Professor Scott E. Denmark University of Illinois, Urbana-Champaign. Activating Acids with Bases: Theory and Applications An Homage to G. N.

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1 Professor Scott E. Denmark University of Illinois, Urbana-Champaign Activating Acids with Bases: Theory and Applications An omage to G. N. ewis Ischia Advanced School of rganic Chemistry 2006 Ischia, Italy September 2006 QuickTime and a Photo - JPEG decompressor are needed to see this picture. G. N. ewis ( )

2 (Asymmetric) Catalysis: The Chemical Evergreen reagents catalysts

3 pportunities for Catalysis in the ain Group? ewis Acidity: B(3), Al(3), Ga(3), In(3) (4), Sn(2, 4), Pb(4) P(5), Sb(3, 5), Bi(3, 5) (2), S(2, 4, 6), Se(2, 4, 6), Te(2, 4, 6) F(1), (1, 3, 5, 7), Br(1, 3, 5, 7), l(1, 3, 5, 7) Catalyzed Chemical Processes Carbonyl addition reactions (aldol, allylation, ene) Acetal addition reactions Friedel-Crafts reactions Conjugate addition reactions Azomethine addition reactions Epoxide opening reactions Cycloadditions ([42], hetero [42], [32]), Electrocyclic reactions gmatropic (and other) rearrangements

4 Strategies for odulating ewis Acidity: Structural structural perturbations ( strain-release ewis acidity ) p orbital sp n hybrid distort B (ihkailov) N Δ 0 = kcal/mol N B θ = 109Þ distort θ = 90Þ F 3 C CF3 B 94Þ F 3 C CF 3 (J. C. artin) F 3 C F 3 C CF 3 CF 3 B θ = 77Þ e e e e e e Ph intramolecular silicon transfer e e e

5 Strategies for odulating ewis Acidity: Electronic electronic perturbations (electrophilic) B B Binding equilibrium becomes more favorable as electron deficiency at increases: = N 2 < < halide < Tf ~Tf 2 N B B electronic perturbations (nucleophilic?) F F Gutmann s Fourth ule spillover effect _ F " although a donor-acceptor B F F - interaction will result in a net transfer of B F electron density from a donor species F F to an acceptor species, it will, in the case of polyatomic species, actually electron deficient more electron deficient!! lead to a net increase of electron P2: q(au) density at the donor atom of the donor P2: q(au) species and to a net decrease of C. Cramer, private communication electron density at the acceptor atom of the acceptor species." Sb C CC net decrease net increase

6 Structure, Bonding and Charge Distribution in ypercoordinate licon Compounds sp 3 tetrahdral (T d ) formal bond order: Å charge charge ewis base () (3c-4e) p formal bond order (apical): 0.75 formal bond order (basal): 0.83 charge charge tbp (C 3v ) sp 2 ewis base () (a), -0139(b) (3c-4e) p sp octahedron (D 4h or C 2v ) formal bond order: Å charge charge Coordination by by both both neutral neutral and and anionic anionic ligands ligands results results in in a decrease in in the the electron density density at at the the central central silicon silicon atom atom and and an an increase in in electron density density on on the the ligands ypervalent bonding is is highly highly ionic ionic in in character and and dissociation can can be be facile. facile ypervalent bonds bonds favor favor electronegative ligands, sp sp bonds bonds favor favor electropositive ligands ligands. Gordon, J. Phys. Chem. 1990, 94, 8125

7 The ypervalent 3-Center/4 Electron Bond σ (U) n (NB) σ () hypervalent bonds formed from the p y and p z orbitals covalent bonds from sp-hybrids obtained from p x and s-orbitals ' ' hypervalent (3c-4e) bonds (p x and p z orbitals) binding site for s-donors binding site for s-acceptors covalent bonds (p y and s orbitals) N(2) C(12) (2) (2) (3) N(1) (1) (1) (4) C(11) -(1)/(2): Å -(3)/(4): Å

8 D ewis Base Activation of ewis Acids δ δ δ δ A D A D A increased positive charge ewis base ewis acid increased negative charge - The The kinetically significant (strong) ewis ewis acid acid is is generated only only in in the the presence of of the the ewis ewis base base thus thus negating the the achiral achiral background reaction. eactions can can be be run run with with a stoichiometric amount of of the the weak weak ewis ewis acid acid Increased rates rates Product inhibition is is minimized D ewis base ewis acid D D 3 ther ther electrophiles: enals, enals, enones, azomethines, epoxides, nitrones, nitroalkenes Pro Pro Nucleophiles: Nu- Nu- 3 = 3 allylsilanes (stannanes) enol enol silanes, silyl silyl ketene ketene acetals, etc. etc.

