[Cp2TiCH2CHMe(SiMe3)]+, an alkyl-titanium complex which (a) exists in equilibrium between a ß-agostic and a lower energy γ-agostic isomer and (b) undergoes hydrogen atom exchange between α-, ß-, and γ-sites via a combination of conventional ß-hydrogen elimination-reinsertion and a nonconventional CH bond activation process which involves proton tunnelling.

The compound [Cp2Ti(Me)(CD2Cl2)][B(C6F5)4] reacts with trimethylvinylsilane (TMVS) to form the 1,2-insertion product [Cp2TiCH2CHMe(SiMe3)](+) (III), which exists in solution as equilibrating ß- and γ-agostic isomers. In addition, while free rotation of the ß-methyl group results in a single, averaged γ-H atom resonance at higher temperatures, decoalescence occurs below ~200 K, and the resonance of the γ-agostic hydrogen atom at δ ~ -7.4 is observed. Reaction of [Cp2Ti(CD3)(CD2Cl2)](+) with TMVS results in the formation of [Cp2TiCH2CH(CD3)(SiMe3)](+), which converts, via reversible ß-elimination, to an equilibrium mixture of specifically [Cp2TiCH2CH(CD3)(SiMe3)](+) and [Cp2TiCD2CD(CH3)(SiMe3)](+). Complementing this conventional process, exchange spectroscopy experiments show that the ß-H atom of [Cp2TiCH2CHMe(SiMe3)](+) undergoes exchange with the three hydrogen atoms of the ß-methyl group (ß-H/γ-H exchange) but not with the two α-H atoms. This exchange process is completely shut down when [Cp2TiCH2CH(CD3)(SiMe3)](+) is used, suggesting an H/D kinetic isotope effect much larger (apparently >16,000) than the maximum possible for an over-the-barrier process. It is proposed that ß-H/γ-H exchange is facilitated by quantum mechanical proton tunnelling in which a hydrogen atom of the 2-methyl group of the alkene-hydride deinsertion product [Cp2TiH{CH2═CMe(SiMe3)}](+) undergoes reversible exchange with the hydride ligand via the allyl dihydrogen species [Cp2TiH2{(η(3)-CH2C(SiMe3)CH2}](+). Complementing these findings, DFT calculations were carried out to obtain energies and NMR parameters for all relevant species and thence to obtain better insight into the agostic preference(s) of complex III and the observed exchange processes. In all cases where comparisons between experimental and calculated data were possible, agreement was excellent.

The impact of body mass index on heterotopic ossification.

PURPOSE: To analyze the impact of different body mass index (BMI) as a surrogate marker for heterotopic ossification (HO) in patients who underwent surgical repair (SR) for displaced acetabular fractures (DAF) followed by radiation therapy (RT). METHODS AND MATERIALS: This is a single-institution retrospective study of 395 patients. All patients underwent SR for DAF followed by RT ± indomethacin. All patients received postoperative RT, 7 Gy, within 72 h. The patients were separated into four groups based on their BMI: <18.5, 18.5-24.9, 25-29.9, and >30. The end point of this study was to evaluate the efficacy of RT ± indomethacin in preventing HO in patients with different BMI. RESULTS: Analysis of BMI showed an increasing incidence of HO with increasing BMI: <18.5, (0%) 0/6 patients; 18.5-24.9 (6%), 6 of 105 patients developed HO; 25-29.9 (19%), 22 of 117; >30 (31%), 51 of 167. Chi-square and multivariate logistic regression analysis showed that the correlation between odds of HO and BMI is significant, p < 0.0001. As the BMI increased, the risk of HO and Brooker Classes 3, 4 HO increased. The risk of developing HO is 1.0× (10%) more likely among those with higher BMI compared with those with lower BMI. For a one-unit increase in BMI the log odds of HO increases by 1.0, 95% CI (1.06-1.14). Chi-square test shows no significant difference among all other factors and HO (e.g., indomethacin, race, gender). CONCLUSIONS: Despite similar surgical treatment and prophylactic measures (RT ± indomethacin), the risk of HO appears to significantly increase in patients with higher BMI after DAF. Higher single-fraction doses or multiple fractions and/or combination therapy with nonsteroidal inflammatory drugs may be of greater benefit to these patients.

