Anion binding in Catalysis

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1 Anion binding in Catalysis Asymmetric and on-asymmetric Examples Andy Mcally MacMillan Group eting 2/04/09

2 Chiral Anion diated Chemistry Introduction! The use of 'cationic' counter-ion chemsitry far outweighs anion-binding! +!!! + Counter-ion Substrate vs Counter-ion Substrate! Ion-pair catalysis has been known for a very long time - phase transfer catalysis! Ion-pairing involving a catalytic anionic component has only recently emerged! ew strategy for catalysis:! Unexplored reactivity! Enhanced reactivity vs ligand based approaches! ew asymmetric variants and entirely new transformations

3 Chiral Anion diated Asymmetric Chemistry From umble Beginings to ew Strategies for Catalysis! The chiral pool provides a convenient source of enantiomerically pure anions 2 C C 2 C 2 C 2 C C 2 Sb Sb 2 F 3 C Eu 4 S 3 C eview: Lacour, J. Chem. Soc. ev. 2003, 32,

4 B B B B B B P P P

5 Chiral Anion diated Asymmetric Chemistry From umble Beginings to ew Strategies for Catalysis! Uses of chira anions: determination of enantiomeric purity P 3 P C 3 CD 3 t-bu S Mn(C 3 eview: Lacour, J. Chem. Soc. ev. 2003, 32,

6 Chiral Anion diated Asymmetric Chemistry From umble Beginings to ew Strategies for Catalysis! Uses of chira anions: purification and enantiomeric separation of cations X X (X = or 2 ) (X = or Br) P eview: Lacour, J. Chem. Soc. ev. 2003, 32,

7 Chiral Anion diated Asymmetric Chemistry From umble Beginings to ew Strategies for Catalysis! First transition metal-catalysed enantioselective transformation using chiral anions Cu(C) 4 B Ts ITs Benzene Arndstsen, B. A. rg. Lett. 2000, 2,

8 Chiral Anion diated Asymmetric Chemistry From umble Beginings to ew Strategies for Catalysis! Aziridination under 'classical' conditions displays a pronounced counteranion effect 10 mol% CuX, 0 ºC ITs t-bu (11 mol%) t-bu Ts X % ee (benzene) % ee (C) Tf PF Arndstsen, B. A. rg. Lett. 2000, 2,

9 Chiral Anion diated Asymmetric Chemistry From umble Beginings to ew Strategies for Catalysis! Synthesis of copper-boronate catalyst 1) 2 BBrS 2 2) Ag 2 C 3 Ag B Cu C Cu(C) 4 B Arndstsen, B. A. rg. Lett. 2000, 2,

10 Chiral Anion diated Asymmetric Chemistry From umble Beginings to ew Strategies for Catalysis! Ion-pair crystal structure Cu-, 2.16 Å

11 Chiral Anion diated Asymmetric Chemistry From umble Beginings to ew Strategies for Catalysis! Enantiocontrol from chiral boronate is low Cu(C) 4 B ITs (1-3 mol% Cu-B(*) 4 ) 1-3 mol% L Ts (S)-Cu-B(*) 4 ()-Cu-B(*) 4 (S)-Cu-B(*) 4 ()-Cu-B(*) 4 no ligand 7% ee (S) t-bu t-bu t-bu t-bu ()-Cu-B(*) 4 no ligand 13% ee () 12% ee () 7% ee () 10% ee () Arndstsen, B. A. rg. Lett. 2000, 2,

12 Chiral Anion diated Asymmetric Chemistry From umble Beginings to ew Strategies for Catalysis! Enantiocontrol from chiral boronate is low Cu(C) 4 B ITs (1-3 mol% Cu-B(*) 4 ) 1-3 mol% L Ts (S)-Cu-B(*) 4 ()-Cu-B(*) 4 (S)-Cu-B(*) 4 ()-Cu-B(*) 4 no ligand 7% ee (S) t-bu t-bu t-bu t-bu ()-Cu-B(*) 4 no ligand 13% ee () 12% ee () 7% ee () 10% ee () Arndstsen, B. A. rg. Lett. 2000, 2,

13 Chiral Anion diated Asymmetric Chemistry From umble Beginings to ew Strategies for Catalysis! Crystal structure of (bipy)cu( 2 C=C) + ()-B(*) 4 Cu-, 2.55Å

