dd, J = 5.8, 2.6 Hz, 1H), 6.40 (dd, J = 7.3, 3.1 Hz, 1H), 3.69 – 3.60 (m, 2H), 3.51 – 3.44 (m, 2H), 3.02 (s, 6H), 2.96 (s, 6H), 2.44 – 2.29 (m, 4H), 2.32 – 2.16 (m, 4H). 13C{1H} NMR (126 MHz, THF-d8) δ 171.3, 161.5, 154.9, 153.2, 147.6, 147.4, 107.7, 105.7, 104.2, 103.7, 66.9, 62.8, 58.4, 38.2, 37.9, 31.7, 30.5, 24.8. 2.4.8. Borylation of fluorochlorobenzene with 6 and 7 Reaction performed according to the general procedure with the following minor changes: 6 (0.008 g, 0.02 equiv) was weighed into a test tube in place of L4/dtbpy, and the reaction was stirred for 3 47 h. Conversion was found to be 80% by 19F NMR analysis, with a regioisomeric ratio of 6.5:1.0 meta:ortho to F. Reaction performed according to the general procedure with the following minor changes: 7 (0.012 g, 0.02 equiv) was weighed into a test tube in place of L4/dtbpy and [Ir(OMe)cod]2, and the reaction was stirred at 40 °C for 3 h. Conversion was found to be 75% by 19F NMR analysis, with a regioisomeric ratio of 6.5:1.0 meta:ortho to F. 2.4.9. Preparation of dmadph-borane Adduct for X-ray Crystallography In a N2 filled glovebox, a 20 mL scintillation vial was charged with a stir bar and dmadph (0.046 g, 0.16 mmol, 1 equiv). Then, 3.0 mL of MeCN was added to the vial and stirred. Afterwards, pinacolborane (0.40 mL, 0.28 mmol, 1.75 equiv) was added with a syringe and stirred for 4 h. The addition of pinacolborane turned the clear, colorless slurry to a light-yellow and caused the solution to warm and bubble. An additional 4.0 mL of MeCN was added to fully dissolve everything and was then stirred for another 20 h. After stirring the scintillation vial was placed in a -34 °C freezer for 2 days and upon returning, yellow needles precipitated (0.051 g, 78%) that were suitable for X-ray crystallography. 48 1H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 5.8 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.33 (br s, 1 H), 7.04 (d, J = 2.2 Hz, 1H), 6.63 (dd, J = 7.1, 2.4 Hz, 1H), 6.48 (dd, J = 5.6, 2.2 Hz, 1H), 3.06 (s, 6 H), 3.04 (s, 6H), 1.25 (s, 6H), 1.20 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 157.1, 155.3, 154.9, 147.9, 142.9, 139.6, 105.8, 105.2, 105.1, 102.6 79.5, 39.4, 39.3, 26.8, 26.0. 11B NMR (160 MHz, CDCl3) δ 2.92 (s, 𝜔1/2 = 49 Hz) HRMS (ESI+) m/z calculated for C21H32N6O2B+ ([MH]+) 411.2680, found m/z 411.2698. 2.4.10. NMR Tube Borylation of Pentafluorobenzene In a N2 filled glovebox, [Ir(OMe)cod]2 (0.0070 g, 0.01 mmol), dmadph (0.0060 g, 0.02 mmol), were weighed into separate test tubes. Then, 1.0 mL of THF was added to both test tubes. To the solution of Ir, HBpin (300 µL, 2 mmol) was added and shaken briefly, turning the light-yellow solution into a golden-yellow. The solution of Ir and pinacolborane was then pipetted into the solution of dmadph and transferred into a scintillation vial with a stir bar. The combined solution was stirred vigorously for 5 minutes, turning the solution dark red. Using a microsyringe, 400 µL of the combined solution was added to a J-young tube, followed by pentafluorobenzene (20 µL, 0.18 mmol) and 0.3 mL of THF-d8. The J-young was capped, inverted and thoroughly mixed. The tube was then transferred into a preheated oil bath at 40 °C and monitored by 1H, 19F, and 11B NMR. 49 See Figure S58 for the 11B NMR of the reaction at t = 3.5 h. The resonance at δ 25.36 is typical for a N–B bond where boron is 3-coordinate27. 2.4.11. Crystallographic Data for 6 Slow crystallization of 6 from MeCN in a glovebox at –34 °C provided crystals suitable for X-ray diffraction analysis. Single yellow needle crystals of 6 used as received. A suitable crystal with dimensions 0.38 × 0.10 × 0.04 mm3 was selected and mounted on a nylon loop with paratone oil on a Bruker APEX-II CCD diffractometer. The crystal was kept at a steady T = 173(1) K during data collection. The structure was solved with the ShelXT38 solution program using dual methods and by using Olex239 as the graphical interface. The model was refined with ShelXL40 using full matrix least squares minimisation on F2. Figure S2.1. Representation of the solid-state structure of 6 at 50% probability ellipsoids. Co- crystallized H2O and CH3CN are shown. 50 following hydrogen Figure S2.2. The bonding interactions with a maximum D-D distance of 3.2 Å and a minimum angle of 110 ° are present in 6: N1–O1_1: 3.158 Å, C3–N4: 2.843 Å, C5–O2_2: 3.179 Å. Compound 6 1981016 CCDC C21.4H31.8BN6.2O2.6 Formula 1.236 Dcalc./ g cm-3 0.669 /mm-1 428.34 Formula Weight yellow Colour needle Shape 0.38×0.10×0.04 Size/mm3 173(1) T/K monoclinic Crystal System P21/n Space Group 13.9473(5) a/Å 6.8875(3) b/Å 24.6074(11) c/Å 90 /° 103.062(3) /° 90 /° 2302.67(17) V/Å3 4 Z 1 Z' 1.54178 Wavelength/Å Radiation type CuK 3.688 min/° 68.228 max/° 18482 Measured Refl's. Ind't Refl's 4193 Refl's with I > 2(I) 2066 Rint Parameters Restraints Largest Peak Deepest Hole GooF wR2 (all data) wR2 R1 (all data) R1 0.1398 295 5 0.557 -0.263 1.015 0.2476 0.1965 