Office: CHBA 219 Phone: (405) 325-3696 Email: KNicholas@ou.edu Group Homepage Link Full Publications List	Kenneth M. Nicholas George Lynn Cross Research Professor B.S. (S.U.N.Y. at Stony Brook) 1969 Ph.D. (University of Texas) 1972 Teaching-Research Postdoctoral Fellow (Brandeis University) 1972-1973 Alfred P. Sloan Foundation Fellow, 1980-1984. Regents' Award for Superior Accomplishment in Research, 1989. Regents' Award for Superior Teaching, 1990. George Lynn Cross Research Professor, 1993.
Division: Organic, Organometallic and Bioorganometallic Chemistry. Research Interests reactivity of molecules coordinated to transition metals; role and applications of organotransition metal compounds as intermediates and catalysts in organic synthesis and biochemistry

Research Description

Our research interests and efforts are in the area of organotransition metal chemistry, bridging the traditional disciplines of organic, inorganic and biological chemistry.  The major theme in these studies centers on the unique reactivity of transition metal-coordinated molecules.  As we seek new understanding of this effect in chemical and biological systems, we are also exploiting this effect for the invention of new reactions and their application in organic synthesis. Two major projects are currently underway in our group. 

Transition Metal-Catalyzed Nitrogenation of Hydrocarbons

Organonitrogen compounds, both naturally-occuring and synthetic, are of immense importance as pharmaceuticals, agrochemicals, synthetic intermediates, etc.  However, few methods are available for the direct synthesis of these compounds from abundant hydrocarbons.  During the past several years our group has sought to discover new transition metal-mediated reactions for the conversion of alkenes and alkynes into organonitrogen compounds (nitrogenation).  In the process we are also investigating the role of reactive nitrogen intermediates, both coordinated and free, in the reactions.  Recently, we discovered that [CpM(CO)₂]₂ and related complexes (1, M=Fe,Ru) catalyze the reductive reactions of olefins and alkynes with nitroorganics to produce allyl amines and indoles, respectively (Fig. 1).  Both of these new reactions occur with remarkable regioselectivity with respect to the alkene and alkyne; both classes of products are valuable as synthetic intermediates and bioactive targets.  Recent findings include: 1) the development of intramolecular aminations leading to important heterocycles, including quinolines and indazoles; and 2) experimental and computational evidence that the indole-forming reactions involve metal-mediated deoxygenation steps which bracket a novel cycloaddition between nitrosoarenes and alkynes.  Current efforts are focused on: 1) identifying the organometallic and organic intermediates in the reactions; 2) finding more efficient catalysts and convenient nitrogenating agents; 3) discovering new nitrogenation reactions, especially of saturated and aromatic hydrocarbons; and 4) applying these reactions for the synthesis of bioactive products, including the indolocarbazole enzyme inhibitors.

Bionic Transition Metal Catalysts

Transition metal centers in protein environments (as found in metalloenzymes) can catalyze remarkably efficient and highly selective reactions, including hydrolyses, oxidation/reduction and carbon-carbon bond formation.  To better understand the molecular basis for such exceptional catalytic activity/selectivity and to develop useful catalysts for organic synthesis or biomedical applications, we are seeking hybrid synthetic/natural (bionic) transition metal complexes.  Our general approach is to engineer a biomimetic poly(imidazole)-metal complex (typical of many metalloenzymes) and a substrate binding domain into a natural or synthetic protein-like environment. 

Our initial efforts, in collaboration with the K.D. Janda group at the Scripps Research Institute, involved the construction of a bis(imidazole)-copper cofactor that was covalently attached to an antibody protein (38C2, Fig. 2).  The resulting bionic complex proved to be a remarkably active catalyst for ester hydrolysis, exceeding the activity of the unbound copper complex by 10⁴! 

In a new approach we are taking advantage of the ability of the immune response to produce diverse antibody proteins that bind tightly and selectively to transition state-like antigens (haptens) to produce catalytic antibodies with transition metal active sites.  A current project seeks to construct biomimetic and bionic catalysts for the regio- and stereoselective hydroperoxidation/hydroxylation of dienes, mimicking the action of the biologically important and mechanistically intriguing lipoxygenase (LO) enzymes (Fig. 3). We are using two approaches: 1) the synthesis of iron-tris-imidazole-carboxylate complexes and studies of their reactivity towards dienyl H-donors; 2) the elicitation of monoclonal antibody co-catalysts by synthetic cofactor hapten-protein conjugates.  The ability of the derived complementary antibodies and peptides, together with appropriate iron co-catalysts, to catalyze the synthetically attractive hydroperoxidation of 1,4-dienic substrates will then be investigated.

