Biomedical subjects
Publications and source records attributed to Robert G Bergman.
[reaction: see text] A tetrahydrobis(benzofuran) mescaline analogue has been prepared in six steps and 38% overall yield from (4'-O-methyl)methyl gallate. The key step in this synthesis is a tandem cyclization reaction via directed C[bond]H activation followed by olefin insertion.
The mechanism of the oxidation of di-tert-butyl disulfide (1) to the chiral thiosulfinate (2) by H(2)O(2) catalyzed by bis(acetylacetonato)oxovanadium and a chiral Schiff-base ligand (3) has been investigated. Techniques included (51)V NMR spectroscopy, solvent effects on reaction enantioselectivity, and the isolation and full characterization of a 2:1 ligand-to-vanadium catalyst precursor. A model for the dramatic solvent effect on the enantioselectivity of this reaction was developed, based on the identification of a competing nonselective oxidation pathway. From this model, strategies for limiting this competing pathway were developed.
The parent amido complex cis-(PMe(3))(4)Ru(H)(NH(2)) (2) has been prepared via the deprotonation of [cis-(PMe(3))(4)Ru(H)(NH(3))(+)][BPh(4)(-)]. The amido complex is a somewhat weaker base than the DMPE analogue trans-(DMPE)(2)Ru(H)(NH(2)) but is still basic enough to quantitatively deprotonate fluorene and reversibly deprotonate 1,3-cyclohexadiene and toluene. Complex 2 exhibits very labile phosphine ligands, two of which can be replaced by DMPE to yield the mixed complex cis-(PMe(3))(2)(DMPE)Ru(H)(NH(2)). Because of the ligand lability, 2 also undergoes hydrogenolysis and rapid exchange with labeled NH(3). The amide complex reacts with alkyl halides to yield E2 and S(N)2 products, along with ruthenium hydrido halide complexes including the ruthenium fluoride cis-(PMe(3))(4)Ru(H)(F). Ruthenium hydrido ammonia halide ion pair intermediates [cis-(PMe(3))(4)Ru(H)(NH(3))(+)][X(-)] are observed in some deprotonation and E2 reactions, and measurement of the equilibrium constants for NH(3) displacement from these complexes suggests that they benefit from significant hydrogen bonding between X(-) and NH(3) groups. Cumulenes also react with complex 2 to afford the products of insertion into an NH bond. The rates of neither these NH insertion reactions nor the reversible deprotonation reactions show any dependence on the concentration of PMe(3) present, suggesting that these reactions take place directly at the NH(2) group and do not involve precoordination of substrate to the metal center.
This reports first intermolecular coupling of unactivated alkenes, including isomerizable alkenes, to a range of heterocycles using a Rh(I) catalyst. A variety of functional groups were incorporated, including esters, nitriles, and acetals. The intermolecular coupling became possible after it was discovered that weak acids dramatically increase the rate of both the inter- and intramolecular reactions.
The photochemical C-H activation reactions of eta(3)-TpRh(CO)(2) (Tp = HB-Pz(3), Pz = 3,5-dimethylpyrazolyl) and CpRh(CO)(2) (Cp = C(5)H(5)) have been studied in a series of linear, cyclic, and aromatic hydrocarbon solvents on a femtosecond to microsecond time scale. These results have revealed that the structure of the hydrocarbon substrate affects the final C-H bond activation step, which is in accordance with the known preference of bond activation toward primary C-H sites. In the case of aromatic C-H activation, the reaction is divided into parallel channels involving sigma- and pi-solvated intermediates. Results for the analogous CpRh(CO)(2) molecule have shown that the coordination of the cyclopentadienyl ligand does not play a direct role in the dynamics of the reaction, in contrast to the C-H activation mechanism observed in eta(3)-TpRh(CO)(2) studies.
