Reactivity of Diarylnitrenium Ions.

Hydride abstraction from diarylamines with the trityl ion is explored in an attempt to generate a stable diarylnitrenium ion, Ar2 N+ . Sequential H-atom abstraction reactions ensue. The first H-atom abstraction leads to intensely colored aminium radical cations, Ar2 NH.+ , some of which are quite stable. However, most undergo a second H-atom abstraction leading to ammonium ions, Ar2 NH2 + . In the absence of a ready source of H-atoms, a unique self-abstraction reaction occurs when Ar=Me5 C6 , leading to a novel iminium radical cation, Ar=N.+ Ar, which decays via a second self H-atom abstraction reaction to give a stable iminium ion, Ar=N+ HAr. These products differ substantially from those derived via photochemically produced diarylnitrenium ions.

The Strongest Acid: Protonation of Carbon Dioxide.

The strongest carborane acid, H(CHB11F11), protonates CO2 while traditional mixed Lewis/Brønsted superacids do not. The product is deduced from IR spectroscopy and calculation to be the proton disolvate, H(CO2)2(+). The carborane acid H(CHB11F11) is therefore the strongest known acid. The failure of traditional mixed superacids to protonate weak bases such as CO2 can be traced to a competition between the proton and the Lewis acid for the added base. The high protic acidity promised by large absolute values of the Hammett acidity function (H0) is not realized in practice because the basicity of an added base is suppressed by Lewis acid/base adduct formation.

Myths about the proton. The nature of H+ in condensed media.

Recent research has taught us that most protonated species are decidedly not well represented by a simple proton addition. What is the actual nature of the hydrogen ion (the "proton") when H(+), HA, H2A(+), and so forth are written in formulas, chemical equations, and acid catalyzed reactions? In condensed media, H(+) must be solvated and is nearly always dicoordinate, as illustrated by isolable bisdiethyletherate salts having H(OEt2)2(+) cations and weakly coordinating anions. Even carbocations such as protonated alkenes have significant C-H···anion hydrogen bonding that gives the active protons two-coordinate character. Hydrogen bonding is everywhere, particularly when acids are involved. In contrast to the normal, asymmetric O-H···O hydrogen bonding found in water, ice, and proteins, short, strong, low-barrier (SSLB) H-bonding commonly appears when strong acids are present. Unusually low frequency IR νOHO bands are a good indicator of SSLB H-bonds, and curiously, bands associated with group vibrations near H(+) in low-barrier H-bonding often disappear from the IR spectrum. Writing H3O(+) (the Eigen ion), as often appears in textbooks, might seem more realistic than H(+) for an ionized acid in water. However, this, too, is an unrealistic description of H(aq)(+). The dihydrated H(+) in the H5O2(+) cation (the Zundel ion) gets somewhat closer but still fails to rationalize all the experimental and computational data on H(aq)(+). Researchers do not understand the broad swath of IR absorption from H(aq)(+), known as the "continuous broad absorption" (cba). Theory has not reproduced the cba, but it appears to be the signature of delocalized protons whose motion is faster than the IR time scale. What does this mean for reaction mechanisms involving H(aq)(+)? For the past decade, the carborane acid H(CHB11Cl11) has been the strongest known Brønsted acid. (It is now surpassed by the fluorinated analogue H(CHB11F11).) Carborane acids are strong enough to protonate alkanes at room temperature, giving H2 and carbocations. They protonate chloroalkanes to give dialkylchloronium ions, which decay to carbocations. By partially protonating an oxonium cation, they get as close to the fabled H4O(2+) ion as can be achieved outside of a computer.

The strongest Brønsted acid: protonation of alkanes by H(CHB(11)F(11)) at room temperature.

What is the strongest acid? Can a simple Brønsted acid be prepared that can protonate an alkane at room temperature? Can that acid be free of the complicating effects of added Lewis acids that are typical of common, difficult-to-handle superacid mixtures? The carborane superacid H(CHB11 F11 ) is that acid. It is an extremely moisture-sensitive solid, prepared by treatment of anhydrous HCl with [Et3 SiHSiEt3 ][CHB11 F11 ]. It adds H2 O to form [H3 O][CHB11 F11 ] and benzene to form the benzenium ion salt [C6 H7 ][CHB11 F11 ]. It reacts with butane to form a crystalline tBu(+) salt and with n-hexane to form an isolable hexyl carbocation salt. Carbocations, which are thus no longer transient intermediates, react with NaH either by hydride addition to re-form an alkane or by deprotonation to form an alkene and H2 . By protonating alkanes at room temperature, the reactivity of H(CHB11 F11 ) opens up new opportunities for the easier study of acid-catalyzed hydrocarbon reforming.

