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Tomislav Pintauer Department of Chemistry and Biochemistry Duquesne University

Highly Efficient Copper Mediated Atom Transfer Radical Addition and Cyclization Reactions in the Presence of Reducing Agents. Tomislav Pintauer Department of Chemistry and Biochemistry Duquesne University Pittsburgh, PA 15282.

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Tomislav Pintauer Department of Chemistry and Biochemistry Duquesne University

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  1. Highly Efficient Copper Mediated Atom Transfer Radical Addition and Cyclization Reactions in the Presence of Reducing Agents • Tomislav Pintauer • Department of Chemistry and Biochemistry • Duquesne University • Pittsburgh, PA 15282 12th Annual Green Chemistry and Engineering Conference, Washington DC

  2. Introduction and Background • Carbon-carbon bond formation is a fundamental reaction in organic synthesis. • One way to form such a bond and, thus, extend a carbon chain is by the addition of a polyhalogenated alkane to an alkene to form a 1:1 adduct: • This reaction was first reported in the 1940s and today is known as Kharasch addition or atom transfer radical addition(ATRA). • Historically, ATRA reactions were conducted in the presence of radical initiators and light (high yields of monoadduct for ATRA of CX4 to α-olefins, but low for styrene and methyl acrylate). Curran, D. P. Synthesis1988, 6, 417. Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science1945, 102, 128.

  3. Kharasch Addition Reaction • Free Radical Mechanism • Initiated by light or radical initiators (e.g. AIBN) • PRINCIPLE PROBLEMS: • Unavoidable radical-radical coupling reactions (kt≈1.0×109 M-1s-1) • Repeating radical addition to alkene to generate oligomers/polymers • Low chain transfer constant (ktr/kp) • SOLUTIONS: • Search for better halogen transfer agents (transition metal complexes) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science1945, 102, 128.

  4. Transition Metal Catalyzed (TMC) ATRA • Transition metal complexes of Fe, Ru, Co, Ni and Cu are particularly effective halogen transfer agents. • Variety of alkenes and alkyl halides can be utilized. • TO ACHIEVE HIGH YIELDS: • Radical concentration must be low (ka,1 and ka,2<<kd,1 and kd,2) • Further activation of the monoadduct should be avoided (ka,1>>ka,2 and ka,2≈0) • The formation of oligomers/polymers should be suppressed (kd,2[CuIILmX]>>kp[alkene]) Minisci, F. Acc. Chem. Rec.1975, 8, 165. Clark, A. J. Chem. Soc. Rev.2002, 31, 1. Severin, K. Curr. Org. Chem.2006, 10, 217.

  5. TMC ATRA in Organic Synthesis • Can be conducted intermolecularly and intramolecularly. • Atom transfer radical cyclization (ATRC) particularly attractive tool because it enables synthesis of functionalized ring systems. γ-lactones and γ-lactams Domino TMC ATRA Clark, A. J. Chem. Soc. Rev.2002, 31, 1.

  6. Current Drawbacks of TMC ATRA • TMC ATRA despite being discovered nearly 40 years before tin mediated radical addition to olefins and iodine atom transfer radical addition is still not fully utilized as technique in organic synthesis. • The principal reason is that TMC ATRA typically requires between 5 and 30 mol% of catalyst relative to alkene. • Problems in product separation and catalyst recycling. • Process is environmentally unfriendly and expensive. • Methodologies developed to overcome these drawbacks: • Design of solid supported catalysts • Use of biphasic systems (fluorous solvents) • Development of highly active complexes based on ligand design • Catalyst regeneration in the presence of reducing agents✓ Clark, A. J. Chem. Soc. Rev.2002, 31, 1.

  7. Catalyst Regeneration in the Presence of Reducing Agents • The rate of alkene consumption in ATRA depends on the ratio of concentrations of activator (CuI) and deactivator (X-CuII): • Deactivator accumulates during the process as a result of radical termination reactions. • Reducing agents can be used to regenerate activator. • Originally developed for atom transfer radical polymerization (ATRP). • Successfully adopted to ATRA catalyzed by copper(II) and ruthenium(III) complexes. 1. Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T. Eur. J. Inorg. Chem.2007, 563-571. 2. Eckenhoff, W. T.; Pintauer, T. Inorg. Chem.2007, 46, 5844-5846. 3. Quebatte, L.; Thommes, K.; Severin, K. J. Am. Chem. Soc.2006, 128, 7440-7441. 4. Matyjaszewski, K.; Jakubowski, W.; Min, K.; Tang, W.; Huang, J.; Braunecker, W. A.; Tsarevsky, N. V. Proc. Natl. Acad. Sci. U.S.A.2006, 103, 15309-15314.

  8. ATRA Catalyzed by CuI(TPMA)Cl Complex in the Presence of Reducing Agent AIBN TPMA • Can be conducted using either copper(I) or copper(II) complex. • TONs for 1-octene (4350-6700) and 1-hexene (4900-7200)highest so far for copper mediated ATRA. • Previous TONs ranged between 0.1 and 10! Eckenhoff, W. T.; Pintauer, T. Inorg. Chem.2007, 46, 5844-5846.