The four-membered metallacycles Cp*Ir((NAr)2C=Z) have been prepared for Z = NAr and Z = O. These complexes undergo facile exchange with free heterocumulenes. This exchange process can be employed to effect the rapid, catalytic metathesis of aryl carbodiimides at room temperature and the metathesis of aryl carbodiimides with aryl isocyanates at slightly elevated temperature. The exchange process appears to proceed via a novel associative mechanism involving ring expansion to form a six-membered metallacycle rather than cycloreversion to give an imido complex. Observation of key intermediates and the results of crossover experiments support this hypothesis.
The rapid synthesis of 4-aryl-2,2'-bipyridines is described leading to some previously reported compounds in good yields in addition to some new functionalized bipyridines.
Hydrogenolysis of [Cp(PMe(3))Rh(Me)(CH(2)Cl(2))](+)BAr'(4)(-) (4, Ar' = 3,5-C(6)H(3)(CF(3))(2)) in dichloromethane afforded the nonclassical polyhydride complex [Cp*PMe(3))Rh(H)(H(2))](+)BAr'(4)(-) (1), which exhibits a single hydride resonance at all accessible temperatures in the (1)H NMR spectrum. Exposure of solutions of 1 to D(2) or T(2) gas resulted in partial isotopic substitution in the hydride sites. Formulation of 1 as a hydride/dihydrogen complex was based upon T(1) (T(1)(min) = 23 ms at 150 K, 500 MHz), J(H-D) (ca. 10 Hz), and J(H-T) (ca. 70 Hz) measurements. The barrier (Delta G(++)) to exchange of hydride with dihydrogen sites was determined to be less than ca. 5 kcal/mol. Protonation of Cp(PMe(3))Rh(H)(2) (2) using H(OEt(2))(2)BAr'(4) resulted in binuclear species [(Cp(PMe(3))Rh(H))(2)(mu-H)](+)BAr'(4)(-) (3), which is formed in a reaction involving 1 as an intermediate. Complex 3 contains two terminal hydrides and one bridging hydride ligand which exchange with a barrier of 9.1 kcal/mol as observed by (1)H NMR spectroscopy. Additionally, the structures of 3 and 4, determined by X-ray diffraction, are reported.
[reaction: see text]. Tetrakisamido titanium complexes are significantly more active than Cp2TiMe2 (1) in the intramolecular hydroamination of aminoalkynes and aminoallenes. In the latter case, the regioselectivity of the transformation depends on the nature of the precatalyst, yielding the most selective and reactive catalysis with the bis(sulfonamido) complex 11.
trans-(DMPE)(2)Ru(H)(NH(2)) (1) dehydrogenates cyclohexadiene and 9,10-dihydroanthracene to yield benzene (or anthracene), (DMPE)(2)Ru(H)(2), and ammonia. Addition of fluorene to 1 results in the formation of the ion pair [trans-(DMPE)(2)Ru(H)(NH(3))(+)][A(-)] (A(-) = fluorenide, 4a). Complex 1 also reacts with weak acids A-H (A-H = phenylacetylene, 1,2-propadiene, phenylacetonitrile, 4-(alpha,alpha,alpha-trifluoromethyl)phenylacetonitrile, cyclobutanone, phenol, p-cresol, aniline) to form ammonia and trans-(DMPE)(2)Ru(H)(A) (7, 8, 9a, 9b, 10, 11b, 11c, 12, respectively). In the cases where A-H = phenylacetylene, cyclobutanone, aniline, phenol, and p-cresol, the reaction was observed to proceed via ion pairs analogous to 4a. Compound 1 is reactive toward even weaker acids such as toluene, propylene, ammonia, cycloheptatriene, and dihydrogen, but in these cases deuterium labeling studies revealed that only H/D exchange between A-H and the ND(2) group is observed, rather than detectable formation of ion pairs or displacement products. Addition of triphenylmethane to 1 results in the formation of an equilibrium mixture of 1, triphenylmethane, and the ruthenium/triphenylmethide ion pair 4h. If the energetics of ion-pair association are ignored, this result indicates that the basicity of 1 is similar to that of triphenylmethide. All these observations support the conclusion that the NH(2) group in amido complex 1 is exceptionally basic and as a result prefers to abstract a proton rather than a hydrogen atom from a reactive C-H bond. The energetics and mechanism of these proton-transfer and -exchange reactions are analyzed with the help of DFT calculations.