A prolonged time interval between trauma and prophylactic radiation therapy significantly increases the risk of heterotopic ossification.

PURPOSE: To ascertain whether the time from injury to prophylactic radiation therapy (RT) influences the rate of heterotopic ossification (HO) after operative treatment of displaced acetabular fractures. METHODS AND MATERIALS: This is a single-institution, retrospective analysis of patients referred for RT for the prevention of HO. Between January 2000 and January 2009, 585 patients with displaced acetabular fractures were treated surgically followed by RT for HO prevention. We analyzed the effect of time from injury on prevention of HO by RT. In all patients, 700 cGy was prescribed in a single fraction and delivered within 72 hours postsurgery. The patients were stratified into five groups according to time interval (in days) from the date of their accident to the date of RT: Groups A ≤3, B ≤7, C ≤14, D ≤21, and E >21 days. RESULTS: Of the 585 patients with displaced acetabular fractures treated with RT, (18%) 106 patients developed HO within the irradiated field. The risk of HO after RT increased from 10% for RT delivered ≤3 days to 92% for treatment delivered >21 days after the initial injury. Wilcoxon test showed a significant correlation between the risk of HO and the length of time from injury to RT (p < 0.0001). Chi-square test and multiple logistic regression analysis showed no significant association between all other factors and the risk of HO (race, gender, cause and type of fracture, surgical approach, or the use of indomethacin). CONCLUSIONS: Our data suggest that there is higher incidence and risk of HO if prophylactic RT is significantly delayed after a displaced acetabular fracture. Thus, RT should be administered as early as clinically possible after the trauma. Patients undergoing RT >3 weeks from their displaced acetabular fracture should be informed of the higher risk (>90%) of developing HO despite prophylaxis.

The impact of class III (morbid) obesity on heterotopic ossification outcomes.

PURPOSE: Obesity is associated with a chronic low inflammatory process that may act as common soil for the pathogenesis of obesity-related comorbidities including heterotopic ossification (HO). The purpose of this study is to compare the incidence of HO between patients with body mass index (BMI) <40 versus ≥40 after operative treatment of displaced acetabular fractures followed by radiation therapy (RT) ± indomethacin. METHODS AND MATERIALS: This is a single institution retrospective chart review of 419 patients. All patients with well-documented BMI underwent operative treatment followed by RT ± indomethacin. All patients received 700 cGy to the soft tissues around the proximal femur and acetabulum without bone shielding. All RT were given postoperatively within 72 hours. The patients were divided into 2 groups: Group (A) BMI < 40 and Group (B) BMI ≥40. HO was assessed with X-ray. BMI was used as a surrogate measure to test the risk of HO despite prophylaxis. RESULTS: The incidence of HO among all patients is 21% (89 of 419), while among those in group A (BMI <40), 68 of 374 patients developed HO (18%); in the morbidly obese group (BMI ≥40) 21of 45 patients developed HO (47%). The difference between the rates of HO in the 2 groups was 29%; the χ(2) test showed a significant difference between the 2 BMI groups (P < .001 at α = 0.05). CONCLUSIONS: There is a higher incidence of HO among the morbidly obese patients despite RT ± indomethacin. RT doses for HO prophylaxis in morbidly obese patients need to be reassessed; also, understanding the signaling pathways in target tissues in obese patients at which adipokines control metabolism may reveal novel therapies. Higher radiation doses ± indomethacin may need to be considered and optimally evaluated in the context of a prospective, randomized clinical trial.

Remarkable reactions and intermediates in titanocene(IV) chemistry: migratory insertion reactions of 2,2-disubstituted-1-alkenes, intramolecular 1,5-σ bond metathesis via ε-agostic interactions, and a rare example of a ß-agostic alkyltitanocene complex.

