Research Interests

Summary

Bioinorganic Chemistry: Multidisciplinary research based in inorganic chemistry. The research involves organic synthesis, physical and analytical techniques, manipulation of air sensitive compounds, and computational methods. The research is focused on the synthesis and characterization of small molecules that resemble the active-sites of metalloenzymes. We also work on the assembly of nanostructures through DNA and RNA interactions and biodegradable matrices for the growth of stem cells. 


Projects

Synthesis of Structural and Functional Models for Cupin Metalloenzymes


The cupin superfamily comprise one of the most functionally diverse collection of enzymes and are linked by a common protein fold possessing either one or multiple domains. Enzymatic functions in this family include isomerization, epimerization, dioxygenation, and transcription regulation. Although the majority of the cupins contain iron as an active site metal, other members contain either copper, zinc, cobalt, nickel or manganese ions as cofactors, with each cofactor and active site residues allowing a different type of chemistry to occur within the conserved tertiary structure. In many cases, the metal binding regions consists of ligands derived from three histidines and one glutamate. Understanding how nature has employed a similar protein fold for different biochemical reactions by varying the metal is interesting from an evolutionary point of view. The proposed work aims to develop small molecule models for the active sites of these enzymes which will help to understand the role of various metals in this family and help to probe the mechanisms involved for these enzymes. To accomplish this goal, both known and new organic ligands possessing the correct donor atoms and geometries found in the cupin metal binding region will be synthesized. Metal complexes of these ligands (Cu Fe, Ni, and Mn) will be synthesized and thoroughly characterized. Spectroscopic characteristics of these model compounds will be compared with their respective enzymes. Assays will be developed to assess the reactivity of these models towards enzymatically relevant substrates. It is anticipated that intermediate species will be isolated and characterized for these reactions. The importance of the proposed research to public health is as follows: This research will develop new methodologies for organic synthesis which in turn will provide routes for the synthesis of new drugs and therapeutics. Catalysts developed from this research will have applications in bioremediation and green chemistry and thus assist in minimizing persistence of toxic substances generated through industrial means. These studies will also generate potential therapeutic agents for the diagnosis and treatment of disease as well as allow students to gain experience in biomedical research and therefore acquire the abilities necessary to succeed in a health related scientific career.


N,N'-Dimethylformamide-Derived Products from Catalytic Oxidation of 3-Hydroxyflavone

In this study, 3-hydroxyflavone, a quercetin mimic, is catalytically oxidized by a quercetin 2,3-dioxygenase model compound. The reaction occurs under mild conditions in DMF in the presence of dioxygen. Along with previously reported oxidized products, two new solvent derived products are seen. The new compounds have been characterized by spectroscopic methods and X-ray crystallography. Evidence for steps involved in the formation of these new products is included.




Inorg. Chem. 2007, 46, 2950-2952.




Synthesis, Structure, and Characterization of Dichloro-(1-Benzyl-4-Acetato-1,4,7-Triazacyclononane)Iron(III)


The synthesis, structure and aqueous solution behavior of [FeL1Cl2] (1, L1 = 1-benzyl-4-acetato-1,4,7-triazacyclononane) is reported. The X-ray structure of 1 reveals iron(III) in distorted octahedral geometry bonded to three amine nitrogens and one carboxylate oxygen along with two cis chlorides. Electrochemical measurements of 1 in acetonitrile indicate that E1/2 = -200 mV vs Ag/AgCl. The stability of the +3 oxidation state is attributed to the hard Namine and carboxylate ligand donors.  In acetonitrile, 1 is mononuclear, possessing an S = 5/2 spin state. The presence of a m-oxo bridge upon dissolution of 1 in water is supported by EPR and solution magnetic susceptibility NMR studies. pH-metric titrations and UV-vis studies indicate the presence of a total of four acidic protons. At low pH, L1(OH2)Fe-O-Fe(OH2)L1 is proposed to be stabilized while at high pH, L1(OH)Fe-O-Fe(OH)L1 is suggested to persist.




