Louis J Farrugia

Publications of Louis J Farrugia

• Stereoselective synthesis of functionalised carbocyclic amides: construction of the syn-(4aS,10bS)-phenanthridone skeleton.

  Authors: Sajjad Ahmad, Michael D Swift, Louis J Farrugia, Hans Martin Senn, Andrew Sutherland

  Organic & biomolecular chemistry. 04/2012;

  A new synthetic approach has been developed for the preparation of 7-deoxypancratistatin analogues bearing a syn-(4aS,10bS)-phenanthridone ring junction. A one-pot tandem process involving aA new synthetic approach has been developed for the preparation of 7-deoxypancratistatin analogues bearing a syn-(4aS,10bS)-phenanthridone ring junction. A one-pot tandem process involving a substrate-directed Overman rearrangement and ring closing metathesis reaction was developed for the stereoselective synthesis of a carbocyclic allylic trichloroacetamide. Conversion to a 6-bromopiperonyl amide, followed by a Heck reaction generated a homoallylic alcohol and completed the syn-(4aS,10bS)-phenanthridone carbon skeleton. Stereoselective epoxidation and dihydroxylation of the syn-(4aS,10bS)-phenanthridone framework was then investigated leading to the preparation of new analogues of 7-deoxypancratistatin.

• Evidence for side-chain π-delocalization in a planar substituted benzene: an experimental and theoretical charge density study on 2,5-dimethoxybenzaldehyde thiosemicarbazone.

  Authors: Louis J Farrugia, Aliakbar Dehno Khalaji

  The journal of physical chemistry. A. 05/2011; 115(45):12512-22.

  The charge density in 2,5-dimethoxybenzaldehyde thiosemicarbazone (1) has been studied experimentally using Mo-K(α) X-ray diffraction at 100 K, and by theory using DFT calculations at theThe charge density in 2,5-dimethoxybenzaldehyde thiosemicarbazone (1) has been studied experimentally using Mo-K(α) X-ray diffraction at 100 K, and by theory using DFT calculations at the B3LYP/6-311++G(2d,2p) level. The quantum theory of atoms in molecules (QTAIM) was used to investigate the extent of π-delocalization in the thioamide side-chain, which is virtually coplanar with the benzene ring. The experimental and theoretical ellipticity profiles along the bond paths were in excellent agreement, and showed that some of the formal single bonds in the side-chain have significant π-bond character. This view was supported by the magnitudes of the topological bond orders and by the delocalization indices δ(Ω(A), Ω(B)). An orbital decomposition of δ(Ω(A), Ω(B)) demonstrated that there was significant π-character in all the interchain non-H chemical bonds. On the other hand, the source function referenced at the interchain bond critical points could not provide any evidence for π-delocalization, showing instead only limited σ-delocalization between nearest neighbors. Overall, the topological evidence and the atomic graphs of the oxygen atoms did not provide convincing evidence for π-delocalization involving the methoxy substituents.

• Metal-metal and metal-ligand bonding at a QTAIM catastrophe: a combined experimental and theoretical charge density study on the alkylidyne cluster Fe3(μ-H)(μ-COMe)(CO)10.

  Authors: Louis J Farrugia, Hans Martin Senn

  The journal of physical chemistry. A. 12/2010; 114(51):13418-33.

