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X reductive elimination
LnM + X Y -2 2
2. A mechanism the simplest LnM
Y oxidative addition
rationalization that is consistent with all
of the available data.
bond metathesis LnM R
MLn R
0 0
X M' 4-centered reaction X M'
3. A mechanism should provide
experimentally testable
predictions and can only be L insertion
disproved, never proven. LnM LnM L R -2 0
R de-insertion
Lewis acid
activation of
electrophile
LnM E + Nu LnM E Nu 0 0
M.C. White, Chem 153 Mechanism -2- Week of September 18th, 2012
1. Ligand Association/Dissociation
ligand dissociation
MLn MLn-1 + L
ligand association
Example:
Topics Discussed
1.Associative
2.Dissociative
M.C. White, Chem 153 Mechanism -3- Week of September 18th, 2012
Nu L
L L L L Nu L L L L
M M L M M M
L X L X L Nu L Nu
X
L X
16 e- 18 e- intermediates 16 e-
M = Ni(II), Pd(II),
Pt(II), Rh(I), Ir(I).
dx 2-y2
b1g
dxy
M.C. White, Chem 153 Mechanism -5- Week of September 18th, 2012
MeOH 1 1549
CH3CO2- <100
CO <100 N
Basicity of the incoming ligand
F- <158 N
(nucleophile) plays only a minor
2754
role in its reactivity for soft
metal centers. In general, the 158 N
H
softest (i.e. most polarizable) N
nucleophiles react fastest with
soft metals like Pt(II) via CH3O- <250 Br- 15,000
associative substitution. Steric (Et)3N 1175 I- 2.9 x 105
hinderance at the nucleophile C6H11CN 2.2 x 106
(i.e. picoline vs pyridine) can (CH3O)3P 1.7 x 107
retard the rate of substition. 1349
PhS- 1.5 x 107
N Ph3P 8.5 x 108
H
Et3P 9.8 x 108
Cl- 1096
NH3 1175
M.C. White, Chem 153 Mechanism -6- Week of September 18th, 2012
Et3P Et3P
PtII N , rt PtII + Cl
-
Et3P Cl Et3P Py
k2 =
100,000 M-1 sec-1
, rt
Et3P
PtII
N Et3P
PtII + Cl-
Et3P Cl k2 = Et3P Py
200 M -1 sec-1
Et3P N , rt Et3P
PtII PtII + Cl-
Et3P Cl k2 = Et3P Py
1 M -1 sec-1
+ (BAr'4) - (BAr'4) -
N N N
(BAr'4) -
Pd Pd Pd
N CH3 N CH3 N CH3
(BAr'4 )-
N CH3 R
= Pt
N
M.C. White, Chem 153 Mechanism -8- Week of September 18th, 2012
(BAr'4) (BAr'4)
- -
N N
Pd Pd
CH3 N CH3
N
+ + +
R - R (BAr'4 )-
R (BAr'4 )-
(BAr'4 )
N N CH3 N CH3
Pd High Mw
Pd Pd
CH3 insertion polymer N
polymers
N N
H propagation
R R R
-hydride
elimination
+ + + +
R (BAr'4 )- R (BAr'4 )- R R
(BAr'4 )- (BAr'4 )-
associative
N N displacement N N
Pd CH3 Pd CH3 Pd
Pd
N H N H N H N H
R R R R
Low Mw
polymers
rxn coordinate
0.20 1.65
t-Bu
P t-Bu
P t-Bu t-Bu
P Fe
Fe Pd0 P
P Fe Pd0 Fe
P catalyst "resting state"
P
P t-Bu t-Bu
t-But-Bu
"ineffective catalyst"
+L dissociative -L
The steric bulk of the bidentate phosphine
ligand is thought to weaken the Pd-P bond, t-Bu
t-Bu
thereby favoring ligand dissociation required P
to form the catalytically active species.
catalytically active
Fe Pd0
species
P
t-Bu
t-Bu
Cl + H2N N
NaOt-Bu H
Ligand dissociation: or hv
coordinatively and
electronically unsaturated
complexes capable of
oxidatively adding into
unactivated C-H bonds.
hv or
RhI CO RhI RhIII H
OC CO OC OC
18 e- 16 e- 18 e-
M-CO M-CO H
RhI
OC
hv
proposed
intermediate
P(Me)Ph2
Ir (PF 6- )
P(Me)Ph2
cat.
