Course overview Instructor. Professor m-Christina White: whiteachemistrv. harvard. edu Mallinckrodt 314: office hrs. by appointment Teaching Fellows Qinghao Chen: chen @fas. harvard. edu Matthew Kanan: kanan @fas. harvard. edu Mark Taylor: mstavlor @fas. harvard. edu Course meeting Lectures: Tuesday and Thursday, 8: 30-10 AM Pfizer Lecture hall Sections: Alternate Wednesdays Mallinckrodt Rm. 318 Section 1: 1-2 30 PM Section 2: 2: 30-4 PM Section 3: 4-5 30 PM Introduction to transition metal-mediated organic chemistry. Organometallic mechanisms will be discussed in the context of homogeneous catalytic systems currently being used in organic synthesis(e.g. cross coupling, olefin metathesis, asymmetric hydrogenation, etc. ) Emphasis will be placed on developing an understanding of the properties of transition metal complexes and their interactions with organic substrates that promote chemical Course requirements: Exams: 20 pts(each) In class exams(three)will be given every 7-8 lectures. Although these exams will focus primarily on recent lecture topics, they will be cumu Exam I: October 10 Exam ll: November 12 Exam Ill: December Literature Discussions& Summaries: 20 pts Three papers from the recent literature will be distributed in class on alternating weeks and will be posted on the web. A one-page summary of one paper is due in section (JACS communication format recommended). All papers will be discussed in section and a familiarity with each is expected and may be tested for on exams. Literature summaries should clearly and succinctly convey the principal objective, results, and conclusions of the paper. A detailed, step-wise mechanism of the transition metal mediated reaction must be p roposed (preferably through figures)that describes the chemistry going on at the metal(d-electron count, complex electron count, oxidation state, ligand association/dissociation, etc)and at the organic substrate. Summaries submitted that exceed the l page limit will not be graded-no exceptions. No late summaries will be graded. Final Project: 20 pts well-characterized transition metal complex from the inorganic literature, propose its development into a viable catalytic system plication towards a 时1 process. NIH doctoral fellowship style recommended may not exceed all figures and ferences). Papers submitted that exceed the 4 page limit will not be graded-no exceptions. No late papers will be graded. Due January 15, 2003
Course Overview Instructor: Professor M.-Christina White: white@chemistry.harvard.edu Mallinckrodt 314: office hrs. by appointment Teaching Fellows: Qinghao Chen: qchen@fas.harvard.edu Matthew Kanan: kanan@fas.harvard.edu Mark Taylor: mstaylor@fas.harvard.edu Course Meeting: Lectures :Tuesday and Thursday, 8:30-10 AM Pfizer Lecture Hall Sections: Alternate Wednesdays Mallinckrodt Rm. 318 Begin September 25 Section 1: 1-2:30 PM Section 2: 2:30-4 PM Section 3: 4-5:30 PM Course Objective: Introduction to transition metal-mediated organic chemistry. Organometallic mechanisms will be discussed in the context of homogeneous catalytic systems currently being used in organic synthesis (e.g. cross coupling, olefin metathesis, asymmetric hydrogenation, etc.). Emphasis will be placed on developing an understanding of the properties of transition metal complexes and their interactions with organic substrates that promote chemical transformations. Course Requirements: Exams: 20 pts (each) In class exams (three) will be given every 7-8 lectures. Although these exams will focus primarily on recent lecture