Mechanistic analysis of iridium(III) catalyzed direct C-H arylations: a DFT study

In a recent experimental work the Ir complex [Ir(cod)(py)(PCy(3))](PF(6)) (that is, Crabtree's catalyst) has been shown to catalyze the C-H arylation of electron-rich heteroarenes with iodoarenes using Ag(2)CO(3) as base. For this process, an electrophilic metalation mechanism, (S(E)Ar) has been proposed as operative mechanism rather than the concerted metalation-deprotonation (CMD) mechanism, widely implicated in Pd-catalyzed arylation reactions. Herein we have investigated the C-H activation step for several (hetero)arenes catalyzed by a Ir(III) catalyst and compared the data obtained with the results for the Pd(II)-catalyzed C-H bond activation. The calculations demonstrate that, similar to Pd(II)-catalyzed reactions, the Ir(III)-catalyzed direct C-H arylation occurs through the CMD pathway which accounts for the experimentally observed regioselectivity. The transition states for Ir(III)-catalyzed direct C-H arylation feature stronger metal-C((arene)) interactions than those for Pd(II)-catalyzed C-H arylation. The calculations also demonstrate that ligands with low trans effect may decrease the activation barrier of the C-H bond cleavage.     

Tandem cyclization-cycloaddition behavior of rhodium carbenoids with carbonyl compounds: stereoselective studies on the construction of novel epoxy-bridged tetrahydropyranone frameworks

Investigations and stereoselective studies on the tandem reactions of carbonyl ylides generated from alpha-diazo ketones in the presence of carbonyl compounds are presented in this paper. Intramolecular cyclization of rhodium carbenoids generated the transient five- or six-membered-ring carbonyl ylide dipoles, which efficiently underwent 1,3-dipolar cycloaddition reactions with various dipolarophiles such as aromatic aldehydes 15, alpha,beta-unsaturated aldehydes 18/24, alpha,beta-unsaturated ketones 27/28/31, and dienone 34. The transient carbonyl ylides underwent cycloadditions with various aromatic aldehydes to furnish diverse epoxy-bridged tetrahydropyranone ring systems in a diastereoselective manner. The cycloaddition of carbonyl ylides with alpha,beta-unsaturated aldehydes 18/24 or dienone 34 afforded C=O addition products in a chemoselective manner despite the presence of C=C bonds in the above dipolarophiles. Alternatively, the cycloaddition of carbonyl ylides with alpha,beta-unsaturated ketones 27/28 provided both the C=O and C=C cycloaddition products. The cycloaddition of carbonyl ylides with carbonyl compounds occurred in good yields and was found to be highly regio- and stereoselective. Single-crystal X-ray analyses were performed to unambiguously establish the structure and stereochemistry of the novel epoxy-bridged tetrahydropyranone ring systems 35a/38. Compound 35a exhibited both intermolecular C-H...O and intramolecular C-H...pi interaction motifs in the solid-state architecture. The regio-, chemo-, and stereoselectivity observed in these reactions have been investigated by semiempirical AM1 MO calculations. FMO analyses and transition state calculations have been performed for the cycloaddition of carbonyl ylides with alpha,beta-unsaturated carbonyl compounds such as tetracyclone (34) and cyclopentenone (27a). Both FMO and transition state calculations correctly predicted the regio- and stereochemistry of the cycloadducts. The calculations further revealed that a severe steric interaction caused by the phenyl rings present in dipolarophile 34 with dipole 14a increases the activation barrier of the transition state during the cycloaddition process.     

