Hinkle Group
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Robert J. Hinkle

Associate Professor of Organic Chemistry,

NIH Postdoctoral Fellow, With Professor Larry. E. Overman, University of California, Irvine, 1994-1996
Ph.D., with Professor Peter J. Stang, University of Utah 1994
A.B. Bowdoin College 1986

(757)-221-1501; e-mail: rjhink@wm.edu

Presentations Publications Curriculum Vitae Courses

Research Interests Bismuth Chemistry Links Organic Chemistry Links

Research Interests

Our research encompasses two distinct areas of chemistry: the Catalytic Use of Bi(III) Compounds for the synthesis of ethers and the chemistry of Iodonium Salts.

Bismuth Catalysis:

In 2002, we began to work in an area of catalysis in which 5-15 mole percent of bismuth(III) compounds can be used to efficiently synthesize cyclic ethers from acyclic precursors. The initial reactions were conducted while I was on sabbatical in P. Andrew Evans' laboratories at Indiana University. Professor Evans has recently moved to The University of Liverpool where he is the Professor and Heath Harrison Chair of Organic Chemistry. The initial reactions showed that highly diastereoselective reactions can be carried out using allyltimethylsilane as a nucleophile in a Tandem Cyclization-Addition sequence. The stereochemistry of allylation is completely consistent with that known for cyclic six-membered oxocarbenium ions. For definitive work on oxocarbenium ion stereochemistry, see publications listed on Prof. Keith Woerpel's Home page on the University of California, Irvine's chemistry website (UCI website )

Since that initial investigation, we have extended the range of nucleophiles which can participate in this reaction. The use of ketene silyl acetals (reagent in red over lower arrow) provides diastereselective additions, but the addition is much lower than with allylsilane above. These results imply that the diastereoselectivity is inversely proportional to the strength of the pi-nucleophile during addition to the intermediate ion.

We are currently expanding our emphasis to include numerous new electrophiles and nucleophiles in tandem and three-component addition-cyclization reactions with Bi(III) "catalysts." Please see J. Org. Chem. 2006, 71, 7071.

Iodonium Salts:

Iodine is a very large element and because of its size as well as great polarizeability, iodine can adopt oxidation states such as -1, +3 and +5. Our Early work in the area of iodonium salts (iodine +3) showed the remarkable leaving group ability of the hypervalent iodine moiety found in alkenyl(aryl)iodonium salts. Under very mild conditions, the salts, (E)-7a-c, fragment into three vinyl triflates as well as iodobenzene (eq 1).

We originally interpreted this fragmentation as evidence for the formation of a primary vinyl cation, which had been unobserved in solution. Further work from our labs as well as a lab in Japan (Okuyama's lab) indicated that the primary vinyl cation (A) shown in Scheme 2 is, indeed, not necessary to interpret the results of this thermal reaction.

More recently we have become much more interested in compounds which contain both iodonium and diazo functional groups in the same molecule. We are currently developing reactions in which the phenyliodonio (red) moiety can selectively be replaced while the diazo group (N2) remains. Both of these functionalities are quite useful in organic synthesis.

Current Courses

Chem. 150W Beyond Petroleum as a Fuel (Fall T/Th 11:00)

Chem 457/657 Organic Synthesis (Fall, T/Th 12:30)

Chem 206, Introductory Organic Chemistry, I: (M,W,F, 10:00 and 11:00, Spring) **Co-taught with Prof. Elizabeth Harbron

Chem 252, Introductory Organic Chemistry Laboratory, I: (W, Th, Spring)

Chem 353 Introductory Organic Chemistry Laboratory, II: (M, T, Fall)

Research Students

Academic Year 2006-2007

Kristie Schmidt (M. S. 2007)

Joshua Pahng (B. S. 2008)

Heather E. Stevenson (B. S. 2007)

H. Danielle Johnson (B. S. 2007)

Christine Forgues (B. S. 2007)

Elizabeth J. Cline (B. S. 2007)

Academic Year 2005-2006

Timothy J. Brown (B. S. 2006)

Yajing Lian (M. S. 2005)