topics, they will be cumulative. Exam I: October 10 Exam II: November 12 Exam III: December 12 Literature Discussions & Summaries: 20 pts Three papers from the recent literature will be distributed in class on alternating weeks and will be posted on the web. A one-page summary of one paper is due in section (JACS communication format recommended). All papers will be discussed in section and a familiarity with each is expected and may be tested for on exams. Literature summaries should clearly and succinctly convey the principal objective, results, and conclusions of the paper. A detailed, step-wise mechanism of the transition metal mediated reaction must be p roposed (preferably through figures) that describes the chemistry going on at the metal (d-electron count, complex electron count, oxidation state, ligand association/dissociation, etc) and at the organic substrate. Summaries submitted that exceed the 1 page limit will not be graded- no exceptions. No late summaries will be graded. Final Project: 20 pts Starting with a well-characterized transition metal complex from the inorganic literature, propose its development into a viable catalytic system for application towards a synthetically useful process. NIH postdoctoral fellowship style recommended. Length may not exceed 4 pages (including all figures and references). Papers submitted that exceed the 4 page limit will not be graded- no exceptions. No late papers will be graded. Due January 15th, 2003
References of material in this are provided on the appropriate slides The following texts have been used as general reference guides in the preparation of these Crabtree, R.H. The Organometallic Chemistry of the Transition Metals; 3rd Edition Wiley: New York; 2001. (Available at the Harvard Coop) Huheey, J.E.; Keiter, E.A.; Keiter, R.L. Inorganic Chemistry: Principles of Structure and Reactivity; 4" Edition, Harper Collins: New York; 1993 Chemistry: 6 Edition, Wiley: New York: 1999 Collman, J. P; Hegedus, L S. Norton, J.R.; Finke, R.G. Principles and Applications of Organotransition Metal Chemistry, University Science: Mill Valley, CA; 1987 Hegedus, L.S. Transition Metals in the Synthesis of Complex Organic Molecules, Spessard, G.O.; Miessler, G L Organometallic Chemistry. Prentice Hall: Upper Saddle River. NJ Fleming, I. Frontier Orbitals and Organ ic Chemical Reactions. W iley: New York Corey, E.J. Cheng, X.-M. The Logic of Chemical Synthesis. Wiley: New York; 1989 Nicolaou, K.C.: Sorensen, EJ in Total Synthesis. VCH: Weinheim, Germany 1996 Non-Standard Journal abbreviations ACIEE Angewandte Chemie International Edition(English) HCa Helvetica Chimica Acta JACS Journal of the American Chemical Society Joc Journal of Organic Chemistry JOMC Journal of Organometallic Chemistry OL Organic Letters TL Tetrahedron letters
References The majority of material in this course is drawn from the primary literature. References are provided on the appropriate slides. The following texts have been used as general reference guides in the preparation of these lectures: · C rabtree, R.H. The Organometallic Chemistry of the Transition Metals; 3rd Edition; Wiley: New York; 2001. (Available at the Harvard Coop). · Huheey, J.E.; Keiter, E.A.; Keiter, R.L. Inorganic Chemistry: Principles of Structure and Reactivity; 4th Edition; HarperCollins: New York; 1993. · Co tton, F.A.; Wilkinson, G.; Murillo, C.A.; Bochmann, M. A dvanced Inorganic Chemistry; 6th Edition; Wiley: New York; 1999. · Collman, J.P.; Hegedus, L.S.; Norton, J.R.; Finke, R.G. Principles and Applications of Organotransition Metal Chemistry; University Science: Mill Valley, CA; 1987. · Hegedu s, L.S. Transition Metals in the Synthesis of Complex Organic Molecules; University Science: Mill Valley, CA; 1994. · Spessard, G.O.; Miessler, G.L. Organometallic Chemistry. Prentice Hall: Upper Saddle River, NJ; 1996. · Fleming, I. Frontier Orbitals and Organ ic Chemical Reactions. W iley: New York; 1976. · Corey, E.J.; Cheng, X.