William J. Leigh

Bimolecular Hydrogen Abstraction from Phenols by Aromatic Ketone Triplets

Abstract Absolute rate constants for hydrogen abstraction from 4-methylphenol (para-cresol) by the lowest triplet states of 24 aromatic ketones have been determined in acetonitrile solution at 23°C, and the results combined with previously reported data for roughly a dozen other compounds under identical conditions. The ketones studied include various ring-substituted benzophenones and acetophenones, α,α,α-trifluoroacetophenone and its 4-methoxy analog, 2-benzoylthiophene, 2-acetonaphthone, and various other polycyclic aromatic ketones such as fluorenone, xanthone and thioxanthone, and encompass n,π*, π,π*(CT) and arenoid π,π* lowest triplets with (triplet) reduction potentials (Ered*) varying from about −10 to −38 kcal mol−1. The 4-methylphenoxyl radical is observed as the product of triplet quenching in almost every case, along with the corresponding hemipinacol radical in most instances. Hammett plots for the acetophenones and benzophenones are quite different, but plots of log kQ vs Ered* reveal a common behavior for most of the compounds studied. The results are consistent with reaction via two mechanisms: a simple electron-transfer mechanism, which applies to the n,π* triplet ketones and those π,π* triplets that possess particularly low reduction potentials, and a coupled electron-/proton-transfer mechanism involving the intermediacy of a hydrogen-bonded exciplex, which applies to the π,π* ketone triplets. Ketones with lowest charge-transfer π,π* states exhibit rate constants that vary only slightly with triplet reduction potential over the full range investigated; this is due to the compensating effect of substituents on triplet state basicity and reduction potential, which both play a role in quenching by the hydrogen-bonded exciplex mechanism. Ketones with arenoid π,π* states exhibit the fall-off in rate constant that is typical of photoinduced electron transfer reactions, but it occurs at a much higher potential than would be normally expected due to the effects of hydrogen-bonding on the rate of electron-transfer within the exciplex.

Kinetics and mechanisms of the reactions of Si=C and Ge=C double bonds

The kinetics and mechanisms of a number of characteristic reactions of SioC and GeoC double bonds have been studied in solution, using laser flash photolysis of sila- and germacyclobutanes for generation of the silene and germene reactive intermediates under conditions where they can be detected directly. Substituent, solvent, isotope, and temperature effects on the rate constants for reaction of Ph 2SioCH2 with alcohols, amines, carboxylic acids and ketones suggest that these reagents react by a common mechanism, involving initial nucleophilic attack at silicon followed by proton transfer within the initially formed Lewis acid-base complex between the silene and the nucleophile. The reactivity of Ph2GeoCH2 is significantly lower than that of the silene. Reaction with alcohols in acetonitrile solution proceeds by a mechanism leading to a second order dependence of the rate on alcohol concentration, probably involving initial complexation followed by general base catalysed proton transfer. Reaction with primary amines in the same solvent is faster, and follows a first order dependence on amine concentration. The photochemistry of the corresponding 1,1,3,3- tetraphenyldimetallacyclobutanes, formed by dimerization of the silene and germene, affords some insight into the mechanism of dimerization.

Merostabilization in radical ions, triplets, and biradicals. 5. The thermal cis–trans isomerization of para-substituted tetraphenylethylenes

The cis- and trans-isomers of four para-substituted (three disubstituted and one tetrasubstituted) tetraphenylethylenes have been synthesized, separated, and characterized by either dipole moment or X-ray analysis. The rates of thermal isomerization of the disubstituted derivatives in benzene solution correlate with a substituent parameter reflecting substituent effects on benzylic radical stabilities (σ•), which reflects the biradical nature of the transition state for thermal isomerization in this system. A significant rate enhancement is observed for the tetrasubstituted derivative, in which merostabilization of the transition state is possible.The Arrhenius parameters for thermal isomerization in benzene were determined. From the variation observed for the disubstituted derivatives, an estimate of 35.5 kcal mol−1 for the rotational barrier in tetraphenylethylene is obtained. The activation energy for thermal isomerization of the tetrasubstituted derivative is 2 kcal mol−1 lower than those of the other...

Merostabilization in radical ions, triplets, and biradicals. Substituent effects on the n,π* triplet energy of benzophenone

An empirical approach is developed for the assessment of the importance of merostabilization in influencing the n,π* triplet energies of unsymmetrically substituted benzophenones.

Silanones and Silanethiones from the Reactions of Transient Silylenes with Oxiranes and Thiiranes in Solution. The Direct Detection of Diphenylsilanethione.

