Lawrence A. Huck

A glimpse at the chemistry of GeH2 in solution. Direct detection of an intramolecular germylene-alkene π-complex.

The photochemistry of 3-methyl-4-phenyl-1-germacyclopent-3-ene (4) and a deuterium-labeled derivative (4-d(2)) has been studied in solution by steady state and laser flash photolysis methods, with the goal of detecting the parent germylene (GeH(2)) directly and studying its reactivity in solution. Photolysis of 4 in C(6)D(12) containing acetic acid (AcOH) or methanol (MeOH) affords 2-methyl-3-phenyl-1,3-butadiene (6) and the O-H insertion products ROGeH(3) (R = Me or Ac) in yields of ca. 60% and 15-30%, respectively, along with numerous minor products which the deuterium-labeling studies suggest are mainly derived from hydrogermylation processes involving GeH(2) and diene 6. The reaction with AcOH also affords H(2) in ca. 20% yield, while HD is obtained from 4-d(2) under similar conditions. Photolysis of 4 in THF-d(8) containing AcOH affords AcOGeH(3) and 6 exclusively, indicating that the nucleophilic solvent assists the extrusion of GeH(2) from 4 and alters the mechanism of the trapping reaction with AcOH compared to that in cyclohexane. Laser flash photolysis of 4 in hexanes yields a promptly formed transient exhibiting λ(max) ≈ 460 nm, which decays on the microsecond time scale with the concomitant growth of a second, much longer-lived transient exhibiting λ(max) ≈ 390 nm. The spectrum and reactivity of the 460 nm species toward various germylene trapping agents are inconsistent with those expected for free GeH(2); rather, the transient is assigned to an intramolecular Ge(II)-alkene π-complex of one of the isomeric substituted hydridogermylenes derived from a solvent-cage reaction between GeH(2) and its diene (6) coproduct, formed by addition of HGe-H across one of the C=C bonds. These conclusions are supported by the results of DFT calculations of the thermochemistry associated with π-complexation of GeH(2) with 6 and the formation of the isomeric vinylgermiranes and 1,2-hydrogermylation products. A different species is observed upon laser photolysis of 4 in THF solution and is assigned to the GeH(2)-THF complex on the basis of its UV-vis spectrum and rate constants for its reaction with AcOH and AcOD.

Photoinduced Intramolecular Macrocyclization Reaction between a Bpa and a Met Residue in a Helical Peptide: 3D Structures of the Diastereomeric Products

The 3-(4-benzoylphenyl)alanyl (Bpa) residue has been extensively used as a probe in the photoaffinity scanning approach for studies of intermolecular labelled (peptide) ligand–receptor (protein) interactions, despite the significant rotational freedom of some of its side-chain bonds which may encompass a radius for cross-linking as large as 10 . Photoexcitation of the benzophenone chromophore at 350–360 nm results in the efficient formation of its n,p* triplet state, which is able to abstract a hydrogen atom from a geometrically accessible C H s bond. In the second step of this process, the resulting ketyl radical combines with the newly generated carbon radical, thus covalently linking the two moieties. Using a set of simple model compounds (terminally-blocked protein amino acids), it was demonstrated that the excited benzophenone preferentially alkylates the Gly a carbon and the two (g and e) carbon atoms adjacent to sulfur in the Met side chain. All reactions generate two or multiple diastereomeric products. In actual ligand–receptor studies the preferential selectivity of Bpa for Met over all other amino acids in the target protein is even more pronounced, so that terms and methodologies such as “Metmagnetic effect” and “Met-proximity assay” have been introduced and designed. In a related perspective, Bpa has been biosynthetically incorporated into proteins, allowing photocross-linking to other proteins in their vicinity. If the hydrogen atom is abstracted from a remote carbon of the same molecule, the resulting biradical can react intramolecularly (Yang photocyclization) to yield an annular system. Intramolecular side-chain to side-chain ring formation is an approach currently extensively exploited to achieve more robust peptide conformations, reduce the barrier to membrane penetration, and improve resistance towards proteolytic attack. More specifically, stapled helices may overcome some of the drawbacks that have hampered the development of peptide drugs. In connection with our investigations of intramolecular macrocyclization reactions in helical peptides, we are currently carrying out a first detailed study of the Yang photocyclization reaction in a set of four, backbone rigidified, terminally protected, potentially 310-helical [9] hexapeptides of general sequence Boc-(Aib)x-l-Bpa-(Aib)y-l-Met-(Aib)zOMe, where Boc is tert-butyloxycarbonyl, Aib is a-aminoisobutyric acid or C-dimethylglycine, OMe is methoxy, and x+y+z=4. In this investigation we aim to determine the effects induced by the length of the peptide spacer, which is entirely based on the strongly helicogenic Aib residue, on the extent of formation of the regioand stereoselective reaction products and the rate of the intramolecular excited state reaction. In this article, we describe the results of our study on Boc-Aib-l-Bpa-(Aib)2-l-MetAib-OMe (hereafter called starting hexapeptide, SH), which, amongst other things, has allowed for the first time the unambiguous, detailed chemical and configurational characterization of the diastereomeric peptides arising from the intramolecular photoreaction of the Bpa and Met residues. A preliminary account of part of this work has already been reported. The synthesis of SH was performed step-by-step by solution methods (see the Supporting Information). The results of a concentration-dependent FT-IR absorption/H NMR analysis (see below and Figure S1 and S2 in the Supporting Information) clearly indicate that this hexapeptide is essentially monomeric and overwhelmingly folded in a 310-helical [a] Dr. A. Moretto, Dr. M. Crisma, Prof. F. Formaggio, Prof. C. Toniolo Istituto di Chimica Biomolecolare, CNR, Unit di Padova Dipartimento di Scienze Chimiche, Universit di Padova via Marzolo 1, 35131 Padova (Italy) Fax: (+39)049-827-5239 E-mail : claudio.toniolo@unipd.it [b] Dr. L. A. Huck, Dr. D. Mangion, Prof. W. J. Leigh Department of Chemistry, McMaster University Hamilton, ON, L8S 4M1 (Canada) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200802066.