14 Chiral Anion diated Asymmetric Chemistry From umble Beginings to ew Strategies for Catalysis! Peptide derived chiral boranate cannot provide useful levels of enantioselectivity C 2 C 2 Cu(C) B C 2 C 2 C 2 Et C 2 Et 2 Et 1 mol%, C 2 2 max ee's 19% 34% 1:1 dr 3% yield Arndstsen, B. A. Tetrahedron: Asymmetry 2005, 16,

15 Titanium (IV) Catalysed Allylation Anion Binding With Useful Levels of Selectivity! Braun allylation of ethers is an overlooked reaction within this class t-bu TMS TMS Ti-cat. 10 mol% t-bu TMSTMS 96% 98.9% ee TiF 2 (S) 3 SiTiL*F 2 (±) TMS 3 SiTiL*F 2 () Braun, M. Angew. Chem. Intl. Ed 2004, 43,

16 Gold diated Counteranion Catalysis The Toste Story! Gold Catalysed enantioselective transformations were predicted to be difficult Large Distance Ligand Au + Substrate

17 Gold diated Counteranion Catalysis The Toste Story! Solution one: Development of bis(gold)-phosphine complexes t-bu Au Piv Ar 2.5 mol% cat. 5 mol % AgSbF 6 Ar Piv 60-85% 76-94% ee P P Au t-bu t-bu t-bu 2 2 ()-DTBM-SEGPS-(Au) mol% cat. * t-bu n 5 mol % AgSbF 6 Au n = 0, 67%, 93% ee n = 1, 96%, 88% ee P P t-bu t-bu 2 Ts 2.5 mol% cat. 5 mol % AgSbF 6 Ts 99%, 99% ee Au t-bu 2 (S)-DTBM-BIPEP-(Au) 2 Short eviews: Krause. Angew. Chem. Intl. Ed. 2008, 47, ; Widenhoefer. Chem. Eur. J. 2008, 14,

18 Gold diated Counteranion Catalysis The Toste Story! Chiral anion strategy may also overcome inherent proximity problem Large Distance Ligand Au + Substrate Counter-ion Short Distance

19 Gold diated Counteranion Catalysis The Toste Story! Counter-ion effects had already been identified in ligand controlled reactions Ts Ts Au P P 2 Au 2 ()-xylyl-biap-(au) 2 P Au P Au + BF 4 P Au 2+ 2BF 4 * * * P Au P Au P Au 3 mol% cat, 3 mol% AgBF 4 3 mol% cat, 6 mol% AgBF 4 81% 51% ee 82% 1% ee Toste, D. F. J. Am. Chem. Soc. 2007, 129,

20 Gold diated Counteranion Catalysis The Toste Story! Initial investigations: ligand vs anion control 3 mol% L(Au) 2, 3 mol% AgX C 2 2 P 2 P 2 P 2 P 2 AgBF4 Ag-C 2-4-( 2 )-C % ee Toste, D. F. Science 2007, 317,

21 Gold diated Counteranion Catalysis The Toste Story! Initial investigations: ligand vs anion control LAu or L(Au) 2, AgCat C 2 2 P Ag L = P 3 (5 mol%), 5 mol% ()-Agcat L = dppm (2.5 mol%), 5 mol% ()-Agcat L = dppm (2.5 mol%), 5 mol% ()-Agcat (benzene) 89% 48% ee 76% 65% ee 90% 98% ee dppm = 2 P P 2 Toste, D. F. Science 2007, 317,

22 Gold diated Counteranion Catalysis The Toste Story! Initial investigations: ligand vs anion control mol% dppm(au) 2 5 mol% Agcat. 1 n benzene, 23 C 3 1 n % 90-99% ee mol% (C S 2 s 3 ) 2 PAu 5 mol% Agcat. 1 1 benzene, 23 C 1 1 S 2 s % 96-99% ee Toste, D. F. Science 2007, 317,

23 Gold diated Counteranion Catalysis The Toste Story! Chiral amplification via ligand-counter ion relay Large Distance Ligand Au + Substrate Counter-ion Short Distance Toste, D. F. Science 2007, 317,

24 Gold diated Counteranion Catalysis The Toste Story! Chiral amplification via ligand-counter ion relay Large Distance Ligand Au + Substrate Interaction Counter-ion Chiral Amplification? Toste, D. F. Science 2007, 317,