Hydrogen bonding versus hyperconjugation in condensed-phase carbocations.

Hyperconjugative stabilization of positive charge in tertiary carbocations is the textbook explanation for their stability and low frequency νCH bands in their IR spectra have long been taken as confirming evidence. While this is substantiated in the gas phase by the very close match of the IR spectrum of argon-tagged t-butyl cation with that calculated under C(s) symmetry, the situation in condensed phases is much less clear. The congruence of νCH(max) of t-Bu(+) in superacid media (2830 cm(-1)) with that in the gas phase (2834 cm(-1)) has recently been shown to be accidental. Rather, νCH(max) varies considerably as a function of counterion in a manner that reveals the presence of significant C-H···anion hydrogen bonding. This paper addresses the question of the relative importance of hyperconjugation versus H-bonding. We show by assigning IR spectra in the νCH region to specific C-H bonds in t-butyl cation that the low frequency νCH(max) band in the IR spectrum of t-butyl cation, long taken as direct evidence for hyperconjugation, appears to be due mostly to H-bonding. The appearance of similar low frequency νCH bands in the IR spectra of secondary alkyl carboranes such as i-Pr(CHB11Cl11), which have predominant sp(3) centres rather than sp(2) centres (and are therefore less supportive of hyperconjugation), also suggests the dominance of H-bonding over hyperconjugation.

The R3O+···H+ hydrogen bond: toward a tetracoordinate oxadionium(2+) ion.

Oxatriquinanes are tricyclic oxonium ions which are known to possess remarkable solvolytic stability compared to simple alkyl oxonium salts. Their rigid, hemispherical structure presents an oxygen at the apex of three fused five-membered rings. While trivalent oxygen species like these have been well described in the literature, the ability of oxygen to enter into a fourth covalent bonding relationship has been visited in theory and suggested by the outcome of certain reactions conducted in superacidic media, but has never been established by the characterization of a stable, persistent R(3)OH(2+) or R(4)O(2+) ion. In this study, the nucleophilicity of the oxatriquinane oxygen was evaluated first by a series of protonation studies using the Brønsted superacid H(CHB(11)Cl(11)) both in the solid state and in liquid HCl solution. The interaction of the oxatriquinane oxygen with a bridging carbocation was also examined. A strong case could be made for the occurrence of hydrogen bonding between H(CHB(11)Cl(11)) and oxatriquinane using IR spectroscopy. Under the most forcing protonation conditions, the oxatriquinane ring is cleaved to give a bridged, dicationic, protonated tetrahydrofuran-carbenium ion.

RB and p53 cooperate to prevent liver tumorigenesis in response to tissue damage.

BACKGROUND & AIMS: The tumor suppressors retinoblastoma (RB) and p53 are important regulators of the cell cycle. Although human cancer cells inactivate RB and p53 by many mechanisms, the cooperative roles of these proteins in tumorigenesis are complex and tissue specific. We analyzed the cooperation of RB and p53 in liver development and pathogenesis of hepatocellular carcinoma. METHODS: Spontaneous and carcinogen-induced (diethylnitrosamine) tumorigenesis were studied in mice with liver-specific deletions of Rb and/or p53 (Rbf/f;albcre+, p53f/f;albcre+ and Rbf/f; p53f/f;albcre+ mice). Genotype, histologic, immunohistochemical, microarray, quantitative polymerase chain reaction, immunoblot, and comparative genomic hybridization analyses were performed using normal and tumor samples. Comparative microarray analyses were performed against publicly available human microarray data sets. RESULTS: Deletion of RB and p53 from livers of mice deregulated the transcriptional programs associated with human disease. These changes were not sufficient for spontaneous tumorigenesis; potent quiescence mechanisms compensated for loss of these tumor suppressors. In response to hepatocarcinogen-induced damage, distinct and cooperative roles of RB and p53 were revealed; their loss affected cell cycle control, checkpoint response, and genome stability. In damaged tissue, combined loss of RB and p53 resulted in early lesion formation, aggressive tumor progression, and gene expression signatures and histologic characteristics of advanced human hepatocellular carcinoma. CONCLUSIONS: The effects RB and p53 loss are determined by the tissue environment; cell stresses that promote aggressive disease reveal the functions of these tumor suppressors.