0.1665 0.0809 51 2.4.12. NMR Data 1H NMR of 4-(dimethylamino)picolinic acid hydrogen chloride (500 MHz, D2O) 52 13C NMR of 4-(dimethylamino)picolinic acid hydrogen chloride (125 MHz, D2O) 53 1H NMR of ethyl-4-(dimethylamino)picolinate (500 MHz, CDCl3) 54 13C NMR of ethyl-4-(dimethylamino)picolinate (125 MHz, CDCl3) 55 1H NMR of bis((4-dimethylamino)pyridine)methylene hydrazine (dmadph) (500 MHz, CDCl3) 56 13C NMR of bis((4-dimethylamino)pyridine)methylene hydrazine (dmadph) 125 MHz, CDCl3) 57 1H NMR of dmadph-HBpin adduct (500 MHz, CDCl3) 58 13C NMR of dmadph-HBpin adduct (126 MHz, CDCl3) 59 11B NMR of dmadph-HBpin adduct (160 MHz, CDCl3) 60 1H NMR of 4a (500 MHz, CDCl3) 61 19F NMR of 4a (470 MHz, CDCl3) 62 13C NMR of 4a (126 MHz, CDCl3) 63 11B NMR of 4a (160 MHz, CDCl3) 64 1H NMR of 4b (160 MHz, CDCl3) 65 13C NMR of 4b (126 MHz, CDCl3) 66 11B NMR of 4b (160 MHz, CDCl3) 67 1H NMR of 4c (500 MHz, CDCl3) 68 19F NMR of 4c (470 MHz, CDCl3) 69 13C NMR of 4c (126 MHz, CDCl3) 70 11B NMR of 4c (160 MHz, CDCl3) 71 1H NMR of 4d (500 MHz, CDCl3) 72 19F NMR of 4d (470 MHz, CDCl3) 73 13C NMR of 4d (126 MHz, CDCl3) 74 11B NMR of 4d (160 MHz, CDCl3) 75 1H NMR of 4e (500 MHz, CDCl3) 76 19F NMR of 4e (470 MHz, CDCl3) 77 13C NMR of 4e (126 MHz, CDCl3) 78 11B NMR of 4e (160 MHz, CDCl3) 79 1H NMR of 4f (500 MHz, CDCl3) 80 19F NMR of 4f (470 MHz, CDCl3) 81 13C NMR of 4f (126 MHz, CDCl3) 82 11B NMR of 4f (160 MHz, CDCl3) 83 1H NMR of 4g (500 MHz, CDCl3) 84 19F NMR of 4g (470 MHz, CDCl3) 85 13C NMR of 4g (126 MHz, CDCl3) 86 11B NMR of 4g (160 MHz, CDCl3) 87 1H NMR of 4h (500 MHz, CDCl3) 88 19F NMR of 4h (470 MHz, CDCl3) 89 13C NMR of 4h (126 MHz, CDCl3) 90 11B NMR of 4h (160 MHz, CDCl3) 91 1H NMR of 4i (500 MHz, CDCl3) 92 19F NMR of 4i (470 MHz, CDCl3) 93 13C NMR of 4i (126 MHz, CDCl3) 94 11B NMR of 4i (160 MHz, CDCl3) 95 1H NMR of 4j (500 MHz, CDCl3) 96 19F NMR of 4j (470 MHz, CDCl3) 97 13C NMR of 4j (126 MHz, CDCl3) 98 11B NMR of 4j (160 MHz, CDCl3) 99 1H NMR of 4k (500 MHz, CDCl3) 100 19F NMR of 4k (470 MHz, CDCl3) 101 50. 13C NMR of 4k (126 MHz, CDCl3) 102 11B NMR of 4k (160 MHz, CDCl3) 103 1H NMR of 4l (500 MHz, CDCl3) 104 53. 19F NMR of 4l (470 MHz, CDCl3) 105 13C NMR of 4l (126 MHz, CDCl3) 106 11B NMR of 4l (160 MHz, CDCl3) 107 1H NMR of 7 (500 MHz, THF-d8). 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Chem. Soc. 2015, 137 (25), 8058–8061. (37) Newby, J. A.; Blaylock, D. W.; Witt, P. M.; Pastre, J. C.; Zacharova, M. K.; Ley, S. V.; Browne, D. L. Design and Application of a Low-Temperature Continuous Flow Chemistry Platform. Org. Process Res. Dev. 2014, 18 (10), 1211–1220. (38) Sheldrick, G. M. SHELXT - Integrated Space-Group and Crystal-Structure Determination. Acta Crystallogr A Found Adv 2015, 71 (Pt 1), 3–8. (39) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2: A Complete Structure Solution, Refinement and Analysis Program. J. Appl. Crystallogr. 2009, 42 (2), 339–341. (40) Sheldrick, G. M. A Short History of SHELX. Acta Crystallogr. A 2008, 64 (Pt 1), 112– 113 CHAPTER 3. HYDROGEN PRESSURE EFFECTS IN IRIDIUM-CATALYZED BORYLATIONS WITH A DI-PYRIDYL HYDRAZONE LIGAND: EVIDENCE OF TRANSFER BORYLATION AND EQUILIBRIUM 3.1. Introduction Traditional C–H activation borylation via group 8-9 transition metal catalysts typically operate under the two principal mechanisms: oxidative addition and reductive elimination or σ- bond metathesis. The metal first reacts with the functionalizing reagent, either a diboron (B2gly2, gly = glycolate) or a borane (HBgly) to generate the metal boryl complex that performs the direct borylation reaction. Diborons are generally well tolerated by most functional groups, but boranes such as pinacolborane can be problematic for some reactive functional groups. Moreover, utilizing diborons does not avoid this problem, as stoichiometric amounts of boranes are generated after CHB. In efforts to avoid their generation to allow more broad functional group tolerance, hetero(aryl) or vinyl boronate esters are being investigated as a boron source in functional group transfer catalysis. This relatively new concept for borylation was found and investigated by the Fontaine1,2 and Dydio3 groups with organocatalysts and transition metal catalysts respectively and, accordingly, operate in distinct mechanisms. The Fontaine group demonstrated 2-mercaptopyridine as a simple, though not ideal, catalyst for the isodesmic borylation of pyrroles, indoles, and thiophenes from 2-furyl(Bcat) (Figure 3.1.1A). This isodesmic approach is driven by thermodynamic equilibrium, as the borylated products are favored over 2-furyl(Bcat) by 1-4 kcal·mol–1.1 Furthermore, furan can be removed from the mixture due to its volatility, taking advantage of Le Chatelier's principle to further drive the reaction. 