25 Gold diated Counteranion Catalysis The Toste Story! Chiral amplification vis ligand-counterion relay 5 mol% Agcat. benzene, 23 C P Ag 2 P P 2 dppm 2.5 mol% dppm(au) 2 96% 80% ee Toste, D. F. Science 2007, 317,

26 Gold diated Counteranion Catalysis The Toste Story! Chiral amplification vis ligand-counterion relay 5 mol% Agcat. benzene, 23 C P Ag P P 2.5 mol% [(S,S)-DIPAMP](Au) 2 96% 92% ee (S,S)-DIPAMP Toste, D. F. Science 2007, 317,

27 Gold diated Counteranion Catalysis The Toste Story! Chiral amplification vis ligand-counterion relay 5 mol% L(Au) 2 5 mol% Agcat. benzene, 23 C P Ag P 2 P 2 dppm ()-AgCat. ()-BIAP ()-AgCat. (S)-BIAP ()-AgCat. 89% 12% ee (S) 91% 3% ee () 88% 82% ee (S) BIAP Toste, D. F. Science 2007, 317,

28 Chiral Couneranion-Aided Asymmetric ydrogenation Asymmetric Imine eduction! Imine hydrogenation via an ionic mechanism ' M M ' ' M ' ' ' M M + 2 orton, J.. J. Am. Chem. Soc. 2005, 127,

29 Chiral Couneranion-Aided Asymmetric ydrogenation Asymmetric Imine eduction! Imine hydrogenation via an ionic mechanism ' M M ' BF4 P 2 ' M ' 2 mol % Cpu(P-P) P 2 50 psi 2 (,)-orphos ' ' M M + 74% 54% ee 2 orton, J.. J. Am. Chem. Soc. 2005, 127,

30 Chiral Couneranion-Aided Asymmetric ydrogenation Asymmetric Imine eduction! Ir(III)-osphoric acid system leads to high enantioselectivities via ligand-anion control * L L M X* L * M L X* Xiao, J. J. Am. Chem. Soc. 2008, 130,

31 Chiral Couneranion-Aided Asymmetric ydrogenation Asymmetric Imine eduction! Ir(III)-osphoric acid system leads to high enantioselectivities via ligand-anion control * L L M X* L * M L X* [Ir] (1mol%) Pacid (6mol%) 2 (20 bar), toluene, 20 ºC Ar 2 S Ar 2 S Ar 2 S Ir Ir Ir P 0% 0% ee 30% 81% ee (Ar = 4-C 3 C 6 4 ) 27% 3% ee ( = 2,4,6-(2-C 3 7 ) 3 C 6 2 ) Xiao, J. J. Am. Chem. Soc. 2008, 130,

32 Chiral Couneranion-Aided Asymmetric ydrogenation Asymmetric Imine eduction! Ir(III)-osphoric acid system leads to high enantioselectivities via ligand-anion control * L L M X* L * M L X* [Ir] (1mol%) Pacid (x mol%) 2 (20 bar), toluene, 20 ºC Ar 2 S Ar 2 S Ir Ir + 1 mol% Pacid 2 P 2 * P * * * 76% 97% ee 92% 97% ee (Ar = 2,3,4,5,6-(C 3 ) 5 C 6 ) P ( = 2,4,6-(2-C 3 7 ) 3 C 6 2 ) Xiao, J. J. Am. Chem. Soc. 2008, 130,

33 Chiral Couneranion-Aided Asymmetric ydrogenation Asymmetric Imine eduction! Ir(III)-osphoric acid system leads to high enantioselectivities via ligand-anion control Ar 2 S 1 2 (Ar = 2,3,4,5,6-(C 3 ) 5 C 6 ) Ir P * * + 1 mol% Pacid 1 2 (20 bar), toluene, 20 ºC 2 2 PMB PMB 92-95% 84-97% ee 93% 91% ee 88% 95% ee PMB PMB P ( = 2,4,6-(2-C 3 7 ) 3 C 6 2 ) 90% 92% ee 91% 94% ee Xiao, J. J. Am. Chem. Soc. 2008, 130,

34 Chiral Counteranions in Transition tal Catalysis Chiral Co-Catalysts - List! Pd/Brønsted acid-catalysed direct allylation of aldehydes P 2 (1.0 equiv) 2 1 (1.5 mol%) Pd(P 3 ) 4 3 mol% 5A MS, MTBE, 40 ºC, 8-24 hr 1 1 = Ar: 40-89% 83-97% ee 1 = Alkyl: 45-65% 80-90%ee List, B. J. Am. Chem. Soc. 2007, 129,