Copper hydroxylase enzymes, which catalyze unique enantioselective hydroxylations of C-H bonds, are also of interest to us (Fig. 4). We are seeking to better understand their reaction mechanisms and also to produce synthetic mimics of these poly(imidazole)-copper catalysts. Three systems are under investigation to achieve these goals: 1) synthesis and reactivity studies of tripodal poly(imidazole)-copper complexes (e.g. below); 2) structural and reactivity studies of copper complexes of histidine-rich peptides (e.g. the histatins); and 3) evolution of new catalysts by reversible cyclo-oligomerization of histidine-based building blocks templated by metal ions and transition state analogs.

S. Asirvatham, M.A. Khan and K.M. Nicholas, "A Decairon Cluster Devoid of Polydentate Ligands", Inorg. Chem. 2000, 39, 2006.

K. L. Salazar and K. M. Nicholas, "(Alkynyl)dicobalt Hexacarbonyl-Mediated Radical Cyclizations", Tetrahedron (Symposium in Print), 2000, 56, 2211.

S. Asirvatham, M.A. Khan and K.M. Nicholas, "Reductive Nitrosylation of MoO₂(dedtc)₂ by Hydroxylamine", Inorg. Chim. Acta, 2000, 305, 221.

R. J. Franks and K. M. Nicholas, "Palladium-Catalyzed Carboxylative Coupling of Allyl Stannanes and Allyl Halides", Organometallics, 2000, 19, 1458.

M. K. Kolel-Veetil, M.A. Khan and K.M. Nicholas, "A Cyclic Carbamoyl Complex is a Resting State in Allylic Aminations Catalyzed by [Cp*₂Fe(CO)₂]₂", Organometallics, 2000, 19, 3754.

R.L. Halterman, C. Zhu, Z. Chen, M.S. Dunlap, M.A. Khan and K.M. Nicholas, "Preaparation of [2,5-Diisopropylcyclohexane-1,4-bis(indenyl)]titanium Dichloride and [2,5-Diisopropylcyclohexane-1,4-bis(tetrahydroindenyl)]titanium Dichloride and Their Comparison as Catalysts for the Enantioselective Pinacol Coupling of Benzaldehyde", Organometallics, 2000, 19, 3824.

S. Singh and K.M. Nicholas, "2,4-Dinitrophenylhydroxylamine: An Efficient and More General Reagent for Iron-Catalyzed Allylic Amination", Synth. Comm. 2001, 31, 3087-3097.

Arakawa, H.; Aresta, M.; Armor, J. N.; Barteau, M. A.; Beckman, E. J.; Bell, A. T.; Bercaw, J. E.; Creutz, C.; Dinjus, E.; Dixon, D. A.; Domen, K.; DuBois, D. L.; Eckert, J.; Fujita, E.; Gibson, D. H.; Goddard, W. A.; Goodman, D. W.; Keller, J.; Kubas, G. J.; Kung, H. H.; Lyons, J. E.; Manzer, L. E.; Marks, T. J.; Morokuma, K.; Nicholas, K. M.; Periana, R.; Que, L.; Rostrup-Nielson, J.; Sachtler, W. M. H.; Schmidt, L. D.; Sen, A.; Somorjai, G. A.; Stair, P. C.; Stults, B. R.; Tumas, W., "Catalysis Research of Relevance to Carbon Management: Progress, Challenges, and Opportunities", Chem. Rev. 2001, 101, 953-996.

M.S. Dunlap and K.M. Nicholas, "Catalyst Structural Effects in Titanocene-catalyzed Pinacol Coupling: Activity, Stereoselectivity and Mechanistic Implications", J. Organometal. Chem. 2001, 630, 125.

R.S. Srivastava, M.K. Kolel-Veetil and K.M. Nicholas, "Photoassisted, Iron-Catalyzed Allylic Amination of Olefins with Nitroarenes," Tetrahedron Lett. 2002, 43, 931-934.

