Paul Seiler

A New Interpretation of the Disordered Crystal Structure of Ferrocene

X-ray analyses of ferrocene [Fe(CsHs) 2, CmH~0Fe] at room temperature and at 173 K yield vibrationalellipsoid patterns that are incompatible with pure rotational disorder of the cyclopentadienyl rings. Below 164 K ferrocene becomes triclinic. Relationships between the diffraction patterns of the monoclinic hightemperature (HT) and triclinic low-temperature (LT) structures suggest that the formally centrosymmetric molecule of the disordered HT phase can be described in good approximation as an averaged superposition of the four molecules present in the primitive LT cell. The molecular centre of symmetry required by the HT space group is thus only statistical in nature, and the crystallographic evidence for the staggered arrangement of the cyclopentadienyl rings in ferrocene and other isomorphous metallocenes has to be revised.

A new class of organic donor-acceptor molecules with large third-order optical nonlinearities

Donor-acceptor molecules with 4-(dimethylamino)phenyl donor and 1,1,4,4-tetracyanobuta-1,3-diene acceptor moieties are readily prepared by short, high-yielding routes. The quite small chromophores are characterised by X-ray crystallography and feature intense intramolecular charge-transfer bands, substantial quinoid character in the donor rings, reversible electrochemical reductions and oxidations and powerful third-order optical nonlinearities.

Fluorine Interactions at the Thrombin Active Site: Protein Backbone Fragments HCαCO Comprise a Favorable CF Environment and Interactions of CF with Electrophiles

In a systematic fluorine scan of a rigid inhibitor to map the fluorophilicity/fluorophobicity of the active site in thrombin, one or more F substituents were introduced into the benzyl ring reaching into the D pocket. The 4‐fluorobenzyl inhibitor showed a five to tenfold higher affinity than ligands with other fluorination patterns. X‐ray crystal‐structure analysis of the protein–ligand complex revealed favorable CF⋅⋅⋅HCαCO and CF⋅⋅⋅CO interactions of the 4‐F substituent of the inhibitor with the backbone HCαCO unit of Asn98. The importance of these interactions was further corroborated by the analysis of small‐molecule X‐ray crystal‐structure searches in the Protein Data Base (PDB) and the Cambridge Structural Database (CSD). In the CF⋅⋅⋅CO interactions that are observed for both aromatic and aliphatic CF units and a variety of carbonyl and carboxyl derivatives, the F atom approaches the CO C atom preferentially along the pseudotrigonal axis of the carbonyl system. Similar orientational preferences are also seen in the dipolar interactions CF⋅⋅⋅CN, CF⋅⋅⋅CF, and CF⋅⋅⋅NO2, in which the F atoms interact at sub‐van der Waals distances with the electrophilic centers.

Crystal structure analyses of 1,4,7,10,13,16-hexaoxacyclooctadecane and its complexes with alkali thiocyanates

The results of crystal structure analyses of 1,4,7,10,13,16-hexaoxacyclooctadecane (CH2CH20)6 and its complexes with NaNCS, KNCS, RbNCS, CsNCS [and Ca(NCS)2] are discussed. In the K*, Rb*, Cs* and Ca 2+ complexes the unsubstituted hexaether adopts a conformation with virtual Ds~ symmetry although the larger Rb + and Cs + ions are displaced by more than 1 ,~, from the mean plane of the ligand. In the Na* complex, the ring is strongly distorted from its symmetrical conformation to accommodate the smaller cation. The uncomplexed hexaether has a centrosymmetric conformation containing three different types of monomeric subunit. The shortening of the C-C bonds found in these and related complexes is discussed and judged to be mainly an artificial effect arising from inadequate treatment of curvilinear vibrations.

Organic super-acceptors with efficient intramolecular charge-transfer interactions by [2+2] cycloadditions of TCNE, TCNQ, and F4-TCNQ to donor-substituted cyanoalkynes.