Kinetic and mechanistic studies of the reactions of diarylgermylenes and tetraaryldigermenes with carbon tetrachloride

The mechanisms of the reactions of diphenylgermylene (GePh2) with CCl4 in hydrocarbon solvents and in THF solution have been studied, employing 3,4-dimethyl-1,1-diphenylgermacyclopent-3-ene (6a) and 1,1-diphenylgermacyclo- butane (17) as photochemical precursors to GePh2. In hydrocarbon solvents, the reaction produces Ph2GeCl2 (10) and Ph2Ge(Cl)CCl3 (12) in a ratio of 10:12 & 7, along with a variety of other radical-derived products and small amounts of Ph2GeH(D)Cl (11), which is formed partly by reaction of GePh2 with adventitious HCl. The reaction is much cleaner in THF, where 12 is formed as the major product (10:12 & 0.8); a similar product distribution is obtained in hexanes con- taining 0.05 mol/L THF, while 12 is the exclusive product in hexanes containing 3 mmol/L NEt3. Rate constants for the reactions of CCl4 with GePh2 and five ring-substituted derivatives were determined by laser flash photolysis, as well as Ar- rhenius parameters for reaction of the parent (GePh2), in the two solvents. The reactions of GePh2 with CCl4 and CHCl3 have also been studied in 3-methylpentane solution at 78-90 K. Different reaction mechanisms are clearly operative in hy- drocarbon and complexing solvents, but both involve modest charge donation from germanium to the substrate in the tran- sition state for the rate-determining step. For the reaction in hydrocarbon solvents, the data are consistent with inner- sphere electron transfer following or in concert with weak Lewis acid-base complexation. A similar mechanism is pro- posed for the reaction in THF solution, in competition with a second involving nucleophilic attack of the germylene-THF complex at a chlorine atom of the substrate. Rate constants were also determined for reaction of CCl4 with the correspond- ing tetraaryldigermenes at low halocarbon concentrations in hexanes, along with Arrhenius parameters for the parent (Ge2Ph4). These reactions also proceed via initial Cl-atom abstraction, based on the identity of the products formed in the reaction of CCl4 with tetramesityldigermene.

1,1-Bis[4-(trifluoro-meth-yl)phen-yl]germetane.

The internal C—Ge—C bond angle in the germacyclobutane ring of the title compound, C17H14F6Ge or [Ge(C3H6)(C7H4F3)2], is 77.8 (3)°. The –CF3 groups display rotational disorder [occupancies 0.604 (14):0.396 (14) and 0.410 (6):0.411 (6):0.179 (3)] and the germacyclobutane ring also shows disorder [occupancies 0.604 (14):0.396 (14)].