Investigations of C-H and N-H activation with electron deficient iridium pincer complexes

Transition metal reactions that involve C-H and N-H bond activation provide a potential method for functionalizing hydrocarbons and amines. For the past three decades there have been numerous advances in this field; however, developing new approaches to activation of these bonds continues to be a significant endeavor. Recently pincer ligands have been successfully used to stabilize metal complexes at elevated temperatures. When chelated to iridium, these pincer complexes have been shown to be very active as transfer dehydrogenation catalysts. This has been exemplified by Kaska, Goldman, and Jensen using Ir complexes containing the 2,6-(CH2PtBu2)2C6H3 (PCP) ligand and by Brookhart using the Ir complexes of the more electron-deficient bis(phosphinite) pincer ligand (POCOP). This dissertation explores alternative reactivity of these bis(phosphinite)iridium complexes. Chapter 2 focuses on the reactions of [(POCOP)Ir] with N-H bonds, in particular those of both anilines and benzamides. The electronic character of the anilines plays an important role in the reactivity; more electron-withdrawing anilines favor oxidative addition while the more electron-donating anilines favor ?-bond formation. An explanation for this behavior is provided along with a kinetic analysis of the oxidative addition and reductive elimination of anilines. A comparison of the reactivity of anilines to that of benzamides is also discussed. In Chapter 3, cationic [(POCOP)Ir(H)(L)][BArF] complexes are examined that contain tetrakis(trifluoromethylphenyl)borate (BArF) as a non-coordinating counterion. Since these complexes are cationic, the metal center is even more electron deficient than those mentioned above. The structure of [(POCOP)Ir(H)(H2)][BArF] was determined based on an H-D coupling constant of 33 Hz. In addition to the structural analysis, the rate of exchange between the hydride and the dihydrogen has also been determined. Cationic olefin complexes, [(POCOP)Ir(H)(L)][BArF] (L = C2H4, C3H6, norbornene, methyl acrylate) have also been synthesized. Their dynamic behavior has been assessed using both line-broadening and spin-saturation transfer NMR techniques. The rates of olefin rotation and insertion into the Ir-H bond were analyzed and energy barriers to these processes were calculated. A brief examination of the reactivity of the cationic norbornene complex with nucleophiles has also been explored; however the results showed no C-Nuc bond formation

Reactions of Anilines and Benzamides with a 14-Electron Iridium(I) Bis(phosphinite) Complex: N−H Oxidative Addition versus Lewis Base Coordination

Anilines react with (POCOP)Ir(C6H5)(H), 12, (POCOP = 2,6-(OPtBu2)2C6H3) to yield equilibrium mixtures of 12, the Ir(I) σ-complexes (POCOP)Ir(NH2Ar), 13, and the Ir(III) oxidative addition adducts (POCOP)Ir(H)(NHAr), 14. Quantitative studies of these equilibria for a series of anilines were carried out. Anilines possessing electron-withdrawing groups favor the Ir(III) oxidative addition adduct over the Ir(I) sigma complex. Low temperature studies using p-chloroaniline show that the Ir(I) σ-complex is the kinetic product of reaction and is likely the precursor to the Ir(III) oxidative addition adduct. Reductive elimination of complexes 14 in the presence of ethylene led to the corresponding anilines and the ethylene complex (POCOP)Ir(C2H4). Kinetic analysis of these reactions for 14e,f,g bearing electron-withdrawing aryl groups (Ar- = p-CF3C6H4-, C6F5-, 3,5-bis(CF3)C6H3-) shows the rate is independent of ethylene concentration. The ΔG‡ values for these reductive eliminations fall in the range of 21–22 kcal/mol. X-Ray analysis establishes 14f (Ar- = C6F5-) as a square pyramidal complex with the hydride occupying the apical site. Reaction of 12 with benzamides 21a,b yields quantitatively the Ir(III) oxidative addition adducts, (POCOP)Ir(H)(NHC(O)Ar), 22. X-Ray analysis of 22b (Ar- = C6F5-) shows significant interaction of the carbonyl oxygen with Ir in the site trans to hydride. The barrier to reductive elimination of 22a, 29 kcal/mol, is substantially higher than for complexes 14e,f,g

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management

Dihydrogen Complexes of Iridium and Rhodium

A series of iridium and rhodium pincer complexes have been synthesized and characterized: [(POCOP)­Ir­(H)­(H₂)] [BAr^f₄] (<b>1-H</b>_<b>3</b>), (POCOP)­Rh­(H₂) (<b>2-H</b>_<b>2</b>), [(PONOP)­Ir­(C₂H₄)] [BAr^f₄] (<b>3-C</b>_<b>2</b><b>H</b>_<b>4</b>), [(PONOP)­Ir­(H)₂)] [BAr^f₄] (<b>3-H</b>_<b>2</b>), [(PONOP)­Rh­(C₂H₄)] [BAr^f₄] (<b>4-C</b>_<b>2</b><b>H</b>_<b>4</b>) and [(PONOP)­Rh­(H₂)] [BAr^f₄] (<b>4-H</b>_<b>2</b>) (POCOP = κ³-C₆H₃-2,6-[OP­(<i>t</i>Bu)₂]₂; PONOP = 2,6-(<i>t</i>Bu₂PO)₂C₅H₃N; BAr^f₄ = tetrakis­(3,5-trifluoromethylphenyl)­borate). The nature of the dihydrogen–metal interaction was probed using NMR spectroscopic studies. Complexes <b>1-H</b>_<b>3</b>, <b>2-H</b>_<b>2</b>, and <b>4-H</b>_<b>2</b> retain the H–H bond and are classified as η²-dihydrogen adducts. In contrast, complex <b>3-H</b>_<b>2</b> is best described as a classical dihydride system. The presence of bound dihydrogen was determined using both T₁ and ¹<i>J</i>_HD coupling values: <i>T</i>₁ = 14 ms, ¹<i>J</i>_HD = 33 Hz for the dihydrogen ligand in <b>1-H</b>_<b>3</b>, <i>T</i>₁(min) = 23 ms, ¹<i>J</i>_HD = 32 Hz for <b>2-H</b>_<b>2</b>, <i>T</i>₁(min) = 873 ms for <b>3-H</b>_<b>2</b>, <i>T</i>₁(min) = 33 ms, ¹<i>J</i>_HD = 30.1 Hz for <b>4-H</b>_<b>2</b>