Rivaling the best one: Thermal [2+2] cycloadditions of TCNE, TCNQ, and F(4)-TCNQ to N,N-dimethylanilino-substituted cyanoalkynes afforded a new class of organic super-acceptors featuring efficient intramolecular charge-transfer interactions. These acceptors rival the acceptor F(4)-TCNQ in the propensity for reversible electron uptake as well as in electron affinity (see figure), which makes them interesting as p-type dopants for potential application in optoelectronic devices.Thermal [2+2] cycloadditions of tetracyanoethene (TCNE), 7,7,8,8-tetracyanoquinodimethane (TCNQ), and 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F(4)-TCNQ) to N,N-dimethylanilino-substituted (DMA-substituted) alkynes bearing either nitrile, dicyanovinyl (DCV; -CH==C(CN)(2)), or tricyanovinyl (TCV; -C(CN)==C(CN)(2)) functionalities, followed by retro-electrocyclization, afforded a new class of stable organic super-acceptors. Despite the nonplanarity of these acceptors, as revealed by X-ray crystallographic analysis and theoretical calculations, efficient intramolecular charge-transfer (CT) interactions between the DMA donors and the CN-containing acceptor moieties are established. The corresponding CT bands appear strongly bathochromically shifted with maxima up to 1120 nm (1.11 eV) accompanied by an end-absorption in the near infrared around 1600 nm (0.78 eV) for F(4)-TCNQ adducts. Electronic absorption spectra of selected acceptors were nicely reproduced by applying the spectroscopy oriented configuration interaction (SORCI) procedure. The electrochemical investigations of these acceptors by cyclic voltammetry (CV) and rotating disc voltammetry (RDV) in CH(2)Cl(2) identified their remarkable propensity for reversible electron uptake rivaling the benchmark compounds TCNQ (E(red,1)=-0.25 V in CH(2)Cl(2) vs. Fc(+)/Fc) and F(4)-TCNQ (E(red,1)=+0.16 V in CH(2)Cl(2) vs. Fc(+)/Fc). Furthermore, the electron-accepting power of these new compounds expressed as adiabatic electron affinity (EA) has been estimated by theoretical calculations and compared to the reference acceptor F(4)-TCNQ, which is used as a p-type dopant in the fabrication of organic light-emitting diodes (OLEDs) and solar cells. A good linear correlation exists between the calculated EAs and the first reduction potentials E(red,1). Despite the substitution with strong DMA donors, the predicted EAs reach the value calculated for F(4)-TCNQ (4.96 eV) in many cases, which makes the new acceptors interesting for potential applications as dopants in organic optoelectronic devices. The first example of a charge-transfer salt between the DMA-substituted TCNQ adduct (E(red,1)=-0.27 V vs. Fc(+)/Fc) and the strong electron donor decamethylferrocene ([FeCp*(2)]; Cp*=pentamethylcyclopentadienide; E(ox,1)=-0.59 V vs. Fc(+)/Fc) is described. Interestingly, the X-ray crystal structure showed that in the solid state the TCNQ moiety in the acceptor underwent reductive sigma-dimerization upon reaction with the donor.

Preparation and Structure ofβ-Peptides Consisting of Geminally Disubstitutedβ2,2- andβ3,3-Amino Acids: A Turn Motif forβ-Peptides

We report on the synthesis of new and previously described β-peptides (1 – 6), consisting of up to twelve β2,2- or β3,3-geminally disubstituted β-amino acids which do not fit into any of the secondary structural patterns of β-peptides, hitherto disclosed. The required 2,2- and 3,3-dimethyl derivatives of 3-aminopropanoic acid are readily obtained from 3-methylbut-2-enoic acid and ammonia (Scheme 1) and from Boc-protected methyl 3-aminopropanoate by enolate methylation (Scheme 2). Protected (Boc for solution-, Fmoc for solid-phase syntheses) 1-(aminomethyl)cycloalkanecarboxylic-acid derivatives (with cyclopropane, cyclobutane, cyclopentane, and cyclohexane rings) are obtained from 1-cyanocycloalkanecarboxylates and the corresponding dihaloalkanes (Scheme 3). Fully 13C- and 15N-labeled 3-amino-2,2-dimethylpropanoic-acid derivatives were prepared from the corresponding labeled precursors (see asterixed formula numbers and Scheme 4). Coupling of these amino acids was achieved by methods which we had previously employed for other β-peptide syntheses (intermediates 18 – 23). Crystal structures of Boc-protected geminally disubstituted amino acids (16a – d) and of the corresponding tripeptide (23a), as well as NMR and IR spectra of an isotopically labeled β-hexapeptide (2a*) are presented (Figs. 1 – 4) and discussed. The tripeptide structure contains a ten-membered H-bonded ring which is proposed to be a turn-forming motif for β-peptides (Fig. 2).