Addition of 1.0 equiv of Ph3SiH to [Cp*(PMe3)Rh(Me)(CH2Cl2)]+BAr'4- (1) resulted in release of methane and quantitative formation of [Cp*(PMe3)Rh(SiPh3)(CH2Cl2)]+BAr'4- (2). Subsequent addition of 1.0 equiv of MeCN to 2 caused immediate displacement of dichloromethane to form the eta1-nitrile adduct [Cp*(PMe3)Rh(SiPh3)(NCMe)]+BAr'4- (3). Upon standing at room-temperature overnight, complex 3 converted quantitatively to another product which has been characterized as the C-C activation product, [Cp*(PMe3)Rh(Me)(CNSiPh3)]+BAr'4- (5). Addition of other nitrile substrates (R-CN, R = Ph, (4-CF3)Ph, (4-MeO)Ph, iPr, tBu) to 2 also resulted in C-C activation of the R-CN bond to form [Cp*(PMe3)Rh(R)(CNSiPh3)]+BAr'4-. Evidence for an eta2-iminoacyl intermediate complex, [Cp*(PMe3)Rh(eta2-C(R)=N(SiPh3)]+BAr'4-, is also presented.
An N-heterocyclic carbene complex was found to be the active catalyst in the Rh(I)-catalyzed intramolecular coupling of an alkenyl group to a C-H bond of a substituted benzimidazole. Kinetic studies demonstrated that the catalytic cyclization is zero-order in substrate and first-order in catalyst. Furthermore, DFT calculations with a model system suggest that the rate-limiting step involves insertion of the alkenyl double bond into the rhodium-carbene bond.
The air-stable complex Cp(PMe(3))IrCl(2) efficiently catalyzes the exchange of deuterium from D(2)O into both activated and unactivated C-H bonds of organic molecules without added acid or stabilizers. Selectivity is observed in many cases, with activation of primary C-H bonds occurring preferentially. A number of new stoichiometric transformations involving the iridiym catalyst precursor are also presented, including an oxidation-decarbonylation reaction with primary alcohols.
A detailed mechanistic study of arene C [bond] H activation in CH(2)Cl(2) solution by Cp(L)IrMe(X) [L = PMe(3), P(OMe)(3); X = OTf, (CH(2)Cl(2))BAr(f); (BAr(f) = B[3,5-C(6)H(3)(CF(3))(2)](4))(-)] is presented. It was determined that triflate dissociation in Cp(L)IrMe(OTf), to generate tight and/or solvent-separated ion pairs containing a cationic iridium complex, precedes C [bond] H activation. Consistent with the ion-pair hypothesis, the rate of arene activation by Cp(L)IrMe(OTf) is unaffected by added external triflate salts, but the rate is strongly dependent upon the medium. Thus the reactivity of Cp(PMe(3))IrMe(OTf) can be increased by almost 3 orders of magnitude by addition of (n-Hex)(4)NBAr(f), presumably because the added BAr(f) anion exchanges with the OTf anion in the initially formed ion pair, transiently forming a cation/borate ion pair in solution (special salt effect). In contrast, addition of (n-Hex)(4)NBAr(f) to [CpPMe(3)Ir(Me)CH(2)Cl(2)][BAr(f)] does not affect the rate of benzene activation; here there is no initial covalent/ionic pre-equilibrium that can be perturbed with added (n-Hex)(4)NBAr(f). An analysis of the reaction between Cp(PMe(3))IrMe(OTf) and various substituted arenes demonstrated that electron-donating substituents on the arene increase the rate of the C [bond] H activation reaction. The rate of C(6)H(6) activation by [Cp(PMe(3))Ir(Me)CH(2)Cl(2)][BAr(f)] is substantially faster than [Cp(P(OMe)(3))Ir(Me)CH(2)Cl(2)][BAr(f)]. Density functional theory computations suggest that this is due to a less favorable pre-equilibrium for dissociation of the dichloromethane ligand in the trimethyl phosphite complex, rather than to a large electronic effect on the C [bond] H oxidative addition transition state. Because of these combined effects, the overall rate of arene activation is increased by electron-donating substituents on both the substrate and the iridium complex.
