Capturing and analyzing the excited-state structure of a Cu(I) phenanthroline complex by time-resolved diffraction and theoretical calculations.

Time-resolved crystallography and density functional theory calculations are used to analyze the geometric and electronic changes that occur upon photoexcitation of [Cu(I)(dmp)(dppe)](+) in crystalline [Cu(I)(dmp)(dppe)][PF(6)] [dmp = 2,9-dimethyl-1,10-phenanthroline; dppe = 1,2-bis(diphenylphosphino)ethane]. In the pump-probe experiment, laser and X-ray pulses are synchronized to capture an image of the instantaneous molecular distortions in the transient triplet state. Parallel theoretical calculations, with the phenyl groups replaced by methyl groups, yield information on the distortion of the isolated cation and the change in electron density upon excitation. The experimental distortions are significantly less than the calculated values and are different for the two independent molecules in the asymmetric unit; these findings are attributed to the constraining influence of the crystal matrix. The calculations indicate that the electron transfer upon excitation is mostly from the dmpe ligand to the dmp ligand, while the Cu atomic charge changes by only approximately +0.1e, although the charge distribution on Cu is significantly affected. As found for homoleptic [Cu(I)(dmp)(2)](+), the change in the population of the Cu atom is close to the calculated difference between the corresponding Cu(II) and Cu(I) complexes. Charge density difference maps confirm these conclusions and show a large rearrangement of the electron density on the Cu atom upon excitation.

Flexible cyclic ethers/polyethers as novel P2-ligands for HIV-1 protease inhibitors: design, synthesis, biological evaluation, and protein-ligand X-ray studies.

We report the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors. The inhibitors incorporate stereochemically defined flexible cyclic ethers/polyethers as high affinity P2-ligands. Inhibitors containing small ring 1,3-dioxacycloalkanes have shown potent enzyme inhibitory and antiviral activity. Inhibitors 3d and 3h are the most active inhibitors. Inhibitor 3d maintains excellent potency against a variety of multi-PI-resistant clinical strains. Our structure-activity studies indicate that the ring size, stereochemistry, and position of oxygens are important for the observed activity. Optically active synthesis of 1,3-dioxepan-5-ol along with the syntheses of various cyclic ether and polyether ligands have been described. A protein-ligand X-ray crystal structure of 3d-bound HIV-1 protease was determined. The structure revealed that the P2-ligand makes extensive interactions including hydrogen bonding with the protease backbone in the S2-site. In addition, the P2-ligand in 3d forms a unique water-mediated interaction with the NH of Gly-48.

Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance.

Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.

Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M.

The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V, and L90M, which provide resistance to the major clinical inhibitors. The inhibition constants (K(i)) of TMC-114 for mutants PR(D30N), PR(I50V), and PR(L90M) were 30-, 9-, and 0.14-fold, respectively, relative to wild-type PR. The molecular basis for the inhibition was analyzed using high-resolution (1.22-1.45 A) crystal structures of PR mutant complexes with TMC-114. In PR(D30N), the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PR(I50V) the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PR(L90M) structure compared to the PR structure, leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.

Neutral and ionic complexes of C60 with metal dibenzyldithiocarbamates. Reversible dimerization of C60*- in ionic multicomponent complex [Cr(I)(C6H6)2*+].(C60*-).0.5[Pd(dbdtc)2].

New molecular complexes of C60 with metal(II) dibenzyldithiocarbamates, M(dbdtc)2.C60.0.5(C6H5Cl), where M=Cu(II), Ni(II), Pd(II), and Pt(II) and an ionic multicomponent complex [Cr(I)(C6H6)2*+].(C60*-).0.5[Pd(dbdtc)2] (Cr(C6H6)2: bis(benzene)chromium) were obtained. According to IR, UV-visible-NIR, and EPR spectra, involve neutral components, whereas 5 comprises neutral Pd(dbdtc)2 and C60*- and Cr(I)(C6H6)2*+ radical ions. The crystal structure of at 90 K reveals strongly puckered fullerene layers alternating with those composed of Pd(dbdtc)2. The Cr(I)(C6H6)2*+ radical cations are arranged between the layers. Fullerene radical anions form pairs within the layer with an interfullerene C...C contact of 3.092(2) A, indicating their monomeric state at 90 K. This contact is essentially shorter than the sum of van der Waals radii of two carbon atoms, and consequently, C60*- can dimerize. According to SQUID and EPR, single-bonded diamagnetic (C60-)2 dimers form in below 150-130 K on slow cooling and dissociate above 150-170 K on heating. The hysteresis was estimated to be 20 K. For the (C60-)2 dimers in, the dissociation temperature is the lowest among those for ionic complexes of C60 (160-250 K). Fast cooling of the crystals within 10 min from room temperature down to 100 K shifts dimerization temperatures to lower than 60 K. This shift is responsible for the retention of a monomeric phase of at 90 K in the X-ray diffraction experiment.