Evidence for C-H hydrogen bonding in salts of tert-butyl cation.

Environmentally sensitive: A combination of C-H anion hydrogen bonding and hyperconjugative charge delocalization explains the sensitivity of the IR spectrum of the tert-butyl cation to its anion (see high-resolution X-ray structure with a CHB(11)Cl(11)(-) counterion). The νCH vibration of the cation scales linearly with the basicity of carborane anions on the νNH scale. The same also holds for the C(6)H(7)(+) benzenium ion.

Unique impact of RB loss on hepatic proliferation: tumorigenic stresses uncover distinct pathways of cell cycle control.

The retinoblastoma (RB) tumor suppressor pathway is disrupted at high frequency in hepatocellular carcinoma. However, the mechanisms through which RB modulates physiological responses in the liver remain poorly defined. Despite the well established role of RB in cell cycle control, the deletion of RB had no impact on the kinetics of cell cycle entry or the restoration of quiescence during the course of liver regeneration. Although these findings indicated compensatory effects from the RB-related proteins p107 and p130, even the dual deletion of RB with p107 or p130 failed to deregulate hepatic proliferation. Furthermore, although these findings suggested a modest role for the RB-pathway in the context of proliferative control, RB loss had striking effects on response to the genotoxic hepatocarcinogen diethylnitrosamine. With diethylnitrosamine, RB deletion resulted in inappropriate cell cycle entry that facilitated secondary genetic damage and further uncoupling of DNA replication with mitotic entry. Analysis of the mechanism underlying the differential impact of RB status on liver biology revealed that, while liver regeneration is associated with the conventional induction of cyclin D1 expression, the RB-dependent cell cycle entry, occurring with diethylnitrosamine treatment, was independent of cyclin D1 levels and associated with the specific induction of E2F1. Combined, these studies demonstrate that RB loss has disparate effects on the response to unique tumorigenic stresses, which is reflective of distinct mechanisms of cell cycle entry.

Oligomeric carbocation-like species from protonation of chloroalkanes.

The protonation of chloroethane by the strongest known solid superacid, the carborane acid H(CHB(11)Cl(11)), has been studied by quantitative IR spectroscopic methods to track mass balance and uncover previously unobserved chemistry. In the first step, an intermediate EtCl·H(CHB(11)Cl(11)) species without full proton transfer to EtCl can be observed when d(5)-deuterated chloroethane is used. It rapidly eliminates HCl (but not DCl) to form ethyl carborane, Et(CHB(11)Cl(11)), which binds a second molecule of chloroethane to form the Et(2)Cl(+) chloronium ion. This undergoes a slower, previously unrecognized HCl elimination reaction to form a butyl carborane, Bu(CHB(11)Cl(11)), beginning an oligomerization process whereby unsymmetrical dialkylchloronium ions decompose to alkyl carboranes of formula Bu(C(2)H(4))(n)(CHB(11)Cl(11)) up to n = 4. Over time, a parallel competing process of de-oligomerization take place in the presence of free carborane acid that finishes with the formation of hexyl or butyl carboranes. Upon heating to 150 C, the final products are all converted to the remarkably stable tert-butyl cation carborane salt.

Planar subporphyrin borenium cations.

Subporphyrin borenium cations with a carborane counterion have been prepared by treatment of B-methoxy subporphyrins with the silylium reagent Et(3)Si(CH(6)B(11)Br(6)). In contrast to the distinctly domed subphthalocyanine borenium cation, a nearly planar structure with sp(2) hybridized boron is found in the X-ray structure of the triphenylsubporphyrin borenium cation. The cations exhibit absorption and fluorescence spectra that are quite similar to those of B-methoxy subporphyrins. B-phenyl subporphyrins were prepared in good yield by reaction of subporphyrin borenium cations with phenyllithium.

Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells.

