Photoisomerisation of Exo-Imine Complexes and the Role of MECP in the Reverse Thermal Equilibrium: An Experimental and DFT Computational Investigation.

Complexes [MCl2 Cp*]2 (M=Ir, Rh), [RuCl2 (p-cymene)]2 and [Ir(C^N)2 Cl]2 (HC^N=a, phenylpyridine ; b, phenylpyrazole,) react with imine ligands derived from ο-aminophenol to yield complexes with an exocyclic C=N bond which has a cis or trans configuration. The trans isomer is favoured except for sterically crowded complexes Cp*M (M=Ir, Rh) when the imine has a mesityl substituent, for which the cis isomer is favoured. The complexes undergo photoisomerisation in visible light but revert back to the original isomer over time or when heated. The rate of the thermal reverse isomerisation depends on the imine substituent and the metal fragment. DFT calculations correctly reproduce the favoured isomer and suggest that the reverse isomerisation occurs by a rehybridisation at the N atom as found in organic imines. In addition, a triplet state, thermally accessible by a Minimum Energy Crossing Point (MECP) provides a low energy pathway for reverse isomerisation in the case of the half-sandwich complexes.

Essential anatomy for core clerkships: A clinical perspective.

Clerkships are defining experiences for medical students in which students integrate basic science knowledge with clinical information as they gain experience in diagnosing and treating patients in a variety of clinical settings. Among the basic sciences, there is broad agreement that anatomy is foundational for medical practice. Unfortunately, there are longstanding concerns that student knowledge of anatomy is below the expectations of clerkship directors and clinical faculty. Most allopathic medical schools require eight "core" clerkships: internal medicine (IM), pediatrics (PD), general surgery (GS), obstetrics and gynecology (OB), psychiatry (PS), family medicine (FM), neurology (NU), and emergency medicine (EM). A targeted needs assessment was conducted to determine the anatomy considered important for each core clerkship based on the perspective of clinicians teaching in those clerkships. A total of 525 clinical faculty were surveyed at 24 United States allopathic medical schools. Participants rated 97 anatomical structure groups across all body regions on a 1-4 Likert-type scale (1 = not important, 4 = essential). Non-parametric ANOVAs determined if differences existed between clerkships. Combining all responses, 91% of anatomical structure groups were classified as essential or more important. Clinicians in FM, EM, and GS rated anatomical structures in most body regions significantly higher than at least one other clerkship (p = 0.006). This study provides an evidence-base of anatomy content that should be considered important for each core clerkship and may assist in the development and/or revision of preclinical curricula to support the clinical training of medical students.

Experimental and Computational Studies on the Acetate-Assisted C-H Activation of N-Aryl Imidazolium Salts at Rhodium and Iridium: A Chloride Additive Changes the Selectivity of C-H Activation.

Combined experimental and computational mechanistic studies of the reactions of unsymmetrical, para-substituted N-aryl imidazolium salts, L2-R1,R2, at [MCl2Cp*]2 (M = Rh, Ir) in the presence of NaOAc are reported. These proceed via intermediate N-heterocyclic carbene complexes that then allow an internal competition between two differently substituted aryl rings toward C-H activation to be monitored. At 348 K in dichloroethane C-H activation of the aryl with the more electron-withdrawing substituents is generally favored. DFT calculations show similar barriers for proton transfer and dissociative HOAc/Cl- ligand substitution, with proton transfer favoring electron-donating substituents, and ligand substitution favoring electron-withdrawing substituents. Microkinetic simulations reproduce the experimental preference implying that the ligand substitution step dominates selectivity. For several substrates, notably L2-F,OMe and L2-F,H, running the C-H activation reactions at 298 K in the presence of added [Et4N]Cl reverses the selectivity. The greater availability of chloride in solution makes an alternative dissociative interchange ligand substitution mechanism accessible, leaving proton transfer as selectivity determining and so favoring electron-donating substituents. Our results highlight the potential importance of the ligand substitution step in the interpretation of substituent effects and demonstrate how a simple additive, [Et4N]Cl, can have a dramatic effect on selectivity by changing the mechanism of ligand substitution.