  The charge density in the tri-iron methoxymethylidyne cluster Fe(3)(μ-H)(μ-COMe)(CO)(10) (1) has been studied experimentally at 100 K and by DFT calculations on the isolated molecule using theThe charge density in the tri-iron methoxymethylidyne cluster Fe(3)(μ-H)(μ-COMe)(CO)(10) (1) has been studied experimentally at 100 K and by DFT calculations on the isolated molecule using the Quantum Theory of Atoms in Molecules (QTAIM). The COMe ligand acts as a nearly symmetric bridge toward two of the Fe atoms (Fe-C = 1.8554(4), 1.8608(4) Å) but with a much longer interaction to the third Fe atom, Fe-C = 2.6762(4) Å. Complex 1 provides a classic example where topological QTAIM catastrophes render an exact structure description ambiguous. While all experimental and theoretical studies agree in finding no direct metal-metal interaction for the doubly bridged Fe-Fe vector, the chemical bonding between the Fe(CO)(4) unit and the Fe(2)(μ-H)(μ-COMe)(CO)(6) moiety in terms of conventional QTAIM descriptors is much less clear. Bond paths implying direct Fe-Fe interactions and a weak interaction between the COMe ligand and the Fe(CO)(4) center are observed, depending on the experimental or theoretical density model examined. Theoretical studies using the Electron Localizability Indicator (ELI-D) suggest the metal-metal bonding is more significant, while the delocalization indices imply that both Fe-Fe bonding and Fe···C(alkylidyne) bonding are equally important. The source functions at various interfragment reference points are similar and highly delocalized. The potential-energy surface (PES) for the migration of the alkylidyne group from a μ(2) to a semi-μ(3) coordination mode has been explored by DFT calculations on 1 and the model complexes M(3)(μ-H)(μ-CH)(CO)(10) (M = Fe, 2; Ru, 3; and Os, 4). These calculations confirm a semi-μ(3) bridging mode for the alkylidyne ligand as the minimum-energy geometry for compounds 2-4 and demonstrate that, for 1, both Fe-Fe and Fe···C(alkylidyne) interactions are important in the cluster bonding. The PES between μ(2) and semi-μ(3) alkylidyne coordination for 1 is extremely soft, and the interconversion between several topological isomers is predicted to occur with almost no energy cost. Analysis of the density ρ(r) and the Laplacian of the density ▽(2)ρ(r(b)) in the methoxymethylidyne ligand is consistent with a partial π-bond character of the C-O bond, associated with an sp(2) hybridization for these atoms.

• The first members of the octasubstituted naphthalene spider-host series with type I (abababab) conformation: gateway to new nano-host gas storage materials.

  Authors: Louis J Farrugia, James H Gall, David D MacNicol, Ross MacSween

  Chemical communications (Cambridge, England). 08/2010; 46(29):5241-3.

  Octakis(m-tolyloxymethyl)naphthalene, the first Type I spider host produced, crystallises from tetraglyme forming a novel channel structure with the host molecule attaining exact D(2) symmetry. TheOctakis(m-tolyloxymethyl)naphthalene, the first Type I spider host produced, crystallises from tetraglyme forming a novel channel structure with the host molecule attaining exact D(2) symmetry. The (flexible) channel structure is retained for guest CS(2), the host now only having exact C(2) symmetry. The octa-sulfone octakis(m-tolylsulfonylmethyl)naphthalene is also of Type I in its triclinic DMSO clathrate. DNMR establishes a substantial difference in molecular flexibilities in solution.

• Experimental and Theoretical Charge Density Study of Polymorphic Isonicotinamide-Oxalic Acid Molecular Complexes with Strong O...H...N Hydrogen Bonds.

  Authors: Marc Schmidtmann, Louis J Farrugia, Derek S Middlemiss, Matthias J Gutmann, Garry J McIntyre, Chick C Wilson

  The journal of physical chemistry. A. 11/2009;

  Two polymorphs of the 2:1 molecular complex of isonicotinamide and oxalic acid have been characterized by combined X-ray charge density and single-crystal neutron diffraction studies at 100 K. BothTwo polymorphs of the 2:1 molecular complex of isonicotinamide and oxalic acid have been characterized by combined X-ray charge density and single-crystal neutron diffraction studies at 100 K. Both polymorphs show strong O-H...N intermolecular hydrogen bonding between the acid and the pyridine base. As is typical of short, strong hydrogen bonds (SSHBs), the covalent O-H bonds are considerably elongated to 1.161(3) and 1.235(5) A, and the H...N interactions are correspondingly short at 1.398(3) and 1.313(6) A in Forms I and II, respectively. The neutron diffraction data indicate no pronounced H dynamics in the SSHBs, and in the case of Form II the SSHB can be described as quasicentered. In addition to the experimental charge densities, theoretical charge densities have been determined from ab initio calculations within the full periodic environment of the crystalline state. The SSHBs are found to be covalent in nature according to the topological analysis of the experimental and theoretical charge densities and application of the source function. Aside from the SSHBs, moderate N-H...O and weak C-H...O interactions are also present in the molecular complexes, for which hydrogen bond energies are estimated from energy densities and independent ab initio calculations. Finally, an attempt is made to evaluate the intermolecular interactions governing the manifestation of polymorphism in this compound.

