Some artwig Chemistry Experimental Approaches and Detailed chanistic Analysis b. 1964 1986 A.B. Princeton U, Maitland Jones 1990.D. UC Berkeley, obert Bergman and ichard Anderson 1990-92 Post-doc, MIT, Stephen Lippard 1992 Yale Faculty Stoltz Group eting 15 March 2004, 8:00pm 147 Noyes aissa Trend
Experimental Approaches to and Detailed chanistic Analysis of Fundamental rganometallic eactions 1) eductive elimination of from Palladium(II) 2) β-ydrogen elimination from (I) NM I rganometallic Synthesis Kinetic analysis Equilibrium analysis -ray crystallography Computational analysis Microscopic reverse GC Simple, observable systems ther topics: Amination of aryl halides and sulfonates a-arylation of carbonyl compounds egiospecific funcionalization of alkanes with h and B lefin hydroamination Enantioselective allylic amination and etherification
Fundamental eactions and Common Steps in Catalysis From reductive elimination to unsaturated arylpalladium(ii) halide intermediates: L n 0 L n II L n II M M What can we learn about oxidative addn. by studying reductive elimination of aryl halides? eductive elimination of aryl halides: oy; artwig. JACS, 2001, 1232. Monomeric complexes with one dative ligands: Stambuli; Bühl, artwig. JACS, 2002, 9346 Directly observed eductive elimination: oy; artwig. JACS, 2003, 125, 13944. Monomeric complexes full paper: Stambuli; Incarvito, Bühl, artwig. JACS, 2004, 1184.
eductive Elimination of yl alides from (II) More electron-donating ligands undergo faster oxidative addition greater driving force for oxidation of a more electron-rich metal P SUPISING ESULT: eductive elimination is induced by addition of (tbu) 3 P and is thermodynamically favored over oxidative addition eaction studied: 1 3 (o-tol) 3 P 2 2 4 reductive elimination 70 C C 6 D 6 oxidative addition 2 [ ] 2 2 2 P(o-tol) 3 1 3 2 t-bu = Cl = Br = I t-bu = Cl = Br Qualitative rates observed eactions initiated from both sides of the reaction K eq values, yields obtained
eductive Elimination of yl alides from (II) 1 3 (o-tol) 3 P 2 2 4 reductive elimination 70 C C 6 D 6 oxidative addition 2 [ ] 2 2 2 P(o-tol) 3 1 3 2 Dimer yield K eq rate a. b. c. 1 = t-bu, 2 =, = Cl 70 9(3) x 10 2 1 = t-bu, 2 =, = Br 70 2.3(3) x 10 3 1 = t-bu, 2 =, = I 39 3.7(2) x 10 5 Slower Faster Yields for for the red. elim. paralled thermodynamic driving force, but rates did not. d. 3 = t-bu, = Cl 30 n.d. e. 3 = t-bu, = Br 75 3.3(6) x 10 4 Amt of added was crucial for high yields of. o-substitution increases K eq by factor of 10 (compare b and e). K eq for each halide is different by factor of 100 (compare a c). x. Addn. of to -dimer does not occur for c and e in the absence of P(o-tol) 3. ed. Elim occurs from a monomer? What is the monomer and how does it form? Is formation or reaction of the monomer rate determinig?