Z. Anorg. Allg. Chem. 2008, 634, 1087-1092.



Synthesis and structure and magnetic properties a new binuclear Ni(II) complex supported by 1, 4, 8-triazacycloundecane


A new synthetic binuclear nickel(II) ([Ni2(tacud)2(m-H2O)(m-Cl)2]Cl2 (1); tacud = 1,4,8-triazacycloundecane) is reported. Compound 1 contains two Ni(II) ions bridged by two chloro and one aqua ligand resulting in a short Ni···Ni distance of 3.0187(10) Å. Each nickel is capped by terminal tacud ligands and possesses distorted octahedral geometry. This compound exhibits a new structural motif for metal complexes supported tacud. Compound 1 exhibits two solvent dependent transitions in the UV-vis spectrum. Variable temperature SQUID magnetic susceptometry studies on 1 indicate mild ferromagnetism exists at room temperature (meff = 4.78 mB) which increases upon temperature lowering. Magnetic analysis of 1 in the temperature range 2 – 300 K confirm weakly ferromagnetic behavior with J = +2.28 cm-1.




Inorg. Chem. Commun. 2008, 11, 1023-1026.


New Binuclear MnII and FeII Complexes Supported by 1,4,8-Triazacycloundecane


Two new binuclear metal complexes supported by 1,4,8-triazacycloundecane (tacud) are reported. [Fe2(tacud)2(m-Cl)2Cl2] (1) and [Mn2(tacud)2(m-Cl)2Cl2] (2) are isomorphs consisting of bis(m-chloro) bridged metal centers along with terminal chloro groups and tacud ligands. Both compounds 1 and 2 crystallize in the P space group. For 1, a = 7.7321(12) Å, b = 7.8896(12) Å, c = 11.4945(17) Å, a = 107.832(2)°, b = 107.827(2)°, g = 92.642(2)°, V = 627.85(17) Å3, and Z = 1. For 2, a = 7.7607(12) Å, b = 7.9068(12) Å, c = 11.6111(18) Å, a = 108.201(2)°, b = 108.041(2)°, g = 92.118(3)°, V = 636.47(17) Å3, and Z = 1. Variable-temperature and variable-field magnetic susceptibility studies on 1 indicate the presence of weak ferromagnetic interactions between the high-spin iron(II) centers in the dimer (J = + 1.6 cm–1) and the crystalline field anisotropy of the ferrous ion (D = – 2.8, E = – 0.1 cm–1). Variable temperature magnetic susceptometry studies on 2 indicated that weak antiferromagnetic coupling exists between the manganese(II) centers (J = – 1.8 cm–1). Compounds 1 and 2 retain their dinuclearity in weakly coordinating or low polarity solvents while both become mononuclear in solvents such as methanol.




Dalton Trans. 2011, 40, 2926-2931.



Synthesis, Structure, and Characterization of [FeIIILCl3] (L = 1,4,8-triazacycloundecane, 1,4,7-triazacyclononane)


The structures of [FeIII(tacud)Cl3] (1) and [FeIII(tacn)Cl3] (2) (tacud = 1,4,8-triazacycloundecane, tacn = 1,4,7-triazacyclononane) are reported. Both compounds crystallize in the orthorhombic space group Pnma with a = 12.5570(9), b = 12.0028(9), c = 8.2577(6) Å, V = 1244.59(16) Å3, and Z = 4 for 1 and a = 12.095(4), b = 11.125(4), c = 7.963(3) Å, V = 1071.5(6) Å3, and Z = 4 for 2. The structures of 1 and 2 feature iron(III) in distorted octahedral geometry with three facially coordinated nitrogen ligands and three chlorides. Bidirectional intermolecular hydrogen bonding between N-H groups and coordinated chlorides is seen for 1 and 2. Compound 1 is the first example of iron(III) bonded to tacud and compound 2 is only the second structure reported of a 1:1 complex between iron and tacn. The Fe3+/2+ redox couple for 1 is observed at E1/2 = 0.25 V (DEp = 99 mV) while for 2, E1/2 = 0.09 V (DEp = 108 mV) vs NHE in DMF at 298 K. Comparison of structural, magnetic, and electrochemical properties for 1 and 2 reveal subtle differences consistent with the stronger coordinating properties of tacn relative to tacud.