The compound Cp(2)TiMe(2) reacts with [Ph(3)C][B(C(6)F(5))(4)] in CD(2)Cl(2) at 205 K to give, inter alia, [Cp(2)TiMe(CD(2)Cl(2))][B(C(6)F(5))(4)]. This solvent-separated ion pair reacts in turn with 2,4-dimethyl-1-pentene (DMP) to give a series of cationic species, the first being the alkene complex [Cp(2)TiMe(DMP)](+), which undergoes ready migratory insertion to form the σ-alkyl complex [Cp(2)Ti(CH(2)CMe(2)CH(2)CHMe(2))](+). The latter, which does not contain a ß-hydrogen atom, rearranges rapidly via an unprecedented 1,5-σ bond metathesis reaction involving two isomeric ε-agostic species to give the σ-alkyl species [Cp(2)Ti(CH(2)CHMeCH(2)CMe(3))](+); this does contain a ß-hydrogen atom and, in concurrent processes, eliminates H(2) or 2,4,4-trimethyl-1-pentene (a major product) to form respectively the allylic complex [Cp(2)Ti{η(3)-(CH(2))(2)CCH(2)CMe(3)}](+) (a major product) or the hydride complex [Cp(2)TiH](+). The latter reacts reversibly with free DMP to give the insertion product [Cp(2)Ti(CH(2)CHMeCH(2)CHMe(2))](+) (V, a major product), in which the italicized hydrogen atom engages in a ß-agostic interaction with the metal atom. Compound V is a rare example of both a ß-agostic derivative of a group 4 metallocene and a ß-agostic compound of any metal in which the (1)H resonance of the agostic hydrogen can be identified in the (1)H NMR spectrum (δ -3.43). Interestingly, a NOESY experiment on V indicates slow mutual exchange between the agostic hydrogen atom, the hydrogen atoms on C(1), and those of Me(2). These observations are consistent with the intermediacy of the allylic dihydrogen species [Cp(2)Ti(H(2)){η(3)-(CH(2))(2)CCH(2)CHMe(2)}](+), which loses H(2) to form [Cp(2)Ti{η(3)-(CH(2))(2)CCH(2)CHMe(2)}](+) (a minor product). Support for all steps of the proposed reaction scheme comes from product distributions, from labeling studies utilizing [Cp(2)Ti(CD(3))(CD(2)Cl(2))](+), and from extensive DFT calculations. The observed titanocene-based chemistry stands in stark contrast to that of the analogous zirconium system, in which the unusual but well-characterized cationic methyl alkene complex [Cp(2)ZrMe(DMP)](+) does not undergo migratory insertion and subsequent reactions.

An investigation of the influence of R on the abilities of the polar monomers CH2=CH(CH2)8OR (R = Me, PhCH2, Ph3C, Me3Si, Ph3Si) to participate in O- rather than eta(2)-coordination to metallocene alkene polymerization catalysts; an unanticipated role for ether oxygen coordination in promoting polymerization.

Copolymerization of ethylene and propylene with polar monomers of the types CH(2)=CH(CH(2))(n)OH (n = 1-12) in order to introduce polar functionality into the resulting polymers is possible in principle if the hydroxyl groups of the polar monomers are masked such that they cannot coordinate to Lewis acidic catalyst sites and prevent eta(2)-alkene coordination. Although the use of hydrolysable ethers of the types CH(2)=CH(CH(2))(n)OR (R = alkyl, silyl; n = 1-12) is a protecting group strategy, which has been investigated somewhat, in fact this approach has not been investigated systematically and little is known of the effectiveness of various R groups in hindering oxygen coordination to e.g. metallocene polymerization catalyst systems. We report here the results (a) of an NMR study of reactions of an archetypal metallocene polymerization catalyst, Cp(2)ZrMe(mu-Me)B(C(6)F(5))(3), with the polar monomers CH(2)=CH(CH(2))(8)OR (R = Me, PhCH(2), Ph(3)C, Me(3)Si, Ph(3)Si), all protected versions of the readily available, long chain polar monomer 9-decen-1-ol, and (b) of an investigation of the copolymerization reactions of these same polar monomers with ethylene and propylene catalyzed by the well known rac-C(2)H(4)(Ind)(2)ZrCl(2)/MAO catalyst system. While increasing the steric requirements of the groups R does decrease the apparent abilities of the ethers to displace [BMe(C(6)F(5))(3)](-) from the [Cp(2)ZrMe](+) cation, there is no correlation of size of R with the degrees of incorporation of the polar monomers into copolymers of ethylene and propylene. Instead, a heretofore unsuspected role for catalyst activation by the ether linkage is suggested.

