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M.C. White, Chem 153
C-H Activation -241-
Week of November 4, 2002
The Holy Grail of Catalysis
R
R
CH3
CH2[M]
?
R
CH2R'
C-H activation: Process where a strong C-H bond (90-105 kcal/mol)
undergoes substitution to produce a weaker C-M bond (50-80 kcal/mol).
Functionalization: Metal-C bond is replaced by any bond except C-H.
Methods have been identified to regioselectivity effect C-H activation. Recall that there is both a
kinetic and thermodynamic preference to form the less sterically hindered 1o C-M intermediate (see
Structure & Bonding; pg. 32). The challenge lies in finding ways to selectively form the C-M
intermediate under synthetically useful, mild conditions that enable functionalization and catalyst
renewal.
ARTHUR: Yes we seek the Holy Grail (clears throat very quietly). Our quest is
to find the Holy Grail.
KNIGHTS: Yes it is.
ARTHUR: And so we’re looking for it.
KNIGHTS: Yes we are.
BEDEVERE: We have been for some time.
KNIGHTS: Yes.
ROBIN: Months.
ARTHUR: Yes…and any help we get is…is very…helpful.
Bergman Acc. Chem. Res. 1995 (28) 154. Exerpt from “Monty Python and the Holy Grail”; 1974.
M.C. White, Chem 153
C-H Activation -242-
Week of November 4, 2002
Bergman:C-H Activation via Late, Nucleophilic Complexes
H
H
M
π-backbonding>>
σ-donation
Hydrido(alkyl)metal
complex
M
oxidative addition
C
C
σ-complex
regioselectivity: sp2 C-H > 1o sp3C-H> 2 o sp 3 C-H >>> 3o sp3 C-H. There is both a kinetic and thermodynamic preference to form the least sterically
hindered C-M σ bond. Kinetic preference: activation barrier to σ-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).
MIII
H
H
Me3P
M = Ir, 1
Rh, 2
hv or ∆
These hydrido(alkyl)metal complexes are
prone to non-productive reductive elimination
in the presence of oxidants and non-productive
protonolysis in the presence of protic reagents
π-donor
H2
MI
MI
ligand
dissociation
oxidative
addition
L
16 e-
MI
CO
hv or ∆
coordinatively and
electronically unsaturated
intermediate
H
L
proposed
σ-complex
intermediate
OC
CO
low OS metals capable of
18 edonating electrons in σ-bond
M = Ir, 3
formation. Highly prone to air
Rh, 4
oxidation.
Bergman JACS 1982 (104) 352 (Cmp. 1).
Bergman OM 1984 (3) 508 (competition exp).
Graham JACS 1983 (105) 7190 (Cmp. 3).
Bergman JACS 1994 (116) 9585 (Cmp. 4).
MIII
with acyclic substrates
the Rh complex inserts
only into 1o C-H bonds
arbitrarily set at 1
H
L
18 eRelative rate constants for attack at a single
C-H bond by 1 and 2 at -60 oC.
C-H bond
benzene
cyclopropane
n-hexane (1o)
n-hexane (2o)
propane (1o)
propane (2o)
cyclopentane
cyclohexane
krel (Rh, 2) krel (Ir, 1)
3.9
19.5
2.1
10.4
2.7
5.9
0.2
0
1.5
2.6
0.3
0
1.1
1.8
1.0
1.0
M.C. White, Q. Chen Chem 153
C-H Activation -243-
Week of November 4, 2002
Evidence for intermolecular σ-complex formation
CD3
D3C
CD3
CD3
RhI
CO
D
hv (flash), Kr (165K)
OC
CO
18 e-
RhI
RhI [Kr]
RhIII
D2C
OC
-1
CD3
D3C
CO v (1946 cm )
D3C
CD3
CO v (1947 cm-1)
Bergman JACS 1994 (116) 9585.
CD2
OC
OC
D
CD3
CD3
CO v (2008 cm-1)
σ-complex
‡
D
Rh
∆G (kcal/mol)
OC
CD2(C(CD3)3
+ 6.9 kcal/mol
RhI [Kr]
OC + (CD3)4C
-3.2 kcal/mol
to products
RhI
OC
D
D2C
CD3
D3C CD3
The reaction of Cp*Rh(CO)2 with neopentane-d12 was monitored using low-temperature IR flash kinetic spectroscopy. The CO stretch at 1946 cm-1 was assigned to the
initial intermediate Cp*Rh(CO)(Kr) complex, which after photolysis-mediated formation shows rapid decay. During this time, a second CO stretch at 1947 cm-1 grows in and
then decays; this absorption is assigned to a transient intermediate Rh---CD σ-complex. The absorption at 2008 cm-1 is known to correspond to the product
Cp*Rh(CO)(D)(C5D11), which increases steadily throughout the course of the reaction. Note that this entire process occurs in less than 1.5 ms.