-M. The Logic of Chemical Synthesis. Wiley: New York; 1989. · Nicolaou, K.C.; Sorensen, E.J. Classics in Total Synthesis. VCH: Weinheim, Germany; 1996. Non-Standard Journal Abbreviations ACIEE Angewandte Chemie International Edition (English) HCA Helvetica Chimica Acta JACS Journal of the American Chemical Society JOC Journal of Organic Chemistry JOMC Journal of Organometallic Chemistry OL Organic Letters OM Organometallics TL Tetrahedron Letters
M C. White. Chem 153 Structure bonding-I Week of september 17. 2002 Organotransition Metal chemistry Organotransition Metal Chemistry(MCw definition): Transition metal mediated reactions that solve (or have potential to solve) challenging problems in the synthesis of organic molecules Coordination Chemistry Organometallic Chemistry The chemistry of transition metal complexes that have The chemistry of transition metal complexes that have noncarbon ligands(Werner complexes). Classification M-C bonds(organometallic complexes). Classification applies to the catalyst and all reaction intermediates applies to the catalyst and/or reaction intermediates R(O HCN NCCH3 HICCN Sharpless titanium-tartrate Trost enyne cycloisomerization catalyst epoxidation catalyst OTf NOH+-BuOOH 4A CH2Cl2,-20C CO,Me CO,Me 0 C(O) proposed intermediate oposed intermediate OH 70-90% yield CO,Me 94>98%ee Sharpless JACS 1987(109)5765 Trost JACS2002(124)5025 de lera synthesis 1995 285
M.C. White, Chem 153 Structure & Bonding -1- Week of September 17, 2002 Organotransition Metal Chemistry Organotransition Metal Chemistry (MCW definition): Transition metal mediated reactions that solve (or have potential to solve) challenging problems in the synthesis of organic molecules. Coordination Chemistry: The chemistry of transition metal complexes that have noncarbon ligands (Werner complexes). Classification applies to the catalyst and all reaction intermediates. Organometallic Chemistry: The chemistry of transition metal complexes that have M-C bonds (organometallic complexes). Classification applies to the catalyst and/or reaction intermediates. Ru H3CCN NCCH3 H3CCN (PF6-) R R Ru NCCH3 (PF6-) R Trost enyne cycloisomerization catalyst Trost JACS 2002 (124) 5025. + + proposed intermediate PPh3 Pd Ph3P PPh3 Ph3P Suzuki cross-coupling catalyst B(OH)2 N OTf CO2Me Ph3P Pd Ph3P N CO2Me proposed intermediate N CO2Me de Lera Synthesis 1995 285. O TiIV RO RO O TiIV O O O R'(O)C R' OR R' O OR OH t-BuOOH, 4Å MS O TiIV RO OR O TiIV O O R'(O)C CO2R O O R' O O t-Bu R R R OH O Sharpless JACS 1987 (109) 5765. Sharpless titanium-tartrate epoxidation catalyst CH2Cl2, -20oC 70-90% yield 94->98% ee proposed intermediate C(O)R' C(O)R
MC.White,Chem 153 Structure bonding-2 Week of September 17, 200 Complexity generating Reactions Wender's 5+2] Cycloadditions co C4H4CI2, 80 C, 3.5h OHH OH 90% Wender OL 2001(3)2105 Tandem heck Php Aco Ag,CO3, THF, reflux TBSO 82% OTBS Overman JOC 1993(58)5304
M.C. White, Chem 153 Structure & Bonding -2- Week of September 17, 2002 Complexity Generating Reactions OH O 1 3 10 12 O OH H OC Rh OC Cl Cl Rh CO CO 0.5 mol% C4H4Cl2, 80oC, 3.5h 90% 1 3 6 6 10 12 Wender's [5+2] Cycloadditions Wender OL 2001 (3) 2105. Tandem Heck O I O H TBSO O O H OTBS AcO Pd Ph3P OAc PPh3 10mol% Ag2CO3, THF, reflux 82% Overman JOC 1993 (58) 5304