BACKGROUND & AIMS: Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide; current chemotherapeutic interventions for this disease are largely ineffective. The retinoblastoma tumor suppressor (RB) is functionally inactivated at relatively high frequency in hepatocellular carcinoma and hepatoma cell lines. Here, we analyzed the ability of CDK4/6 inhibition to inhibit hepatocyte proliferation and the effect of RB status on this process. METHODS: Hepatoma cell lines and xenograft models harboring RB knockdown and mice harboring liver-specific Rb deletion were used to define the role of RB function in response to CDK4/6 inhibition. RESULTS: Our study shows that CDK4/6-dependent cell cycle progression in hepatoma cells was readily arrested by inhibition of CDK4/6 by PD-0332991 or p16ink4a irrespective of RB status. Interestingly, upon CDK4/6 inhibition, p107 protein stability was dramatically increased as a function of RB loss. This engagement of compensatory mechanisms was critical for cell cycle inhibition in the absence of RB, because both the E1A oncoprotein and overexpression of E2F proteins were capable of overcoming the effect of CDK4/6 inhibition. These findings were recapitulated in xenograft models. Furthermore, to determine how these findings relate to hepatocyte proliferation in vivo, mice were exposed to carbon tetrachloride to induce liver regeneration followed by treatment with PD-0332991. This treatment significantly inhibited hepatocyte proliferation. Strikingly, this facet of PD-0332991 function was retained even in RB-deficient livers. CONCLUSIONS: These data show that CDK4/6 inhibition is a potent mediator of cytostasis and that RB loss can be readily compensated for in the context of both hepatoma cell lines and liver tissue.

H(+), CH(3)(+), and R(3)Si(+) carborane reagents: when triflates fail.

For decades, triflic acid, methyl triflate, and trialkylsilyl triflate reagents have served synthetic chemistry well as clean, strong electrophilic sources of H(+), CH(3)(+), and R(3)Si(+), respectively. However, a number of weakly basic substrates are unreactive toward these reagents. In addition, triflate anion can express undesired nucleophilicity toward electrophilically activated substrates. In this Account, we describe methods that replace triflate-based electrophilic reagents with carborane reagents. Using carborane anions of type CHB(11)R(5)X(6)(-) (R = H, Me, X; X = Br, Cl), members of a class of notably inert, weakly nucleophilic anions, significantly increases the electrophilicity of these reagents and shuts down subsequent nucleophilic chemistry of the anion. Thus, H(carborane) acids cleanly protonate benzene, phosphabenzene, C(60), etc., while triflic acid does not. Similarly, CH(3)(carborane) reagents can methylate substrates that are inert to boiling neat methyl triflate, including benzene, phosphabenzenes, phosphazenes, and the pentamethylhydrazinium ion, which forms the dipositive ethane analogue, Me(6)N(2)(2+). Methyl carboranes are also surprisingly effective in abstracting hydride from simple alkanes to give isolable carbocation salts, e.g., t-butyl cation. Trialkylsilyl carborane reagents, R(3)Si(carborane), abstract halides from substrates to produce cations of unprecedented reactivity. For example, fluoride is extracted from freons to form carbocations; chloride is extracted from IrCl(CO)(PPh(3))(2) to form a coordinatively unsaturated iridium cation that undergoes oxidative addition with chlorobenzene at room temperature; and silylation of cyclo-N(3)P(3)Cl(6) produces a catalyst for the polymerization of phosphazenes that functions at room temperature. Although currently too expensive for widespread use, carborane reagents are nevertheless of considerable interest as specialty reagents for making reactive cations and catalysts.

The structure of the hydrogen ion (H(aq)+) in water.

The hydrogen ion in water, H(aq)(+), is a unique H(13)O(6)(+) entity that defines the boundary of positive-charge delocalization. Its central unit is neither a C(3v) H(3)O(+) Eigen-type ion nor a typical H(5)O(2)(+) Zundel-type ion. IR spectroscopy indicates that the H(13)O(6)(+) ion has an unexpectedly long central O...O separation (>>2.43 A), showing that in comparison with the gas and solid phases, the environment of liquid water is uniquely proficient in delocalizing positive charge. These results will change the description of H(aq)(+) in textbooks of chemistry, and a more extensive delocalization of positive charge may need to be incorporated into descriptions of mechanisms of aqueous proton transport.

Dialkyl chloronium ions.