M.C. White, Chem 153
C-H Activation -244-
Week of November 4, 2002
Evidence for concerted C-H oxidative addition
crossover experiment: evidence in support of a concerted mechanism.
H
IrI
H 3C
OC
IrIII
H
IrIII
D
OC
D12
IrI
hv
CO
OC
IrI
OC
CO
18 e-
IrI
D
OC
OC
D11
D11
σ-complexes
Less than 7% of the crossover products were observed by 1 HNMR. This may be indicative of a minor radical pathway.
H2C
D11
II
Ir
H
IrII
+
OC
Bergman JACS 1983 (105) 3929.
OC
IrIII
D
OC
IrIII
H
OC
D11
D
M.C. White, Chem 153
C-H Activation -245-
Week of November 4, 2002
Dehydrogenation of alkanes to alkenes
-H2
R
R
H2
Catalyst requirements:
H2,
regeneration via olefin dissociation and
elimination of H2. H2 must be rapidly and
irreversibly removed to avoid olefin
hydrogenation and isomerization
R
H
3L
H
MLnx
MLnx-3
18e-
"14e-"
H
R
R
oxidative addition
metal
capable
of
shuttling between Mn
and Mn-2 oxidation states
β -hydride R
MLn-2x-1 elimination
MLn-2x
H
16e-
H
18e-
complex capable of accomodating
3 ligands from the substrate in its
coordination sphere mid-cycle
The first report:
O
PPh3
(BF4
Ir(III)
H
Ph3P
(coe)
+
H
O
recall: intermediate in cationic
hydrogenation catalysts
Crabtree JACS 1979 (101) 7738.
-)
10 eq
o
+
H
CD2Cl2, -60 C
Ir(III)
Ph3P
observed to form
quantitatively by
NMR
PPh3
+
(BF4-)
o
o
-10 C->40 C
Ir(I)
H
PPh3
(BF4-)
PPh3
75%
recall: hydrogenation catalyst
M.C. White, Chem 153
C-H Activation -246-
Week of November 4, 2002
Crabtree:thermal dehydrogenation of alkanes to alkenes
P(p-FC6H4) 3
O
H
CF3
Ir(III)
solvent
+
150oC
14 days
355 mM
sacrificial H2 acceptor with
unusually high heat of
hydrogenation
56% (54%)
4% (3%)
P(p-FC6H4) 3 7.1 nM
t-Bu
+
+
O
H
18% (17.5%)
yields based on
catalyst.
+
t-B u
trans-3-hexene 14% (18.5 %)
cis-3-hexene 8% (7.5 %)
2d, 1.4 tn
2d, 3 tn
tn = turnover #
Proposed Mechanism:
H
hydrogenation
H
Ir(III)
CF3
F
Ir(III)
β-hydride
elimination
"tail-biting"
H
Ir(III)
(p-FC6H4)3P
(C6H4p-F)3P
OC(O)CF3
CF3
O
Crabtree JACS 1987 (109) 8025.
(p-FC6H4)3P
CF3
H
O
Ir
14 e-
Ir(III)
OC(O)CF3
Ir(III)
CF3
O
t-Bu
(p-FC6H4)3P
O
P(p-FC6H 4) 3
(I)
hydrogenation
pathway
P(p-FC6H 4) 3
t-Bu
P(p-FC6H 4) 3
O
Ir(I)
R
isomerization
pathway
H
t-Bu
(C6H4p-F)3P
OC(O)CF3
P(p-FC6H4) 3
(C6H4p-F)3P
(C6H4p-F)3P
R
Ir(III)
R
(p-FC6H4)3P
H
oxidative
addition
R
OC(O)CF3
H
O
R
P(p-FC6H4) 3
H
H
P(p-FC6H4) 2
H
isomerization
P(p-FC6H 4) 3
OC(O)CF3
(p-FC6H4)3P
Ir(III)
H
t-Bu
P(p-FC6H4) 3
H
H
O
H
P(p-FC6H 4) 3
R
O
Ir(III)
2d, 9 tn
P(p-FC6H 4) 3
P(p-FC6H4) 3
R
Product distributions of linear alkenes
are thought to result from isomerization
of the initial kinetic 1-ene product via
intermediate Ir hydride species.