Photoinduced oxygen transfer and double-linkage isomerism in a cis-(NO)(NO2) transition-metal complex by photocrystallography, FT-IR spectroscopy and DFT calculations.

Photocrystallographic experiments show that laser exposure of crystals of [Ru(bpy)2(NO)(NO2)](PF6)2 at 90 K produces a double isonitrosyl-nitrito linkage isomer and provide the detailed geometry of the metastable species generated. The analysis indicates that the isomerization is accomplished through an intramolecular redox reaction involving oxygen transfer from the nitro to the nitrosyl group. At 200 K only a single (nitrito) linkage isomer is formed with a U-shaped conformation of the nitrito group rather than the Z conformation observed at 90 K. A mechanism for the isomerization is proposed based on the crystallographic results and FTIR data collected at low temperatures during the isomerization process. The study presents the first structural evidence for double linkage isomerization in transition-metal complexes.

Shedding light on the structure of a photoinduced transient excimer by time-resolved diffraction.

Time-resolved single-crystal diffraction performed with synchrotron radiation shows that the 53(1) micros phosphorescent state, generated in the crystalline phase of trimeric {[3,5-(CF3)(2)Pyrazolate]Cu}(3) molecules by exposure to 355 nm of light at 17 K, is due to the formation of an excimer rather than the shortening of the intramolecular Cu...Cu distances within the trimeric units, or the formation of a continuous chain of interacting molecules. One of the intermolecular Cu...Cu distances contracts by 0.56 Angstroms from 4.018(1) to 3.46(1) Angstroms;, whereas the interplanar spacing of the trimers is reduced by 0.65 Angstroms; from 3.952(1) to 3.33(1) Angstroms. Density-functional theory calculations support the formation of a Cu...Cu bond through the intermetallic transfer of a Cu 3d electron to a molecular orbital with a large 4p contribution on the reacting Cu atoms.

The structure of short-lived excited states of molecular complexes by time-resolved X-ray diffraction.

Experimental and computational methods for time-resolved (TR) diffraction now allow the determination of geometry changes on molecular excitation. The first results indicate significant changes in the interatomic distances and molecular shape on photo-excitation, but also a dependence of the induced changes on the molecular environment. Though the use of high-brightness synchrotron sources is essential, it limits the time resolution to the width of the synchrotron pulse which is currently 70-100 ps. The experiments discussed fall into two categories: (i) picosecond powder diffraction experiments on the molecular excitation to a singlet state, and (ii) microsecond experiments on the excited states of inorganic complexes. Both involve reversible processes for which a stroboscopic technique can be applied.

Cu(I)(2,9-bis(trifluoromethyl)-1,10-phenanthroline)2+ complexes: correlation between solid-state structure and photoluminescent properties.

The 90K solid-state structures, room temperature absorption, and room temperature and 17 K emission spectra of seven different salts of [Cu(I)(bfp)(2)](+) (bfp = 2,9-bis(trifluoromethyl)-1,10-phenanthroline) have been determined. To quantify the distortion of the Cu coordination environment, a distortion parameter zeta is defined that is a combined measure of the flattening, rocking, and wagging distortions of the complex cations. In general, the distortion in the (bfp) cations is less than found previously for Cu(I)(dmp)(2) (dmp = 2,9-dimethyl-1,10-phenanthroline) salts, in particular the flattening is reduced because of the bulkier 2,9-substituents. The 17 K lifetimes range up to 1.8 mus in the series of solids examined and, with the marked exception of the BF(4)(-) salt, correlate linearly with the distortion parameter zeta. The emission wavelength red-shifts with decreasing lifetime, which implies that an increased ground-state distortion is associated with a smaller energy gap.

Solid-state spectroscopic properties and the geometry of binuclear rhodium(I) diisocyanoalkane complexes.