35 Iminium Catalysis - An Alternative Approach Chiral Co-Catalysts - List! Proposed mechanism ()-TIP ()-TIP * P * P * * 1 Pd(0) 1 * * P Pd 1 List, B. J. Am. Chem. Soc. 2007, 129,

36 Chiral Anion ase Transfer Catalysis Chiral Borate Anions! everse of roles commonly associated in phase transfer systems ASYMMETIC IG PEIG F MES-AZIIDIIUM IS Anion cat. uc uc X (±) Et 3 + B P Ag elson <15% ee Toste >90% ee

37 Chiral Anion ase Transfer Catalysis Chiral Borate Anions! everse of roles commonly associated in phase transfer systems ASYMMETIC IG PEIG F MES-AZIIDIIUM IS Anion cat. uc uc X (±) Et 3 + B P Ag elson <15% ee Toste >90% ee

38 Chiral Anion ase Transfer Catalysis Chiral Borate Anions! everse of roles commonly associated in phase transfer systems ASYMMETIC IG PEIG F MES-AZIIDIIUM IS (±) 50 mol% cat. TF-Toluene 100 C *B() 4 2 A + Yield % ee % A + B Et Et () 3 18% 25% 30% 6% 15% 3% (, ) 8% (S, S) a + 12% 7% elson, A. Tetrahedron: Asymmetry 2003, 14,

39 Chiral Anion ase Transfer Catalysis Chiral Borate Anions! Ion-pairing M studies 3 + B Tf B A C A B C! Borate salt was found to be soluabalised but the aziridinium triflate in CD 3! Proton and carbon shifts vary linearly with amount of borate salt present! Lack of spliting of enatiotopic protons in the aziridium salt indicates poor discrimination from the chiral anion elson, A. Tetrahedron: Asymmetry 2003, 14,

40 Chiral Anion ase Transfer Catalysis Chiral osphonate Anions! everse of roles commonly associated in phase transfer systems ASYMMETIC IG PEIG F MES-AZIIDIIUM IS Anion cat. uc uc X (±) Et 3 + B P Ag elson <15% ee Toste >90% ee

41 Chiral Anion ase Transfer Catalysis Chiral osphonate Anions! alide abstraction method requires regeneration of chiral silver salt ASYMMETIC IG PEIG F MES-AZIIDIIUM IS Cat.Ag uc uc Ag Cat. Cat. (±)! Addition of an achiral Ag(I) source must not introduce an interfereing counteranion B AgCat. -al AgB alide Abstraction Agal Cat. + Cat. -uc uc

42 Chiral Anion ase Transfer Catalysis Chiral osphonate Anions! alide abstraction method requires regeneration of chiral silver salt ASYMMETIC IG PEIG F MES-AZIIDIIUM IS Cat.Ag uc uc Ag Cat. Cat. (±)! Addition of an achiral Ag(I) source must not introduce an interfereing counteranion B AgCat. -al AgB Agal Cat. ucleophilic Addition + Cat. -uc uc

43 Chiral Anion ase Transfer Catalysis Chiral osphonate Anions! alide abstraction method requires regeneration of chiral silver salt ASYMMETIC IG PEIG F MES-AZIIDIIUM IS Cat.Ag uc uc Ag Cat. Cat. (±)! Addition of an achiral Ag(I) source must not introduce an interfereing counteranion B AgCat. -al AgB ase Transfer Agal Cat. + Cat. Use solid phase Ag(I) solid-liquid PTC -uc uc

44 Chiral Anion ase Transfer Catalysis Chiral osphonate Anions! Suitability of silver(i) sources is crucial for the catalyst control ASYMMETIC IG PEIG F MES-AZIIDIIUM IS 15 mol% cat. Toluene, 50 C AgB Cat. (±) P Ag AgTs Ag 2 C 3 Ag 2 C 3 (4A MS) 88% 56% ee 77% 94% ee 84% 94% ee Toste, F. D. J. Am. Chem. Soc. 2008, 130,