Subjecting 1-hexene to the reaction
conditions
gives similar
olefin
distributions (in parentheses).
OC(O)CF3
R
only trifluoroacetate complexes
were
active
in
alkene
dehydrogenations. Their greater
lability with respect to acetate
may allow
more
facile
interconversion from η3 to η1
necessary to provide an open
coordination site for H2
acceptor binding.
M.C. White, Chem 153
C-H Activation -247-
Week of November 4, 2002
Crabtree:photochemical dehydrogenation of alkanes to alkenes
P(Cy)3
(III)
CF3
Ir
O
H
solvent
+
7.1 nM
P(Cy)3
hv (254 nm)
7 days
t-Bu
tbe
355 mM
+
t-B u
2.77tn (1.6)
+ H2
2.19 tn (3.84)
0.85 tn (0.32)
1.26 tn (0.82)
tn w/out tbe present (in parentheses).
Irradiation with light of the appropriate
wavelength promotes reductive elimination of
the dihydride catalyst leading directly to the
catalytically active 14e- complex. It's interesting
to note that no reaction takes place with tbe in
the absence of 254 nm light. This implies that
tbe acts as a H 2 acceptor from a photochemically
excited intermediate.
P(Cy)3
R
H
isomerization
pathway
P(Cy)3
OC(O)CF3
O
Ir(III)
CF3
O
H
P(Cy)3
Ir(III)
+
+
Proposed Mechanism:
H
Under conditions of hv and tbe,
methylcyclohexane is the preferred
product. This is thought to result from a
kinetic preference to form the sterically less
hindered
M-C
bond.
Methylenecyclohexane subjected to the
reaction conditions results in only 25%
conversion to the thermodynamically more
stable 1-methylcyclohexene. Although the
reaction proceeds w/out tbe, the product
ratios reflect more isomerization activity.
O
H
H
Ir(III)
hv, 254nm
P(Cy)3
OC(O)CF3
H
H
R
(Cy)3P
H
β -hydride
elimination
H
Ir(III)
OC(O)CF3
O
O
P(Cy)3
O
Ir(I)
CF3
O
(Cy)3P
H2
H
(Cy)3P
oxidative
addition
R
t-B u
(Cy)3P
R
Crabtree JACS 1987 (109) 8025.
CF3
Ir(III)
H
(Cy)3P
P(Cy)3
*
P(Cy)3
H2
R
(Cy)3P
(Cy)3P
Ir(I)
14 e-
OC(O)CF3
t-B u
Some free H2
is formed even
in the presence
of tbe.
M.C. White, Chem 153
C-H Activation -248-
Week of November 4, 2002
Tanaka: photochemical dehydrogenation
OC
Rh(I)
PMe3
Cl 0.7mM
Me3P
hv, rt, N 2
27 h, 155 tn
(solvent)
PMe3/Rh
2
5
5
10
10
Proposed Mechanism:
time (h)
1-
1
3
22
3
22
1
12
6
28
10
+
+
+
1:79:20
138 tn, 17 h
A theoretical amount
of H2 was detected
in the gas phase.
When a N2 stream
was
used,
tn
increased to 195 tn.
H2
hexenes
2311
4
4
4
3.4
2
1
1
1
1
Added phosphine ligand decreases the efficiency of
the reaction but increases the regioselectivity
towards formation if 1-hexene. Within the same
PMe3/Rh ratio, an erosion in regioselectivity is
observed upon prolonged reaction times. This is
indicative of catalyst mediated alkene isomerization.
Could this ratio also be reflective of the rates of
olefin hydrogenation? Exposure of 1-hexene to the
reaction conditions results in 2-hexene (35%) and
hexane (63%) after 22 h.
TN
5.4
4.0
18.7
0.6
7.2
OC
Added phosphine ligand may take up a
vacant coordination site cis to the
M-alkyl, preventing formation of the
agostic interaction necessary to effect
β-hydride elimination. A decrease in
both alkane dehydrogenation and
olefin isomerization results.