A series of crystalline dinuclear rhodium complexes with different bridging diisocyano ligands and different counter ions have been studied by low-temperature crystallographic and solid-state spectroscopic techniques. The Rh-Rh distances vary from 4.5153(3) to 3.0988(7) angstroms, and the twist angles around the Rh-Rh line from 58.3(1) to 0 degree, both depending on the size and conformational rigidity of the bridging ligand. For very long distances as occur in the [Rh(2)(dimen)(4)](2+) salts the absorption is significantly blue-shifted compared to other complexes. For a given cation a shorter Rh-Rh bond gives a red shift of the phosphorescence emission band, indicating a smaller energy gap between the ground and emitting excited states. An exception occurs for the [Rh(2)(1,6-diisocyanohexane)(4)](2+) ion, in which dimer formation in the calixarate salt lengthens the Rh-Rh intramolecular bond length without affecting the emission spectrum.

A very large Rh-Rh bond shortening on excitation of the [Rh2(1,8-diisocyano-p-menthane)4]2+ ion by time-resolved synchrotron X-ray diffraction.

A very large Rh-Rh contraction of approximately 0.85 A occurs on excitation of the [Rh(2)(1,8-diisocyano-p-menthane)(4)](2+) ion to its triplet state.

Single- and double-linkage isomerism in a six-coordinate iron porphyrin containing nitrosyl and nitro ligands.

Density Functional theoretical calculations confirm the experimental observation that the low-temperature photolysis of (TPP)Fe(NO)(NO2) (as a KBr pellet) results in the generation of linkage isomers involving the axial NO and NO2 groups and suggest the possible formation of the double linkage isomer (TPP)Fe(ON)(ONO). The energy difference between the ground state (porphine)Fe(NO)(NO2) and the double-linkage isomer (porphine)Fe(ON)(ONO) is 1.57 eV, which is comparable to the 1.59 eV calculated previously for the nitrosyl-to-isonitrosyl linkage isomerism in the five-coordinate (porphine)Fe(NO) analogue.

Geometry changes of a Cu(I) phenanthroline complex on photoexcitation in a confining medium by time-resolved X-ray diffraction.

Using a stroboscopic technique, in which the molecule is repeatedly excited and the structural change is probed more than 5000 times per second immediately after excitation, we performed a 16 K time-resolved single-crystal study of the microsecond lifetime triplet state of the Cu(I)phenanthroline derivative[Cu(I)(dmp)(dppe)][PF6] (dppe = 1,2-bis(diphenylphosphino)ethane). The geometry changes on excitation differ for the two symmetry-independent molecules, but are in the same direction as calculated for an isolated reference molecule, although the flattening distortion in the crystal is significantly smaller, implying that the reorganization energy is greatly affected by the confining medium.

Solid-state structure dependence of the molecular distortion and spectroscopic properties of the Cu(I) bis(2,9-dimethyl-1,10-phenanthroline) ion.

The relation between the geometry and spectroscopic properties of a series of salts of the Cu(I) bis(2,9-dimethyl-1,10-phenanthroline) ion, (Cu((I))(dmp)(2))(+), is explored. The distortions from the idealized D(2)(d)() geometry, which include flattening, rocking of the dmp ligands, and displacement of the Cu atoms out of the dmp planes, show considerable variation, indicating the importance of packing forces in the crystalline environment. The change in the absorption spectra upon flattening of the complex, expressed as the variation of the angle between the dmp planes, which varies from 88 degrees in the BF(4) and tosylate salts to 73 degrees in the picrate, agrees qualitatively with parallel DFT calculations. No correlation is found between ground state geometry and luminescence lifetimes, recorded both at room temperature and at 16 K. The low temperature lifetimes vary by a factor of 8 among the (Cu((I))(dmp)(2))(+) salts examined, the longest lifetime (2.4 micros at 16 K) being observed for the tosylate salt.

Light-induced metastable linkage isomers of ruthenium sulfur dioxide complexes.