TOF = mol reduced substrate/mol catalyst/h Crabtree Acc Chem Res 1979 (12) 331.
M.C. White, Chem 153 Mechanism -13- Week of September 18th, 2012
X reductive elimination
LnM LnM + X Y
Y oxidative addition
Me
*Cp(Me3P)Ir Ir(PMe3)Cp* *Cp(Me3P)Ir
-C6H12 H
H
Ir(III), 18 e- Ir(I), 16 e- Ir(III), 18 e-
Topics Discussed
3.Mechanistic probes
M.C. White, Chem 153 Mechanism -14- Week of September 18th, 2012
R +
oxidative addition
LMn + R X L M (n+2) or L M(n+2) R X-
"Nu:" "E+" reductive elimination X
Reductive elimination (RE): microscopic reverse of oxidative addition where two M-L bonds are broken to form one substrate bond. RE
results in the addition of two electrons into the metal d electron count. This is reflected in a two unit decrease in the metal's oxidation state. The
breaking of 2 M-L bonds is accompanied by a decrease in the metal's coordination number by 2 units. The result is a 2 unit decrease in the
electron count of the metal complex (e.g. 18e- to 16 e-). The two M-L bonds undergoing reductive elimination must be oriented cis to each
other. Currently, RE is the most common way to form C-C bonds via transition metal complexes.
General OA Mechanisms:
Concerted (generally for non-polar substrates) Nucleophilic displacement (generally for polar substrates)
A A
A A + -
n (n+2) +
LxM + LxM n LxM LxM n
LxMn A X LxM(n+2) A
+ + X-
B B X
B
3-centered TS cis addition
Oxidative Addition
Metal Complex: electron rich metals in low oxidation states, with strong donor ligands and a site of coordinative unsaturation.
d10, tetrahedral, 18 e- --> d10, ML2, 14e - --> d8 , ML4, square planar, 16e - (e.g. Ni0 , Pd0 , Pt0)
d8, ML4 , square planar, 16 e- --> d6 , ML6, octahedral, 18e- (e.g. RhI, IrI)
H
+
H
P(Cy)3
IrI (PF 6- ) IrIII
H2
P(Cy)3
N
N
16e-
18 e-
Substrates: two groups segregated into non-polar and polar. Currently, the most facile way to form C-M bonds is with polar substrates
(e.g. alkyl, aryl, and vinyl halides).
Non-polar substrates: R-H Polar substrates: R-X where X = I, Br, Cl, OTf
H O X O
H2, R3Si-H, R2 B-H, RCH2-H, R H , , , R H-X, RCH2-X, , , R
H X
H X
M.C. White, Chem 153 Mechanism -16- Week of September 18th, 2012
-complex: intermolecular binding of a substrate via it's -bond to a metal complex. -complexes are
thought to be along the pathway for oxidative addition of non-polar substrates to low valent, e-rich metal
complexes. Analogous to the Dewar-Chatt-Duncanson model for olefin metal-bonding, -bonding is thought
to occur via a 2 way donor-acceptor mechanism that involves -donation from the bonding -electrons of the
substrate to empty -orbital of the metal and -backbonding from the metal to the * orbitals of the
substrate. These bonding principles have been applied to non-polar -bonds such as H-H, C-H, Si-H, B-H
and even C-C bonds.
H H
H H
LxM n + LxM n LxM n LxM (n+2) >1.6
H H H
0.74 0.84 H
Concerted mechanism: -complex formation precedes an early (little -bond breaking), 3-centered
transition state where strong -backbonding results in oxidative addition of the bound substrate to the metal.
