Dihydrophenanthrene Open-Shell Singlet Diradicals and Their Roles in the Mallory Photocyclization Reaction.

A computational study (ωB97X-D/6-31G(d)) of the Mallory photocyclization reaction has revealed that the well-established dihydrophenanthrene (DHP) intermediates can adopt either closed-shell (CS) or open-shell-diradical (OS) singlet ground states. A detailed study of the properties of DHPs allowed their classifications as OS, borderline-OS, borderline-CS, or CS intermediates. The triplet electronic state and higher energy CS* isomer of all the OS singlet diradicals were computationally located, and the expected relationship between the diradical index, yo, and the triplet energy and the OS-CS* energy gaps was established. The importance of aromaticity in stabilizing the OS singlet diradicals was confirmed by using the Harmonic Oscillator Model of Aromaticity (HOMA). The thermal decompositions of DHPs by cycloreversions to regenerate the Mallory starting materials were also studied. The cycloreversion mechanism was described as a homolytic cleavage characterized by an anchimeric assistance continuum promoted by bis-ß-homolytic cleavage.

Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice.

4-Phosphoryloxy-N,N-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin is a prodrug for 4-hydroxy-N,N-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT2A). Several other 4-position ring-substituted tryptamines are present in psilocybin-containing mushrooms, including the secondary amine 4-phosphoryloxy-N-methyltryptamine (baeocystin) and the quaternary ammonium 4-phosphoryloxy-N,N,N-trimethyltryptamine (aeruginascin), but these compounds are not well studied. Here, we investigated the structure-activity relationships for psilocybin, baeocystin, and aeruginascin, as compared to their 4-acetoxy and 4-hydroxy analogues, using in vitro and in vivo methods. Broad receptor screening using radioligand binding assays in transfected cells revealed that secondary and tertiary tryptamines with either 4-acetoxy or 4-hydroxy substitutions display nanomolar affinity for most human 5-HT receptor subtypes tested, including the 5-HT2A and the serotonin 1A receptor (5-HT1A). The same compounds displayed affinity for 5-HT2A and 5-HT1A in mouse brain tissue in vitro and exhibited agonist efficacy in assays examining 5-HT2A-mediated calcium mobilization and ß-arrestin 2 recruitment. In mouse experiments, only the tertiary amines psilocin, psilocybin, and 4-acetoxy-N,N-dimethyltryptamine (psilacetin) induced head twitch responses (ED50 0.11-0.29 mg/kg) indicative of psychedelic-like activity. Head twitches were blocked by 5-HT2A antagonist pretreatment, supporting 5-HT2A involvement. Both secondary and tertiary amines decreased body temperature and locomotor activity at higher doses, the effects of which were blocked by 5-HT1A antagonist pretreatment. Across all assays, the pharmacological effects of 4-acetoxy and 4-hydroxy compounds were similar, and these compounds were more potent than their 4-phosphoryloxy counterparts. Importantly, psilacetin appears to be a prodrug for psilocin that displays substantial serotonin receptor activities of its own.

Self-assembly of an organometallic Fe9O6 cluster from aerobic oxidation of (tmeda)Fe(CH2tBu)2.

Aerobic oxidation of (tmeda)Fe(CH2tBu)2 in toluene or THF solution leads to the self-assembly of a magic-sized all-ferrous oxide cluster containing the Fe9O6 subunit and bearing organometallic and diamine ligands. Mössbauer studies of the cluster are consistent with an all-ferrous assignment and magnetometry reveals complex intracluster and intercluster magnetic interactions.

Tridentate Phosphine Ligands Bearing Aza-Crown Ether Lariats.

Crown ethers are useful macrocycles that act as size-selective binding sites for alkali metals. These frameworks have been incorporated into a number of macromolecular assemblies that use simple cations as reporters and/or activity triggers. Incorporating crown ethers into secondary coordination sphere ligand frameworks for transition metal chemistry will lead to new potential methods for controlling bond formation steps, and routes that couple traditional ligand frameworks with these moieties are highly desirable. Herein we report the syntheses of a family of tridentate phosphine complexes bearing tethered aza-crown ethers (lariats) designed to modularize the variation of aza-crown size, lariat length, and distal phosphine substituents, followed by the synthesis and solid-state structures of Mo(III) complexes bearing cations in the pendent crown ethers.