Experimental and computational studies on the mechanism of N-heterocycle C-H activation by Rh(I)

Evidence is presented for a proposed mechanism of C-H activation of 3-methyl-3,4-dihydroquinazoline (1) by (PCy(3))(2)RhCl. One intermediate (3), a coordination complex of 1 with (PCy(3))(2)RhCl, was identified along the path to the Rh-N-heterocyclic carbene product of this reaction (2). Isotopic labeling and reaction-rate studies were used to demonstrate that C-H activation takes place intramolecularly on the reaction coordinate between 3 and 2. Computational studies corroborate the proposed mechanism and suggest that the rate-limiting step is oxidative addition of the C-H bond to the metal center. The consequences of this mechanism for coupling reactions of N-heterocycles that occur via Rh-catalyzed C-H bond activation are discussed.     

DFT study of the mechanism of benzocyclobutene formation by palladium-catalysed C(sp3)-H activation: role of the nature of the base and the phosphine

DFT(B3PW91) calculations of the mechanism of the intramolecular C(sp(3))-H arylation of 2-bromo-tert-butylbenzene to form benzocyclobutene catalysed by Pd(PR(3)) (R = Me, (t)Bu) and a base (acetate, bicarbonate, carbonate) show that the preferred mechanism is highly dependent on the nature of the phosphine and the base used in the calculations. With the experimental reagents (P(t)Bu(3) and carbonate) the rate-determining step is C-H activation with the base coordinated trans to the C-H bond. An agostic interaction of a geminal C-H bond with respect to the bond to be cleaved induces a lowering of the activation barrier.     

Approaching and bond breaking energies in the C-H activation and their application in catalyst design

It was found that the C-H activation barrier can be divided into two parts: C-H approaching and bond breaking energies. The C-H approaching process starts from the reactant and ends at a cross-point structure which is followed by the C-H breaking process. This finding was proved by the intrinsic reaction coordinate (IRC) analysis, vibration frequency (VF) analysis, atom-centered density matrix propagation (ADMP) calculation, and potential energy surface (PES) scan. Further research revealed that the C-H bond breaking energy was related to the electronic structure of the catalyst and the C-H bond dissociation energy of the substrate, whereas the C-H approaching energy was highly relative with the interaction between the substrate and catalyst. These results may be helpful in designing a more effective catalyst.     

Mechanistic investigations of the ZnCl2-mediated tandem Mukaiyama aldol lactonization: evidence for asynchronous, concerted transition states and discovery of 2-oxopyridyl ketene acetal variants

The ZnCl(2)-mediated tandem Mukaiyama aldol lactonization (TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides a versatile, highly diastereoselective approach to trans-1,2-disubstituted β-lactones. Mechanistic and theoretical studies described herein demonstrate that both the efficiency of this process and the high diastereoselectivity are highly dependent upon the type of ketene acetal employed but independent of ketene acetal geometry. Significantly, we propose a novel and distinct mechanistic pathway for the ZnCl(2)-mediated TMAL process versus other Mukaiyama aldol reactions based on our experimental evidence to date and further supported by calculations (B3LYP/BSI). Contrary to the commonly invoked mechanistic extremes of [2+2] cycloaddition and aldol lactonization mechanisms, investigations of the TMAL process suggest a concerted but asynchronous transition state between aldehydes and thiopyridyl ketene acetals. These calculations support a boat-like transition state that differs from commonly invoked Mukaiyama "open" or Zimmerman-Traxler "chair-like" transition-state models. Furthermore, experimental studies support the beneficial effect of pre-coordination between ZnCl(2) and thiopyridyl ketene acetals prior to aldehyde addition for optimal reaction rates. Our previously proposed, silylated β-lactone intermediate that led to successful TMAL-based cascade sequences is also supported by the described calculations and ancillary experiments. These findings suggested that a similar TMAL process leading to β-lactones would be possible with an oxopyridyl ketene acetal, and this was confirmed experimentally, leading to a novel TMAL process that proceeds with efficiency comparable to that of the thiopyridyl system.     