• On the Interpretation of the Source Function.

  Authors: Louis J Farrugia, Piero Macchi

  The journal of physical chemistry. A. 09/2009;

  The chemical information present in the source function (SF) is analyzed in several case studies by decomposition into the relative contributions from the core and valence densities. BothThe chemical information present in the source function (SF) is analyzed in several case studies by decomposition into the relative contributions from the core and valence densities. Both experimental and quantum derived densities are examined, and for the latter case, the decomposition of the SF into contributions from the individual Kohn-Sham molecular orbitals is also investigated. For pairs of atoms A and B, the orbital decomposition of the SF at the A-B bond critical point SF(A-B)(bcp) is compared with that for the delocalization index delta(Omega(A),Omega(B)). For second and third period atoms, the valence density generally provides the determining contribution to the total SF, but for heavier elements such as transition metals, the core density plays an increasingly important role. Moreover, when the reference point is close to the nodal plane of an orbital, this orbital makes a low to negligible contribution to the SF, which has clear implications for the interpretation of pi-interactions. This leads us to recommend caution in associating some chemical concepts with features of the SF, especially for heavier elements.

• Model systems for flavoenzyme activity: an investigation of the role functionality attached to the C(7) position of the flavin unit has on redox and molecular recognition properties.

  Authors: Stuart T Caldwell, Louis J Farrugia, Shanika Gunatilaka Hewage, Nadiya Kryvokhyzha, Vincent M Rotello, Graeme Cooke

  Chemical communications (Cambridge, England). 04/2009;

  We describe the role functionality attached to the C(7) position of a family of flavin derivatives has in tuning their redox and recognition properties and the subsequent exploitation of two of theseWe describe the role functionality attached to the C(7) position of a family of flavin derivatives has in tuning their redox and recognition properties and the subsequent exploitation of two of these derivatives as a three-component electrochemically controllable molecular switch.

• The QTAIM Approach to Chemical Bonding Between Transition Metals and Carbocyclic Rings: A Combined Experimental and Theoretical Study of (eta(5)-C(5)H(5))Mn(CO)(3), (eta(6)-C(6)H(6))Cr(CO)(3), and (E)-{(eta(5)-C(5)H(4))CFCF(eta(5)-C(5)H(4))}(eta(5)-C(5)H(5))(2)Fe(2).

  Authors: Louis J Farrugia, Cameron Evans, Dieter Lentz, Max Roemer

  Journal of the American Chemical Society. 01/2009;

  Experimental charge densities for (C(5)H(5))Mn(CO)(3) (2), (eta(6)-C(6)H(6))Cr(CO)(3) (3), and (E)-{(eta(5)-C(5)H(4))CFCF(eta(5)-C(5)H(4))}(eta(5)-C(5)H(5))(2)Fe(2) (4) have been obtained byExperimental charge densities for (C(5)H(5))Mn(CO)(3) (2), (eta(6)-C(6)H(6))Cr(CO)(3) (3), and (E)-{(eta(5)-C(5)H(4))CFCF(eta(5)-C(5)H(4))}(eta(5)-C(5)H(5))(2)Fe(2) (4) have been obtained by multipole refinement of high-resolution X-ray diffraction data at 100 K. The resultant densities were analyzed using the quantum theory of atoms in molecules (QTAIM). The electronic structures of these and related pi-hydrocarbyl complexes have also been studied by ab initio density functional theory calculations, and a generally good agreement between theory and experiment with respect to the topological parameters was observed. The topological parameters indicate significant metal-ring covalency. A consistent area of disagreement concerns the topology of the metal-ring interactions. It is shown that because of the shared-shell bonding between the metal and the ring carbons, an annulus of very flat density rho and very small big dn tri, openrho is formed, which leads to topologically unstable structures close to catastrophe points. This in turn leads to unpredictable numbers of metal-C bond paths for ring sizes greater than four and fewer M-C bond paths than expected on the basis of the formal hapticity. This topological instability is a general feature of metal-pi-hydrocarbyl interactions and means that a localized approach based on individual M-C(ring) bond paths does not provide a definitive picture of the chemical bonding in these systems. However, other QTAIM indicators, such as the virial paths, the delocalization indices, and the source function, clearly demonstrate that for the n-hapto (eta(n)-C(n)H(n))M unit, there is generally a very similar level of chemical bonding for all M-C(ring) interactions, as expected on the basis of chemical experience.