MC.White,Chem 153 Structure bonding -3- Week of September 17, 200 Reactive Site Selectivity in Multifunctional Molecules No protecting groups used! The majority of the mass recovered after reaction termination was unreacted starting material OMe OMe PPh3 OMe Ru DH H O H PPh3 10 mol% CH] Ch, rt, 22h Meo 49% Meo E:z:1:1 HO HO Meo OMe OMe Schreiber JAcs1997(119)5106
M.C. White, Chem 153 Structure & Bonding -3- Week of September 17, 2002 Reactive Site Selectivity in Multifunctional Molecules HO MeO O OH N O H O O O OH OMe OMe O H HO MeO O OH N O H O O O OH OMe OMe O HO MeO O OH N O H O O O OH OMe OMe O H H H FK 506 Ru PPh3 PPh3 Cl Cl Ph H 10 mol% CH2Cl2, rt, 22h 49% E:Z ; 1:1 Schreiber JACS 1997 (119) 5106. No protecting groups used! The majority of the mass recovered after reaction termination was unreacted starting material
M C. White. Chem 153 Structure& Bonding-4. Week of september 17, 2002 Nobel Prizein chemistry 2001 William S. Knowles, Ryoji noyori Asymmetric catalysis The monsanto process K. Barry Sharpless wilkinson: Investigations into the reactivity of(PPh3)RhCl uncovered its Meo COH high activity as a homogeneous hydrogenation catalyst. This was the I homogeneous catalyst that compared in rates with heterogeneous NHAc counterparts(e. g. PtO,) Ph3P PhaP CI H2(I atm) wilkinson /.Chem. Soc: (A)19661711 BF4 H2 OMe w. Knowles: Replacement of achiral PPh, ligands with non-racemic phosphines((-)-methylpropylphenylphosphine, 69%ee)demonstrated that a chiral transition metal complex could transfer chirality to a non-chiral substrate during hydrogenation Pr(Ph)(Me)P, P(Me)(Ph)Pr Meo CO,H CO,H CO,H Pr(Ph)(M Cl H NHAc Knowles Chem. Commun. 1968. 144 15%ee 95%ee, 100 yield Electronically tuning the metal center and using a C2 symmetric, bidentate chiral phosphine ligand led to highly enantioselective hydrogenations of H30+ enamides (very good substrates for asymmetric hydrogenations). The Monsanto Process(1974)that resulted is the 1"commercialized asymmetric Meo CO,H is using a chiral transition metal complex. Asymmetric hydrogenation is the key step in the industrial synthesis of L-DOPA (arare Royal Swedish Academy H NH] ofScienceswww.kva.seAco amino acid used to treat Parkinsons disease) L-DOPA
M.C. White, Chem 153 Structure & Bonding -4- Week of September 17, 2002 Asymmetric Catalysis Nobel Prizein Chemistry 2001: William S. Knowles, Ryoji Noyori, K. Barry Sharpless Wilkinson : Investigations into the reactivity of (PPh3)RhCl uncovered its high activity as a homogeneous hydrogenation catalyst. This was the 1st homogeneous catalyst that compared in rates with heterogeneous counterparts (e.g. PtO2). Rh Ph3P Ph3P Cl PPh3 H2 (1 atm) Wilkinson J.Chem. Soc. (A) 1966 1711. MeO AcO CO2H NHAc Rh P P OMe OMe + BF4- H2 MeO AcO CO2H H NHAc 95% ee, 100 % yield MeO AcO CO2H H NH2 H3O+ L-DOPA cat. The Monsanto Process W. Knowles: Replacement of achiral PPh3 ligands with non-racemic phosphines ((-)-methylpropylphenylphosphine, 69%ee) demonstrated that a chiral transition metal complex could transfer chirality to a non-chiral substrate during hydrogenation. CO2H Rh Pr(Ph)(Me)P Pr(Ph)(Me)P Cl P(Me)(Ph)Pr CO2H Electronically tuning the metal center and using a C2 symmetric, bidentate chiral phosphine ligand led to highly enantioselective hydrogenations of enamides (very good substrates for asymmetric hydrogenations). The Monsanto Process (1974) that resulted is the 1st commercialized asymmetric synthesis using a chiral transition metal complex. Asymmetric hydrogenation is the key step in the industrial synthesis of L-DOPA (a rare amino acid used to treat Parkinson's disease). H2 (1 atm) * * * KnowlesChem. Commun. 15 % ee 1968, 1445. Royal Swedish Academy of Sciences:www.kva.se