A superior precursor for palladium(0)-based cross-coupling and other catalytic reactions.

The easily synthesized, easily handled compound Pd(eta(3)-1-PhC(3)H(4))(eta(5)-C(5)H(5)) (II) reacts readily with mono- and bidentate tertiary phosphines to produce the corresponding bis-phosphine palladium(0) complexes in good yields; II is thus an excellent precursor, perhaps the most efficacious and reliable available, for the synthesis of palladium(0) cross-coupling catalysts.

Structures and properties of nonchelated, d0 alkyl alkene complexes of the type [Cp2ZrMe(alkene)]+: elusive intermediates during Ziegler-Natta polymerizations of alkenes.

Caught in the act: An alkyl alkene Zr(IV) complex (see picture; Cp = C(5)H(5)) has been synthesized and characterized for the first time. The alkene bonding mode is highly asymmetric, and C2 is quite carbocationic. There is also evidence for rotation about the C1-C2 bond. This extremely unusual complex provides an exemplar of previously unknown intermediates in Ziegler-Natta and carbocationic polymerization reactions of alkenes.

Synthesis, characterization and Stat3 inhibitory properties of the prototypical platinum(IV) anticancer drug, [PtCl3(NO2)(NH3)2] (CPA-7).

This paper describes a reinvestigation of the literature concerning the synthesis and structural characterization of the platinum(IV)-based anticancer drug known as CPA-7 and believed to be the compound fac-[PtCl3(NO2)(NH 3)2]. CPA-7 has previously been extensively investigated for its ability to control tumor cell growth by inhibition of Stat3 signaling, but very little information is available concerning its synthesis or spectroscopic properties. A reproducible synthetic route is shown to produce an active material which is characterized by IR and (1)H, (14)N, (15)N, and (195)Pt NMR spectroscopy, and single crystal X-ray crystallography. The freshly prepared drug is obtained as a single isomer which may in fact be fac- or mer-[PtCl3(NO2)(NH3)2], but recrystallization resulted in a disordered crystal containing approximately equal amounts of the two geometric isomers.

Synthesis of the new, weakly coordinating anions [RB(C6F5)3]- (R = CH2Me, CHMe2, CH2CMe3); utilization of [HNMe2Ph][Me3CCH2B(C6F5)3] to activate zirconocene catalysts for propylene polymerization.

The compound [HNMe2Ph][NpB(C6F5)3](Np =(CH3)3CCH2) reacts with dimethylzirconocenes to give active propylene polymerization catalysts which are significantly more active and give higher molecular weight polypropylene than do the catalysts obtained using B(C6F5)3; the [NpB(C6F5)3]- anion is for steric reasons more weakly coordinating than is [MeB(C6F5)3]-.

Three 18-Electron Tantalum(I) Compounds, TaCl(CO)(2)(dppe)(2), [TaCl(CO)(2)(dppe)(2)](2x), and TaCl(CO)(4)(dppe) (dppe = 1,2-Bis(diphenylphosphino)ethane), Which Exhibit Low Levels of Paramagnetism.

Reductive carbonylation of TaCl(5) in the presence of 1,2-bis(diphenylphosphino)ethane (dppe) under the appropriate conditions results in the formation of TaCl(CO)(2)(dppe)(2) (1), as the major product, and the possibly cyclic oligomer [TaCl(CO)(2)(dppe)(2)](2)(x)() (2, 2x >/= 4) as a minor product. Carbonylation of 1 (1 atm) results in the rapid but reversible formation of TaCl(CO)(4)(dppe) (3). Solutions of all three compounds exhibit low levels of paramagnetism, possibly attributable to thermal population of low-lying triplet excited states. Crystal data for the toluene solvate of 1, C(68)H(64)ClO(2)P(4)Ta: triclinic, P&onemacr; (No. 2), a = 13.937(12) Å, b = 14.811(7) Å, c = 14.929(9) Å, alpha = 102.30(5) degrees, beta = 95.60(7) degrees, gamma = 98.41(5) degrees, Z = 2.