• Synthesis, characterisation and anti-protozoal activity of carbamate-derived polyazamacrocycles.

  Authors: Jennifer M Wilson, Federica Giordani, Louis J Farrugia, Michael P Barrett, David J Robins, Andrew Sutherland

  Organic & biomolecular chemistry. 12/2007; 5(22):3651-6.

  A short, highly efficient approach for the synthesis of a novel class of polyazamacrocycles containing N-functionalised carbamate side-chains has been developed. The key steps involved aA short, highly efficient approach for the synthesis of a novel class of polyazamacrocycles containing N-functionalised carbamate side-chains has been developed. The key steps involved a phase-transfer mediated macrocyclisation to form the ring system as well as a tin-catalysed reaction with isocyanates to introduce the carbamate side-chains. X-Ray crystallography confirmed successful formation of the 1,4,7,10-tetraazacyclododecane ring and N-functionalisation of all the amine centres. Preliminary testing of the biological activity of the compounds revealed significant anti-parasitic activity against bloodstream form African trypanosomes.

• Linking chiral clusters with molybdate building blocks: from homochiral helical supramolecular arrays to coordination helices.

  Authors: De-Liang Long, Paul Kögerler, Louis J Farrugia, Leroy Cronin

  Chemistry, an Asian journal. 10/2006; 1(3):352-7.

  The synthesis of four new oxo-centered Fe clusters (1 a-c, 2) of the form [Fe(III)3(mu3-O)(CH2=CHCOO)6] with acrylate as the bridging ligand gives rise to potentially intrinsically chiralThe synthesis of four new oxo-centered Fe clusters (1 a-c, 2) of the form [Fe(III)3(mu3-O)(CH2=CHCOO)6] with acrylate as the bridging ligand gives rise to potentially intrinsically chiral oxo-centered {M3} trimers that show a tendency to spontaneously resolve upon crystallization. For instance, 1 a, [Fe(III)3(mu3-O)(CH2=CHCOO)6-(H2O)3]+, crystallizes in the chiral space group P3(1) as a chloride salt. Crystallization of 1 b, [Fe3(mu3-O)(C2H3CO2)6(H2O)3]NO3 x 4.5 H2O, from aqueous solution followed by recrystallization from acetonitrile also gives rise to spontaneous resolution to yield the homochiral salt [Fe3(mu3-O)(C2H3CO2)6-(H2O)3]NO3 x CH3CN of 1 c (space group P2(1)2(1)2(1)). Furthermore, the reaction of 1 a with hexamolybdate in acetonitrile gives the helical coordination polymer {[(Fe3(mu3-O)L6(H2O))(MoO4)-(Fe3(mu3-O)L6(H2O)2)] x 2 CH3CN x H2O}infinity 2 (L: H2C=CHCOO), which crystallizes in the space group P2(1). The nature of the ligand geometry allows the formation of atropisomers in both the discrete (1 a-c) and linked {Fe3} clusters (2), which is described along with a magnetic analysis of 1 a and 2.

• Chemical bonds without "chemical bonding"? A combined experimental and theoretical charge density study on an iron trimethylenemethane complex.

  Authors: Louis J Farrugia, Cameron Evans, Marcus Tegel

  The journal of physical chemistry. A. 07/2006; 110(25):7952-61.

  High-resolution X-ray diffraction data, in conjunction with DFT(B3LYP) quantum calculations, have been used in a QTAIM analysis of the charge density in the trimethylenemethane (TMM) complexHigh-resolution X-ray diffraction data, in conjunction with DFT(B3LYP) quantum calculations, have been used in a QTAIM analysis of the charge density in the trimethylenemethane (TMM) complex Fe(eta(4)-C[CH(2)](3))(CO)(3). The agreement between the theoretical and experimental topological properties is excellent. Only one bond path is observed between the TMM ligand and the Fe atom, from the central C(alpha) atom. However, much evidence, including from the delocalization indices and the source function, suggests that there is a strong chemical interaction between the Fe and C(beta) atoms, despite the formal lack of chemical bonding according to QTAIM.

• Experimental X-ray charge density studies on the binary carbonyls Cr(CO)6, Fe(CO)5, and Ni(CO)4.