The concerted mechanism is thought to operate primarily for non-polar substrates (i.e. H-H,C-H, Si-H, B-H)
with electron rich, low valent metals. The spectroscopic identification of metal dihydrogen -complexes with
H-H bond distances stretched between the non-bonding (0.74 ) and dihydride extremes (>1.6) provides
strong support for this mechanism with H2.
M.C. White, Chem 153 Mechanism -17- Week of September 18th, 2012
C
-complex
regioselectivity: sp 2 C-H > 1o sp3C-H> 2o sp3 C-H >>> 3o sp3 C-H. There is both a kinetic and thermodynamic preference to
form the least sterically hindered C-M bond. Kinetic preference: activation barrier to -complex formation is lower for less
sterically hindered C-H bonds and bonds with more s character. Thermodynamic preference: stronger C-M bonds are formed
(see Structure and Bonding, pg. 32).
Evidence in support of a -complex intermediate:
CD3
D3C CD3
CD3
D
hv (flash), Kr (165K) RhIII D
RhI CO RhI [Kr] RhI
D2C CD2
OC
OC CO OC OC
CD3 D3C
CO v (1946 cm -1) CD3
18 e- D3C CD3 CD3
-complex
H
IrI IrIII H
H3C OC OC
D12
hv
IrI CO IrI
OC CO OC
D
18 e-
IrI IrIII D
OC OC
D11 D11
-complexes
Less than 7% of the crossover products were observed by 1 HNMR. This may be indicative of a minor radical pathway.
H2C
D11
IrII H + IrII D IrIII H IrIII D
OC OC OC OC
OA: sp3C-sp3C
C
CR3 -backbonding>>
-donation
M M
oxidative addition
C
R
R R C
Even though BDE's of C-C bonds are lower than those of analogous C-H bonds (e.g. C6H5-CH3:100 kcal/mol vs.
C6H5-H: 110 kcal/mol), transition metal mediated OA's into C-C bonds are much more rare than those for
analogous C-H bonds. Formation of the -complex is kinetically disfavored by steric repulsion between the metal
complex and the carbon substituents and by the high directionality of the sp3C-sp3C bond that localizes the
bonding orbital deep between the carbon nuclei. Milstein and coworkers are able to overcome the kinetic barrier
by approximating the C-C bond at the metal center.
R
R
LxM n + X oxidative addition LxM (n+2)
X
Rate of OA X = I>Br>Cl>>F
1. Concerted process with unsymmetrical, 2. SNAr-like with highly charged 3. Single-electron transfer processes with
minimally-charged, 3-centered transition state transition state oppositely-charged, radical intermediates
LxM (n+1)( )
Csp2 LxM n
LxM n
X
X X
M.C. White, Chem 153 Mechanism -22- Week of September 18th, 2012
OA: Csp3-X:alkyl, allyl, and benzyl halides
A + -
+
LxM n + LxM n A X LxM (n+2) A + X-
X
" Stereochemistry is the single most valuable type of mechanistic evidence in reactions that make or
break bonds to tetrahedral carbon." G.M. Whitesides (JACS 1974 (96) 2814).
+
CO2Me CO2Me CO2Me
(PPh3)4Pd
5 mol% (OAc-)
inversion
MeO 2C
+
CO2Me
OAc Na
(Ph3P) 2PdII
MeO 2C CO2Me
MeO 2C
inversion
net retention
Trost Acc. Chem. Res. 1980 (13) 385.
MeO 2C
Mes +
P (OTf- )
Pd II +
Mes Ph (OTf- )
P P
2 mol%
Mes
Ph Pd II + Ph
H2N
P
OH NH2 NHPh
Mes
Reductive elimination is a key transformation in transition metal mediated catalysis, often representing the product
forming step in a catalytic cycle.