Increasing the rate of hydrogen oxidation without increasing the overpotential: a bio-inspired iron molecular electrocatalyst with an outer coordination sphere proton relay.

Oxidation of hydrogen (H2) to protons and electrons for energy production in fuel cells is currently catalyzed by platinum, but its low abundance and high cost present drawbacks to widespread adoption. Precisely controlled proton removal from the active site is critical in hydrogenase enzymes in nature that catalyze H2 oxidation using earth-abundant metals (iron and nickel). Here we report a synthetic iron complex, (CpC5F4N)Fe(PEtN(CH2)3NMe2 PEt)(Cl), that serves as a precatalyst for the oxidation of H2, with turnover frequencies of 290 s-1 in fluorobenzene, under 1 atm of H2 using 1,4-diazabicyclo[2.2.2]octane (DABCO) as the exogenous base. The inclusion of a properly tuned outer coordination sphere proton relay results in a cooperative effect between the primary, secondary and outer coordination spheres for moving protons, increasing the rate of H2 oxidation without increasing the overpotential when compared with the analogous complex featuring a single pendant base. This finding emphasizes the key role of pendant amines in mimicking the functionality of the proton pathway in the hydrogenase enzymes.

Rapid, reversible heterolytic cleavage of bound H2.

Heterolytic cleavage of dihydrogen into a proton and a hydride ion is a fundamentally important step in many reactions, including the oxidation of hydrogen by hydrogenase enzymes and ionic hydrogenation of organic compounds. We report the facile, reversible heterolytic cleavage of H2 in a manganese complex bearing a pendant amine, leading to the formation of a manganese hydride and a protonated amine that undergo H(+)/H(-) exchange at an estimated rate of >10(7) s(-1) at 25 °C.

Carbon-carbon bond formation from azaallyl and imine couplings about metal-metal bonds.

Typical C-C bond-forming processes feature oxidative addition, insertion, and reductive elimination reactions. An alternative strategy toward C-C bond formation involves the generation of transient radicals that can couple at or around one or more metal centers. Generation of transient azaallyl ligands that reductively couple at CH positions possessing radical character is described. Two C-C bonds form, and the redox non-innocence of the resulting pyridine-imines may be critical to formation of a third C-C bond via dinuclear di-imine oxidative coupling. Unique metal-metal bonds are a consequence of the chelation.

Pnictogen-hydride activation by (silox)3Ta (silox = (t)Bu3SiO); attempts to circumvent the constraints of orbital symmetry in N2 activation.

Activation of N(2) by (silox)(3)Ta (1, silox = (t)Bu(3)SiO) to afford (silox)(3)Ta═N-N═Ta(silox)(3) (1(2)-N(2)) does not occur despite ΔG°(cald) = -55.6 kcal/mol because of constraints of orbital symmetry, prompting efforts at an independent synthesis that included a study of REH(2) activation (E = N, P, As). Oxidative addition of REH(2) to 1 afforded (silox)(3)HTaEHR (2-NHR, R = H, Me, (n)Bu, C(6)H(4)-p-X (X = H, Me, NMe(2)); 2-PHR, R = H, Ph; 2-AsHR, R = H, Ph), which underwent 1,2-H(2)-elimination to form (silox)(3)Ta═NR (1═NR; R = H, Me, (n)Bu, C(6)H(4)-p-X (X = H (X-ray), Me, NMe(2), CF(3))), (silox)(3)Ta═PR (1═PR; R = H, Ph), and (silox)(3)Ta═AsR (1═AsR; R = H, Ph). Kinetics revealed NH bond-breaking as critical, and As > N > P rates for (silox)(3)HTaEHPh (2-EHPh) were attributed to (1) ΔG°(calc)(N) < ΔG°(calc)(P) ∼ ΔG°(calc)(As); (2) similar fractional reaction coordinates (RCs), but with RC shorter for N < P∼As; and (3) stronger TaE bonds for N > P∼As. Calculations of the pnictidenes aided interpretation of UV-vis spectra. Addition of H(2)NNH(2) or H(2)N-N((c)NC(2)H(3)Me) to 1 afforded 1═NH, obviating these routes to 1(2)-N(2), and formation of (silox)(3)MeTaNHNH2 (4-NHNH(2)) and (silox)(3)MeTaNH(-(c)NCHMeCH(2)) (4-NH(azir)) occurred upon exposure to (silox)(3)Ta═CH(2) (1═CH(2)). Thermolyses of 4-NHNH(2) and 4-NH(azir) yielded [(silox)(2)TaMe](µ-N(α)HN(ß))(µ-N(γ)HN(δ)H)[Ta(silox)(2)] (5) and [(silox)(3)MeTa](µ-η(2)-N,N:η(1)-C-NHNHCH(2)CH(2)CH(2))[Ta(κ-O,C-OSi(t)Bu(2)CMe(2)CH(2))(silox)(2)] (7, X-ray), respectively. (silox)(3)Ta═CPPh(3) (1═CPPh(3), X-ray) was a byproduct from Ph(3)PCH(2) treatment of 1 to give 1═CH(2). Addition of Na(silox) to [(THF)(2)Cl(3)Ta](2)(µ-N(2)) led to [(silox)(2)ClTa](µ-N(2)) (8-Cl), and via subsequent methylation, [(silox)(2)MeTa](2)(µ-N(2)) (8-Me); both dimers were thermally stable. Orbital symmetry requirements for N(2) capture by 1 and pertinent calculations are given.