Z. Anorg. Allg. Chem.  2012, 638, 1473-1477.



Synthesis, Structure, and Properties of Bis(2-(1-Ethyl-1H-Imidazol-4-yl)Acetate) Copper(II)


Ethylation of imidazole-4-acetate methyl ester affords 1-ethyl-1H-Imidazol-4-ylacetic acid methyl ester (1) and 1-ethyl-1H-Imidazol-5-ylacetic acid methyl ester (2) in a 3:1 ratio. Both 1 and 2 can be converted to their respective potassium carboxylate salts, 3 and 4, respectively. Reaction of 3 with CuCl2 in methanol yields [Cu(eia)2]∙4MeOH (5∙4MeOH) (eia- = 1-ethyl-1H-imidazol-4-yl)acetate). EPR measurements of 5 in methanol glass exhibits near axial symmetry with g^ ( gx = 2.060, gy = 2.087) and g|| = gz = 2.293 with A||Cu = AzCu = 152 G, and AyN = 13.6 G. Accordingly, the structure of 5∙4MeOH reveals Cu(II) in tetragonally distorted octahedral geometry with with O,N coordination from the eia- and elongated bonding (2.506 Å) to methanol oxygens in the axial positions. An infinite 1-dimensional hydrogen bonding network involving methanol molecules is present. DFT studies have been carried out to assist in assignment of electronic transitions. Electrochemical studies on 5 in methanol and DMF reveal quasi-reversible redox behavior for the CuII/I couple while for MeCN a CuI/0 stripping process is seen.





 Inorg. Chim. Acta 2013, 405, 295-301.



Spin-State Tuning in Iron(II) Triaza Macrocyclic Complexes


The structures of [FeII(tacn)2](OTf)2×DMF (1×DMF), [FeII(tacd)2](OTf)2 (2), [FeII(tacud)2](OTf)2 (3) (tacn = 1,4,7-triazacyclononane, tacd = 1,4,7-triazacyclodecane, tacud = 1,4,8-triazacycloundecane) are reported. In the solid state, compounds 1 and 2 exhibit temperature-dependent gradual and reversible one-step spin-crossover between the high-spin (S = 2) and low-spin (S = 0) states with estimated T1/2 = 330 and 320 K, respectively. Compound 1 exhibits somewhat reversible magnetic behavior during the heating and cooling cycle while 2 is more reversible. Compound 2 is only the third example of a spin-crossover compound possessing secondary amine ligands exclusively. Complex 3 is HS at temperatures measured. Systematic comparison of properties for 1-3 indicates that the structural-magnetic properties correlate with ligand donor strength. There is also a close correlation with room temperature solution spin state and E1/2 in acetonitrile for these compounds.




Eur. J. Inorg. Chem. 2013, 40, 2115-2121.



Highest recorded N-O stretching frequency for 6-coordinate {Fe-NO}7 complexes: An Iron-nitrosyl model for His3 active sites


We report the synthesis, structure, and reactivity of [Fe(T1Et4iPrIP)(OTf)2] (1, T1Et4iPrIP = tris(1-ethyl-4-isopropyl-imidazolyl) phosphine). Compound 1 reacts reversibly with nitric oxide to afford [Fe(T1Et4iPrIP)(NO)-(THF)(OTf)](OTf) (2) which is the first example of a 6-coordinate {FeNO}7 S = 3/2 complex containing a linear Fe-N-O group. 2 exhibits the highest n(NO) for compounds in this class. DFT studies reveal an enhanced degree of b electron transfer from the p*(NO) to the iron d orbitals accounting for the large stretching frequency.






Oxalate Oxidase Model Studies: Substrate Reactivity


The synthesis and structure of [MnLCl]0.5H2O (1∙0.5H2O, L = 1-benzyl-4-acetato-1,4,7-triazacyclononane) is reported. 1 exists as a coordination polymer in the solid state with MnII bonded to three amine nitrogens, one carboxylate oxygen, a chloride, and an adjacent carboxylate in a chelating fashion affording a 7-coordinate center. Dissolution of 1 in acetonitrile containing excess oxalate results in a monomeric species. When mixtures of 1 and oxalate are exposed to oxygen under ambient conditions, a dark pink EPR-silent species is generated which is believed to be [MnIII(ox)2]- resulting from displacement of the ligand L- by oxalate. Decomposition of this species ultimately results in formation of one equiv CO2/oxalate consumed, HCO3-, and a MnII species. Further reaction of the resulting MnII species with excess oxalate in the presence of oxygen leads to additional oxalate degradation.




 Eur. J. Inorg. Chem. 2015, 646−655.