Melissa Sprachman (B.S. 2006)

Kristie Schmidt (M. S. 2007)

Tim Brown (B. S. 2006)

Current and Past Funding

Camille and Henry Dreyfus Foundation--Henry Drefus Teacher-Scholar Award (2002-2007)

Early CAREER Development Award from the National Science Foundation (2000-2006)

Cottrell College Science Award from the Research Corporation (1997-2001)

Thomas F. and Kate Miller Jeffress Foundation of Virginia (1998-2006)

Petroleum Research Fund of the American Chemical Society (1997-2001)

Arnold and Mabel Beckman Foundation (Beckman Scholarships to Melissa Sprachman (B.S. 2006), Ann Mikowski (B.S. 2003) and Anne McNeil (B. S. 1999)

Eli Lilly Pharmaceutical Corporation (Summer Fellowship for M. Christa Mattern--B.S. 2005)

Publications

William and Mary Undergraduate Students are in Bold

1) Lian, Y.; Hinkle, R. J. ”B iBr3-Initiated Tandem Addition/Silyl-Prins Reactions to 2,6-Disubstituted Dihydropyrans,” J. Org. Chem. 2006, 71, 7071-7074.

2) Robert J. Hinkle, Lian, Y.; Litvinas, N. D.; Jenkins, A. T.; Burnette, D. C. "Bismuth(III) Bromide Initiated Cyclization-Addition Reactions: Effect of Nucleophile and Total Synthesis of (+)-(S,S)-(cis-6-methyltetrahydropyran-2-yl)acetic Acid and its trans-Diastereomer," Tetrahedron 2005, 61, 11679-11685

3 ) Evans, P. A.; Cui, J.; Gharpure, S. J; Hinkle, R. J. “ Stereoselective Construction of Cyclic Ethers using a Tandem Two-Component Etherification: Elucidation of the Role of Bismuth Tribromide,” J. Am. Chem. Soc. 2003, 125,11456-11457.

4) Hinkle, R. J. "Mikowski, A.M. "Kinetics of Stereoisomeric 2-Methyl-1-butenyl(aryl)iodonium triflates," Included in a special issue of ARKIVOC 2003, vi, 201-212, published 25 July 2003: http://www.arkatusa.org/ark/journal/2003/Varvoglis/AV745A/745A.pdf.

5) Tykwinski, R. R. †; Kamada, K. ‡; Bykowski, D. †; Hegmann, F. A. †; Hinkle, R. J. "Nonlinear Optical Properties of Thienyl and Bithienyl Iodonium Salts as Measured by the Z-scan Technique," J. Opt. A: Pure Appl. Opt. 2002, 4, S202-206. .

6) Bykowski, D. †; McDonald, R. †; Hinkle, R. J.; Tykwinski, R. R. † "Structural and Electronic Characteristics of Thienyl(aryl)iodonium Triflates," J. Org. Chem., 2002, 67, 2798-2804.

7) Hinkle, R. J.; McDonald, R. †, "(Z)-2-Methyl-1-buten-1-yl(aryl)iodonium Triflates Containing Electron-Withdrawing Groups on the Aryl Moiety." Acta Cryst. C. 2002, C58, o117-o121.

8) McNeil, A. J. ; Hinkle, R. J.; Rouse, E. A.; Thomas, Q. A.; Thomas, D. B. "Vinyl Carbocations: Solution Studies of Alkenyl(aryl)iodonium Triflate Fragmentations," J. Org. Chem. 2001 , 66, 5556-5565.

9) Hinkle, R. J.; Leri, A. C.; David, G. A.; Erwin, W. M. "Addition of Benzylzinc Halides to Alkenyl(phenyl)iodonium Triflates: Stereoselective Synthesis of Trisubstituted Alkenes," Org. Lett. 2000, 2, 1521-1523.

10) Hinkle, R. J.; McNeil, A. J.; Thomas, Q. A.; Andrews, M. N. “Vinyl Cations in Solution: Kinetics and Products of Alkenyl(aryl)iodonium Salt Fragmentations,” J. Am. Chem. Soc. 1999, 121, 7437-7438.