114 Notably, this methodology can access electron-rich aromatics unlike prior aminoborane systems,4 though, the reaction of N,N-dimethylaniline only reached 9% conversion. Simple alkyl substituted thiophenes and furans were marginal in their reactivity. While these select substrates did not work well under the catalytic conditions, substituted pyrroles and indoles were excellent candidates for transfer borylations. Olefins, alkynes, nitriles, and halogens were all tolerant of the conditions of borylation underscoring the compatibility of reactive functional groups to the catalysis. Figure 3.1.1. Known examples of transfer borylation chemistry The Dydio group demonstrated a rhodium catalyst bearing the xantphos ligand is effective for the transfer borylation of alkenes (Figure 3.1.1B) from vinylBpin with excellent functional 115 group tolerance, regio- and stereoselectivity. The reaction in this case is mildly exergonic (ΔG° = –0.57 kcal·mol–1) and is primarily driven by release of ethylene. They propose an unprecedented β-boryl elimination to form the active RhI boryl from vinylBpin. The olefins after transfer borylation also have high E-selectivity due to faster β-hydride elimination in the product forming step of the cycle. This Rh-catalyzed process operates under kinetic control and is not driven by the thermodynamics of the borylated products, opposite to Fontaine’s organocatalytic transfer borylation. Importantly, these two examples serve as the only two reports of transfer borylation chemistry reported. They lay the foundational concepts for understanding how these catalytic systems operate in addition to the attractive features of isodesmic functionalizations. Herein, the first example of an Ir-catalyzed transfer borylation and product isomerization process is described. Investigations into the catalyst structure and a mechanism distinct from the canonical CHB is proposed to account for the transfer borylation. 3.2. Results and Discussion Scheme 3.2.1. Initial observation of selectivity difference a Data from reference 5. Ratios of products were determined by 19F NMR analysis. The initial work that lead to this observation was in the borylation of 3- fluorochlorobenzene (Scheme 3.2.1). The initial work investigating dmadph was to first replicate 116 the results of prior studies investigating the ligand. The meta-selectivity of the reaction I performed was superior to the results found previously. The only difference experimentally was that previous reactions were performed in well plates that would not fully seal, and any pressure generated during the reaction could escape. To examine whether hydrogen pressure generated during the reaction affected the observed selectivity, the borylation was run in an open system and a closed system under a constant pressure of hydrogen (Scheme 3.2.2). Scheme 3.2.2. Borylation of fluoroarenes in open and closed systemsa aReaction conditions: fluoroarene (1.0 mmol), HBpin (2.0 mmol) or B2pin2 (1.0 mmol), [Ir(OMe)cod]2 (1.0 mol %), ligand (2.0 mol %), solvent (2.0 mL). Ratios of products were determined by 19F NMR analysis. The borylation for 3-fluorochlorobenzene resulted in the same behavior as previously observed, with the open system decreasing further in meta-selectivity. While this decrease in selectivity is moderate, borylation of a substrate that is more selective for meta-to-F functionalization resulted in an even larger shift in the selectivity. The borylation of 2-chloro-6- 117 fluoropyridine in an open system decreased the selectivity to 8.0:1.0 with the meta isomer as the major product, which is a substantial shift in the selectivity of the reaction. This is the first observation of selectivity dependence on hydrogen pressure in iridium-catalyzed C–H borylations. With this in mind, we wondered if hydrogen pressure also affected the regioselectivity in the borylation of fluorobenzene (Scheme 3.2.3). The reaction was monitored over time by 19F and 11B NMR to assess both the regioselectivity and conversion respectively. After 2 h, the borylation was essentially complete (82% conversion) and the regioselectivity was found to 1.5:5.7:1.0 of the ortho:meta:para borylated isomers. At 3h, the conversion was determined to be 98%, and the mixture was isolated (mass balance = 0.218 g). It is generally understood that C–H scission is rate- limiting in iridium-catalyzed CHBs, and thus the product distribution should not change after functionalization. Prolonged heating of the reaction for 24 h, however, resulted in the product distribution changing to a nearly equimolar mixture (1.0:1.6:1.0 ortho:meta:para, mass balance = 0.220 g) of the borylated isomers. The reaction was repeated in an open system and after 24 h of heating, the regioselectivity remained nearly identical to what was observed after 1 h. These results suggest that hydrogen pressure is responsible for the product redistribution. Due to the regioisomer distribution changing over time, this suggests a thermodynamic equilibrium is operative. If this is true, the thermodynamic stabilities of the products should correspond to the ratio of products observed after equilibration. To