The carborane acid H(CHB(11)Cl(11)) reacts with chloroalkanes RCl to give isolable dialkylchloronium ion salts, [R(2)Cl][CHB(11)Cl(11)], that are stable at room temperature. X-ray crystal structures have been obtained for R = CH(3) and CH(2)CH(3), revealing bent cation structures with C-Cl-C angles of 101.5 and 105.8 degrees , respectively. The dimethylchloronium ion salt loses CH(3)Cl upon heating and forms sublimable CH(3)(CHB(11)Cl(11)), providing a clean synthetic route to an extremely potent electrophilic methylating agent. IR spectra of all species have been interpreted, including the C-Cl stretch in CH(3)-ClCHB(11)Cl(10).

High yield C-derivatization of weakly coordinating carborane anions.

Unlike the "parent" carborane anion CHB(11)H(11)(-), halogenated carborane anions such as CHB(11)H(5)Br(6)(-) can be readily C-functionalized in high yield and purity, enhancing their utility as weakly coordinating anions.

Searching for intermediates in Prins cyclisations: the 2-oxa-5-adamantyl carbocation.

The 2-oxa-5-adamantyl carbocation 4 is shown to be a viable intermediate in several S(N)1 substitution reactions. However, attempts to observe the formation of 4 from various precursors by NMR methods (which succeed for the 1-adamantyl cation 5) failed, suggesting that 4 does not survive on longer timescales. DFT calculations suggest that the retro-Prins process (beta-cleavage, Grob fragmentation) to give enantiomeric (1R,5R)- and (1S,5S)-7-methylene-2-oxoniabicyclo[3.3.1]non-2-ene cations 22 is the only realistic unimolecular escape route for 4. With the 6-31G(d) basis set, B3LYP calculation predicts that 4 is only 11 kJ mol(-1) more stable than 22, and the barrier separating 4 and 22 is calculated to be only 15 kJ mol(-1), so rapid equilibration of these species is likely on the laboratory time scale. The implications of this study for the mechanism of the Prins cyclisation are discussed.

H(aq)+ structures in proton wires inside nanotubes.

The hydrated carborane acid H(CHB(11)I(11)).8H(2)O crystallizes in nanometer-diameter tubes of H(aq)(+) enclosed by walls of carborane anions. Three different types of H(aq)(+) clusters are found in these tubes: a symmetrical H(13)O(6)(+) ion with an unusually elongated Zundel-type H(5)O(2)(+) core, two hydrated H(7)O(3)(+) ions, and an unprecedented H(17)O(8)(+) ion having a nearly square core. All of the H(aq)(+) cations show unexpectedly longer O...O separations than in discrete H(aq)(+) ions, indicating greater delocalization of positive charge. The centrosymmetric H(aq)(+) ions are linked via short H bonds, forming a true one-dimensional proton wire.

Investigating the weak to evaluate the strong: an experimental determination of the electron binding energy of carborane anions and the gas phase acidity of carborane acids.

Five CHB(11)X(6)Y(5)(-) carborane anions from the series X = Br, Cl, I and Y = H, Cl, CH(3) were generated by electrospray ionization, and their reactivity with a series of Brønsted acids and electron transfer reagents were examined in the gas phase. The undecachlorocarborane acid, H(CHB(11)Cl(11)), was found to be far more acidic than the former record holder, (1-C(4)F(9)SO(2))(2)NH (i.e., DeltaH degrees (acid) = 241 +/- 29 vs 291.1 +/- 2.2 kcal mol(-1)) and bridges the gas-phase acidity and basicity scales for the first time. Its conjugate base, CHB(11)Cl(11)(-), was found by photoelectron spectroscopy to have a remarkably large electron binding energy (6.35 +/- 0.02 eV) but the value for the (1-C(4)F(9)SO(2))(2)N(-) anion is even larger (6.5 +/- 0.1 eV). Consequently, it is the weak H-(CHB(11)Cl(11)) BDE (70.0 kcal mol(-1), G3(MP2)) compared to the strong BDE of (1-C(4)F(9)SO(2))(2)N-H (127.4 +/- 3.2 kcal mol(-1)) that accounts for the greater acidity of carborane acids.

Superacidity of boron acids H2(B12X12) (X = Cl, Br).

Acid remarks: The anhydrous diprotic boron acids H(2)(B(12)X(12)) (X = Cl, Br; see picture, B orange, X green) are the first examples of diprotic superacids and may be the strongest acids yet isolated. Both protons protonate benzene to give benzenium ion salts that are stable at room temperature. These acids owe their existence to the stability of the icosahedral B(12) cluster with its dinegative charge buried beneath a layer of halide substituents.