  Authors: Louis J Farrugia, Cameron Evans

  The journal of physical chemistry. A. 11/2005; 109(39):8834-48.

  The experimental charge densities in the binary carbonyls Cr(CO)(6) (1), Fe(CO)(5) (2), and Ni(CO)(4) (3) have been investigated on the basis of high-resolution X-ray diffraction data collected atThe experimental charge densities in the binary carbonyls Cr(CO)(6) (1), Fe(CO)(5) (2), and Ni(CO)(4) (3) have been investigated on the basis of high-resolution X-ray diffraction data collected at 100 K. The nature of the metal-ligand interactions has been studied by means of deformation densities and by topological analyses using the Atoms in Molecules (AIM) approach of Bader. A detailed comparison between the experimental results and theoretical results from previous work and from gas-phase and periodic DFT/B3LYP calculations shows excellent agreement, both on a qualitative and quantitative level. An examination of the kappa-restricted multipole model (KRMM) for Cr(CO)(6), using theoretically derived structure factors, showed it to provide a somewhat worse fit than a model with freely refined kappa' values. The experimental atomic graphs for the metal atoms in 2 and 3 were found to be dependent on the multipole model used for that atom. In the case of compound 2, restriction of the multipole populations according to idealized site symmetry of D(3h) gave an atomic graph in essential agreement with the theoretical gas-phase study. For compound 3, all multipole models fail to reproduce the atomic graph obtained from the theoretical gas-phase study. The atomic quadrupole moments for the C atoms in all compounds were consistent with significant pi back-donation from the metal atoms.

• Reactions of a {Mo16}-type polyoxometalate cluster with electrophiles: a synthetic, theoretical and magnetic investigation.

  Authors: De-Liang Long, Paul Kögerler, Louis J Farrugia, Leroy Cronin

  Dalton transactions (Cambridge, England : 2003). 05/2005;

  A medium-nuclearity mixed-valence polyoxomolybdate [H2Mo16O52]10-={Mo16}(1a) was synthesized using an approach that employed protonated hexamethylenetetramine (HMTAH+) as counter ion and yieldedA medium-nuclearity mixed-valence polyoxomolybdate [H2Mo16O52]10-={Mo16}(1a) was synthesized using an approach that employed protonated hexamethylenetetramine (HMTAH+) as counter ion and yielded (HMTAH)10 1a.34 H2O (1). The {Mo16} cluster anion exhibits significant nucleophilicity and traps electrophiles such as divalent transition metal ions, resulting in a family of isostructural compounds based on {Mo16M2}-type anions [M(H2O)8H2Mo16O52]6- (M=FeII (2), MnII (3), CoII (4)). The highly reactive nature of the {Mo16} system is also revealed by rearrangement and decomposition reactions of to either slowly form a sodium-bridged heptamolybdate-based chain compound (5) when left in the reaction solution or, in the presence of very high concentrations of electrophiles, to heptamolybdate-based cluster compounds [M2(H2O)9Mo7O24]2- of the {M2Mo7}-type (M=FeII (6), MnII (7)). Compounds were characterised by single crystal X-ray diffraction, elemental analysis, IR spectroscopy, magnetic susceptibility measurements, and density functional theory calculations.

• A novel design strategy for stable metal complexes of nitrogen mustards as bioreductive prodrugs.

  Authors: Laurie L Parker, Stephen M Lacy, Louis J Farrugia, Cameron Evans, David J Robins, C Caroline O'Hare, John A Hartley, Mohammed Jaffar, Ian J Stratford

  Journal of medicinal chemistry. 12/2004; 47(23):5683-9.