45 Chiral Anion ase Transfer Catalysis Chiral osphonate Anions! Utility - alcohol and amine fucntionality TBS 81% 92% ee 67% 94% ee 85% 97% ee 50% 92% ee % 92% ee 70% 99% ee 76% 94% ee 80% 94% ee, 94% de Toste, F. D. J. Am. Chem. Soc. 2008, 130,

46 Chiral Anion ase Transfer Catalysis Chiral osphonate Anions! Utility - alcohol and amine fucntionality TBS 81% 92% ee 67% 94% ee 85% 97% ee 50% 92% ee % 92% ee 70% 99% ee 76% 94% ee 80% 94% ee, 94% de Toste, F. D. J. Am. Chem. Soc. 2008, 130,

47 Chiral Anion ase Transfer Catalysis Chiral osphonate Anions! Extention to meso-episulfonium ions uses a modified system ASYMMETIC IG PEIG F MES-EPISULFIUM IS C 3 15 mol% cat. S (±) S Toluene, 23 C Cat. S 90-98% yield 87-92%ee P! chanistically distinct from other phosphoric acid catalysed reactions enantioselectivity results from -bonding to the electrohile! ing opening of the meso-episulfonium is the enantiodetermining step. Ion-pairing is responsible for the stereoselectivity Toste, F. D. J. Am. Chem. Soc. 2008, 130,

48 ydrogen Bonding diated Counterion Catalysis Anion ecognition! Ureas and thioureas are proven motifs towards anion-binding using hydrogen bonding eview: Schmidtchen, F. P. Chem. ev. 1997, 97,

49 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! The stereoselectivity achieved by thiourea catalysts appears unusual 2 ' 1) 'C, 3A MS 2) Ac, 2,6-lutidine Cat. (5-10 mol%) Et 2, 30 to 60 ºC Ac ' 65-81%, 85-95%ee

50 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! The stereoselectivity achieved by thiourea catalysts appears unusual 2 ' 1) 'C, 3A MS 2) Ac, 2,6-lutidine Cat. (5-10 mol%) Et 2, 30 to 60 ºC Ac ' 65-81%, 85-95%ee ' S t-bu (i-bu) 2! "The ability to activate a weakly Lewis basic -acyliminium ion towards enantioselective transformations presents new opportunities for catalysis and raises intriguing questions as to the nature of this interaction." Jacobsen, E.. J. Am. Chem. Soc. 2004, 126,

51 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! -Bond donor - anion binding catalysis is proposed in n=1, 2 TMS, TBME Cat. (10 mol%) 55 ºC or 78 ºC n=1, 2! S 2 chanism 52-94%, 81-99%ee! Alkylated derivatives react significantly faster than reduced compounds. S 1 mechanism. Jacobsen, E.. J. Am. Chem. Soc. 2008, 127,

52 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! Two S 1-type mechanisms are likely t-bu S direct pathway spiro pathway 2 S 1

53 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! Two S 1-type mechanisms are likely t-bu S direct pathway! DFT calculations of fully ionised -acyliminium ions interacting with thiourea derivatives failed to converge on any ground state structure. spiro pathway 2 S 1

54 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! Two S 1-type mechanisms are likely t-bu S direct pathway! Pronounced counter ion effect: X ee 97% spiro pathway Br 68% I <5% 2 S 1

55 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! Two S 1-type mechanisms are likely t-bu S direct pathway! Pronounced solvent effect solv ee TBDME 97% spiro pathway TF 34% DCM <5% 2 S 1 see also: Jacobsen, E.. rg. Lett,2008, 10,

56 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! A versatile method for other highly reactive cationic species? ACYL-IMIIUM I STABILISATI XCABEIUM I STABILISATI? t-bu S t-bu S 3 4 uc 1 2 uc

57 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! A versatile method for other highly reactive cationic species? ACYL-IMIIUM I STABILISATI XCABEIUM I STABILISATI? t-bu S t-bu S 3 4 uc 1 2 uc! Cyclic oxo-carbenium ions are extremely unstable species (lifetime ~ s)! Enantioselective addtions to oxo-carbenium ions are extememly rare with only two examples reported (Braun: Angew. Intl. Ed. 2004, 43, and Evans: JACS, 2005, 127, ).