9 Catalytic Enantioselective Passerini eaction Ugi 3 3 N C C N * 2 1 multicomponent reactions for for molecular diversity 2 C 3 N 2 3 C 1 NC 2 2 C N C C C* C Passerini N 1 C N C 1 3 Isocyanide bears bears divalent carbon carbon atom atom with with electrophilic and and nucleophilic properties Up Up to to four four new new bonds bonds and and one one stereocenter created in in very very useful usefulα acyloxy amides amides Auxiliary-based approaches but but no no examples of of catalytic enantioselective process!!

10 Passerini eaction: ewis Base Activation of ewis Acid product release chloride capture 2 3 N n * 3 catalyst turnover 2 N 1 3 B 2 * 2 N ( 5 ) 2 addition ewis base catalyst (B*) C N [B 2 * 3 ] 2 activation of ewis acid 3 B 2 * 0.5 ( 6 ) ( 6 ) 2 binding to aldehyde activated silyl silyl cation cation preferentially binds binds carbonyl substrate, instead instead of of the the isocyanide attenuated ewis ewis acidity acidity of of the the silicon silicon center center in in imidoyl imidoyl chloride results results facile facile turnover catalyst turnover becomes the the release release of of the the ewis ewis base, base, instead insteadof of the the ewis ewis acid acid

11 Catalytic Enantioselective Passerini eaction: Aldehyde Survey t-bunc (1.2 equiv) 4 catalyst (1.1 equiv) (5 mol %) C 2 2 / -78 C 4 h yield 96% er: > 99/1 Nt-Bu yield 95% er: > 99/1 e e 3 N t-bu yield 89% er: 98.3/1.7 Nt-Bu F 3 C NaC 3 (aq) or 1. e 2. NaC 3 (aq) yield 89% er: 96.5/3.5 Nt-Bu Nt-Bu or e yield 93% er: > 99/1 Nt-Bu Nt-Bu e Nt-Bu Nt-Bu Nt-Bu yield 81% er: 97.8/2.2 yield 71% er: 97.9/2.1 yield 83% er: 95.9/4.1 yield 53% er: 87.1/12.9 yield 76% er: 77.0/23.0 yield 92% er: 81.9/18.1 Nt-Bu yield 88% er: 81.8/18.2 e e N N P N e e cat. e N P N N e e

12 Cast and Sponsors iping iping Su Su obert obert A. A. Stavenger Son Son Pham Pham Jiping Jiping Fu Fu Yu Yu Fan Fan Greg Greg Beutner Tommy Tommy Bui Bui Dr. Dr. Diane Diane Coe Coe Dr. Dr. Brian Brian Griedel Griedel Dr. Dr. Stephen B. B. D. D. Winter Winter Dr. Dr. Ken-Tsung Wong Wong Prof. Prof. Yutaka Yutaka Nishigaichi Dr. Dr. Sunil Sunil K. K. Ghosh Ghosh Dr. Dr. Thomas Wynn Wynn Dr. Dr. Steven Steven acneil Dr. Dr. arcel arcel Schleusner Dr. Dr. artin artin Eastgate Dr. Dr. ichael Edwards John John eemstra, Jr. Jr. Won-jin Chung Chung William William Collins Collins Tyler Tyler Wilson Wilson Peter Peter Yao Yao Dr. Dr. Brian Brian Eklov Eklov Dr. Dr. oballigh Ahmad Ahmad Funding National Science Foundation Eastman Kodak Kodak Company Boehringer Ingelheim Pharmaceuticals inistry of of Science and and Education (Japan) GlaxoSmithKline (UK) (UK) Pharmacia Corporation Abbott Abbott aboratories