assess this, the thermodynamic stability of the borylated isomers of fluorobenzene were calculated using DFT with B3LYP/6-31G (d,p) basis set (Figure S3.3). Unsurprisingly, all three isomers have nearly equivalent ground state energies, and thus the ratio of products can be approximated to be 1:1:1. This ratio is nearly reached in the borylation of fluorobenzene with dmadph in Scheme 3.2.3. Prolonged heating (72 h) of the reaction did not further change the regioisomer distribution, nor did increased heating at 80 °C. 118 The experimental ratio of products, although, are in near agreement with those predicted. This provides evidence that the transfer borylation process is thermodynamically controlled as opposed to the kinetically controlled CHB. Scheme 3.2.3. Borylation of fluorobenzene over timea aRatios of products were determined by 19F NMR analysis. To probe if this behavior is unique to dmadph or if hydrogen pressure also affects regioselectivity with other ligands, the borylation was repeated with the analogous dipyridylmethane ligands and dtbpy (Scheme 3.2.3). For all other ligands examined, the regioselectivity observed initially was essentially the same as that observed after full consumption of pinacolborane as expected. These experiments demonstrate that the regioselectivity shift is unique to dmadph and that hydrogen pressure is causing this behavior. When considering mechanistically how the regioisomer distribution is changing over time, there are two possibilities that could occur. The regioisomers could be scrambling from some isomerization process (i.e. olefin chain walking)6, and the boryl group remains on the substrate. The second possibility is that the boryl is removed from the substrate back to the metal via oxidative addition or sigma bond metathesis and the substrate is borylated again in a transfer 119 borylation type process. To probe the possibility of either, the experiments in Scheme 3.2.4 were carried out. The borylation of 2-methylthiophene occurs first very rapidly (<15 min for full consumption of HBpin) and fully consumes the borylating reagent. After full conversion, 3- fluorophenylBpin was added to the mixture. If the regioisomers were observed due to isomerization, all borylated isomers of fluorobenzene should be observed and only mono-borylated thiophene. Conversely, if it is a transfer borylation process, all isomers of fluorobenzene should be observed in addition to the di-borylated isomer of the more electronically activated thiophene. The reaction performed with dmadph gave evidence of the latter, as 46% of the thiophene was di- borylated and all isomers of fluorobenzene were observed. When the reaction was performed in an open system, there was no di-borylation detected by 1H NMR and only the 3-borylated isomer of fluorobenzene as was found when dtbpy was used as the ligand. Scheme 3.2.4. Probing for transfer borylationa aSee SI for full experimental details. 3.3. Investigating the Catalyst Structure With these unusual effects of hydrogen pressure and evidence of transfer borylation, the catalyst itself was investigated. An NMR tube study of the borylation of pentafluorobenzene was performed to study the ligand identity and to observe any catalyst resting states to understand the system. The aromatic region of the 1H NMR shows a mixture of several ligand species within 120 solution (Figure 3.3.1). There is a significant amount of the hydrazone-boronate adduct in solution that also remains throughout the reaction indicating that the ligand is not fully binding to the metal during catalysis. One major species was present that does not correlate with the free ligand, adduct, or iridium hydrazido complex and the intensity of the resonances gradually increased over the course of the reaction. The integration of the exchangeable N–H proton in the 1H NMR being less than one in addition to the 11B resonance at δ 19.7 ppm suggests that it is partially N-borylated in solution. Accordingly, the possible structures of this species are proposed in Figure 3.3.3. With the observation of iridium boryls in 11B (δ 33.9 ppm), the oxidation state of iridium could be either +3 or +5 where the IrV complex bears two additional Bpin or H ligands and the IrIII complex does not. Furthermore, with partial N-borylation of the ligand observed, none of the proposed structures can be ruled out. Analysis of the hydride region of the 1H NMR (Figure 3.3.2) was particularly complicated as multiple hydrides were observed throughout the course of the reaction. After 1.5 h, however, a hydride resonance observed at δ -8.39 ppm was identified as the corresponding Ir– fluoroaryl complex after C–H activation due to its apparent overlapping triplet of triplet of doublets (ttd) splitting pattern. This assignment was confirmed via {1H}19F where it collapsed into a singlet. A similar Hg complex, HgH(C6F5), was also reported7 with a ttd splitting pattern. This is a significant observation, suggesting that the intermediate Ir–aryl is a resting state for the catalyst thus altering the inherent mechanism by which borylation occurs. 