Imidozirconocene complexes (Cp(2)Zr=NR(THF)) possess a rich reaction chemistry, in contrast to many imido complexes of later transition metals. The synthesis and structural characteristics of these compounds are briefly described, along with a qualitative molecular orbital description of the metallocene-imido interaction. Imidozirconocene complexes react at the Zr=N linkage with a variety of X-H bonds, and undergo overall [2 + 2] cycloaddition reactions with a wide range of unsaturated organic and organometallic compounds. Results of studies detailing the scope and mechanism of these reactions are presented herein, along with applications to catalytic hydroamination, imine metathesis, and asymmetric transformations.
Complexes containing bonds between heteroatoms such as nitrogen and oxygen and "late" transition metals (i.e., those located on the right side of the transition series) have been implicated as reactive intermediates in numerous important catalytic systems. Despite this, our understanding of such M-X linkages still lags behind that of their M-H and M-C analogues. New synthetic strategies have now made possible the isolation and study of a variety of monomeric late-metal alkoxide, aryloxide, and amide complexes, including parent hydroxide and amide species. The heteroatoms in these materials form surprisingly strong bonds to their metal centers, and their bond energies do not necessarily correlate with the energies of the corresponding H-X bonds. The M-X complexes typically exhibit nucleophilic reactivity, in some cases form strong hydrogen bonds to proton donors, and even deprotonate relatively weak acids. These observations, as well as thermodynamic investigations, suggest that late metal-heteroatom bonds are strongly polarized and possess significant ionic character, properties that play an important role in their interactions with organic compounds.
Treatment of the diazametallacycle Cp(2)Zr(N(t-Bu)C=N(SiMe(3))N(SiMe(3))) (4a) with diphenylacetylene resulted in the formation of the azametallacyclobutene Cp(2)Zr(N(t-Bu)C(Ph)=C(Ph)) (6a) and Me(3)SiN=C=NSiMe(3) in high yield. A kinetic study using UV-vis spectroscopy was carried out on the transformation. Saturation kinetic behavior was observed for the system, which is supportive of a mechanism that involves a reversible formal [2 + 2] retrocycloaddition of 4a to generate the transient imido species Cp(2)Zr=N-t-Bu (7a) and Me(3)-SiN=C=NSiMe(3). Trapping 7a with diphenylacetylene in an overall [2 + 2] cycloaddition reaction affords zirconacycle 6a. The study of cycloreversion/cycloaddition reactions between diazametallacycle complexes and diphenylacetylene was extended to other zirconocene systems. Detailed kinetic studies were performed for the exchange reactions between the diazametallacycle complexes Cp(2)Zr(N(2,6-Me(2)Ph)C=N(SiMe(3))N(SiMe(3))) (8a) and Cp(2)Zr-(N(2,6-Me(2)Ph)C=N(t-Bu)N(t-Bu)) (8b) with diphenylacetylene (5a) to give the corresponding azametallacyclobutene complex Cp(2)Zr(N(2,6-Me(2)Ph)C(Ph)=C(Ph)) (6c) and extruded carbodiimides (Me(3)SiN=C=NSiMe(3) for 8a and (t-Bu)N=C=N(t-Bu) for 8b). For both systems, the reactions were found to be first order in metallacycle and zero order in alkyne. Treatment of the diazametallacycle complexes Cp(2)Zr(N(2,6-i-Pr(2)Ph)C=N(Cyc)N(Cyc)) (9a) and Cp(2)Zr-(N(2,6-i-Pr(2)Ph)C=N(i-Pr(2))N(i-Pr(2))) (9b) with alkyne 5a resulted in the formation of the six-membered zirconacycles 10a,b, respectively, upon heating at 75 degrees C. The products 10a,b are generated from the overall insertion of alkyne 5a into the