eductive Elimination of yl alides from (II) tbu (o-tol) 3 P Br 2 reductive elimination 55 C C 6 D 6 oxidative addition [ ] 2 P(o-tol) 3 tbu Br Varied [P(t-Bu 3 )], [P(o-tol) 3 ], and [-dimer] first-order appearance of each product was observed. xns monitored by 1 NM A B Plot A: Plot B: k obs faster at higher [P(tBu) 3 ] reaction induced by Inverse dependence of 1/k obs on [P(otol) P(tBu) 3 (Lineweaver-Burk) 3 ] k obs slowed by P(o-tol) 3 Non-zero y-intercept for Plot A = 1/V max, where V max is the limiting rate at high [P(tBu) 3 ]. Non-zero y-intercept for Plot B: V max is the limiting rate with no [P(o-tol) 3 ]. v = V max [S] K m [S] 1 1 = v i V max K m 1 V max [S] 0
eductive Elimination of yl alides from (II) Possible Paths 2 L 2 2 L 2 [ ] 2 2 P(o-tol) 3 Path A k 1 k 1 Path B 2 k 1 k 1 L k 2 L k 3 2 2 [ ] 2 (o-tol) 3 P Br 2 k 1 k 1 L L Path C k 2 L L k 3 [ ] 2 1/2 dimer L Path E Path D L k 1 k 1 L L (t-bu) 3 P L (t-bu) 3 P L k 4 [ ] 2 1/2 dimer L (t-bu) 3 P L (t-bu) 3 P L k 4 [ ] 2 1/2 dimer
(o-tol) 3 P Br eductive Elimination of yl alides from (II) Path E All data are consistent with Path E Features: ate law: 2 reversible dissociative ligand substitution unusual for square-planar geometry. Cleavage of the dinuclear species before reductive elimination. reversible association of : eversible association of, irreversible dimer cleavage: rate = k obs [dimer] rate = k obs [dimer] k 1 [ ] k obs = k obs = K 1K 2 k 3 [ ] k 1 [P(o-tol) 3 ] [ ] [P(o-tol) 3 ] 1 k 1[P(o-tol) 3 ] = k obs k 1 [ ] 1 k 1 y-intercept = 0 Path E k 1 k 1 L L Predicts positive slopes and non-zero y-intecepts for Plots A and B. First-order behavior in [dimer] = irreversible monomer formation. If y-intercept is non-zero, step must be irreversible. Every substitution event leads to reductive elimination ---> formation of monomers and reductive elimination is faster than dissociation of. L (t-bu) 3 P L k 3 (t-bu) 3 P L k 4 [ ] 2 1/2 dimer
eductive Elimination of yl alides from (II) Conclusions 1 3 (o-tol) 3 P 2 2 4 reductive elimination 70 C C 6 D 6 oxidative addition 2 [ ] 2 2 2 P(o-tol) 3 1 3 2 Some "fundamental principles" uncovered: eductive elimination is induced by coordination of a strongly electrondonating ligand, ; coupled with steric crowding, the thermodynamics can be altered so mcuh that reductive elimination of becomes favord thermodynamically. Despite the weak driving force, oxidative addition of occurs rapidy to ligated (0) in catalysis. Ligand subsitituion is the square-planar system is dissociative, probably due to steric situtation. Implies aromatic halide exchange is feasible. Equilibrium measurements Kinetic evaluation Forward and reverse reactions But: Species undergoing reductive elimination was never directly observed.
The Next Step Synthesis of a Monomeric ylpalladium alide Can the unsaturated species that are often intermediates in organometallic reactions be observed directy? P (dba) 2 1 L >10 TF or neat 25 C = Br or I 1-AdP(t-Bu) 2 L 2 40 TF or neat 70 C L = or P 2-AdP(t-Bu) 2 Proposed chanism: (dba) 2 L dba dba dba L L P Addition to (dba) 2 formed side products at > 0.1 M xidative additions to L 2 were slower than those to 1:1 mixture of (dba) 2 and ligand. eactions cannot occur through L 2 (0). Parallels reactivity in catalytic reactions JACS 2002, 124, 9346
A Monomeric ylpalladium alide Characterization and Agostic Interaction Monomeric T-shaped 2.27 Å 2.33 Å Ligand with greatest steric demand binds to the least hindered position. Covalent ligand with the largest trans effect binds trans to the open site. P Br P I Similar structures present in solution: 31 P and 13 C NM: 31 P NM chemical shifts of arypalladium halide complexes usually downfield from the (0) complex upfield shift observed. Cis disposition of and L indicated by small J P C for C1. No definitive 1 NM evidence (upfield signal). I: =, = Br, L = 2-AdP(t-Bu) 2 showed medium-strong band at 2710 cm -1, reduced relative to free ligand, which indicates a strong agostic interaction.