58 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! Importance of catalyst structure EATISELECTIVE ADDITIS T XCABEIUM IS 2 2 SI mol% cat. TBDME, 78 C 2 C % 74-97%ee 3º amide important for reactivity and selectivity CF 3 t-bu S eactivity at low temp CF 3 F Aryl group crucial for selectivity - engages oxocarbenium ion in TS? Jacobsen, E.. J. Am. Chem. Soc. 2008, 130,

59 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! Importance of catalyst structure EATISELECTIVE ADDITIS T XCABEIUM IS 2 2 SI mol% cat. TBDME, 78 C 2 C % 74-97%ee F C 2 C 2 C 2 C 2 87% 87% ee 71% 90% ee 70% 90% ee 96% 74% ee Jacobsen, E.. J. Am. Chem. Soc. 2008, 130,

60 ydrogen Bonding diated Counterion Catalysis The Jacobsen Story! Importance of catalyst structure EATISELECTIVE ADDITIS T XCABEIUM IS 2 2 SI mol% cat. TBDME, 78 C 2 C % 74-97%ee C 2 C 2 C 2 C 2 92% 92% ee 84% 94% ee 85% 92% ee 87% 93% ee Jacobsen, E.. J. Am. Chem. Soc. 2008, 130,

61 Iminium Catalysis - An Alternative Approach Chiral Co-Catalysts - List! Explotation of ion-pair intermediate in iminium catalysis X X Amine Controlled Stereoselectivity X* 1 2 X* Anion Controlled Stereoselectivity X* X* 'Matched' Ion-Pair Control 1 2

62 Iminium Catalysis - An Alternative Approach Chiral Co-Catalysts - List! eaction works across a range of aromatic aldehydes P 2 2 C C 2 (20 mol%) (1.1 equiv) Ar Dioxane, 50 C, 24 hr Ar 63-90% 96-99% ee List, B. Angew. Chem. Intl. Ed. 2006, 45,

63 Iminium Catalysis - An Alternative Approach Chiral Co-Catalysts - List! Achieving previously unatainable results - sterically unhindered aliphatic aldehydes P 2 2 C C 2 (20 mol%) (1.1 equiv) TF, r.t., 24 hr (E)-Citral ()-Citronellal 71% 90% ee TFA TFA 58% 40% ee 82% 40% ee List, B. Angew. Chem. Intl. Ed. 2006, 45,

64 Iminium Catalysis - An Alternative Approach Chiral Co-Catalysts - List! Extention to enone hydrogenation - matched-mismatched effects P 3 + C 2 t-bu 2 C C 2 (20 mol%) (1.1 equiv) Bu 2, 60 ºC, 24 hr CF 3 C ()-TIP ()-TIP 3 + (S)-TIP 3 + C 2 t-bu C 2 t-bu C 2 t-bu C 2 t-bu 66% 54% ee 66% 48% ee 81% 94% ee 45% 16% ee List, B. J. Am. Chem. Soc. 2006, 128,

65 Iminium Catalysis - An Alternative Approach Chiral Co-Catalysts - List! Extention to enone hydrogenation - substrate tolerance P 3 + C 2 t-bu Et 2 C C 2 Et (5 mol%) (1.2 equiv) n Bu 2, 60 ºC, 48 hr n 68-78% 96-98% ee 89-99% 90-98% ee 99% 96% ee = C 2 Et: 99% 90% ee = : 81% 70% ee List, B. J. Am. Chem. Soc. 2006, 128,

66 Iminium Catalysis - An Alternative Approach Chiral Co-Catalysts - List! Extention to enal epoxidation F 3 C CF 3 P 2 t-bu (10 mol%) F 3 C CF 3 (1.1 equiv) Dioxane, 35 ºC, 72 hr = Ar: 60-84%, 98:2->99:1 dr 90-96% ee = n-hex: 67%, 94:6 dr 70% ee (maj), 92% ee (min) List, B. Angew. Chem. Intl. Ed. 2008, 47,

67 Iminium Catalysis - An Alternative Approach Chiral Co-Catalysts - List! Tri-substituted enals have proven to be elusive substrates F 3 C CF 3 (10 mol%) P t-bu (1.1 equiv) 1 2 TBDME, 0 ºC, 24 hr 1 F 3 C 2 CF 3 2 Et Et 83% 94%ee 85% 94%ee 75% 90% ee 85% 72:28 dr 76% ee (trans), 92% ee (cis) List, B. Angew. Chem. Intl. Ed. 2008, 47,