121 Figure 3.3.1. 1H NMR (THF-d8) comparison of the aromatic region in pentafluorobenzene borylation 122 Figure 3.3.2. 1H NMR (THF/THF-d8) of the hydride region. Inset is a comparison of the 1H and {19F}1H of the hydride split into a ttd 123 Figure 3.3.3. Proposed structures of species observed during catalysis The IrI hydrazido was then reacted with 1 equivalent of pinacolborane (Scheme 3.3.2) to see if the catalyst could be further assembled, and the IrIII hydridoboryl complex could be isolated. In practice, this reaction was more complicated than a simple oxidative addition of HBpin to iridium as intractable mixtures of products formed upon reaction. Strong bubbling after addition of HBpin to the solution indicated evolution of hydrogen, thus N–borylation competed with the oxidative addition. The 11B NMR of the mixture after drying showed evidence of a 3-coordinate N–B bond (δ 24.9 ppm), an iridium boryl (δ 38.5 ppm), and a 4-coordinate boron species (δ 5.2 ppm). The 4-coordinate species is likely not the hydrazone-boronate adduct as the resonance is downfield shifted by nearly 2 ppm compared to the isolated adduct. The 3-coordinate boron resonance was also observed in the NMR tube borylation of pentafluorobenzene at the same chemical shift and is tentatively assigned as the N-borylated IrI hydrazido complex. Due to their instability, the products could not be separated and isolated. 124 Scheme 3.3.2. Reaction of IrI hydrazido with pinacolborane Qualitative KIE Study of dmadph. The catalytic manifold was examined through a KIE experiment to determine if a large, primary kinetic isotope effect is observed similar to the Hartwig8 system with dtbpy and our previous studies on dmadpm.9 In both cases, large primary kinetic isotope effects were observed (kH/kD > 3.5) suggesting that C–H scission is rate limiting. If no KIE (kH/kD = 1.0) or an inverse kinetic isotope effect (kH/kD < 1.0) were observed, a different mechanism where C–H scission is not rate limiting, is engaged using dmadph. Scheme 3.3.3. KIE determination in a parallel conversion experiment of C6H6 and C6D6 Utilizing the improved method developed and described by Miller,9 a GC-MS method with a slow temperature ramp and a long isothermal plateau was able to separate the protiated products from the deuterated to determine the relative KIE from the reaction in Scheme 3.3.3.. The relative KIE was found to be 4.5, which is on the order found with dmadpm but lower than the kH/kD of 5.0 found by Hartwig. These experiments support that C–H activation when using dmadph is still rate limiting. Thus, it is probable that C–H activation and borylation operate under the canonical IrIII/IrV catalytic cycle, but the transfer borylation chemistry operates in a separate, distinct mechanism. 125 3.4. Conclusions In summary, the first example of an Ir-catalyzed transfer borylation enabled by the dipyridyl hydrazone ligand, dmadph, is described. The H2 pressure generated during catalysis was found to be a requirement for both the functional group transfer chemistry and product isomerization. Kinetic isotope effect experiments demonstrated that for the C–H activation and borylation, C–H scission is rate-limiting and likely operates according to the accepted mechanism for CHB. NMR studies during catalytic borylation identified an Ir–fluoroaryl complex as a resting state of the catalyst for either the CHB or the transfer borylation chemistry, though the KIE studies support that it is a resting state for the latter. 3.5. Experimental 3.5.1. General Information Pinacolborane (HBpin) (97% stabilized with 1% triethylamine) was purchased commercially and used as received without further purification. The iridium catalyst, bis(η4-1,5- cyclooctadiene)-di-µ-methoxy-diiridium (I), [Ir(OMe)(cod)]2, was prepared by a literature procedure.11 All substrates were obtained commercially. Liquid substrates were purified by distillation and solid substrates were purified by sublimation or recrystallization. All reactions were prepared in 3.0 mL Wheaton microreactor vials equipped with stir bars and pressure caps in a glovebox under a nitrogen atmosphere and then transferred to a preheated aluminum block outside of the glovebox. THF and n-hexane were obtained from wet stills refluxing over sodium and benzophenone. Methylene chloride and acetonitrile were obtained from dry stills according to the literature procedure.12 126 Reactions were monitored by 19F NMR, and crude reaction ratios were verified by 1H NMR or 19F NMR for fluorine containing substrates. NMR spectra were recorded on a Varian 500 MHz DD2 Spectrometer equipped with a 1H-19F/15N-31P 5mm Pulsed Field Gradient (PFG) Probe. Spectra were taken in deuterated solvents referenced to residual solvent signals in 1H NMR and 13C{1H} NMR. 13C{1H} NMR resonances