Synthesis and Characterization of 4-, 5-, and 6-Coordinate Tris(1-ethyl-4-isopropyl-imidazolyl-қN)phosphine Cobalt(II) Complexes


Herein we report the synthesis and characterization of [Co(T1Et4iPrIP)X2] (where T1Et4iPrIP = tris(1-ethyl-4-iPr-imidazolyl)phosphine; X = OTf- (1), Cl- (2), Br- (3)) and [Co(T1Et4iPrIP)(CH3CN)3](OTf)2 (4). In compounds 1 and 4, T1Et4iPrIP binds in a tridentate fashion while 2 and 3 feature bidentate ligation. Compound 1 additionally coordinates two triflate ligands completing distorted square pyramidal geometry. Compound 4 also binds three acetonitrile ligands affording distorted octahedral geometry. Compounds 2 and 3 exhibit distorted tetrahedral geometry with ligands comprising two imidazole nitrogens and two halides. Bidentate coordination using a tris-imidazolylphosphine ligand is unprecedented. Compounds 2 and 3 can be derived from 1 by the addition of either Cl- or Br- salts, respectively while 4 can be generated by dissolving 1 in acetonitrile. DFT studies indicate that the HOMO-LUMO gap for all compounds is comparable, however, steric factors stabilize the formation of 2 and 3 over 1 in the presence of the halide ligands. A theoretical fit of the variable temperature magnetic data for 1-3 yielded the following parameters: D = 78.9 (7) cm-1, g =2.55(1), Na = 8x10-5 cm3mol-1 and zJʹ= -0.12(2) cm-1 for 1; D = 12.4 (3) cm-1, g =2.34(1), Na = 1x10-4 cm3mol-1 and zJʹ= -0.08(7) cm-1 for 2 and D = 10.8 (3) cm-1, g =2.14(1), Na = 7x10-5 cm3mol-1 and zJʹ = -0.04(4) cm-1 for 3.





Eur. J. Inorg. Chem. 2015, 2092-2100.



Synthesis, Structure and Properties of Tris(1-Ethyl-4-Isopropyl-Imidazolyl-қN)Phosphine Copper(II)


In this study we report the synthesis and characterization of [Cu(T1Et4iPrIP)(CH3OH)Cl]Cl (1) (T1Et4iPrIP = tris(1-ethyl-4-isopropyl-imidazolyl)phosphine). T1Et4iPrIP serves a His3 biomimetic ligand binding metals through the 3-nitrogen of the imidazolyl group. The structure of 1 features copper(II) bonded to three nitrogen ligands from T1Et4iPrIP along with an oxygen ligand from methanol and a chloride ligand to form slightly distorted square pyramidal geometry with an imidazole group occupying the axial position and the methanol and chloride ligands situated in the basal plane. The weak sigma donation of the ligand set results in low energy d-d electronic transitions and small A|| (131 G). Time-dependent DFT calculations (B3LYP, 6-311+G(d,p)) on the optimized structure of 1 in methanol solvent allowed for the assignment of specific electronic transitions in the UV-Vis spectrum. The highest occupied molecular (HOMO) was noted to consist of 65% Cu-d character identified as the dx2-y2 orbital.




Inorg. Chim. Acta 2015, 434, 79-84. 





Synthesis and Characterization of Self-Assembling Biodegradable Hydrogel Scaffolds


Self-assembling biocompatible and biodegradable nanomaterials have promising applications in tissue engineering and regenerative medicine as well as drug delivery. Ideally suitable and active biological scaffolds will stimulate and promote cell differentiation. Self-assembling scaffolds could help repair tissues which are difficult to regenerate and structures such as spinal cord, tendon and cartilage. We have investigated several synthetic nanomaterials (such as polycaprolactone, poly (ethylene oxide), poly(lactic acid), and poly(lactic acid co-glycolic acid) and biomolecules (such as proteins, peptides, and carbohydrates) for use in developing scaffolds that mimic in vivo microenvironments for 3-D tissue engineering. The scaffolds promoted cellular growth of embryonic and cord blood stem cells and their differentiation into osteogenic, chondrogenic, and neural lineages. We are currently developing nanomaterials that self-assemble to produce scaffolds for generating tissues of various organs such as heart and liver. In this study we synthesized thiol-functionalized dextran (Dex-SH, Mn 25K) and investigated it for in situ hydrogel scaffold formation via Michael type addition using poly(ethylene glycol)tetra-acrylate (PEG-4-Acr). Dex-SH was prepared by activation of the hydroxyl groups of dextran with 4-nitrophenyl chloroformate and the subsequent reaction with cysteamine. The Dex-SH is highly air sensitive in aqueous solution and must be handled under nitrogen.