The magnitude of [C-H...O] hydrogen bonding in molecular and supramolecular assemblies

Ab initio calculations at the MP2/6-311++G** level on model systems (N-methylpyridinium complexes of dimethyl ether and dimethyl phosphate anion) provide quantitative measures of the large stabilization energies that arise from [C-H...O] contacts in charged systems. These attractive interactions control (i) the self-assembly of bipyridinium-based catenanes and rotaxanes in solution, (ii) the self-organization of left-handed Z-DNA with alternating [dC-dG] sequences in the solid state, and (iii) the binding of pyridinium derivatives with single- and double-stranded DNA. Slightly attractive interactions occur between the donor ether and phosphate moieties and a neutral pyridine molecule in the gas phase. Electrostatic potential and solvation calculations demonstrate that [C-H...O] interactions which involve a cationic [C-H] donor are dominated by electrostatic terms.     

Origin of the attraction in aliphatic C-H/pi interactions: infrared spectroscopic and theoretical characterization of gas-phase clusters of aromatics with methane

An attractive intermolecular interaction between an aliphatic C-H bond and a pi-electron system (C-H/pi interaction) was characterized on the basis of infrared spectroscopy and high level ab initio calculations. Infrared spectroscopy was applied to several isolated methane clusters with benzene, toluene, p-xylene, mesitylene, and naphthalene in the gas phase, and the spectral changes of the C-H stretch bands in the methane moiety upon the cluster formation were observed. In the theoretical approach, interaction energies of the clusters were evaluated by high-level ab initio calculations. The forbidden symmetric C-H stretch transition weakly appeared in the IR spectra of the clusters, and it confirmed the small deformation of the methane moiety from the T(d)() symmetry, which was predicted by the ab initio calculations. On the other hand, the degenerated asymmetric C-H stretch band showed complicated splitting, which is qualitatively interpreted by a hindered rotor model. Low-frequency shifts upon the cluster formation were seen in the symmetric C-H stretch frequency, though the magnitude of the shifts was extremely small and no clear correlation with the interaction energy was found. On the other hand, the size of the calculated interaction energy well correlates with the polarizability of aromatics. The S(1)-S(0) electronic transition of the aromatic moiety was also observed, and it showed low-frequency shifts upon cluster formation. These results support the dominance of the dispersion interaction over the electrostatic and charge-transfer terms in the aliphatic C-H/pi interaction.     

Do N-heterocyclic aromatic rings prefer π-stacking?

The IR-UV double resonance spectroscopy of phenylacetylene complexes with triazine, pyrazine and pyridine in the acetylene C-H group of phenylacetylene was investigated. These spectra indicate that in the complexes of triazine, pyrazine and pyridine the acetylenic group is minimally perturbed and the predominant interaction is with the π electron density of the phenyl ring of phenylacetylene. Geometries of the complexes optimized at M06-2X/aug-cc-pVDZ and MP2/aug-cc-pVDZ levels, combined with highly accurate energy calculations at the complete basis set (CBS) limit of CCSD(T), indicate the formation of π-stacked complexes in all the three cases. Additionally, a C-H...N hydrogen-bonded complex between pyridine and phenylacetylene was also observed. The present results indicate that N-heterocyclic aromatic rings favor formation of π-stacked complexes.     

Intramolecular rhodium-catalyzed activation of α-amino C-H bonds: decisive influence of conformational factors in the synthesis of bicyclic aminals from N-sulfamoyloxyacetyl azacycloalkanes

The activation of α-amino C-H bonds in azacycloalkanes by way of intramolecular rhodium-catalyzed amination is reported. In this study, the ‘activating’ sulfamoyloxy group is attached to the endocyclic nitrogen atom with an appropriate linker. The influence of various structural parameters was studied. Results obtained demonstrate the remarkable conformational control that is possible with such azacycloalkane systems. This work leads to the first example of a successful intramolecular catalyzed amination of a tertiary sulfamic ester, a substrate known to be highly prone to elimination and/or nucleophilic displacement.     