for the boron-bearing carbon atom were not observed due to quadrupolar relaxation. NMR spectra were processed for display using the MNova software with only phasing and baseline corrections applied. For all NMR spectra, no peaks were manually corrected, suppressed or altered in any form, and unprocessed fids are available upon request. Silica used for purification of crude material was standard laboratory grade 230 - 400 mesh designed for flash chromatography applications. Purification of crude materials on a 1 mmol scale was achieved by standard flash chromatography methods employing 2-3 g silica gel plugs in small chromatography columns of dimension approximately 2 x 30 cm. The concentrated crude materials were dissolved in a minimum amount of solvent, applied to the silica gel with a Pasteur pipette and eluted into test tubes. Compounds that eluted were visualized by spotting on TLC plates and irradiating with 254 nm UV light. 127 3.5.2. Hydrogen Pressure Experiments General procedure for borylations under H2 pressure (A): In a nitrogen-filled glovebox, a 3.0 mL Wheaton pressure vial equipped with a stir bar was charged with a 1.0 mL THF solution of [Ir(OMe)cod]2 (6.6 mg, 0.01 equiv). To this solution, pinacolborane (0.290 mL, 2 mmol, 2.0 equiv) was added with a syringe while stirring, turning the light-yellow solution into a golden orange. Then, in a small test tube, a 1.0 mL THF solution of dmadph (5.6 mg, 0.02 equiv) was made and added to the iridium solution with a syringe and the solution immediately turned dark red in color. Last, the substrate (1 mmol) was added neat to this solution and capped. The vial was then removed from the glovebox and transferred into a Parr reactor vessel fitted with a glass reactor liner and a stirbar and immediately capped. The vessel was filled with H2 and evacuated three times. Then, H2 at the desired pressure was filled into the vessel and stirred. Upon returning, the vessel was evacuated, and the reaction mixture was transferred to a 20 mL scintillation vial using CH2Cl2 and the volatiles were removed under reduced pressure and the crude mixture was analyzed by 1H, 19F, and 11B NMR. General procedure for open-system borylation (B): In a nitrogen-filled glovebox, a 10 mL Schlenk flask equipped with a stir bar was charged with a 1.0 mL THF solution of [Ir(OMe)cod]2 (6.6 mg, 0.01 equiv). To this solution, pinacolborane (0.290 mL, 2 mmol, 2.0 equiv) was added with a syringe while stirring, turning the light-yellow solution into a golden orange. Then, in a small test tube, a 1.0 mL THF solution of dmadph (5.6 mg, 0.02 equiv) was made and added to the iridium solution with a syringe and the solution immediately turned dark red in color. Last, the substrate (1 mmol) was added neat to this solution and capped with a septum. The flask was transferred out of the glovebox and attached to a N2 line. Under positive N2 pressure, a reflux condenser was attached, and the flask was immediately submerged 128 in a preheated oil bath at 40 °C and stirred. When the reaction finished, the crude reaction mixture was transferred to a 20 mL scintillation vial using CH2Cl2 and the volatiles were removed under reduced pressure and the crude mixture was analyzed by 1H, 19F, and 11B NMR. Borylation of 2-chloro-6-fluoropyridine under H2 pressure Borylation was performed according to general procedure A at 40 °C under 5 atm of H2 for 1 h. For full spectral characterization, see pages 41–42. The ratio of regioisomers was determined to be >20:1.0 meta:ortho to fluorine by 19F NMR. The conversion determined by 19F NMR was >99%. Open system borylation of 2-chloro-6-fluoropyridine Borylation was performed according to general procedure B at 40 °C for 5 h. For full spectral characterization, see pages 41–42. The ratio of regioisomers was determined to be 8.0:1.0 meta:ortho to fluorine by 19F NMR. The conversion determined by 19F NMR was 95%. 129 Borylation of 3-fluorochlorobenzene under H2 pressure Borylation was performed according to general procedure A at 40 °C under 5 atm of H2 for 1 h. For full spectral characterization, see pages 45–46. The ratio of regioisomers was determined to be 7.3:1.0 meta:ortho to fluorine by 19F NMR. The conversion determined by 19F NMR was >99%. Open system borylation of 3-fluorochlorobenzene Borylation was performed according to general procedure B at 40 °C for 5 h. For full spectral characterization, see pages 45–46. The ratio of regioisomers was determined to be 4.0:1.0 meta:ortho to fluorine by 19F NMR. The conversion determined by 19F NMR was 95%. General procedure for the borylation of fluorobenzene (C) In a nitrogen-filled glovebox, a 3.0 mL Wheaton pressure vial equipped with a stir bar was charged with a 1.0 mL THF solution of [Ir(OMe)cod]2 (6.6 mg, 0.01 equiv). To this solution, pinacolborane (0.290 mL, 2 mmol, 2.0 equiv) was added with a syringe while stirring, turning the light-yellow solution into a golden orange. Then, in a