Steric effects on acetate-assisted cyclometallation of meta-substituted N-phenyl and N-benzyl imidazolium salts at [MCl2Cp*]2 (M = Ir, Rh).

meta-Substituted N-phenyl,N'-methyl and N-benzyl,N'-methyl imidazolium salts undergo acetate-assisted cyclometallation to provide mixtures of ortho and para substituted cyclometallated complexes. The effect of the substituents on the isomer ratios is discussed; steric effects are more important in the 6-membered rings derived from the N-benzyl imidazolium salts than 5-membered rings from the N-phenyl salts. Comparisons are made to steric effects with some other common directing groups.

Bis-cyclometallated Ir(III) complexes containing 2-(1H-pyrazol-3-yl)pyridine ligands; influence of substituents and cyclometallating ligands on response to changes in pH.

Bis-cyclometallated Ir(iii) complexes containing 2-(1H-pyrazol-3-yl)pyridine ligands have been synthesised. Their absorption is almost unchanged with changes in pH however the emission intensities vary by a factor of up to three and the complexes have emission pKas in the range 8.0 to 10.0. Substituents on the pyrazole have only a minor effect on the emission pKa. Surprisingly the complexes with phenylpyrazole cyclometallated ligands 3aL1-3 showed an intensity decrease with increasing pH (switch off) whilst the corresponding phenylpyridine ones 3cL1-3 showed an increase in emission intensity with increasing pH. Putting electron-withdrawing CF3 substituents on the cyclometallating phenyls reduced the pKa of the complexes to 6.8-7.8, thereby extending the useful pKa range; however, in general it tended to reduce the magnitude of the change in emission intensity. Surprisingly the CF3-substituted complexes also showed a complete reversal in the direction of the intensity change when compared to their respective unsubstituted congeners.

Steric and electronic effects on acetate-assisted cyclometallation of 2-phenylpyridines at [MCl2Cp*]2 (M = Ir, Rh).

The reactions of substituted 2-phenylpyridines at [MCl2Cp*]2 dimers (M = Ir, Rh) in the presence of NaOAc form cyclometallated complexes Cp*M(Phpyr)Cl. H/D exchange experiments and substrate competition experiments show that kinetic selectivity favours electron donating substituents whilst substrates with electron withdrawing substituents are favoured thermodynamically. Experiments with Ir are mostly irreversible under the conditions used whilst those for Rh are more easily reversible. For meta-substituted phenylpyridines steric effects are important, larger substituents leading to formation of the para-substituted cyclometallated product.

Understanding electronic effects on carboxylate-assisted C-H activation at ruthenium: the importance of kinetic and thermodynamic control.

Meta- and para-substituted 1-phenylpyrazoles (R-phpyz-H) react with [RuCl2(p-cymene)]2 in the presence of NaOAc to form cyclometallated complexes [M(R-phpyz)Cl(p-cymene)] (where R = NMe2, OMe, Me, H, F, CF3 and NO2). Experimental and DFT studies indicate that product formation can be reversible or irreversible depending on the substituents and the reaction conditions. Competition experiments show that the kinetic selectivity favours electron-donating substituents and correlate well with the Hammett parameter, giving a negative slope (ρ = -2.4) that is consistent with a cationic transition state. However, surprisingly, the thermodynamic selectivity is completely opposite, with substrates featuring electron-withdrawing groups being favoured. These trends are reproduced with DFT calculations that locate a rate-limiting transition state dominated by Ru-O bond dissociation and minimal C-H bond elongation. Detailed computational analysis of these transition states shows that C-H activation proceeds by an AMLA/CMD mechanism through a synergic combination of a C-H→Ru agostic interaction and C-HO H-bonding. NBO calculations also highlight a syndetic bonding term, and the relative weights of these three components vary in a complementary fashion depending on the nature of the substituent. With meta-substituted ligands H/D exchange experiments signal kinetically accessible ortho-C-H activation when R = NMe2, OMe and Me. This is also modelled computationally and the calculations highlight the kinetic relevance of the HOAc/Cl exchange that occurs post C-H bond cleavage, in particular with the bulkier NMe2 and Me substituents. Our study highlights that the experimental substituent effects are dependent on the reaction conditions and so using such studies to assign the mechanism of C-H activation in either stoichiometric or catalytic reactions may be misleading.

The Importance of Kinetic and Thermodynamic Control when Assessing Mechanisms of Carboxylate-Assisted C-H Activation.