nitrogen-carbon bond of the zirconium-containing diazacyclobutane. Complex 10a has been characterized by an X-ray crystallographic study. When the azacyclobutene Cp(2)Zr(N(2,6-i-Pr(2)Ph)C(Ph)=C(Ph)) (6e) was treated with CycN=C=NCyc or (i-Pr)N=C=N(i-Pr), the same six-membered zirconacycle complexes 10a,b were obtained. Kinetic analysis of the reaction of 6e and (i-Pr)N=C=N(i-Pr) to yield 10b supports an associative process wherein alkyne 5a directly inserts into the zirconium-carbon bond of 6e. The diazametallacycle complex 4a underwent a stoichiometric metathetical exchange with symmetrical carbodiimides RN=C=NR (R = p-Tol, m-Tol, i-Pr, Cyc) to generate new cyclic zirconocene complexes and Me(3)SiN=C=NSiMe(3). Kinetic studies were carried out on the exchange reaction between 4a and (m-Tol)N=C=N(m-Tol) to form 4e and Me(3)SiN=C=NSiMe(3). The experimental rate data obtained are consistent with a dissociative mechanism. Additionally, the saturation rate constant derived for this system from the data is the same (within experimental error) as the saturation rate constant obtained from the kinetic study of 4a and diphenylacetylene to form 6a and Me(3)SiN=C=NSiMe(3). These findings provide additional support for a dissociative mechanistic pathway in the exchange reactions, since the rate constant in the formal [2 + 2] retrocycloaddition reaction to generate imidozirconocene species Cp(2)Zr=N-t-Bu (7a) and Me(3)SiN=C=NSiMe(3) should be the same for both reactions.
The titanocene sulfido complex Cp*(2)Ti(S)py (1, Cp* = pentamethylcyclopentadienyl; py = pyridine) is synthesized by addition of a suspension of S(8) to a toluene solution of Cp*(2)Ti-(CH(2)CH(2)) (2) and py. The rate of rotation of the pyridine ligand in solution was determined by (1)H NMR spectroscopy, and the structure of 1 was determined by X-ray crystallography. Complex 1 reacts reversibly with dihydrogen to give Cp*(2)Ti(H)SH (6) and py. Reaction of 1 with HD gives an equilibrium mixture of Cp*(2)Ti(D)SH and Cp*(2)Ti(H)SD; H(2) and D(2) are not formed in this reaction. 1D (1)H NMR magnetization transfer spectra and 2D EXSY (1)H NMR spectra of 6 in the presence of H(2) show that in solution the H(2), hydride, and hydrosulfido hydrogen atoms exchange. A four-center mechanism for this exchange is proposed. The EXSY studies show that the Ti-H and S-H hydrogens exchange with each other more rapidly than either of those hydrogens exchanges with external H(2). A transient dihydrogen complex intermediate is proposed to explain this observation. The infrared spectrum of 6 shows an absorption assigned to the Ti-H stretching mode at 1591 cm(-1) that shifts upon deuteration to 1154 cm(-1). Reaction of 1 with trimethylsilane, diethylsilane, or dimethylsilane gives Cp*(2)-Ti(H)SSiMe(3) (7), Cp*(2)Ti(H)SSiHEt(2) (8), or Cp*(2)Ti(H)SSiHMe(2) (9), respectively. The isotope effect for the reaction producing 7 has been measured, and a mechanism is proposed. Treatment of 1 with an additional equivalent of S(8) results in the formation of the disulfide Cp*(2)Ti(S(2)) (4). Acetylene inserts into the Ti-S bond of 4 to produce the vinyl disulfide complex 5. The structures of 4 and 5 have been determined by X-ray diffraction. Compound 4 reacts with 2 in the presence of py to produce 1. Phosphines react with 4 in the presence of H(2) to provide 6 and the corresponding phosphine sulfide. Reaction of hydrogen with 4 gives Cp*(2)-Ti(SH)(2) (3). The reactions of 1 and 4 with dihydrogen provide a model for possible mechanisms of H(2) activation by metal-sulfide hydrodesulfurization catalysts.