small test tube, a 1.0 mL THF solution of the ligand (0.02 equiv) was made and added to the iridium solution with a syringe and the solution immediately 130 turned dark red in color. Last, fluorobenzene (96 µL, 1.0 mmol) was added to this solution and capped. The reaction was heated at 40 °C and stirred in an aluminum heating block on top of a stir plate outside of the glovebox. Reactions were monitored by 19F and 11B spectroscopies. After 24 h, the volatiles were evaporated, and the crude reaction mixtures were analyzed by 19F, 1H, and 11B NMR. The results are summarized below in Figure S1. Figure S3.1. Ligand screen for the borylation of fluorobenzene according to general procedure C. Regioselectivities and conversions determined by 19F NMR. Open system borylation of fluorobenzene Borylation was performed according to general procedure B at 40 °C for 24 h. For full spectral characterization, see pages 53–54. The ratio of regioisomers was determined to be 1.3:4.6:1.0 of 131 ortho:meta:para to fluorine by 19F NMR. The conversion determined by 19F and 11B NMR was >99%. 3.3.3. NMR Tube Borylations Borylation of 2,3,4,5-tetrafluorotoluene In a N2 filled glovebox, [Ir(OMe)cod]2 (0.0070 g, 0.01 mmol), dmadph (0.0060 g, 0.02 mmol), were weighed into separate test tubes. Then, 1.0 mL of THF was added to both test tubes. To the solution of Ir, HBpin (300 µL, 2 mmol) was added and shaken briefly, turning the light-yellow solution into a golden-yellow. The solution of Ir and pinacolborane was then pipetted into the solution of dmadph and transferred into a scintillation vial with a stir bar. The combined solution was stirred vigorously for 5 minutes, turning the solution dark red. Using a microsyringe, 400 µL of the combined solution was added to a J-young tube, followed by 2,3,4,5-tetrafluorotoluene (30 µL, 0.18 mmol) and 0.3 mL of THF-d8. The J-young was capped, inverted and thoroughly mixed. The tube was then transferred into a preheated oil bath at 40 °C and monitored by 1H, 19F, and 11B NMR. The conversion at 6 h determined by 19F NMR analysis was 13%. Notes: While the reaction did not proceed as readily as the borylation of pentafluorobenzene (vide infra), the aromatic region of the NMR revealed that a similar species as to the one being proposed in the following section is generated. See Figure S14. 132 Borylation of pentafluorobenzene In a N2 filled glovebox, [Ir(OMe)cod]2 (0.0070 g, 0.01 mmol), dmadph (0.0060 g, 0.02 mmol), were weighed into separate test tubes. Then, 1.0 mL of THF was added to both test tubes. To the solution of Ir, HBpin (300 µL, 2 mmol) was added and shaken briefly, turning the light-yellow solution into a golden-yellow. The solution of Ir and pinacolborane was then pipetted into the solution of dmadph and transferred into a scintillation vial with a stir bar. The combined solution was stirred vigorously for 5 minutes, turning the solution dark red. Using a microsyringe, 400 µL of the combined solution was added to a J-young tube, followed by pentafluorobenzene (20 µL, 0.18 mmol) and 0.3 mL of THF-d8. The J-young was capped, inverted and thoroughly mixed. The tube was then transferred into a preheated oil bath at 40 °C and monitored by 1H, 19F, and 11B NMR. Conversion after 3.5 h was determined to be 90% via 19F NMR. After the reaction completed, the NMR tube was placed into a –40 °C freezer. Upon returning to the NMR tube after two days, white solids precipitated from solution. These solids were taken up in CDCl3 and analyzed by 1H, 11B, and 19F NMR. Notes: Mass balance for isolation of the solid material was not taken due to the NMR tube breaking. With no prior knowledge of the stability of the products, NMR analysis was immediately performed. The solids contained a mixture of the Ir complex and C6F5Bpin. 133 In the aromatic and hydride regions of the 1H NMR, an Ir–fluoroaryl complex was identified and the proposed structures are shown below. The tentatively assigned 1H, 11B and 19F NMR resonances are given for the proposed structures. 1H NMR (500 MHz, CDCl3) of Ir–fluoroaryl complex δ 11.12 (s, 1H), 8.54 (d, J = 5.9 Hz, 1H), 8.41 (d, J = 7.0 Hz, 1H), 6.89 (d, J = 14.0 Hz, 2H), 6.65 (d, J = 6.3 Hz, 1H), 6.29 (d, J = 5.1 Hz, 1H), 3.08 (s, 6H), 2.99 (s, 6H), 0.95 (s, 6H), 0.90 (s, 6H), -8.24 – -8.33 (m, 1H)*. *Note: The hydride integral was <1, and this may be due to rapid exchange with residual D2O. 11B NMR (160 MHz, CDCl3) of Ir–fluoroaryl complex δ 22.5 (br s), 2.9 (br s). 19F NMR (470 MHz, CDCl3) δ -116.40, -131.43, -134.39. 