The Trans Effect Kinetic effect of the trans substituents on the lability of a leaving group, and on location of substitution Associative substitution pathway σ and π component C ~ CN ~ C 2 4 > P 3 ~ > C 3 > SC(N 2 ) 2 > C 6 5 > N 2 > ~ SCN ~ I > Br > Cl > py, N 3 ~ ~ 2 very large effect small effect σ Effect: Provide more p orbital to the trans group by moving the LG out of the region of strong overlap when the new group comes in to empty p z orbital. ---> weakening of M bond T y z M Y x π Effect: Trans ligand accomodates excess charge from entering ligand with empty π-symmetry orbitals it lowers the overall activation energy. ---> TS energy lowered. y T z M x Poor trans effect σ-effect π-effect Also called trans infulence
Monomeric ylpalladium alides eactivity and Potential P(1-Ad)(t-Bu) 2 Br 83% L Br eaction inhibited by added phosphine clean inverse first-order behavior. No adduct with added ligand was detected. Transition state of the rate-determining step lacks any coordinated phosphine. a number of other reactions... Dissociation of large phosphine may be necessary to allow olefin binding, or cis disposition of the olefin and the aryl group. P(1-Ad)(t-Bu) 2 Br Kinetically competent as an intermediate in amination of aryl halides: Br P(1-Ad)(t-Bu) 2 Br N 2 45 min, T, 98% N 2 Unique complexes, viable intermediates ---> chanistic studies of a variety of -catalyzed processes
Monomeric Complexes in Action Directly bserved eductive Elimination (0) II First step in almost all cross-coupling reactions. Empirical observation of rates for ox. addn.: I > Br > Cl faster slower Attributed to strengths of bonds. But: No thermodynamic data on oxidative addition. ates for elimination from directly have not been measured. Fundamental issues II Cl Cl (0) Faster than from Br or I if bond strength control relative reaction rates. Slower than from Br or I if properties of the transition state control rates. Address fundamental issues by studying reductive elimination from: L JACS, 2003, 125, 13944.
Directly bserved eductive Elimination Kinetics vs. Thermodynamics (t-bu) 3 P [ ] 2 70 C C 6 D 6 = Cl, Br, I = Br, I a. b. c. d. e. Complex yield K eq = Cl, = o-tol 76 10.9 x 10 2 = Br, = o-tol 98 32.7 x 10 1 = I, = o-tol 79 1.79 x 10 1 = Br, = 68 13.4 x 10 1 = I, = 60 0.51 10 1 rate slowest fastest faster Values of K eq determined by initiating reactions in both directions and establishing equilbrium. ed. Elim. from a more favorable than from b by a factor of 3000, b more favorable than c by a factor of 20. Values of K eq parallel strength of bonds. Kinetics do not correlate with thermodynamics.
Directly bserved eductive Elimination Kinetic Data (t-bu) 3 P 70 C [ ] 2 C 6 D 6 First order appearance of product. Dependence of rate on Br and on. asured by 1 NM. A B Plot A: Plot B: k obs faster at higher [P(tBu) 3 ] reaction induced by Inverse dependence of 1/k obs on Br P(tBu) 3 (Lineweaver-Burk) k obs slowed by Br Non-zero y-intercept for Plot A = 1/V max, where V max is the limiting rate at high [P(tBu) 3 ]. Non-zero y-intercept for Plot B: V max is the limiting rate with no Br v = V max [S] K m [S] 1 1 = v i V max K m 1 V max [S] 0
Directly bserved eductive Elimination Possible Pathways eductive elimination faster from 3-coordinate than from 4-coordinate complexes: Path A (t-bu) 3 P Br [ ] 2 k 1 o-tol (t-bu) 3 P Br Path B k 1 k 1 (t-bu) 3 P (Br) [ ] 2 Br Path C k 1 k 1 (t-bu) 3 P Br [ ] 2
Directly bserved eductive Elimination Path A Path A (t-bu) 3 P Br [ ] 2 k 1 o-tol (t-bu) 3 P Br Features: eductive elimination from starting arylpalladium bromide. In the case where the equilibrium is heavily to the side of reductive elimination: zero-order in [Br] zero-order in [ ] Not consistent with data
Directly bserved eductive Elimination Path B o-tol (t-bu) 3 P Br Path B k 1 k 1 (t-bu) 3 P (Br) [ ] 2 Features: eversible reductive elimination of Br to ligated complex with coordinated Br. Associative ligand substitution of phosphine for Br. ate law: rate = k obs [] k obs = k 1 [ ] k 1 [ ] first-order in zero-order in Br first-order in at low [ ] zero-order in at high [ ] Not consistent with data
Directly bserved eductive Elimination Path C o-tol (t-bu) 3 P Br Path C k 1 k 1 (t-bu) 3 P Br [ ] 2 Features: eversible reductive elimination of Br, with or without inermediate Br complex. Trapping by ate law: rate = k obs [] k obs = k 1 [ ] k 1 [Br] [ ] first-order in inverse first-order in Br when competes with k 1 first-order in at low [ ] zero-order in at high [ ] Consistent with data eaction most likely occurs by Path C
Directly bserved eductive Elimination Conclusions o-tol (t-bu) 3 P Br Path C k 1 k 1 (t-bu) 3 P Br [ ] 2 ate law: rate = k obs [] k obs = k 1 [ ] k 1 [Br] [ ] From Plots A & B: When [Br] = 0, y-intercept of 1/k obs vs. [Br] corresponds to 1/k 1, so k obs = k 1, and is the rate constant for reductive elimination. k 1 / = ratio of relative rate constants for oxidative addition and coordination of phosphine to [ ]. k 1 / 65. xidative addition to [ ] is faster than coordination of ligand. Conclusions: eductive Elimination of was directly observed. Thermodynamic parameters for x. Addn. and ed. Elim determined. igh kinetic barrier for x Addn and ed. Elim of Cl. Evidence for reversible cleavage on the path to ed. Elim. Slow activation of Cl is due to more than relative strength of Cl bond. xidative addition > ligand coordination for [P(tBu) 3 ].