Weak C-H...O and C-H...F-C hydrogen bonds in the oxirane-trifluoromethane dimer

The oxirane-trifluoromethane dimer generated in a supersonic expansion has been characterized by Fourier transform microwave spectroscopy. The rotational spectra of the parent species and of its two (13)C isotopomers in combination with ab initio calculations have been used to establish a C(s)() geometry for the dimer with the two monomers bound by one C-H.O and two C-H.F-C hydrogen bonds. An overall bonding energy of about 6.7 kJ/mol has been derived from the centrifugal distortion analysis. The lengths of the C-H.O and C-H.F hydrogen bonds, r(O.H) and r(F.H), are 2.37 and 2.68 A, respectively. The C-H.F-C interactions give rise to the HCF(3) internal rotation motion barrier of 0.55(1) kJ/mol, which causes the A-E splittings observed in the rotational spectra. The analysis of the structural and energetic features of the C-H.O and C-H.F-C interactions allows us to classify them as weak hydrogen bonds. Ab initio calculations predict these weak interactions to produce blue shifts in the C-H vibrational frequencies and shortenings of the C-H lengths.     

Substitution of hydrogen by deuterium changes the regioselectivity of ethylbenzene hydroxylation by an oxo-iron-porphyrin catalyst

Heme oxo-iron complexes are powerful oxygenation catalysts of environmentally benign hydroxylation processes. We have performed density functional theoretic calculations on a model system, that is, an oxo-iron-porphyrin (Por) complex [(Fe=O)Cl(Por)], and studied its reactivity toward a realistic substrate, namely, ethylbenzene. The calculations showed that the dominant reaction process in the gas phase is benzyl hydroxylation leading to 1-phenylethanol, with an energetic barrier of 9.1 kcal mol(-1), while the competing para-phenyl hydroxylation has a barrier 3.0 kcal mol(-1) higher in energy. This benzyl hydroxylation barrier is the lowest C-H hydroxylation barrier we have obtained so far for oxo-iron-porphyrin complexes. Due to electronic differences between the intermediates in the phenyl and benzyl hydroxylation processes, the phenyl hydroxylation process is considerably stabilised over the benzyl hydroxylation mechanism in environments with a large dielectric constant. In addition, we calculated kinetic isotope effects of the substitution of one or more hydrogen atoms of ethylbenzene by deuterium atoms and studied its effect on the reaction barriers. Thus, in a medium with a large dielectric constant, a regioselectivity change occurs between [H(10)]ethylbenzene and [D(10)]ethylbenzene whereby the deuterated species gives phenol products whereas the hydrogenated species gives mainly 1-phenylethanol products. This remarkable metabolic switching was analysed and found to occur due to 1) differences in strength between a C-H versus a C-D bond and 2) stabilisation of cationic intermediates in a medium with a large dielectric constant. We have compared our calculations with experimental work on synthetic oxo-iron-porphyrin catalysts as well as with enzyme-reactivity studies.     

Enantioselective synthesis of indenopyrazolopyrazolones enabled by dual directing groups-assisted and rhodium(III)-catalyzed tandem C-H alkenylation/[3 + 2] stepwise cycloaddition

The Cp^XRh(III)-catalyzed asymmetric cascade C-H coupling/intramolecular cyclization of azomethine imines with propargyl carbonates has been developed, affording a variety of chiral tetracyclic indenopyrazolopyrazolone frameworks with good substrate/functional group tolerance and enantioselectivity (up to 97:3 er). Combined experimental studies and DFT calculations revealed the Rh(III)-catalyzed stepwise annulation process and clarified the synergy coordination mode of dual directing groups in tuning the selectivity.     