MC.White,Chem 153 Structure&Bonding-5.Week of September17,2002 The Transition metal H He Transition metals (d-block metals ): L elements that can have a partially filled d B valence shell. Typically group 4-10 metals. 11 12 Al d electrons in group 345678910 3 are readily removed 43F45443f443d43dr via ionization those in K Sc i Ti V Cr Mn FeCo Kr group 1l are stable and generally form part of 55240 5s 4d 55 40 53240 55 4d7 5s/44 5s 40 Rb Y Zr Nb Mo Tc Ru Rh Pd: Ag CdIn the core electron configuration 4d 4d 635f263f3|6s25f6s25|63|6s5 La Hf Ta W Re Os Ir Pt i HgTI Rn EARLY LATE valence(d) electron count for complexed transition metals: the (n)d levels are F 4s23d6 below the (n+ I)s and thus get filled first. note that group d electron count (gas phase transition metals: (n+1)s is below(n)d in energy (recall OC-p。CO CO for oxidized metals. subtract the oxidation n= principal quantum # CO ate from the group
The Transition Metals * d electrons in group 3 are readily removed via ionization, those in group 11 are stable and generally form part of the core electron configuration. valence (d) electron count: for complexed transition metals: the (n)d levels are below the (n+1)s and thus get filled first. note that group # = d electron count OC Fe CO CO CO CO 3d8 K Sc Ti V Cr Mn Fe Co Ni Cu Zn Rb Y Zr Nb Mo Tc Ru Rh Pd Ag Cd Cs Hf Ta W Re Os Ir Pt Au Hg Na B Al Ga In Tl Li Ne Ar Kr Xe Rn H He 3 456 7 8 9 10 11 12 13 1 18 4s23d2 4s23d3 3d4 3d5 5s24d2 4d4 5s14d4 4d5 4s13d5 3d6 5s14d5 4d6 6s25d2 5d4 6s25d3 5d5 6s25d4 5d6 4s23d5 4s23d6 3d7 3d8 4s23d7 3d9 4s23d8 3d10 5s24d5 4d7 5s14d7 4d8 5s14d8 4d9 5s04d10 4d10 6s25d5 5d7 6s25d6 5d8 6s25d7 5d9 6s15d9 5d10 Transition metals (d-block metals): elements that can have a partially filled d valence shell. Typically group 4-10 metals.* EARLY LATE La M.C. White, Chem 153 Structure & Bonding -5- Week of September 17, 2002 N N N FeII Cl Cl 3d6 for oxidized metals, subtract the oxidation state from the group #. Fe 4s23d6 for free (gas phase) transition metals: (n+1)s is below (n)d in energy (recall: n = principal quantum #)
M C. White. Chem 153 Structure bonding-6- Week of September 17, 2002 Transition metal valence orbitals (n+D)p orbitals (n+l)s orbital p pr 9 Valence Orbitals: upper limit of 9 bonds may be formed. In most cases a maximum of 6 o bonds are formed and the remaining d orbitals are non-bonding. It's these non-bonding d orbitals that give TM complexes many of their unique properties 18 electron rule: upper limit of 18 e-can be accomodated w/out using antibonding molecular orbitals(MO s (n)d orbita d dxz dr dz and dx" -y orbital lobes located on the axes orbitals oriented 90 with respect to each other dxy, dxz, and dyz lobes located between the axes creating unique ligand overlap possibilities
Transition Metal Valence Orbitals · 18 electron rule: upper limit of 18 e- can be accomodated w/out using antibonding molecular orbitals (MO's). d z 2 dx 2-y 2 dxy dxz dyz (n)d orbitals · dz2 and dx2-y2 orbital lobes located on the axes · dxy, dxz, and dyz lobes located between the axes · orbitals oriented 90o with respect to each other creating unique ligand overlap possibilities p z p x py (n+1)p orbitals z y x (n+1)s orbital s M.C. White, Chem 153 Structure & Bonding -6- Week of September 17, 2002 · 9 Valence Orbitals: upper limit of 9 bonds may be formed. In most cases a maximum of 6 σ bonds are formed and the remaining d orbitals are non-bonding. It's these non-bonding d orbitals that give TM complexes many of their unique properties