134 3.3.4. KIE Experiment In a N2 filled glovebox, [Ir(OMe)cod]2 (0.004 g, 0.06 mmol), dmadph (0.003 g, 0.011 mmol), were weighed into separate test tubes. Then, 1.0 mL of THF was added to both test tubes. To the solution of Ir, HBpin (15.0 µL, 0.10 mmol) was added and shaken briefly, turning the light-yellow solution into a golden-yellow. The solution of Ir and pinacolborane was then pipetted into the solution of dmadph and transferred into a Wheaton vial with a stir bar. The combined solution was stirred vigorously for 5 minutes, turning the solution dark red. Last, benzene (0.46 mL, 5.2 mmol) and d6- benzene (0.50 mL, 5.2 mmol) were added to the combined solution. The vial was capped and taken out of the glovebox and transferred to a preheated aluminum block at 40 °C. The reaction was monitored by GC-MS and 11B NMR. The conversion determined by 11B NMR was >99% at 6 h. Figure S3.2. GC-MS trace of the crude reaction mixture at t = 6 h 135 3.3.5. Experiments Probing for Transfer Borylation Transfer borylation of 2-methylthiophene with dmadph In a nitrogen-filled glovebox, a 3.0 mL Wheaton pressure vial equipped with a stir bar was charged with a 1.0 mL THF solution of [Ir(OMe)cod]2 (6.6 mg, 0.01 equiv). To this solution, pinacolborane (0.145 mL, 1 mmol, 1.0 equiv) was added with a syringe while stirring, turning the light-yellow solution into a golden orange. Then, in a small test tube, a 1.0 mL THF solution of dmadph (5.3 mg, 0.02 equiv) was made and added to the iridium solution with a syringe and the solution immediately turned dark red in color. Last, 2-methylthiophene (98 µL, 1.0 mmol, 1.0 equiv) was added to this solution and capped. The reaction was heated at 40 °C and stirred in an aluminum heating block on top of a stir plate outside of the glovebox for 15 min. The vial was removed from the block, and 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2204 g, 1.0 mmol, 1.0 equiv) was added and the vial immediately capped and heated at 40 °C for 24 h. After 24 h, the volatiles were evaporated, and the crude reaction mixtures were analyzed by 19F, 1H, and 11B NMR. 19F NMR analysis showed all three isomers of mono-borylated fluorobenzene (1.7 : 3.5 : 1.0 of the o:m:p isomers) and fluorobenzene. For full characterization of all isomers of borylated fluorobenzene, see pages 53–54. 1H NMR analysis revealed 46% of the 3,5-diborylated 2- methylthiophene and 54% of the mono-borylated 5-Bpin-2-methylthiophene. 136 Note: Products were not isolated, and crude reaction mixtures after drying were analyzed. Both 3.2.4a13 and 3.2.4b13 matched previously reported literature values. 1H NMR (500 MHz, CDCl3) of 3.2.4a δ 7.40 (d, J = 3.4 Hz, 1H), 6.81 – 6.79 (m, 1 H), 2.49 (s, 3H), 1.29 (s, 12H). 11B NMR (160 MHz, CDCl3) of 3.2.4a δ 30.6 (br s) 1H NMR (500 MHz, CDCl3) of 3.2.4b δ 7.79 (s, 1H), 2.67 (s, 3H), 1.27 (s, 12H), 1.26 (s, 12H). 11B NMR (160 MHz, CDCl3) of 3.2.4b δ 30.6 (br s) Transfer borylation of 2-methylthiophene with dtbpy In a nitrogen-filled glovebox, a 3.0 mL Wheaton pressure vial equipped with a stir bar was charged with a 1.0 mL THF solution of [Ir(OMe)cod]2 (6.6 mg, 0.01 equiv). To this solution, pinacolborane (0.145 mL, 1 mmol, 1.0 equiv) was added with a syringe while stirring, turning the light-yellow solution into a golden orange. Then, in a small test tube, a 1.0 mL THF solution of dtbpy (5.6 mg, 0.02 equiv) was made and added to the iridium solution with a syringe and the solution immediately turned dark red in color. Last, 2-methylthiophene (98 µL, 1.0 mmol, 1.0 equiv) was added to this solution and capped. The reaction was heated at 40 °C and stirred in an aluminum heating block on top of a stir plate outside of the glovebox for 15 min. The vial was removed from the block, and 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2204 g, 1.0 mmol, 1.0 equiv) was added and the vial immediately capped and heated at 40 °C for 24 h. After 24 h, 137 the volatiles were evaporated, and the crude reaction mixtures were analyzed by 19F, 1H, and 11B NMR. 19F NMR analysis showed only starting material and deborylated fluorobenzene. 1H NMR analysis revealed no diborylation of the thiophene and only monoborylated 3.2.4a. Figure S3.3. Calculated ground state energies of borylated fluorobenzene isomers 138 3.3.6. NMR Data 1H NMR (500 MHz, 1:1 THF/THF-d8) of pentafluorobenzene borylation at t = 1.5 h. Top inset shows the aryl region expanded. Bottom inset in red is the hydride region expanded. 139 19F NMR (470 MHz, 1:1 THF/THF-d8) of pentafluorobenzene borylation at t = 0.75 h. 140 11B NMR (160 MHz, 1:1 THF/THF-d8) of pentafluorobenzene borylation at t = 0.75 h. 141 1H NMR (500 MHz, 1:1 THF/THF-d8) of pentafluorobenzene borylation at t = 1.5 h. Top inset shows the aryl region expanded. Bottom inset in red is the hydride region expanded. 142 19F NMR (470 MHz, 1:1 THF/THF-d8) of pentafluorobenzene borylation at t = 1.5 h. 143 1H NMR (500 MHz, 1:1 THF/THF-d8) of pentafluorobenzene borylation at t = 3.5 h. Top inset shows the aryl region expanded. Bottom inset in red is the hydride region expanded. 144 19F NMR (470 MHz, 1:1 THF/THF-d8) of pentafluorobenzene borylation at t = 3.5 h. 145 11B NMR (160 MHz, 1:1 THF/THF-d8) of pentafluorobenzene borylation at t = 3.5 h. 146 19F NMR (470 MHz, 1:1 THF/THF-d8) stacked plot of pentafluorobenzene borylation at t = 3.5 h. 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