General trend for reductive elimination from d 8 square planar complexes:
H H H H C(sp3)
M > M > M > M > M
2 3
H C(sp) C(sp ) C(sp ) C(sp3)
Orbitals with more s character are less directional and lead to better overlap in the transition
state for reductive elimination (RE). Note: cis orientation of the ligands is required for RE
to occur.
Best overlap Worst overlap
TMS
P CH2TMS P CH2TMS
P
C
Pd II 80oC Pd II Pd II
N
P CN k P C P
N
Ph 2 Ph 2
Ph 2 P P
O
P CH2TMS CH2TMS CH2TMS
Pd II Pd II Pd II
CN
P CN P CN O P
bite angle Ph 2 Ph 2 Ph 2
Large bite angles of diphosphines have been shown to enhance the rates of reductive elimination from
square planar complexes presumably by bringing the two departing ligands closer together.
O O F3C
NiII
O O O O
10 mol% O
I
Bu NiII O Bu
O
Pent2Zn Pent
50 mol% Bu
F3C 70% yield, 1h
possible intermediate
w/out -acid: 20%, 15h
3. Transmetallation
Example:
Ph PPh3 Ph PHPh3
Pd + Pd + Bu3SnBr
Bu3Sn
Ph3P Br Ph3P
Topics Discussed
2.Mechanism
3.Complex examples
M.C. White, Chem 153 Mechanism -27- Week of September 18th, 2012
Transmetalation: Definition and Utility
R
M Lr (n)
Lr M (n+2)
X
In generalthe rates of transmetalation of R follow the
order :alkynyl> aryl,vinyl>alkyl
oxidative addition
M= Ni, Pd R X
M.C. White, Chem 153 Mechanism -28- Week of September 18th, 2012
Transmetalation: Mechanism
The mechanism for transmetalation is the least-studied of the basic reaction steps. In a simple picture, the metal
accepting the R group is the electrophile and the M-R bond being transferred is the nucleophile. M-R bond formation
may or may not be simultaneous with M-X bond formation, depending on the nature of X and the actual complexes
involved.
+
M R M R
X M' M' X
With this model, increasing the nucleophilicity of R by altering the ligands on M and increasing the electrophilicity of M
through its ligands will facilitate the transmetalation step. For weakly nucleophilic transmetalation reagents, an added
nucleophile or base often facilitates the transmetalation.
-
R' R' R R
Transmetalation with the -
OR
Suzuki coupling often B B + LnPd II
LnPd
requires added base
OR
RO OR RO
OR X R'
Suzuki Chem. Rev. 1995 (95) 2457.
R R
F- is thought to activate the -
organosilicon reagent for TBAF
R' SiRnF3-n R' SiRnF4-n + LnPd LnPd
transmetalation via
formation of a nucleophilic X R'
pentavalent silicate in a
Hiyama coupling
Hiyama Tet. Lett. 1990 (31) 2719.
M.C. White, Chem 153 Mechanism -29- Week of September 18th, 2012
Suzuki-Miyaura
OBn OBn
H H
O O
9BBN
BnO BnO
OTBS THF, rt
O O O O OTBS
H H H H
BnO H H 9BBN
BnO
OBn
OBn H
H O OBn
O O
OTBS
BnO O OBn
O O H H H
TfO H
H O O
O
BnO H
3M aq. Cs 2CO3, DMF
Pd(Ph3)4, 0C
OBn
71%
Synthetic studies on Ciguatoxin
insertion insertion
CO
LnM COR R
LnM LnM
R de-insertion R de-insertion LnM
Example:
CO
Cp2*Nb Cp2 *Nb
Me Cp2*Nb Me
H CO
Nb(III), 18 e- Nb(III), 16 e- Nb(III), 18 e-
Topics Discussed
1.What is it?