A fluorine scan of the phenylamidinium needle of tricyclic thrombin inhibitors: effects of fluorine substitution on pKa and binding affinity and evidence for intermolecular C–F⋯CN interactions

The H-atoms of the phenylamidinium needle of tricyclic thrombin inhibitors, which interacts with Asp189 at the bottom of the selectivity pocket S1 of the enzyme, were systematically exchanged with F-atoms in an attempt to improve the pharmacokinetic properties by lowering the pK(a) value. Both the pK(a) values and the inhibitory constants K(i) against thrombin and trypsin were decreased upon F-substitution. Interestingly, linear free energy relationships (LFERs) revealed that binding affinity against thrombin is much more affected by a decrease in pK(a) than the affinity against trypsin. Surprising effects of F-substitutions in the phenylamidinium needle on the pK(a) value of the tertiary amine centre in the tricyclic scaffold of the inhibitors were observed and subsequently rationalised by X-ray crystallographic analysis and ab initio calculations. Evidence for highly directional intermolecular C-F...CN interactions was obtained by analysis of small-molecule X-ray crystal structures and investigations in the Cambridge Structural Database (CSD).

Optically Active Cyclophane Receptors for Mono- and Disaccharides: The Role of Bidentate Ionic Hydrogen Bonding in Carbohydrate Recognition

A new family of optically active cyclophane receptors for the complexation of mono- and disaccharides in competitive protic solvent mixtures is described. Macrocycles (−)-(R,R,R,R)-1 – 4 feature preorganized binding cavities formed by four 1,1′-binaphthalene-2,2′-diyl phosphate moieties bridged in the 3,3′-positions by acetylenic or phenylacetylenic spacers. The four phosphodiester groups converge towards the binding cavity and provide efficient bidentate ionic H-bond acceptor sites (Fig. 2). Benzyloxy groups in the 7,7′-positions of the 1,1′-binaphthalene moieties ensure solubility of the nanometer-sized receptors and prevent undesirable aggregation. The construction of the macrocyclic framework of the four cyclophanes takes advantage of Pd0-catalyzed aryl—acetylene cross-coupling by the Sonogashira protocol, and oxidative acetylenic homo-coupling methodology (Schemes 2 and 8 – 10). Several cleft-type receptors featuring one 1,1′-binaphthalene-2,2′-diyl phosphate moiety were also prepared (Schemes 1, 6, and 7). An undesired side reaction encountered during the synthesis of the target compounds was the formation of naptho[b]furan rings from 3-ethynylnaphthalene-2-ol derivatives, proceeding via 5-endo-dig cyclization (Schemes 3 – 5). Computer-assisted molecular modeling indicated that the macrocycles prefer nonplanar puckered, cyclobutane-type conformations (Figs. 7 and 8). According to these calculations, receptor (−)-(R,R,R,R)-1 has, on average, a square binding site, which is complementary in size to one monosaccharide. The three other cyclophanes (−)-(R,R,R,R)-2 – 4 feature, on average, wider rectangular cavities, providing a good fit to one disaccharide, while being too large for the complexation of one monosaccharide. This substrate selectivity was fully confirmed in 1H-NMR binding titrations. The chiroptical properties of the cyclophanes and their nonmacrocyclic precursors were investigated by circular dichroism (CD) spectroscopy. The CD spectra of the acyclic precursors showed a large dependence from the number of 1,1′-binaphthalene moieties (Fig. 9), and those of the cyclophanes were remarkably influenced by the nature of the functional groups lining the macrocyclic cavity (Fig. 11). Profound differences were also observed between the CD spectra of linear and macrocyclic tetrakis(1,1′-binaphthalene) scaffolds, which feature very different molecular shapes (Fig. 10). In 1H-NMR binding titrations with mono- and disaccharides (Fig. 13), concentration ranges were chosen to favor 1 : 1 host−guest binding. This stoichiometry was experimentally established by the curve-fitting analysis of the titration data and by Job plots. The titration data demonstrate conclusively that the strength of carbohydrate recognition is enhanced with an increasing number of bidentate ionic host−guest H-bonds (Table 1) in the complex formed. As a result of the formation of these highly stable H-bonds, carbohydrate complexation in competitive protic solvent mixtures becomes more favorable. Thus, cleft-type receptors (−)-(R)-7 and (−)-(R)-38 with one phosphodiester moiety form weak 1 : 1 complexes only in CD3CN. In contrast, macrocycle (−)-(R,R,R,R)-1 with four phosphodiester groups undergoes stable inclusion complexation with monosaccharides in CD3CN containing 2% CD3OD. With their larger number of H-bonding sites, disaccharide substrates bind even more strongly to the four phosphodiester groups lining the cavity of (−)-(R,R,R,R)-2 and complexation becomes efficient in CD3CN containing 12% CD3OD. Finally, the introduction of two additional methyl ester residues further enhances the receptor capacity of (−)-(R,R,R,R)-3, and efficient disaccharide complexation occurs already in CD3CN containing 20% CD3OD.