  Tumor hypoxia provides a key difference between healthy and cancerous cells. It can be exploited to produce drug selectivity, offering a reductase-rich environment for prodrug activation. NitrogenTumor hypoxia provides a key difference between healthy and cancerous cells. It can be exploited to produce drug selectivity, offering a reductase-rich environment for prodrug activation. Nitrogen mustard drugs are cytotoxic, but usually unselective. Polyamine mustards are candidates for conversion into hypoxia-selective prodrugs via complexation with metals. Reduction to a less stable complex can free the active drug. The novel Cu(II) complexes of N-mustard derivatives of 1,4,7-triazacyclononane (tacn), 1,4,7,10-tetraazacyclododecane (cyclen), and 1,4,8,11-tetraazacyclotetradecane (cyclam) were assessed in vitro as hypoxia-selective cytotoxins. The cyclen mustard complex showed 24-fold selectivity as a hypoxia-selective bioreductive prodrug, with an IC50 value of 2 microM against the lung tumor cell line A549. Reversible redox behavior and stability of the cyclen-Cu(II) complex in aqueous solution correlated with good hypoxia selectivity. The two other related complexes showed irreversible redox behavior and low aqueous stability and were not hypoxia-selective. The use of macrocyclic nitrogen mustard complexes represents a promising new strategy in the design of hypoxia-selective cytotoxins.

• Restraining symmetry in the formation of small polyoxomolybdates: building blocks of unprecedented topology resulting from "shrink-wrapping" [H2Mo16O52]10--type clusters.

  Authors: De-Liang Long, Paul Kögerler, Louis J Farrugia, Leroy Cronin

  Angewandte Chemie (International ed. in English). 10/2003; 42(35):4180-3.

• Experimental charge density in the transition metal complex Mn(2)(CO)(10): a comparative study.

  Authors: Louis J Farrugia, Paul R Mallinson, Brian Stewart

  Acta crystallographica. Section B, Structural science. 05/2003; 59(Pt 2):234-47.

  An accurate experimental charge density study at 100 K of Mn(2)(CO)(10) [bis(pentacarbonylmanganese)(Mn-Mn)] has been undertaken. A comparison with previously reported structural determinationsAn accurate experimental charge density study at 100 K of Mn(2)(CO)(10) [bis(pentacarbonylmanganese)(Mn-Mn)] has been undertaken. A comparison with previously reported structural determinations reveals no evidence for significant Mn-Mn bond lengthening between 100 and 296 K. The nature of the metal-metal and metal-ligand atom interactions has been studied by topological analysis using the Atoms in Molecules (AIM) approach of Bader [(1990), Atoms in Molecules: a Quantum Theory.Oxford: Clarendon Press]. An analysis of the density rho(r), the Laplacian of the density nabla (2)rho(r(b)) and the total energy densities H(r(b)) at the bond critical points is used to classify all the chemical bonds as covalent in nature. The results are compared qualitatively and quantitatively with previous charge density studies on this molecule and DFT calculations at the 6-311+G* B3LYP level. The topological properties of the theoretical and experimental densities are in close agreement.

• Synthesis of 2-substituted benzofurans and indoles using functionalized titanium benzylidene reagents on solid phase.

  Authors: Calum Macleod, Gordon J McKiernan, Emma J Guthrie, Louis J Farrugia, Dieter W Hamprecht, Jackie Macritchie, Richard C Hartley

  The Journal of organic chemistry. 02/2003; 68(2):387-401.

  Titanium(IV) benzylidenes bearing a masked oxygen or nitrogen nucleophile in the ortho position were generated from thioacetals, using low-valent titanocene complex, Cp2Ti[P(OEt)3]2. MethyleneTitanium(IV) benzylidenes bearing a masked oxygen or nitrogen nucleophile in the ortho position were generated from thioacetals, using low-valent titanocene complex, Cp2Ti[P(OEt)3]2. Methylene acetal, alkyl ether, silyl ether, fluoro, tertiary amino, and N-alkyl, N-benzyl, N-prenyl, and N-silyl tert-butyl carbamate groups were tolerated in the titanium alkylidene reagents (Schrock carbenes). Aryl-chlorine bonds were stable to the titanium benzylidene functionality, but there was poor chemoselectivity for the reduction of the thioacetal in the presence of an aryl chloride. The titanium benzylidenes converted Merrifield and Wang resin-bound esters into enol ethers. The oxygen nucleophile was masked as a TMS ether, and when the resin-bound enol ethers bearing this ortho substituent were treated with 1% TFA in dichloromethane, benzofurans were released from resin in high yields. The chameleon catch strategy ensured excellent purity. In a similar way, N-alkylated and N-silylated tert-butyl carbamates were used for the synthesis of N-alkyl and N-Boc indoles, respectively. These traceless solid-phase syntheses of heterocycles are believed to involve postcleavage modification rather than cyclative termination.