John F. Hartwig

Research

Our research aims to discover, develop and understand new transition metal-catalyzed reactions. The scope of our studies ranges from catalytic aromatic substitution to the functionalization of alkanes to the enantioselective formation of C-N and C-O bonds in amines and ethers. The discovery of fundamentally new transition metal chemistry and its development into practical, catalytic synthetic methods is a theme of our research. We reach these goals by obtaining insight from detailed mechanistic studies. The following classes of metal-catalyzed reactions are currently being investigated in my group:

Catalytic Formation of Amines, Ethers and Sulfides. Chemical Formulas

We developed a palladium-catalyzed process that forms arylamines, aryl sulfides, and arylethers. The catalytic chemistry resulted from our detailed mechanistic experiments on transition metal amide, alkoxo and thiolato complexes. Our most recently developed catalyst leads to the formation of arylamines and aryl sulfides with turnover numbers exceeding 10,000 in many cases and ppm levels of palladium in others.

This catalysis is useful for total synthesis, combinatorial synthesis, and the preparation of electronically important organic materials. At the same time, the catalysis involves unprecedented reactions of transition metal compounds. Thus, some students focus on novel inorganic chemistry while others use this reaction as a modular route to nitrogen heterocycles and polyanilines.

Catalytic Alpha Arylation of Carbonyl Compounds.

We have developed a simple method to convert aryl halides and ketones, esters, amides, cyanoesters, malonates, nitriles, and related compounds to alpha aryl carbonyl compounds and nitriles in the presence of base and a palladium catalyst. Familiar compounds that can be generated from these products include Ibuprofen, Naproxin and Tamoxifen. The reaction occurrs in a general fashion and in many cases with low catalyst loadings.

As part of our studies to understand this process, we have generated both O-bound and C-bound palladium enolate complexes. These complexes undergo reductive elimination of the alpha-aryl ketone, ester, or amide product in good yields. Studies on the effects of changing the enolate electronics on reductive elimination rate are in progress.

Transition Metal Boryl- and Borane Complexes. Catalytic, Regiospecific Functionalization of Alkanes

The chemistry of compounds with covalent transition metals and main group bonds is unexplored. While studying this fundamental reactivity, we discovered that metal boryl compounds react with arenes and alkanes to form functionalized products. Most recently, we have developed a regiospecific functionalization of alkanes using borane or diboron reagents in the presence of a rhodium catalyst and a sterecally controlled, iridium-catalyzed functionalization of arenes using the same boron reagents. We are currently exploring improved catalysts, as well as the scope and applications of the functionalization process.

Our mechanistic work on this process has intersected with our fundamental work in the group on borane sigma complexes. These complexes have unusual bonding between a metal hydride and the boryl ligand. In these complexes a partial, intact B-H bond accompanies an M-H and M-B bond. Recently, we have found that complexes of this type are similar to those involved in the alkane functionalization process.

Publications

Wei, C.S.; Jiménez-Hoyos, C.A.; Videa, M.F.; Hartwig, J.F.; Hall, M.B. "Origins of the Selectivity for Borylation of Primary over Secondary C-H Bonds Catalyzed by *-Rhodium Complexes" J. Am. Chem. Soc. 2009, in press.

Carrow, B.P.; Hartwig, J.F. "Ligandless, Anionic, Arylpalladium Halide Intermediates in the Heck Reaction" J. Am. Chem. Soc. 2009, in press.

Mkhalid, A.I.; Barnard, J.H.; Marder, T.B.; Murphy, J.M.; Hartwig, J.F. "C-H Activation for the Construction of C-B Bonds" Chem. Rev. 2009, in press.

Marquard, S.L.; Rosenfeld, D.C.; Hartwig, J.F. "C(sp3)-N Bond-Forming Reductive Elimination of Amines: Reactions of Bisphosphine-Ligated Benzylpalladium(II)Diarylamido Complexes" Angew. Chem. Int. Ed. 2009, early view.

Ueda, M.; Hartwig, J.F. "Iridium-Catalyzed Regio-and Enantioselective Allylic Substitution with Aromatic and Aliphatic Sulfinates" Org. Lett. 2009, ASAP.

Tye, J.W.; Hartwig, J.F. "Computational Studies on the Relative Rates for Migratory Insertions of Alkenes into Square-Planar Methyl, Amido, and -Hydroxo Complexes of Rhodium" J. Am. Chem. Soc. 2009, 131, 14703-14712.

Stanley, L.M.; Hartwig, J.F. "Iridium-Catalyzed Regio- and Enantioselective N-Allylation of Indoles" Angew. Chem. Int. Ed. 2009, 48, 7841-7844 designated as a "Hot Paper."