The irradiation of ruthenium-sulfur dioxide complexes of general formula trans-[Ru(II)(NH(3))(4)(SO(2))X]Y with laser light at low temperature results in linkage isomerization of SO(2), starting with eta(1)-planar S-bound to eta(2)-side S,O-bound SO(2). The solid-state photoreaction proceeds with retention of sample crystallinity. Following work on trans-[Ru(NH(3))(4)Cl(eta(1)-SO(2))]Cl and trans-[Ru(NH(3))(4)(H(2)O)(eta(1)-SO2)](C(6)H(5)SO(3))(2) (Kovalevsky, A. Y.; Bagley, K. A.; Coppens, P. J. Am. Chem. Soc. 2002, 124, 9241-9248), we describe photocrystallographic, IR, DSC, and theoretical studies of trans-[Ru(II)(NH(3))(4)(SO(2))X]Y complexes with (X = Cl(-), H(2)O, or CF(3)COO(-) (TFA(-))) and a number of different counterions (Y = Cl(-), C(6)H(5)SO(3)(-), Tos(-), or TFA(-)). Low temperature IR experiments indicate the frequency of the asymmetric and symmetric stretching vibrations of the Ru-coordinated SO(2) to be downshifted by about 100 and 165 cm(-1), respectively. Variation of the trans-to-SO(2) ligand and the counterion increases the MS2 decay temperature from 230 K (trans-[Ru(II)(NH(3))(4)(SO(2))Cl]Cl) to 276 K (trans-[Ru(II)(NH(3))(4)(SO(2))(H(2)O)](Tos)(2)). The stability of the MS2 state correlates with increasing sigma-donating ability of the trans ligand and the size of the counterion. Quantum chemical DFT calculations indicate the existence of a third eta(1)-O-bound (MS1) isomer, the two metastable states being 0.1-0.6 eV above the energy of the ground-state complex.

The first photocrystallographic evidence for light-induced metastable linkage isomers of ruthenium sulfur dioxide complexes.

Light-induced metastable linkage isomers of trans-[Ru(NH(3))(4)Cl(SO(2))]Cl and trans-[Ru(NH(3))(4)(H(2)O)(SO(2))](C(6)H(5)SO(3))(2) have been identified for the first time using photocrystallographic methods. In both linkage isomers the SO(2) ligand is side bound, but the Ru-O and Ru-S distances are considerably longer and almost equal in the trans-H(2)O isomer. DFT calculations confirm that both isomers correspond to minima on the ground-state potential energy surface and also predict the existence of a second oxygen-bound isomer for both compounds. The decay of the light-induced species has been studied by both DSC and IR. Activation energies for the thermal back-reaction, as derived from the temperature-dependent disappearance of light-induced IR bands, are 50.0 and 58.4 kJ/mol for the two isomers, which is larger than the corresponding numbers for photoinduced side-bound nitrosyl linkage isomers.

Synthesis and structure of multicomponent crystals of fullerenes and metal tetraarylporphyrins.

The preparation of fullerene complexes with metal tetraarylporphyrins in the presence of excess ferrocene (Cp(2)Fe) results in the formation of new solvent-free and multicomponent molecular crystals. New isomorphous complexes of C(60) with PyZnTPP (ZnTPP identical with zinc 5,10,15,20-tetraphenyl-21H,23H-porphyrinate) and PyCoTPP (CoTPP identical with cobalt(II) 5,10,15,20-tetraphenyl-21H,23H-porphyrinate) containing Cp(2)Fe and the isostructural C(70) complex with PyZnTPP have been prepared. The crystal structures of the new layered C(60) complexes CoTMPP x C(60) (obtained in the presence of Cp(2)Fe) and CoTMPP x 2C(60) x 3C(7)H(8) (obtained in the absence of Cp(2)Fe) have been described (CoTMPP identical with cobalt(II) 5,10,15,20-tetrakis(p-methoxyphenyl)-21H,23H-porphyrinate). Cobalt atoms of the PyCoTPP and CoTMPP molecules are weakly coordinated to C(60) with Co...C(C(60)) distances in the 2.64-2.82 A range, whereas zinc atoms of PyZnTPP, as well as cobalt atoms of the CoTMPP molecules in the solvent-free phase, form only van der Waals contacts with fullerenes. Different packing arrangements in the crystals of fullerene-porphyrin complexes have been discussed.

Catalytic asymmetric benzylic C-H activation by means of carbenoid-induced C-H insertions.

Tetrakis[N-[4-dodecylphenyl)sulfonyl]-(S)-prolinate]dirhodium [Rh(2)(S-DOSP)(4)]-catalyzed decomposition of methyl aryldiazoacetates in the presence of substituted ethylbenzenes results in benzylic C-H activation by means of a rhodium-carbenoid-induced C-H insertion. A Hammet study showed that positive charge buildup occurred on the benzylic carbon in the transition state of the C-H activation step. C-H activation of toluene and isopropylbenzene is possible, but a competing double cyclopropanation occurs with these substrates. The C-H activation is highly regioselective and enantioselective, and in certain cases, moderate diastereoselectivity is also possible.