2.Mechanism
3.Beta-hydride elimination
M.C. White, Chem 153 Mechanism -31- Week of September 18th, 2012
Migratory Insertion/De-insertion: Alkyl, H
CH3
Zr Zr
Zr
CH3 C H
H3
The -bonding electrons of the olefin are used in -bond formation with a M-alkyl *. Formation of the new C-C and M-C
bonds are thought to occur simultaneously with breaking of the -bond and alkyl-M bond through a 4-centered concerted transition
state. Migratory insertion of a hydride into a coordinated olefin (the microscopic reverse of -hydride elimination) is thought to
procede via the same mechanism. For metal alkyls, the equilibrium lies to the right, whereas for metal hydrides it lies to the left.
Early TS Late TS
Grubbs and Coates Acc. Chem Res. 1996 (29) 85.
M.C. White, Chem 153 Mechanism -32- Week of September 18th, 2012
-Hydride Elimination
A significant decomposition pathway for metal alkyls is -hydride elimination which converts a metal alkyl into a
hydrido metal alkene complex.
+ (BAr '4)- + (BAr '4)-
R R
+ (BAr '4)-
R
N CH3 hydride N CH3 N
Pd II elimination Pd II Pd CH3
N N N H
H H
R R R
donative agostic interaction concerted transition state
H
-donation >>
M
-backbonding
C
-complex
M.C. White, Chem 153 Mechanism -33- Week of September 18th, 2012
Wacker Oxidation
HCl
H OH
Pd ClPd R
Cl
OH H
R -hydride elimination
O OH HClPd
R R
Computational studies suggest that the higher energy of the Ni(II) vacant d orbital (0.1069 hartree) with respect to that of the
analogous Pd(II) complex (0.0505 hartree) results in a weaker donative agostic interaction with the CH bond. The energetically
optimized geometries of the agostic complexes show a greater lengthening of the C-H bond in the Pd(II) complex than in the Ni(II)
complex, indicative of greater -donation in the former. These computational results are consistent the experimentally observed
greater stability of Ni alkyls towards -hydride elimination that Pd alkyls and can be rationalized based on the greater
electronegativity of Pd(II) vs Ni(II) as reflected in their respective second ionization potentials.
1.10 1.13
H H
NiII PH3 Pd II PH3
H H
second ionization potential
Ni(II): 18.15 eV second ionization potential
Pd(II): 19.9 eV
Morokuma JACS 1985 (107) 7109.
recall: sp3 C-H is 1.09
M.C. White, Chem 153 Mechanism -35- Week of September 18th, 2012
Migratory Insertion/De-insertion: CO
O
H3C O
C C
CO
88.2 o H3C 101.3 o
H3C Pd II H Pd II H Pd II H
119.6 o
88.8 o
PH3 PH3 PH3
alkyl groups migrate Computational studies suggest that in the no oxidation state change at M
preferentially over TS, the methyl group has moved up half
hydrides -2e from the electron count
way towards the carbonyl.
-hydride reductive +
CO
R3P CO R3P insertion R3P elimination R3P elimination O
Pd II Pd II O Pd II O Pd II
R3P -PR3 OC C H C H
H
cis-diethyl complex
CO reductive O
R3P CO R3P R3P
insertion elimination
Pd II Pd II PdII
PR3 -PR3 CO C
O
trans-diethyl complex
R3P Cl R3P Cl Cl
OC R ROC Cl COR
monomer dimer
R Monomer Dimer
N 0% 100%
Me 24% 76%
46% 54%
Cl 73% 27%
NC 100% 0%
Cross J. Chem. Soc., Dalton Trans. 1981, 2317.
M.C. White, Chem 153 Mechanism -37- Week of September 18th, 2012
Heck Arylation
MeO O NCO2Me
MeO O NCO2Me N
N
reasonable intermediates O
O
-hydride
elimination
OCONH2
MeO
MeO OMe
OMe
MeO O NCO2Me
MeO O NCO2Me N
N
O
O
()-FR-900482
93% yield
Danishefsky JACS 1993 (115) 6094.