ngoing Investigation of Unsaturated ylpalladium(ii) alide Complexes L n 0 Improved synthetic methods needed L L n II L n II P 1-Ad P 2-Ad L = P(t-Bu) 2 M M Fe Weak agostic interaction confirmed by computational studies, and in once case, spectroscopically. Geometric distortions accomidate the bulky ligands. A bulky 3 P cannot adopy a conformation that avoids steric interactions in a planar 4-coordinate geometry. =, 2,4-xylyl = Cl, Br, I, Tf t-bu t-bu P Br 1-Ad (o-tol) 3 P Br Br P(o-tol) 3 Factors that dictate nuclearity Factors that control reactivity 100.8 91.4 89.8 87.1 JACS 2004, 126, 1184.
Fundamental eactions and Common Steps in Catalysis β-hydrogen elimination and migratory insertion: L n M =, N, N? L n M Direct observations from alkoxo and amido complexes uncommon. β-ydrogen elimination from M alkoxo is not mechanistically well-defined. Is it similar to the conventional mechanism for metal-alkyls? L n M L n M L n M L n M Pt,, e, and h alkoxide examples show evidence for mechanisms distinct from that for metal-alkyls. -alkoxide β-hydrogen elimination: Zhao, esslink, artwig. JACS, 2001, 123, 7220. -alkoxides as intermediates: Mann, artwig. JACS, 1996, 118, 13109. -amido β-hydrogen elimination: artwig. JACS, 1996, 118, 7010. -hydroxides and N activation: Driver, artwig. rganometallics, 1997, 16, 5706.
Vaska-type Alkoxo Complexes Clean Thermolysis 3 P Na ' TF P 3 Cl 3 P P 3 ' = ' = = ' = =, ' = tbu =, ' = ipr =, ' = Cy P 3 70 C tol-d 8 ' 81 92% (P 3 ) 3 (C) verall β-elimination is irreversible First-order in [] Zero-order in P 3 at low [P 3 ] Small inhibition at high [P 3 ] Similar rates in toluene, TF, -Cl Na TF ' 3 P P 3 = ' = =, ' = =, ' = =, ' = Cl =, ' = CF 3 ' P 3 95-108 C tol-d 8 ' (P 3 ) 3 (C)
β-ydrogen Elimination Kinetic Data [] k obs x 10 4 s -1 2.1 ammett correlation: electron-withdrawing substituents decrease the reaction rate Stability of ketone TS stabilization educed stability of alkoxide? [] 1.9 Migration of atom with hydridic character [] [] [] [] [] t-bu Cy 3.0 2.2 3.5 2.6 1.5 [] starting %ee [P 3 ] tol-d 8 [P 3 ] (M) conv (%) racemization %ee after conv 84 0.3 40 84 84 0.3 75 81 >95 0.02 20 64 >95 0.02 40 18 >95 0.02 80 17 racemization at low [P 3 ] ate does not depend on steric and electronic properties at the β-hydrogen [] [] D D Effect of [P 3 ] on KIE determined kinetic importance of C bond cleavage depends on whether P 3 dissociation and β- elim. are reversible.