11) Hinkle, R. J.; Thomas, D. B. “Facile Fragmentations of Alkenyl(aryl)iodonium Triflates,” J. Org. Chem. 1997, 62, 7534-7535.

12) Hinkle, R. J.; Stang, P. J. "Stereospecific Synthesis of Trisubstituted Alkenyl-(phenyl)iodonium Salts from Vinylstannanes" Synthesis 1994, 313.

13) Hinkle, R. J.; Poulter, G. T.; Stang, P. J. "Palladium(II) and Copper(I) Co-Catalyzed Coupling of Stereodefined Alkenyl(phenyl)iodonium Salts and Unsaturated Tri-n-butylstannanes" J. Am. Chem. Soc. 1993, 115, 11626.

14) Hinkle, R. J.; Stang, P. J.; Arif, A. M. "Vinylplatinum Carbenes and Nitriles, Platinoxa-cyclic Complexes and Heck-Type Coupling Products Formed Via Reaction of ( sigma-2-propenyl)bis(triphenylphosphine)platinum(II) Triflate with Alkynols, Nitriles, and Acrylate Esters. Molecular Structure of [(PPh3)2PtCH2C(O)OCH3][OTf]" Organometallics 1993, 12, 3510.

15) Zhong, Z.; Hinkle, R. J.; Arif, A. M.; Stang, P. J. "Novel Synthesis of eta-3-Allyl)platinum(II) Complexes from Enol Triflates and Simple Olefins and Their Regiospecific Deprotonation" J. Am. Chem. Soc. 1991, 113, 6196.

16) Hinkle, R. J.; Stang, P. J.; Kowalski, M. H. "Vinylphosphonium Salts: Stereoselective Palladium-Catalyzed Vinylation of Triphenylphosphine with Vinyl Triflates" J. Org. Chem. 1990, 55, 5033.

17) Kowalski, M. H.; Hinkle, R. J.; Stang, P. J. "A Simple Highly Stereospecific Preparation of Vinylphosphonium Salts: Palladium-Catalyzed Vinylation of Triphenyphosphine via Vinyl Triflates" J. Org. Chem. 1989, 54, 2783.

18) Pike, R. M.; Mayo, D. W.; Butcher, S. S.; Butcher, D. J.; Hinkle, R. J., "Microscale Organic Laboratory IV: A Simple and Rapid Procedure for Carrying Out Wittig Reactions " J. Chem. Ed. 1986, 63, 917.

† University of Alberta, Edmonton, Alberta, Canada

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Recent External Presentations (Presenter underlined, Undergraduates in Bold)

1) Robert J. Hinkle,* Yajing Lian, Kristie M. Schmidt, Heather Stevenson, and H. Danielle Johnson, “Bi(III)-Initiated Two- and Three-component Addition/silyl-Prins Reactions Toward cis-2,6-Disubstituted Dihydropyrans,” Presented at the 58 th Southeastern Regional Meeting of the American Chemical Society, Augusta, GA, November 01-04, 2006. Oral Presentation 227.

2) Timothy J. Brown, Robert J. Hinkle,* Melissa M. Sprachman, Mamio C. Mattern, Yajing Lian, “ Investigations of p- Nucleophiles in the Synthesis of 2-6 Disubstituted Tetrahydropyrans,” Presented at the 58 th Southeastern Regional Meeting of the American Chemical Society, Augusta, GA, November 01-04, 2006. Poster Presentation 439.

3) Timothy J. Brown, Robert J. Hinkle, Melissa M. Sprachman, M. Christa Mattern, Yajing, Lian. Investigations of p -nucleophiles in the synthesis of 2,6-disubstituted tetrahydropyrans. Abstracts, 38th Middle Atlantic Regional Meeting of the American Chemical Society, Hershey, PA, United States, June 4-7 (2006), Poster Presentation.