The transient silylenes SiMe(2) and SiPh(2) react with cyclohexene oxide (CHO), propylene oxide (PrO), and propylene sulfide (PrS) in hydrocarbon solvents to form products consistent with the formation of the corresponding transient silanones and silanethiones, respectively. Laser flash photolysis studies show that these reactions proceed via multistep sequences involving the intermediacy of the corresponding silylene-oxirane or -thiirane complexes, which are formed with rate constants close to the diffusion limit in all cases and exhibit UV absorption spectra similar to those of the corresponding complexes with the nonreactive O- and S-donors, tetrahydrofuran and tetrahydrothiophene. The SiMe(2)-PrO and SiPh(2)-PrO complexes both exhibit lifetimes of ca. 300 ns, and are longer-lived than the corresponding complexes with CHO, which are both in the range of 230-240 ns. On the other hand, the silylene-PrS complexes are considerably shorter-lived and vary with silyl substituent; the SiMe(2)-PrS complex decays with the excitation laser pulse (i.e., τ ≤ 25 ns), while the SiPh(2)-PrS complex exhibits τ = 48 ± 3 ns. The decay of the SiPh(2)-PrS complex affords a long-lived transient product exhibiting λ(max) ≈ 275 nm, which has been assigned to diphenylsilanethione (Ph(2)Si═S) on the basis of its second order decay kinetics and absolute rate constants for reaction with methanol, tert-butanol, acetic acid, and n-butyl amine, for which values in the range of 1.4 × 10(8) to 3.2 × 10(9) M(-1) s(-1) are reported. The experimental rate constants for decay of the SiMe(2)-epoxide and -PrS complexes indicate free energy barriers (ΔG(‡)) of ca. 8.5 and ≤7.1 kcal mol(-1) for the rate-determining steps leading to dimethylsilanone and -silanethione, respectively, which are compared to the results of DFT (B3LYP/6-311+G(d,p)) calculations of the reactions of SiH(2) and SiMe(2) with oxirane and thiirane. The calculations predict a stepwise C-O cleavage mechanism involving singlet biradical intermediates for the silylene-oxirane complexes, and a concerted mechanism for silanethione formation from the silylene-thiirane complexes, in agreement with earlier ab initio studies of the SiH(2)-oxirane and -thiirane systems.

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.

Charge-transfer interactions in the intramolecular quenching of carbonyl triplets by β-aryl substituents

The triplet decay rates of ten β-aryl-4-methoxypropiophenone derivatives in methanol, acetonitrile, toluene and isooctane solution at 21 °C correlate with δ+ substituent constants (p+–1.8 ± 0.2), indicating that charge-transfer exciplex interactions between the aryl group (donor) and the carbonyl group (acceptor) play a dominant role in the intramolecular β-aryl quenching of carbonyl n,πtriplets.

End-to-end intramolecular quenching of aromatic ketone triplets in aqueous solutions of 2,6-di-(O-methyl)-cyclodextrins

Abstract The photochemistry of para -(4-hydroxyphenyl)ethoxyacetophenone ( 1 ) in aqueous solutions of α-, β- and γ-2,6-di-(O-methyl)-cyclodextrins (α-, β- and γ-MCD respectively) was studied using laser flash photolysis techniques. In acetonitrile solution, the triplet state of 1 (τ ≈ 15 ns) decays by intramolecular phenolic hydrogen abstraction to yield the corresponding 1,13-phenoxyketyl biradical. Laser flash photolysis of aqueous solutions of 1 and equimolar α- and β-MCD yields transient absorptions with λ max = 395 nm, which decay with multiexponential kinetics. Two-component decay analyses show that the main portions (greater than 70%) of the decay in the two solutions have lifetimes of about 900 and 440 ns respectively, whereas the minor components are 4–6 times shorter lived. The transients have been shown to be a result of the triplet state of 1 on the basis of quenching studies with sorbic acid. In 1:1 solutions of 1 and γ-MCD under similar conditions, no transients of lifetime greater than approximately 12 ns are observed. The data are consistent with inclusion complex structures in which only one of the aryl rings of the solute is included in the α- and β-MCD cavities, whereas both are included in the γ-MCD cavity. It is suggested that in the α- and β-MCD complexes, the conformational motions required for formation of the intramolecular abstraction geometry are accompanied by partial disengagement of the solute from the cavity. The effects of increasing the relative concentration of MCD on the tirplet lifetime of 1 are consistent with the formation of termolecular 1:2 1 :MCD complexes at high MCD concentration for the β- and γ-MCD systems.

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.

Organic reactions in liquid crystalline solvents. 5. : Intramolecular phenolic quenching of aromatic ketone triplets as a probe of solute conformational mobility in liquid crystals.

Abstract The effects of liquid crystalline order on the confomational motions involved in end-to-end, intramolecular triplet quenching of aromatic ketones by a suitably situated phenolic moiety have been investigated. Triplet state quenching has been monitored using two independent probes: Norrish II fragmentation quantum yields of valeryl-substituted derivatives and direct lifetime measurements in methyl-substituted ketones, using the corresponding anisyl-substituted ketones as models for triplet state behaviour In the absence of phenolic quenching.Quantum yields for Norrish II fragmentation in the liquid crystalline solvents have been estimated using 4-methoxyvalerophenone (MVP) as the actinometer. The ability of liquid crystalline solvents to inhibit intramolecular phenolic quenching is dependent on both phase type and solute length. In one case, Intramolecular quenching Is completely suppressed In smectic phases, indicating that the conformational motions involved in achieving the quenching geometry are slowed by a factor of at least 10 3 relative to their rates in non-viscous, isotropic solvents. The Norrish II product ratios from photolysis of MVP in the liquid crystalline solvents are also affected dramatically by liquid crystalline order.