  9. ATRA Catalyzed by CuI(TPMA)Cl Complex in the Presence of Reducing Agent AIBN

  10. ATRA Catalyzed by [CuII(TPMA)Br][Br] Complex in the Presence of Reducing Agent AIBN • Highest TONs for copper mediated ATRA • Highly efficient ATRA in the presence of 5-100 ppm of copper Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T. Eur. J. Inorg. Chem.2007, 563-571.

  11. Reaction Kinetics for ATRA of CCl4 to Alkenes Kinetics for 1-Octene Copper(II) • Constant concentration of radicals • Apparent rate constant relatively independent on copper(II) concentration • Rate governed by AIBN decomposition AIBN

  12. Structural Features of CuI(TPMA)Cl and [CuII(TPMA)Cl][Cl] Complexes • Copper(I) and copper(II) complexes are structurally similar. CuI(TPMA)Cl [CuII(TPMA)Cl][Cl] Eckenhoff, W. T.; Pintauer, T. Inorg. Chem.2007, 46, 5844-5846.

  13. Structural Features of CuI(TPMA)Br and [CuII(TPMA)Br][Br] Complexes • Copper(I) and copper(II) complexes are structurally similar. CuI(TPMA)Br [CuII(TPMA)Br][Br] Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T. Eur. J. Inorg. Chem.2007, 563-571.

  14. Structural Features of CuI(TPMA)Br in Solution 1H NMR 400 MHz, (CD3)2CO • Low T 1H NMR consistent with X-ray structure. • Broadening of the spectra is induced by fluxional processes: • Dimer formation unlikely (inequivalent methylene protons). 1. TPMA dissociation 2. Br- dissociation

  15. Structural Features of [CuI(TPMA)]2[ClO4]2 1H NMR (400 MHz, (CD3)2CO) • First example of a dimer where one arm of TPMA ligand coordinates to the second metal center Distorted Tetrahedral Cu1-N1=2.2590(13) Å Cu1-N2=1.9909(12) Å Cu1-N3=2.2213(16) Å Cu1-N4=1.9593(13) Å

  16. Structural Features of [CuI(TPMA)(CH3CN)][BPh4] 1H NMR (400 MHz, (CD3)2CO) Axial elongation of Cu-N bond 90% [CuI(TPMA)(CH3CN)][BPh4] 10% [CuI(TPMA)]2[BPh4]2 180 K [CuI(TPMA)]2[ClO4]2 [CuI(TPMA)(CH3CN)[BPh4] Similar to CuI(TPMA)X Cu1-N1=2.069(6) Å Cu1-N2=2.430(6) Å Cu1-N3=2.077(6) Å Cu1-N4=2.122(6) Å Cu1-N5=1.990(6) Å

  17. Solution Equilibria for CuI(TPMA)X Complexes • Addition of TBABr sharpens 1H NMR spectrum. • Addition of TPMA sharpens 1H NMR spectrum (fast exchange). • Coordination of CH3CN observed. 298 K 1. Halide dissociation 2. TPMA arm dissociation

  18. Cyclic Voltammetry Studies • The role of halide anion coordination to [CuI(TPMA)]+ remains unclear. • Nature of ATRA (ISET or OSET)? • Equilibrium constant for ATRA can be expressed in terms of: For a given alkyl halide KATRA will depend on KET and KHP

  19. More Reducing CuIBr Complexes Higher Activity in ATRA -50 -100 -150 -200 -250 -300 -350 -400 -450 -500 0 E1/2 / mV v.s. SCE Qiu, J.; Matyjaszewski, K.; Thouin, L.; Amatore, C. Macromol. Chem. Phys.2000, 201, 1625-1631. Correlating Redox Potential with Catalyst Activity

  20. Cyclic Voltammetry of [CuI(TPMA)][A] Complexes • Coordination of bromide anion to [CuI(TPMA)]+ results in a formation of much more reducing CuI(TPMA)Br complex. • Kinetically, all complexes showed similar reactivity in ATRA (rate determining step is the decomposition of AIBN). Potentials are reported vs. Fc/Fc+.

  21. Conclusions and Future Outlook • Synthesis, characterization and exceptional activity of [CuII(TPMA)X][X] (X=Br- and Cl-) complexes in ATRA of polyhalogenated compounds to alkenes in the presence of reducing agent AIBN was presented. • [CuII(TPMA)Br][Br] in conjunction with AIBN effectively catalyzed ATRA of CBr4 and CHBr3 to alkenes with concentrations between 5 and 100 ppm, which is the lowest number achieved in copper mediated ATRA. • Counterion was found to greatly affect the redox potential of copper(I) complexes. • Structural and mechanistic studies of this interesting catalytic system are subject to further study. • Possible extension to synthetically more attractive ATRC reactions (including radical cascade reactions) is also considered.

  22. Acknowledgements Group Members Marielle Balili 3rd Year Graduate Student William Eckenhoff 2nd Year Graduate Student Carolynne Ricardo 2nd Year Graduate Student Financial Support Duquesne University Start-Up Fund Duquesne University Faculty Development Fund NSF X-ray Facility Grant (CRIF 0234872) NSF NMR Facility Grant (CHE 0614785) Petroleum Research Fund (PRF 44542-G7)

  23. Duquesne University-Department of Chemistry

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