Liskey, C.W., Wie, C.S., Pahls, D.R., Hartwig, J.F. "Pronounced Effects of Substituents on the Iridium-Catalyzed Borylation of Aryl C-H Bonds" Chem. Commun. 2009, 37, 5603-5605.

Pouy, M.J.; Stanley, L.M.; Hartwig, J.F. "Enantioselective, Iridium-Catalyzed Monoallylation of Ammonia" J. Am. Chem. Soc. 2009, 131, 11312-11313.

Vo, G.D.; Hartwig, J.F. "Palladium-Catalyzed Coupling of Ammonia with Aryl Chlorides, Bromides, Iodides, and Sulfonates: A General Mtthod for the Preparation of Primary Arylamines" J. Am. Chem. Soc. 2009, 131, 11049-11061.

Weix, D.J.; Markovic, D.; Ueda, M.; Hartwig, J.F. "Direct, Intermolecular, Enantioselectivve, Iridium-Catalyzed Allylation of Carbamates to Form Carbamate-Protected, Branched Allylic Amines" Org. Lett. 2009, 11, 2944-2947.

Stanley, L.M.; Hartwig, J.F. "Regio-and Enantioselective N-Allylations of Imidazole, Benzimidazole, and Purine Heterocycles Catalyzed by Single-Component Metallacyclic Iridium Complexes" J. Am. Chem. Soc. 2009, 131, 8971-8983.

Alvaro, E.; Hartwig, J.F. "Resting State and Elementary Steps of the Coupling of Aryl Halides with Thiols Catalyzed by Alkylbisphosphine Complexes of Palladium" J. Am. Chem. Soc. 2009, 131, 7858-7868.

Barrios-Landeros, F.; Carrow, B.P.; Hartwig, J.F. "Effect of Ligand Steric Properties and Halide Identity on the Mechanism for Oxidative Addition of Haloarenes to Trialkylphosphine Pd(0) Complexes" J. Am. Chem. Soc. 2009,131, 8141-8154.

Madrahimov, S.T.; Markovic, D.; Hartwig, J.F. "The Allyl Intermediate in Regioselective and Enantioselectivve Iridium-Catalyzed Asymmetric Substitution Reactions" J. Am. Chem. Soc. 2009, 131, 7228-7229.

Fernandez-Rodriguez, M.A.; Hartwig, J.F. "A General, Efficient, and Functional-Group-Tolerant Catalyst System for the Palladium-Catalyzed Thioetherification of Aryl Bromides and Iodides" J. Org. Chem 2009, 74, 1663-1672.

Previous Publications

See the Hartwig Group website for a full list of Prof. Hartwig's publications.

Awards

• GlaxoSmithKline Scholars Award, 2010
• National Institutes of Health MERIT Award, 2009
• Royal Society of Chemistry Joseph Chatt Award, 2009
• Edward Mack Jr. Memorial Award, Ohio State University, 2009
• Mitsui Chemicals Catalysis Science Award, 2009
• International Catalysis Award (International Association of Catalysis Societies)
• RSC Joseph Chatt Lectureship, 2008
• Paul N. Rylander Award of the Organic Reactions Catalysis Society, 2008
• Tetrahedron Young Investigator Award in Organic Synthesis, 2007
• Mukaiyama Award from the Society of Synthetic Organic Chemistry of Japan, 2007
• Raymond and Beverly Sackler Prize in the Physical Sciences, 2007
• ACS Award in Organometallic Chemistry, 2006
• Thieme-IUPAC Prize in Synthetic Organic Chemistry, 2004
• Leo Hendrik Baekeland Award, 2003
• A. C. Cope Scholar, 1997
• Eli Lilly Grantee, 1997
• Camille Dreyfus Teacher-Scholar Award, 1997
• Alfred P. Sloan Research Fellow, 1996-1998
• Union Carbide Innovative Recognition Award, 1995-1996
• NSF Young Investigator Award, 1994
• DuPont Young Professor Award, 1993
• Dreyfus Foundation New Faculty Award, 1992

Highlights

Recent Publication Highlights

Many of the papers published by the Hartwig group have been highlighted in the secondary literature and are among the most downloaded and cited papers in their respective journals. In the last survey by the ISI citation service, Prof. Hartwig was among the 50 most cited chemists in any field and the most cited of any synthetic chemist in the world his age or younger.

A few of the places that regularly highlight his group's work are work are shown below.

Thieme Chemistry Synfacts
A large fraction of the papers published by Prof. Hartwig's group on synthetic methodology are highlighted in Synfacts. These highlights and the corresponding original papers are listed below.