68 Iminium Catalysis - An Alternative Approach Chiral Co-Catalysts - List! Proposed mechanism - unusual enantiodetermining step TIP Ar 2 Ar TIP Ar 2 Ar 2 TIP TIP Ar Ar Ar Ar t-bu Ar Ar t-bu t-bu TIP List, B. Angew. Chem. Intl. Ed. 2008, 47,

69 Weakly Coordinating Anions in Chemistry Background to Carboranes! on-coordinating anions Fact or fiction? 4 > BF 4 > PF 6 > B(C 6 5 ) 4 decreasing coordinating ability! Weakly coordinating anions or 'superweak anions': considerations PF 6 F abstraction S CF 3 Accessible coordination B(C 6 5 ) 4 Prone to hydrolysis, and oxidation Krossing, I. Angew. Chem. Intl. Ed. 2004, 43,

70 Weakly Coordinating Anions in Chemistry Background to Carboranes! What should we look for in a weakly coordinating anion? (r, how to make a very strong Brønsted acid)! Low nucleophilicity! Chemical inertness (especially to protonation!)! Low redox activity! Charge delocalisation! Large size! Peripheral atoms non-basic! Solubility in nonpolar solvents Krossing, I. Angew. Chem. Intl. Ed. 2004, 43,

71 Weakly Coordinating Anions in Chemistry Background to Carboranes! What should we look for in a weakly coordinating anion? Candidates: CF 3 F 3 C F 3 C F 3 C B CF 3 CF 3 [B(C 6 F 5 ) 4 ] CF 3 CF 3 [CB ] eviews: Strauss, S.. Chem. ev. 1993, 93, ; Seppelt, K. Angew. Chem. Intl. Ed. 1993, 33,

72 Weakly Coordinating Anions in Chemistry Background to Carboranes! A brief introduction to carborane chemistry! Constructed of 2c-2e - and 3c2e- bonds! Delocalised!-bonding (!-aromaticity)! 3D-analogue of benzene! Aromatic properties: delocalised bonding unusual stablilty propensity for substitution reactions! ther idications: resonance energies geometries (bond order indices etc.) magnetic properties! Very strong B- bonds (103 kcal/mol) Michl, J. Chem. ev. 2006, 106,

73 Weakly Coordinating Anions in Chemistry Background to Carboranes! Carborane charge distribution Michl, J. Chem. ev. 2006, 106,

74 Weakly Coordinating Anions in Chemistry Background to Carboranes! Carborane synthesis: B- Insertion route B commercially available but expensive Michl, J. Chem. ev. 2006, 106,

75 Weakly Coordinating Anions in Chemistry Background to Carboranes! Carborane synthesis: B- Insertion route ab 4 + BF 3 (Et)! Carbon insertion route ab % yield a C 3 aet Michl, J. Chem. ev. 2006, 106,

76 Weakly Coordinating Anions in Chemistry Background to Carboranes! Typical reactivity of carboranes n-buli I! Electrophilic substitution I 2, Ac 25 ºC I, DME 65 ºC I, 200ºC Michl, J. Chem. ev. 2006, 106,

Weakly Coordinating Anions in Chemistry Background to Carboranes! (CB 11 11 ) - The strongest known Brønsted acid! "Strong yet gentle": Can protonate C 60 and benzene to form isolable salts.

77 Weakly Coordinating Anions in Chemistry Background to Carboranes! (CB ) - The strongest known Brønsted acid! "Strong yet gentle": Can protonate C 60 and benzene to form isolable salts.! FS 3 /SbF 6 decomposes such molecules! Acidity only measurable by indirect (M) methods. utranks FS 3,! Stability due to weakly basic anion - large size, s-delocalisation, -shielding! Exceptional anion stability (c.f. SbF 6 & [B(C 6 F 5 ) 4 ] eed, C. A. Angew. Chem. Intl. Ed. 2004, 43, J. Am. Chem. Soc. 2006, 128,

78 Weakly Coordinating Anions in Chemistry Background to Carboranes! Solution to an old problem: existence of a trialkylsilylium ion ( 3 Si + )! Three coordinate silicon prone to coordination by anions, solvent and even argon!! Ave. C-Si-C = 116.5º! Si- bond length Å! 29 Si M (115 ppm) therefore 'ion like'.! Exceptional anion stability (c.f. SbF 6 & [B(C 6 F 5 ) 4 ]! ighly Lewis acidic silicon group eed, C. A. Chem. Commun. 2006, 7, Chem. Commun. 2005, 13,