The reactions of substituted 1-phenylpyrazoles (phpyz-H) at [MCl2Cp*]2 dimers (M = Rh, Ir; Cp* = C5Me5) in the presence of NaOAc to form cyclometalated Cp*M(phpyz)Cl were studied experimentally and with density functional theory (DFT) calculations. At room temperature, time-course and H/D exchange experiments indicate that product formation can be reversible or irreversible depending on the metal, the substituents, and the reaction conditions. Competition experiments with both para- and meta-substituted ligands show that the kinetic selectivity favors electron-donating substituents and correlates well with the Hammett parameter giving a negative slope consistent with a cationic transition state. However, surprisingly, the thermodynamic selectivity is completely opposite, with substrates with electron-withdrawing groups being favored. These trends are reproduced with DFT calculations that show C-H activation proceeds by an AMLA/CMD mechanism. H/D exchange experiments with the meta-substituted ligands show ortho-C-H activation to be surprising facile, although (with the exception of F substituents) this does not generally lead to ortho-cyclometalated products. Calculations suggest that this can be attributed to the difficulty of HOAc loss after the C-H activation step due to steric effects in the 16e intermediate that would be formed. Our study highlights that the use of substituent effects to assign the mechanism of C-H activation in either stoichiometric or catalytic reactions may be misleading, unless the energetics of the C-H cleavage step and any subsequent reactions are properly taken into account. The broader implications of our study for the assignment of C-H activation mechanisms are discussed.

Computational Studies of Carboxylate-Assisted C-H Activation and Functionalization at Group 8-10 Transition Metal Centers.

Computational studies on carboxylate-assisted C-H activation and functionalization at group 8-10 transition metal centers are reviewed. This Review is organized by metal and will cover work published from late 2009 until mid-2016. A brief overview of computational work prior to 2010 is also provided, and this outlines the understanding of carboxylate-assisted C-H activation in terms of the "ambiphilic metal-ligand assistance" (AMLA) and "concerted metalation deprotonation" (CMD) concepts. Computational studies are then surveyed in terms of the nature of the C-H bond being activated (C(sp2)-H or C(sp3)-H), the nature of the process involved (intramolecular with a directing group or intermolecular), and the context (stoichiometric C-H activation or within a variety of catalytic processes). This Review aims to emphasize the connection between computation and experiment and to highlight the contribution of computational chemistry to our understanding of catalytic C-H functionalization based on carboxylate-assisted C-H activation. Some opportunities where the interplay between computation and experiment may contribute further to the areas of catalytic C-H functionalization and applied computational chemistry are identified.

Experimental and DFT Studies Explain Solvent Control of C-H Activation and Product Selectivity in the Rh(III)-Catalyzed Formation of Neutral and Cationic Heterocycles.

A range of novel heterocyclic cations have been synthesized by the Rh(III)-catalyzed oxidative C-N and C-C coupling of 1-phenylpyrazole, 2-phenylpyridine, and 2-vinylpyridine with alkynes (4-octyne and diphenylacetylene). The reactions proceed via initial C-H activation, alkyne insertion, and reductive coupling, and all three of these steps are sensitive to the substrates involved and the reaction conditions. Density functional theory (DFT) calculations show that C-H activation can proceed via a heteroatom-directed process that involves displacement of acetate by the neutral substrate to form charged intermediates. This step (which leads to cationic C-N coupled products) is therefore favored by more polar solvents. An alternative non-directed C-H activation is also possible that does not involve acetate displacement and so becomes favored in low polarity solvents, leading to C-C coupled products. Alkyne insertion is generally more favorable for diphenylacetylene over 4-octyne, but the reverse is true of the reductive coupling step. The diphenylacetylene moiety can also stabilize unsaturated seven-membered rhodacycle intermediates through extra interaction with one of the Ph substituents. With 1-phenylpyrazole this effect is sufficient to suppress the final C-N reductive coupling. A comparison of a series of seven-membered rhodacycles indicates the barrier to coupling is highly sensitive to the two groups involved and follows the trend C-N(+) > C-N > C-C (i.e., involving the formation of cationic C-N, neutral C-N, and neutral C-C coupled products, respectively).

Combined experimental and computational investigations of rhodium-catalysed C - H functionalisation of pyrazoles with alkenes.