[(silox)(3)M](2)(mu:eta(1),eta(1)-P(2)) (M = Nb, Ta) and [(silox)(3)Nb](2){mu:eta(2),eta(2)-((c)P(3)-(c)P(3))} from (silox)(3)M (M = NbPMe(3), Ta) and P(4) (silox = (t)Bu(3)SiO).

Complexes containing the mu:eta(1),eta(1)-P(2) binding mode of diphosphorus have been prepared, along with a P(6)-containing byproduct.

Olefin substitution in (silox)3M(olefin) (silox = (t)Bu3SiO; M = Nb, Ta): the role of density of states in second vs third row transition metal reactivity.

The substitution chemistry of olefin complexes (silox)3M(ole) (silox = (t)Bu3SiO; M = Nb (1-ole), Ta (2-ole); ole = C2H4 (as 13C2H4 or C2D4), C2H3Me, C2H3Et, cis-2-C4H8, iso-C4H8, C2H3Ph, cC5H8, cC6H10, cC7H10 (norbornene)) was investigated. For 1-ole, substitution was dissociative (deltaG(double dagger)(diss)), and in combination with calculated olefin binding free energies (deltaG(o)(bind)), activation free energies for olefin association (deltaG(double dagger)(assoc)) to (silox)3Nb (1) were estimated. For 2-ole, substitution was not observed prior to rearrangement to alkylidenes. Instead, activation free energies for olefin association to (silox)3Ta (2) were measured, and when combined with deltaG(o)(bind) (calcd), estimates of olefin dissociation rates from 2-ole were obtained. Despite stronger binding energies for 1-ole vs 2-ole, the dissociation of olefins from 1-ole is much faster than that from 2-ole. The association of olefins to 1 is also much faster than that to 2. Linear free energy relationships (with respect to deltaG(o)(bind)) characterize olefin dissociation from 1-ole, but not olefin dissociation from 2-ole, and olefin association to 2, but not olefin association to 1. Calculated transition states for olefin dissociation from (HO)3M(C2H4) (M = Nb, 1'-C2H4; Ta, 2'-C2H4) are asymmetric and have orbitals consistent with either singlet or triplet states. The rearrangement of (silox)3Nb(trans-Vy,Ph-cPr) (1-VyPhcPr) to (silox)3Nb=CHCH=CHCH2CH2Ph (3) is consistent with a diradical intermediate akin to the transition state for substitution. The disparity between Nb and Ta in olefin substitution chemistry is rationalized on the basis of a greater density of states (DOS) for the products (i.e., (silox)3M + ole) where M = Nb, leading to intersystem crossing events that facilitate dissociation. At the crux of the DOS difference is the greater 5dz2/6s mixing for Ta vs the 4dz2/5s mixing of Nb. This rationalization is generalized to explain the nominally swifter reactivities of 4d vs 5d elements.