79 Weakly Coordinating Anions in Chemistry Background to Carboranes! Solution to an old problem: 3 Si!+ (CB )!! Three coordinate silicon prone to coordination by anions, solvent and even argon!! Ave. C-Si-C = 117.6º! Si- bond length Å! 29 Si M (115 ppm) therefore 'ion like'.! Exceptional anion stability (c.f. SbF 6 & [B(C 6 F 5 ) 4 ]! ighly Lewis acidic silicon group eed, C. A. Chem. Commun. 2006, 7, Chem. Commun. 2005, 13,

80 Weakly Coordinating Anions in Chemistry Background to Carboranes! Uses of a 3 Si + cation: ydrodefluorination reactions catalyst F F catalyst F Si 3 Si 3 F! Challenges: C-F bonds are amongst the most passive functonalities in chemistry (C-F is the strongest single bond to carbon) C-F bond strengths increase as the degree of flourination increases C-F bonds are poor ligands and poor substrates for nuc substitution and oxidative addition Short eview: Braun, T. Angew. Chem. Intl. Ed. 2009, 48, 2-6.

81 Weakly Coordinating Anions in Chemistry Background to Carboranes! Uses of a 3 Si + cation: ydrodefluorination reactions catalyst F F catalyst F Si 3 Si 3 F! Why do we need a hydrodefluorination reaction? Despite the utility of fluorinated compounds (refridgerants, anesthetics, polymers, solvents, ligands, catalysts), the high persistence of fluorocarbons is responsible for their contribution to global warming Short eview: Braun, T. Angew. Chem. Intl. Ed. 2009, 48, 2-6.

82 Weakly Coordinating Anions in Chemistry Background to Carboranes! Uses of a 3 Si + cation: ydrodefluorination reactions Si- C-F Si-F C- favourable by ~ 190 kj / mol

83 Weakly Coordinating Anions in Chemistry Background to Carboranes! Uses of a 3 Si + cation: ydrodefluorination reactions Max T ~ 100 perfluorinated alkanes 0% conv serov,. V. J. Am. Chem. Soc. 2005, 127, Si- C-F Si-F C- favourable by ~ 190 kj / mol

84 Weakly Coordinating Anions in Chemistry Background to Carboranes! Uses of a 3 Si + cation: ydrodefluorination reactions Max T ~ 100 perfluorinated alkanes 0% conv serov,. V. J. Am. Chem. Soc. 2005, 127, Si- C-F Si-F C- favourable by ~ 190 kj / mol Max T ~ 30 perfluorinated alkanes 0% conv alkane solvents only i-bu 2 Al + 3 C + M [i-bu 2 -Al] + [Al(C 6 F 5 ) 4 ] or [i-bu 2 -Al] + [Al{C(CF 3 ) 3 } 4 ] Krossing, I. Tetrahedron Lett. 2007, 48,

85 Weakly Coordinating Anions in Chemistry Background to Carboranes! Uses of a 3 Si + cation: ydrodefluorination reactions 3 C[CB ] Et 3 Si Et 3 Si[CB ] 3 C F F F F CF 3 F F F C 3 F 86%, 0.08 mol% T = 1250 F F CF 3 Et 3 Si Et 3 SiF C 3 >97% conv T = 780 0%, 5% indane remainder higher MW F 3 C F 2 C CF2 F 2 C C2 C 3 28% >97% conv 13% T = % <3% serov,. V. Science 2008, 321,

86 Weakly Coordinating Anions in Chemistry Background to Carboranes! Uses of a 3 Si + cation: ydrodefluorination reactions 3 C[CB ] Et 3 Si Et 3 Si[CB ] 3 C F F F CF 3 F F F 53% + 26% F F F F in o-c (>97% conv. T = 1250) CF 3 Et 3 Si Et 3 SiF 76% in benzene (>97% conv. T = 780) F 3 C F 2 C CF2 F 2 C C2 C 3 28% >97% conv 13% T = % <3%

87 Anion Binding in Chemistry Conclusions! Area has promise for a general catalytic manifold! Much work is needed towards mechanistic understanding! Lots of scope for the design of new catalysts! Many new reactions to be discovered! 4-years is a very short amount of time since breakthrough reactions

Additions to Metal-Alkene and -Alkyne Complexes

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