A. Penoni, J. Volkmann and K.M. Nicholas, "Regioselective Synthesis of Indoles via Reductive Annulation of Nitrosoaromatics with Alkynes", Organic Letters, 2002, 4, 699-701.

A. Penoni and K.M. Nicholas, "Indoles via Metal-Catalyzed Annulation of Nitroaromatics with Alkynes", J. Chem. Soc. Chem. Commun. 2002, 484-486.

K.M. Nicholas, P. Wentworth, Jr., C.W. Harwig, A.D. Wentworth, A. Smith and K.D. Janda, "A Cofactor Approach to Copper-Dependent Catalytic Antibodies", Proc. Nat. Acad. Sci. 2002, 99, 2648-2653. (research done at OU and Scripps).

G.A. Hogan, A.A. Gallo, K.M. Nicholas and R.S. Srivastava, "Cu(I)-Catalyzed Allylic Amination of Olefins", Tetrahedron Lett. 2002, 43, 9505.

D. K. O'Dell and K. M. Nicholas, "Unexpected Products from the Fp₂-Catalyzed Reductive Cyclization of Nitroaromatics Bearing Pendant Unsaturation," Tetrahedron, 2003, 59, 747.

R.S. Srivastava, M. A. Khan and K. M. Nicholas, "Preparation and Molecular Structure of [(h5-C₅H₅)Fe(CO)₂(h¹-PhNO₂)]BF₄", Inorg. Chim. Acta. 2003, 349, 269.

D.K. O'Dell and K.M. Nicholas, "Synthesis of 3-Substituted Quinolines via Transition Metal-Catalyzed Reductive Cyclization of Baylis-Hillman Acetates", J. Org. Chem. 2003, 68, 6427.

K. Lake, M. Dorrell, N. Blackman, M. A. Khan and K. M. Nicholas, "Stereoselective Pinacol Coupling of (Propargyl Aldehyde)Co₂(CO)₆ Complexes", Organometallics, 2003, 22, 4260.

Kalita, Biswajit; Nicholas, Kenneth M. "Synthesis of a-substituted iminodiacetate ligands: a-hexadienyl derivatives for the selection of lipoxygenase mimics", Tetrahedron 2004, 60, 10771-10778.

Volkman, Jerome; Nicholas, Kenneth M.  "Efficient Synthesis of Tris(4-imidazolyl)methanol Derivatives",Organic Letters 2004, 6, 4301-4302. 

O'Dell, David K.; Nicholas, Kenneth M.  "Synthesis of 1H-indazoles by reductive cyclization of ortho-nitro-ketoximes", Heterocycles 2004, 63, 373-382.

Biswajit Kalita and Kenneth M. Nicholas, "Copper-Catalyzed Allylic Hydroxyamination and Amination of Olefins with BOC-Hydroxylamine", Tetrahedron Lett. 2005, 46, 1451.

Radhey S. Srivastava and Kenneth M. Nicholas, Kinetics of the Allylic Amination of Olefins by Nitroarenes Catalyzed by [CpFe(CO)₂]₂, Organometallics, 2005, 24, 1563.

Radhey S. Srivastava, Masood.A. Khan and Kenneth M. Nicholas, "Nitrosoarene-Cu(I) Complexes Are Intermediates in Copper-Catalyzed Allylic Amination", J. Am. Chem. Soc. 2005, 127, 7278.

Jeremy C. Stephens, Masood A. Khan and Kenneth M. Nicholas, "Cyclopentadienyliron Complexes of Nitrosobenzene: Preparation, Structure and Reactivity with Olefins", J. Organomet. Chem. 2005, 690, 4727.

Andrea Penoni, Giovanni Palmisano, Gianluigi Broggini, Ayako Kadowaki and Kenneth M. Nicholas, "Efficient Synthesis of N-Methoxyindoles via Alkylative Cycloaddition of Nitrosoarenes with Alkynes", J. Org. Chem. 2006, 71, 823 -825.

Lei Zhou, Douglas Powell and Kenneth M. Nicholas, "Tripodal Bis(imidazole) Thioether Copper (I) Complexes: Mimics of the Cu(B) Site of Hydroxylase Enzymes", Inorg. Chem. 2006, in press.