A theoretical study of the dynamic behavior of alkane hydroxylation by a compound I model of cytochrome P450

Dynamic aspects of alkane hydroxylation mediated by Compound I of cytochrome P450 are discussed from classical trajectory calculations at the B3LYP level of density functional theory. The nuclei of the reacting system are propagated from a transition state to a reactant or product direction according to classical dynamics on a Born-Oppenheimer potential energy surface. Geometric and energetic changes in both low-spin doublet and high-spin quartet states are followed along the ethane to ethanol reaction pathway, which is partitioned into two chemical steps: the first is the H-atom abstraction from ethane by the iron-oxo species of Compound I and the second is the rebound step in which the resultant iron-hydroxo complex and the ethyl radical intermediate react to form the ethanol complex. Molecular vibrations of the C-H bond being dissociated and the O-H bond being formed are significantly activated before and after the transition state, respectively, in the H-atom abstraction. The principal reaction coordinate that can represent the first chemical step is the C-H distance or the O-H distance while other geometric parameters remain almost unchanged. The rebound process begins with the iron-hydroxo complex and the ethyl radical intermediate and ends with the formation of the ethanol complex, the essential process in this reaction being the formation of the C-O bond. The H-O-Fe-C dihedral angle corresponds to the principal reaction coordinate for the rebound step. When sufficient kinetic energy is supplied to this rotational mode, the rebound process should efficiently take place. Trajectory calculations suggest that about 200 fs is required for the rebound process under specific initial conditions, in which a small amount of kinetic energy (0.1 kcal/mol) is supplied to the transition state exactly along the reaction coordinate. An important issue about which normal mode of vibration is activated during the hydroxylation reaction is investigated in detail from trajectory calculations. A large part of the kinetic energy is distributed to the C-H and O-H stretching modes before and after the transition state for the H-atom abstraction, respectively, and a small part of the kinetic energy is distributed to the Fe-O and Fe-S stretching modes and some characteristic modes of the porphyrin ring. The porphyrin marker modes of nu(3) and nu(4) that explicitly involve Fe-N stretching motion are effectively enhanced in the hydroxylation reaction. These vibrational modes of the porphyrin ring can play an important role in the energy transfer during the enzymatic process.     

Palladium-catalyzed oxidative arylalkylation of activated alkenes: dual C-H bond cleavage of an arene and acetonitrile

Not one but two: The title reaction proceeds through the dual C-H bond cleavage of both aniline and acetonitrile. The reaction affords a variety of cyano-bearing indolinones in excellent yield. Mechanistic studies demonstrate that this reaction involves a fast arylation of the olefin and a rate-determining C-H activation of the acetonitrile.     

Bond insertion, complexation, and penetration pathways of vapor-deposited aluminum atoms with HO- and CH(3)O-terminated organic monolayers

The interaction of vapor-deposited Al atoms with self-assembled monolayers (SAMs) of HS-(CH(2))(16)-X (X = -OH and -OCH(3)) chemisorbed at polycrystalline Au[111] surfaces was studied using time-of-flight secondary-ion mass spectrometry, X-ray photoelectron spectroscopy, and infrared reflectance spectroscopy. Whereas quantum chemical theory calculations show that Al insertion into the C-C, C-H, C-O, and O-H bonds is favorable energetically, it is observed that deposited Al inserts only with the OH SAM to form an -O-Al-H product. This reaction appears to cease prior to complete -OH consumption, and is followed by formation of a few overlayers of a nonmetallic type of phase and finally deposition of a metallic film. In contrast, for the OCH(3) SAM, the deposited Al atoms partition along two parallel paths: nucleation and growth of an overlayer metal film, and penetration through the OCH(3) SAM to the monolayer/Au interface region. By considering a previous observation that a CH(3) terminal group favors penetration as the dominant initial process, and using theory calculations of Al-molecule interaction energies, we suggest that the competition between the penetration and overlayer film nucleation channels is regulated by small differences in the Al-SAM terminal group interaction energies. These results demonstrate the highly subtle effects of surface structure and composition on the nucleation and growth of metal films on organic surfaces and point to a new perspective on organometallic and metal-solvent interactions.     