Detailed experimental and computational studies have been carried out on the oxidative coupling of the alkenes C2 H3 Y (Y=CO2 Me (a), Ph (b), C(O)Me (c)) with 3-aryl-5-R-pyrazoles (R=Me (1 a), Ph (1 b), CF3 (1 c)) using a [Rh(MeCN)3 Cp*][PF6 ]2 /Cu(OAc)2 ⋅H2 O catalyst system. In the reaction of methyl acrylate with 1 a, up to five products (2 aa-6 aa) were formed, including the trans monovinyl product, either complexed within a novel Cu(I) dimer (2 aa) or as the free species (3 aa), and a divinyl species (6 aa); both 3 aa and 6 aa underwent cyclisation by an aza-Michael reaction to give fused heterocycles 4 aa and 5 aa, respectively. With styrene, only trans mono- and divinylation products were observed, whereas with methyl vinyl ketone, a stronger Michael acceptor, only cyclised oxidative coupling products were formed. Density functional theory calculations were performed to characterise the different migratory insertion and ß-H transfer steps implicated in the reactions of 1 a with methyl acrylate and styrene. The calculations showed a clear kinetic preference for 2,1-insertion and the formation of trans vinyl products, consistent with the experimental results.

Tuning the emission lifetime in bis-cyclometalated iridium(III) complexes bearing iminopyrene ligands.

Bis-cyclometalated Ir(III) complexes with the general formula Ir(ppz)2(X^NPyrene), where ppz = 1-phenylpyrazole and X^NPyrene is a bidentate chelate with X = N or O, are reported. Modifications on the ancillary ligand containing pyrene drastically affect the emission lifetimes observed (0.329 to 104 µs). Extended emission lifetimes in these complexes compared to model complexes result from reversible electronic energy transfer or the observation of dual emission containing along-lived pyrene ligand-centered triplet ((3)LC) component. A combination of steady-state and time-resolved spectroscopic techniques are used to observe reversible electronic energy transfer in solution between the iridium core and pyrene moiety in the complex [Ir(ppz)2(NMe^NCH2Pyr)][PF6] (2), where NMe^NCH2Pyr = N-(pyren-1-ylmethyl)-1-(pyridin-2-yl)ethaneimine. Studies on [Ir(ppz)2(NMe^NCH2Pyr)][PF6] in a poly(methyl methacrylate) (PMMA) film reveal that reversible energy transfer is no longer effective, and instead, dual emission with a long-lived (3)LC component from pyrene is observed. Dual emission is observed in additional cyclometalated iridium complexes bearing pyrene-containing ancillary ligands N^NPyrene and O^NPyrene when the complexes are dispersed in a PMMA film.

Combined experimental and computational investigations of rhodium- and ruthenium-catalyzed C-H functionalization of pyrazoles with alkynes.

Detailed experimental and computational studies are reported on the mechanism of the coupling of alkynes with 3-arylpyrazoles at [Rh(MeCN)3Cp*][PF6]2 and [RuCl2(p-cymene)]2 catalysts. Density functional theory (DFT) calculations indicate a mechanism involving sequential N-H and C-H bond activation, HOAc/alkyne exchange, migratory insertion, and C-N reductive coupling. For rhodium, C-H bond activation is a two-step process comprising κ(2)-κ(1) displacement of acetate to give an agostic intermediate which then undergoes C-H bond cleavage via proton transfer to acetate. For the reaction of 3-phenyl-5-methylpyrazole with 4-octyne k(H)/k(D) = 2.7 ± 0.5 indicating that C-H bond cleavage is rate limiting in this case. However, H/D exchange studies, both with and without added alkyne, suggest that the migratory insertion transition state is close in energy to that for C-H bond cleavage. In order to model this result correctly, the DFT calculations must employ the full experimental system and include a treatment of dispersion effects. A significantly higher overall barrier to catalysis is computed at {Ru(p-cymene)} for which the rate-limiting process remains C-H activation. However, this is now a one-step process corresponding to the κ(2)-κ(1) displacement of acetate and so is still consistent with the lack of a significant experimental isotope effect (k(H)/k(D) = 1.1 ± 0.2).

Pyridine imines as ligands in luminescent iridium complexes.