3 P P 3 3 P P 3 P 3 (P 3 ) 3 (C) Path A Path B 3 P P 3 P 3 [] 3 P Path F P 3 K 1 3 P Path C 3 P P 3 Path D k 1 k 1 3 P Path E P 3 P 3 K 1 3 P k 2 3 P 3 P k 3 k 2 3 P 3 P k 3 P 3 [] 3 P P 3 [] [] P 3 []
β-ydrogen Elimination Possible chanistic Paths 3 P P 3 3 P P 3 P 3 (P 3 ) 3 (C) Path A Path B 3 P P 3 P 3 [] 3 P P 3 Path C 3 P 3 P [] Path A: Alkoxide dissociation Dependent on solvent polarity Zero-order in [P 3 ] Stereochemistry independent of [P 3 ] Path B: Direct elimination Independent of solvent polarity Zero-order in [P 3 ] Stereochemistry independent of [P 3 ] Path C: reversible P 3 dissociation Zero-order in [P 3 ] Stereochemistry independent of [P 3 ] None is consistent with data
β-ydrogen Elimination Possible chanistic Paths 3 P Path F P 3 K 1 3 P P 3 Path D k 1 k 1 3 P Path E P 3 K 1 P 3 3 P k 2 3 P k 3 k 2 3 P 3 P k 3 P 3 [] 3 P P 3 [] P 3 [] Path D, E, F: rate = k obs [-] Path D: eversible P 3 dissociation reversible β-hydrogen elimination Inverse first-order in P 3 at high [P 3 ] acemization not accounted for 1 k obs = 1 k 1[P 3 ] k 1 k 1 predictions not consistent with observed data
β-ydrogen Elimination Possible chanistic Paths Path E k 3 3 P P 3 3 P k 3 P 2 K 1 - P 3 [] Path F P 3 K 1 3 P k 2 3 P k 3 P 3 [] Path E: eversible P 3 dissociation eversible β-hydrogen elimination Dissociation of ketone in the last step 1 k obs = 1 k 2[P 3 ] rate = k obs [-] K 1 K 1 k 3 Path F: eversible P 3 dissociation eversible β-hydrogen elimination Associative substitution of P 3 for ketone 1 k obs = k 2 [P 3 ] K 1 k 3 K 1 At low [P 3 ], Path E zero-order in P 3 β- elim >> P 3 recoordination At high [P 3 ] dependent on [P 3 ] recoordination P 3 >> β- elim. P 3 dissociation is reversible. At low [P 3 ], reversible P 3 dissociation, β- elim., associative displacement all occur. Nearly zero-order in P 3 (cancellation). At high [P 3 ], inhibition by [P 3 ]: Assoc. displacement >> ketone reinsertinon; β- elim. is irreversible, P 3 only involved in dissociative preequilibrium.
β-ydrogen Elimination Ligand affect on KIE Effect of [P 3 ] on KIE determined kinetic importance of C bond cleavage depends on whether P 3 dissociation and β- elim. are reversible. [] D [] D 6a-d 1 2-d 1 y-intercept KIE = 2.6 y-intercept KIE = 2.3 Path E 1 k obs = Path F 1 k obs = 1 k 2[P 3 ] K 1 K 1 k 3 k 2 [P 3 ] K 1 k 3 K 1 y-intercept contains rate constant for β- elimination, Path D would not have a significant KIE, because y-intecercept would only contain rate constant for ligand dissociation. β- elimination, C bond cleavage, must be reversible.
β-ydrogen Elimination Distinguishing Paths E and F 3 P P 3 K 1 P 3 3 P k 2 3 P 3 P P 3 K 1 P 3 3 P k 2 3 P Degree of racemization will be different for paths E and F. [P 3 ] alters relative rates for reinsertion and for ketone displacement. Path E: P 3 not involved in reinsertion or displacement. 2 P 3 [] 3 P P 3 3 P Path E P 3 Path F Path F
- β-ydrogen Elimination Conclusions Path F K 1 P 3 3 P k 3 3 P k 2 P 3 [] chanism for β-hydrogen elimination from similar to that for alkyl analogues and does not involve: solvent-assisted ligand dissociation direct elimination bimolecular hydride abstraction alkoxides are far more stable than alkyl analogues, despite open coordination site and labile monodentate phosphines. Vaska alkyl analogues undergo β-hydrogen elimination near 0 C. 3 P P 3 0 C (P 3 ) 3 (C) Alkoxo and amido complexes have simlar elimination rates. ed. Elim. for C << C N. --> coupling of aryl halide alcohol w/ α-hydrogen difficult Imines should be as reactive as ketones towards insertion, but olefins are the fastest.
Experimental Approaches to and Detailed chanistic Analysis of Fundamental rganometallic eactions o-tol (t-bu) 3 P Br Path C k 1 k 1 (t-bu) 3 P Br [ ] 2 eactivity of bonds is not just due to ground-state effects - Path F K 1 P 3 3 P k 3 3 P k 2 P 3 [] -alkoxides react like their alkyl analogues, and are actually more stable. Late transition-metal b-hydrogen elimination can occur by several mechanisms. If you have a system you can study, detailed mechanistic studies can provide insight into basic organometallic transformations that are nevertheless not well understood.