The equilibrium C-H bond length

The equilibrium C-H bond length has been determined up to now for about 40 polyatomic molecules. These data are used to demonstrate the existence of quantitative correlations betweenr _e(C-H), isolated C-H bond stretching frequency and average distancer _g. It is also shown that ab initio calculations are often reliable to calculate the absolute value ofr _e(C-H), if an empirical correction is made. Some other correlations are also discussed. Finally, accurater _e(C-H) values are predicted for simple molecules.     

Hydrogen bond stabilization in 1,3-dimethylimidazolium methyl sulfate and 1-butyl-3-methylimidazolium hexafluorophosphate probed by high pressure: the role of charge-enhanced C-H...O interactions in the room-temperature ionic liquid

The hydrogen bonding structures of room-temperature ionic liquids 1,3-dimethylimidazolium methyl sulfate and 1-butyl-3-methylimidazolium hexafluorophosphate have been studied by infrared spectroscopy. High-pressure infrared spectral profiles and theoretical calculations allow us to make a vibrational assignment of these compounds. The imidazolium C-H bands of 1,3-dimethylimidazolium methyl sulfate display anomalous non-monotonic pressure-induced frequency shifts. This discontinuity in frequency shift is related to enhanced C-H...O hydrogen bonding. This behavior is in contrast with the trend of blue shifts in frequency for the methyl C-H stretching mode at ca. 2960 cm(-1). Our results indicated that the imidazolium C-H groups are more favorable sites for hydrogen bonding than the methyl C-H groups in the pure 1,3-dimethylimidazolium methyl sulfate. Nevertheless, both methyl C-H and imidazolium C-H groups are favorable sites for C-H...O hydrogen bonding in a dilute 1,3-dimethylimidazolium methyl sulfate/D(2)O mixture. Hydrogen bond-like C-H...F interactions were observed between PF(6)(-) and H atoms on the alkyl side chains and imidazolium ring for 1-butyl-3-methylimidazolium hexafluorophosphate.     

C-H键活化反应的密度泛函理论模拟对简化模型的评估

采用密度泛函理论方法, 模拟了Rh(PPh₃)₃Cl催化的C-H键活化/C-C键偶联反应. 将反应机理分为C-H键活化、 迁移插入和还原消除3个过程进行讨论. 计算结果表明, 势能面的最高点为迁移插入的过渡态, 相对于初始原料的自由能为108.3 kJ/mol. 为了探索简化计算模型对模拟反应机理的影响, 使用2种模型催化剂Rh(PMe₃)₃Cl和Rh(PH₃)₃Cl表征相同的反应过程, 结果表明配体简化模型不合理, 主要是因为PPh₃配体的空间效应和熵效应非常明显.     

Kinetico-mechanistic studies of cyclometalating C-H bond activation reactions on Pd(ii) and Rh(ii) centres: The importance of non-innocent acidic solvents in the process

The activation of C-H bonds in homogeneous systems has been the subject of study for many years due to its involvement in important industrial catalytic processes. A large number of reviews on the different areas involved have appeared, but those dealing with kinetic studies, including activation parameters, are rather scarce due to the severe difficulties in interpreting experimental data. In this perspective, the information available from kinetico-mechanistic studies of cyclometalation reactions on Pd(ii) and Rh(ii) centres via C-H bond activation is considered. Experimental results from studies performed on complexes of these metal centres indicate that the historically accepted electrophilic substitution classification is not a satisfactory mechanistic term for the process occurring during the reaction. A definite acid-assisted phenomenon is evident for all the processes studied, which contradicts the expected need for a proton abstractor in the reaction. This is even more surprising when considering the expected hydrolysis of M-C bonds in such acidic media, indicating that metalation prevails under these conditions. Only the presence of coordinated acid molecules in solvolytic carboxylic acid media can explain the observations. The fine tuning between the proton abstraction capacity of a coordinated RCO(2)H molecule and its Lewis basicity results in a unique reactivity trend. DFT calculations carried out for these acid-assisted processes fully agree with the experimental trends observed.