M C. White. Chem 153 Structure bonding -7- Week of September 17, 2002 Electron counting Step 1: Determine the oxidation state of the metal Step 2: Determine the d electron count. Recall: subtract To do this, balance the ligand charges with an equal the metal's oxidation state from its group opposite charge on the metal. This is the metals formal oxidation state Co Rh cO Rh Ph, To determine ligand charges, create an ionic model by Step 3: Determine the electron count of the complex assigning each M-L electron pair to the more by adding the of electrons donated by each ligand to the electronegative atom (L). This should result in metal's d electron count stable ligand species or ones known as reaction ligands: 10e intermediates in solution metal: 8 H H ompl Rh: neutral(0) OC
Electron Counting Ph2P Rh CO P H OC O O O To determine ligand charges, create an ionic model by assigning each M-L electron pair to the more electronegative atom (L). This should result in stable ligand species or ones known as reaction intermediates in solution. CO OC P P O O O RhI H Ph2 -1 neutral (0) Step 1: Determine the oxidation state of the metal. To do this, balance the ligand charges with an equal opposite charge on the metal. This is the metal's formal oxidation state. Co Rh Ir 9 3d9 4d9 5d9 RhI = d8 Step 3: Determine the electron count of the complex by adding the # of electrons donated by each ligand to the metal's d electron count. CO OC P P O O O RhI H Ph2 2e- 2eligands: 10e- metal: 8 e- complex: 18 eM.C. White, Chem 153 Structure & Bonding -7- Week of September 17, 2002 Step 2: Determine the d electron count. Recall: subtract the metal's oxidation state from its group #
M C. White. Chem 153 Structure bonding -8- Week of september 17, 2002 η ligands Formal of e- n-Ligands (monodentate): charge donated lapticity(n): The number of atoms( x)in the ligand bi H(hydride) the metal H3(alkyl) CO 2222 terminal oxo peroxo t-B X(halides -X (bridging OR (2/metal) MM η alkyl p t-Bu u-OR(bridging) (2/metal) Proposed intermediates in VO(acac) catalyzed directed epoxidation of allylic alcohols Sharpless Aldrichimica Acta 1979(12), 63 OR,(ether) 2244 Bridging ligands(]) the ligand bridges 2 or more metals linear u-0XO o(terminal oxo) u-O(bridging) Cl Nr3(amine) 22222 No(nitrosyl)linear + Nishida Chem Lett. 1995 885
η1-Ligands Hapticity (ηx): The number of atoms (x) in the ligand binding to the metal V O O OR O O t-Bu V O O OR O t-Bu O η1-alkyl peroxo terminal oxo η2-alkyl peroxo Proposed intermediates in VO(acac)2 catalyzed directed epoxidation of allylic alcohols. Sharpless Aldrichimica Acta 1979 (12), 63. Bridging ligands (µ): the ligand bridges 2 or more metals Fe N O Fe N N Cl Cl N N N N N Nishida Chem. Lett. 1995 885. linear µ-oxo M.C. White, Chem 153 Structure & Bonding -8- Week of September 17, 2002 M X M M R O M M O M η1 ligands (monodentate): H (hydride) CH3 (alkyl) CO X (halides) µ-X (bridging) OR (terminal alkoxide) µ-OR (bridging) OR2 (ether) O2 (superoxide) O (terminal oxo) µ-O (bridging) PR2 (phosphide) PR3 (phosphine) NR2 (amide) NR3 (amine) imines nitriles NO (nitrosyl ) Formal charge # of edonated -1 -1 0 -1 -1 -1 -1 0 -1 -2 -2 -1 0 -1 0 0 0 +1 2 2 2 2 4 2 4 2 2 4 4 2 2 2 2 2 2 2 (2/metal) (2/metal) (2/metal) linear