Fullerene-acetylene hybrids: Towards a novel class of molecular carbon allotropes

Abstract The synthesis and complete characterization of 17 new fullerene-acetylene covalent derivatives is described. Reaction of 3-bromo-1,5-bis(trimethylsilyl)penta-1,4-diyne (5) with C60 gave bis-protected diethynylmethanofullerene 4 in 56% yield. Unsymmetrically bis-protected diethynylmethanofullerene 6 was synthesized in 53% yield from tosylhydrazone 7 and C60. Proto-desilylation of 4 and 6 gave the corresponding free alkynes 3 and 8 in 83% and 69% yield, respectively. Partial deprotection of 4 afforded mono-protected fullerene 9 in 35% yield. Oxidative hetero-coupling reactions of 3 and 8 under Hay conditions with various monosubstituted acetylenes gave the butadiynylmethanofullerenes 10–13 in yields varying from 25–49%. Homo-coupling of 8 produced dumbbell-shaped fullerene 14, the first dimeric fullerene that could be fully characterized. The X-ray crystal structure analysis of 14 revealed little or no electronic interaction between the two fullerene spheres. Addition of lithium trimethylsilylacetylide to C60 gave access to 1-substituted-2-(trimethylsilylethynyl)fullerenes. The acidity of hydrofullerene 16, synthesized in 58% yield, was studied as a function of base and solvent. Reaction of lithiated fullerene 17 with various electrophiles is discussed. Alcohol 25 was prepared in 57%yield by reaction of 17 with formaldehyde. Under strongly basic conditions, 25 eliminates formaldehyde to give 16 in quantitative yield. Oxidation of 25 afforded aldehyde 27 in 53% yield, a rather unstable compound that is easily converted to hydrofullerene 16. Conversion of 25 to the corresponding tosylate could be performed in 40% yield.

On the steric course of addition of 1-lithio- and 1-magnesio-2-pivaloyl-1,2,3,4-tetrahydroisoquinoline to aldehydes and ketones. An x-ray crystal structure determination of the organomagnesium reagent

Abstract The steric course of the diastereoselective addition of the 1-bromomagnesium derivative 2 of N -pivaloyl-tetrahydroisoquinoline (THIQ) to acetophenone is proved by X-ray crystal structure analysis of the major product 1-(α-hydroxy-α-methylbenzyl)-2-pivaloyl-1,2,3,4-tetrahydroisoquinoline ( 4 ) to be the same as that for aldehydes (relative topicity ul , configuration of the adducts u ). The reaction is much less selective if the lithiated reagent is employed. The crystal structure of the magnesium reagent ( 2 ) was determined. As crystallized from THF, 2 is monomeric, with an octahedrally coordinated Mg with three THF oxygens, the THIQ carbon, the pivaloyl oxygen and a bromine as ligands. A mechanistic proposal derived from the crystal structure explains both the higher selectivity observed with the Mg derivative and the fact that the u -diastereomer is formed preferentially.