Knochel, P.; Thaler, T. "Mild Pd-Catalyzed Amination of Aryl and Heteroaryl Tosylates" Synfacts 2009, 1, 84.

Corresponding original paper:
Ogata, T.; Hartwig, J. F. "Palladium-Catalyzed Amination of Aryl and Heteroaryl Tosylates at Room Temperature" J. Am. Chem. Soc. (Communication), 2008, 130, 13848-13849.

Knochel, P.; Thaler, T. "A Highly Efficient Catalyst for Pd-Catalyzed Amination of Aryl Halides" Synfacts 2008, 8, 859.

Corresponding original paper:
Shen, Q.; Ogata, T.; Hartwig, J. F. "Highly Reactive, General and Long-Lived Catalysts for Palladium-Catalyzed Amination of Heteroaryl and Aryl Chlorides, Bromides and Iodides: Scope and Structure-Activity Relationships" J. Am. Chem. Soc 2008, 130, 6586-6596.

Knochel, P.; Gavryushin, A. "Palladium-Catalyzed α-Arylation of Esters" Synfacts 2008, 7, 750.

Corresponding original paper:
Hama, T.; Hartwig, J. F. "Palladium-Catalyzed α-Arylation of Esters with Chloroarenes" Org. Lett. 2008, 10, 1549-1552.

Lautens, M.; Aureggi, V. "Iridium-Catalyzed Asymmetric Allylic Etherification" Synfacts 2008, 5, 500.

Corresponding original paper:
Ueno, S.; Hartwig, J. F. "Direct, Iridium-Catalyzed Asymmetric Allylic Etherification with Aliphatic Alcohols" Angew. Chem. Int. Ed. 2008, 47, 1928-1931.

Yamamoto, H.; Cheon, C. H. "Difluorphos Complexes of Palladium and Nickel-Catalyzed α-Arylation of Ketones" Synfacts 2008, 4, 385.

Corresponding original paper:
Liao, X.; Weng, Z.; Hartwig J. F. "Enantioselective α-Arylation of Ketones with Aryl Triflates Catalyzed by Difluorphos Complexes of Palladium and Nickel" J. Am. Chem. Soc. 2008, 130, 195-200.

Chemical & Engineering News
Publications from the Hartwig Group have also frequently been highlighted in stories in Chemical & Engineering News. A sample of these is listed below:

Steve Ritter, "Expanding on Hydroaminations" Chem. Eng. News 2008, 86, 12.

Steve Ritter, "Amine Synthesis Gains Utility" Chem. Eng. News 2007, 85, 9.

Steve Ritter, "Ammonia Is Ready for a Transfer" Chem. Eng. News 2005, 83, 12.

"Pd Dimers Let Aryl Halides React Fast Under Mild Conditions" Chem. Eng. News 2002, 80, 31.

"ACS News: Most Requested Article, Journal from 2003" Chem. Eng. News 2004, 82, 39.

Stu Borman "Pin the Tail on the Olefin" Chem. Eng. News 2004, 82, 42-43.

Announcements of recent awards in Chemical & Engineering News include:

"Sackler Prize Winners Announced" Chem. Eng. News 2007, 85, 75-76.

"2007 and 2008 Rylander Award Winners Announced" Chem. Eng. News 2007, 85, 75.

"ACS Award in Organometallic Chemistry" Chem. Eng. News 2006, 84, 50-54.

Angewandte Chemie International Edition
Angewandte Chemie includes articles that highlight papers chosen by other chemists to be particularly noteworthy. Many of these articles highlight work from Prof. Hartwig's Group, and a selection of such recent highlights include:

Willis, M. C. "Palladium-Catalyzed Coupling of Ammonia and Hydroxide with Aryl Halides: The Direct Synthesis of Primary Anilines and Phenols" Angew. Chem., Int. Ed. 2007, 46, 3402-3404.

Christmann, U.; Vilar, R. "Monoligated Palladium Species as Catalysts in Cross-Coupling Reactions" Angew. Chem., Int. Ed. 2005, 44, 366-374.

Braun, T. "Oxidative Addition of NH₃ to a Transition-Metal Complex: A Key Step for the Metal-Mediated Derivatization of Ammonia?" Angew. Chem., Int. Ed. 2005, 44, 5012-5014.

Lloyd-Jones, G. C. "Palladium-Catalyzed α-Arylation of Esters: Ideal New Methodology for Discovery Chemistry" Angew. Chem., Int. Ed. 2002, 41, 953-956.

Other Highlights

Organic Chemistry Portal Highlights

Buchwald-Hartwig Reaction on Wikipedia

Professor John Hartwig Joins Cambridge Major Lab's Scientific Advisory Team