Biscyclometallated iridium complexes [Ir(ppz)2(X^Y)][PF6] (X^Y = pyridine imine) have been synthesised. The pyridineimine ligands are prepared in situ during the complexation. The complexes show room temperature emission between 640 and 780 nm in CH2Cl2 solution. The emission is red shifted compared with the analogous bipyridine complex [Ir(ppz)2(bipy)][PF6]. DFT calculations have been used to shed light on the influence of the imine substituent on the electrochemical and photochemical properties. In particular, the calculations suggests that there is a significant change in geometry between the ground state and the first triplet excited state for arylimines but not for alkylimines, leading to much weaker emission for the arylimine complexes. The work demonstrates that pyridineimines can be used as a substitute for bipyridines in luminescent iridium complexes.

Photophysical behaviour of cyclometalated iridium(III) complexes with phosphino(terthiophene) ligands.

Six new Ir(III) complexes containing the 3'-phosphino-2,2':5',2''-terthiophene (PT3) ligand in three different coordination modes are reported. The electronic properties of the complexes are characterized by cyclic voltammetry, absorption, emission and time-resolved transient absorption spectroscopies and DFT/TDDFT calculations. The electrochemical and photophysical behaviour of the complexes was found to be dominated by the PT3 ligand. For the complexes in which the PT3 ligand is coordinated in a bidentate P,S or P,C mode, the lowest energy absorption band is attributed to π-π* PT3 localized transitions consistent with observations from DFT calculations. Emission quantum yields are low in all cases (<0.07) and emission lifetimes are short (<50 ns). Intersystem crossing leads to a long-lived triplet state ((3)L) also localized on the PT3 group. In the complex where the PT3 ligand is coordinated only via the phosphine, TDDFT calculations suggest that there is some MLCT (and Cl-PT3 CT) character in the lowest energy transition.

Preparation of single enantiomers of chiral at metal bis-cyclometallated iridium complexes.

Reaction of [Ir(C^N)2Cl]2 with chiral bidentate N⁁OH ligands provides complexes [Ir(C^N)2(N^O)] as a 1 : 1 mixture of diastereomers which can be separated by crystallisation. A pure diastereomer can be converted to [Ir(C^N)2(bipy)][CF3CO2] with complete retention of stereochemistry at the metal.

Atropisomerism in a thermally switchable, cyclometallated iridium complex.

Two stable diastereomeric atropisomers of a cyclometallated iridium complex containing a pyrene functionalized pyridine imine ligand have been isolated. These are the first fully characterized examples of metal containing atropisomers in which the rotational axis is not between two chelating atoms. The atropisomers can be converted thermally via a rocking motion of the pyrene moiety.

Luminescent iridium complexes for detection of molybdate.

Reactions of [Ir(C^N)(2)Cl](2) [HC^N = 2-(3-R-phenyl)pyridine, 2-(3-R-phenylpyrazole) R = H, Me] with Me(2)-phencat give luminescent complexes [Ir(C^N)(2)(Me(2)-phencat)][PF(6)] (Me(2)-2a, b, c)[PF(6)]. Deprotection of the methoxy groups with BBr(3) is problematic as simultaneous bromination of the cyclometallated phenyl groups occurs. However, deprotection of Me(2)-phencat with BBr(3) followed by complexation with [Ir(C^N)(2)Cl](2) gives luminescent complexes [Ir(C^N)(2)(H(2)-phencat)][PF(6)] (H(2)-3a, c)[PF(6)], which are luminescent sensors for molybdate.

The scope of ambiphilic acetate-assisted cyclometallation with half-sandwich complexes of iridium, rhodium and ruthenium.

C−−H activation by acetate-assisted cyclometallation of a phenyl group with half-sandwich complexes [{MCl(2)Cp*}(2)] (M=Ir, Rh) and [{RuCl(2)-(p-cymene)}(2)] can be directed by a wide range of nitrogen donor ligands including pyrazole, oxazoline, oxime, imidazole and triazole, and X-ray structures of a number of complexes are reported. All the ligands tested cyclometallated at iridium, however ruthenium and rhodium fail to cause cyclometallation in some cases. As a result, the nitrogen donors have been categorised based on their reactivity with the three metals used. The relevance of these cyclometallation reactions to catalytic synthesis of carbocycles and heterocycles is discussed.

Tuning emission wavelength and redox properties through position of the substituent in iridium(III) cyclometallated complexes.

Cyclometallated phenyls with substituents para to the metal have a larger impact on the redox potentials and emission of complexes [Ir(R-ppz)(2)(bipy)][PF(6)] than substituents at the meta position and hence enable tuning of emission wavelength over a wider range using the same substituent.