4) Robert J. Hinkle, Yajing Lian, Y, M. Christa Mattern, Melissa M. Sprachman, “Bimuth(III)-Initiated Diastereoselective Cyclization-Addition Reactions toward 2,6-Disubstituted Tetrahydropyrans, 230 th ACS National Meeting, 28 August to 01 September 2005, Oral Presentation 538

5) Yajing Lian, Robert J. Hinkle, “Etherification reactions initiated by BiBr3: Total Synthesis of (+)-(S,S)-(cis-6-methyltetrahydropyran-2-yl)acetic Acid and its trans-Diastereomer,” 230 th ACS National Meeting, 28 August to 01 September 2005 , Poster Presentation 115.

6) Melissa M. Sprachman, M. Christa Mattern, Yajing Lian, Robert J. Hinkle, “Selective Tandem Cyclization-Addition Reactions Using catalytic Quantities of BiBr3 and π-Nucleophiles,” 230 th ACS National Meeting, 28 August to 01 September 2005, Poster Presentation 116.

7) Melissa M. Sprachman; Robert J. Hinkle,“The Use of Bismuth Compounds in the Non-Toxic Syntheses of Natural Products,” Arnold and Mabel Beckman Scholars Symposium, Irvine , CA , July 2005. Poster Presentation.

8) Robert J. Hinkle, Yajng Lian; Nichole D. Litvinas; Alex T. JenkinsJenkins; Daniel C. Burnette," BiBr3 Initiated Cyclization-Addition Reactions: Total Synthesis of (+) -(S,S)-(cis-6- Methyltetrahydropyran-2-yl)acetic Acid, its trans-Diastereomer and Effect of Nucleophile on Oxocarbenium Ion Additions, Presented at the National Organic Symposium, Salt Lake City, Utah, June 12-16, 2005. Poster Presentation B21.

9) Robert J. Hinkle, M. Christa Mattern, Melissa M. Sprachman and Nichole D. Litvinas, "Bismuth(III) Initiated Diastereoselective Cyclization-Addition Reactions Toward 2,6- Disubstituted Tetrahydropyrans," Presented at the 56 th Southeastern Regional Meeting of the American Chemical Society, Durham, NC, November 10-13, 2004. Oral Presentation 2004.

10) Yajing Lian, Robert J. Hinkle, Ann M. Mikowski, Michael C. Brochu, Robert R. Knowles, , "Isotope Effects and Mechanism(s) of Fragmentation of Alkenyl Iodonium Triflate Salts," Presented at the 56 th Southeastern Regional Meeting of the American Chemical Society, Durham, NC, November 10-13, 2004. Poster Presentation 255.

11) Melissa M. Sprachman, Nichole D. Litvinas, M. Christa Mattern, Robert J. Hinkle, Alex T. Jenkins, Daniel C. Burnette, "Stereoselective Tandem Cyclization-Addition Reactions Using Catalytic BiBr3," Presented at the 56th Southeastern Regional Meeting of the American Chemical Society, Durham, NC, November 10-13, 2004. Poster Presentation 800.

12) Santosh J. Gharpure, Robert J. Hinkle, Jian Cui, P. Andrew Evans,"Bismuth Catalyzed Diastereo- selective Etherification Reactions: Application to the Synthesis of Non-Adjacent and Fused Polycyclic Ethers," Presented at the National Organic Symposium, Bloomington, IN June 8-12, 2003. Poster Presentation C94.

13) Robert J. Hinkle, P. Andrew Evans, Jian Cui, Benedicte D. Delouvrie, “Diastereoselective Syntheses of Di– and Trisubstituted Cyclic Ethers via Tandem Cyclization-Addition Reactions,” Presented at the 225th American Chemical Society Meeting, New Orleans, LA, March 23-27, 2003. Oral Presentation 666.

Bismuth Chemistry Links

Professor Ram Mohan, Bismuth Expert

Professor P. Andrew Evans, Bismuth Expert

Green Chemistry Link (EPA)

EnvironmentalChemistry.com

US Geological Survey general information

General Information

Organic Chemistry Links

Dave Evans' Organic pKa Table (Harvard)

Herbert Meyer's Nucleophilicity Tables

Professor Scott D. Rychnovsky's TLC Stain Recipe link

Hans Reich's Links