Me3P
CO
Me3P
Rh(I)
PMe3
R
Cl
14 eH
R
β -hydride
elimination
R
H
H
Cl
hv
H2
R
PMe3
16 e-
light-promoted reductive
elimination of H2 ??
reductive
elimination
Rh(I)
PMe3
Rh(III)
Cl
PMe3
R
H
PMe3
Rh(III)
H
Cl
PMe3
H
PMe3
Rh(III)
Cl
PMe3
intermediate in Wilkinson
hydrogenation
930 tn, 69h
N2 stream
M.C. White, Chem 153
C-H Activation -249-
Week of November 4, 2002
Goldman: Wilkinson’s Catalyst Varient
sacrificial alkenes
OC
Rh(I)
Me3P
(solvent)
+
sacrificial alkene
PMe3
, 53 tn
, 59 tn
Cl 0.7mM
H2 (1000 psi), 60oC
1.5 h, x tn
+
t-Bu
, 106 tn
alkane
, 4 tn
A variety of sacrificial alkenes work in the
dehydrogenation of cyclooctane, an
especially reactive substrate. Cyclooctene
has a very low heat of hydrogenation
probably resulting from transannular steric
repulsions in cyclooctane which are less
severe in cyclooctene.
n-hexane gave hexenes in modest
tn (9.6) with norbornene as the H2
acceptor. No mention was made
to the isomer distributions.
Goldman JACS 1992 (114) 9492.
H
Proposed Mechanism:
OC
Rh (I)
Me3P
PMe3
H2
Cl
H
Rh(III)
Me3P
16 e-
PMe3
Cl
CO
18eCO
Formation of octahedral dihydride complex is thought to
initiate ligand dissociation. Wilkinson's hydrogenation
catalyst (see hydrogenation, pg. 142), known to dissociate
PPh3 upon H2 oxidative addition, is cited as precedent for
this. There is no evidence that CO dissociates preferentially
over PMe3. The authors invoke this to arrive at the same 14 eintermediate proposed in Tanaka's photochemical system.
H
H
Rh (III)
PMe3
Cl
PMe3
H
H
16 eH
PMe3
Rh (III)
H
Cl
PMe3
Ph3P
Me3P
Rh (I)
PMe3
Cl
Tanaka's 14 e- intermediate
Rh (III)
PPh3
Cl
M.C. White, Chem 153
C-H Activation -250-
Week of November 4, 2002
Substrate directed dehydrogenation via C-H activation
Possible intermediates:
H3CO
O
N
+
(OTf-)
+
+
H3CO
(OTf-)
O
N
H3CO
(OTf-)
O
N
H
N
PtII
CF3CH2OH
CH3
N
70oC, 60 h
N
N
Sames constructs a ligand for the metal from the
requisite functionality of the target that directs
C-H activation towards only one of the 2 ethyl
susbstituents. This results in selective
dehydrogenation to give the platinum hydride in
>90% yield. The reaction is stiochiometric in
platinum and the metal must be removed via
treatment with aqueous potassium cyanide.
N
PtIV
CH3
CH4
PtII
+
H 3CO
H3CO
O
N
N
N
H
O
Rhazinilam
Sames JACS 2000 (122) 6321.
H
N
Pt
N
H
O
N
(OTf-)
M.C. White, M.S. Taylor Chem 153
C-H Activation -251-
Week of November 4, 2002
Dehydrogenation of n-alkanes to terminal olefins
R = t-Bu, i-Pr
A
R R
P
H
Ir H
P (0.5 mol%)
R R
Longer
reaction
times
150°C
sacrificial hydrogen acceptor
(norbornene, t-butylethylene, or 1-decene)
At low conversions, 1-octene is the major product of the dehydrogenation reaction (90 to >95% selectivity at 5% conversion, depending upon the acceptor used).
Ethylene was not a suitable acceptor, resulting in inhibition of catalysis due to formation of a stable Ir-ethylene complex. As the reaction proceeds, olefin
isomerization via sequential hydrometallation and β-hydride elimination erodes the kinetic selectivity, resulting in a mixture of olefin isomers.
R R
P
H
Ir H
Although the nature and the concentration of the sacrificial
hydrogen acceptor had little effect on the reaction rate, these
factors had a large effect on the observed distribution of
double bond isomers in the product. The authors propose that
the observed isomer distribution is largely determined by the
competition between the sacrificial acceptor and the product
olefin for insertion into the Ir-H bond of the dihydride
intermediate.
A
P
R R
R R
P
n-Oct
Ir H
R R
P
P
R R
P
R R
Ir H
R R
P
Ir
A
Goldman, A. JACS 1999, 121, 4086.
P
R R
A
M.C. White, Chem 153
C-H Activation -252-
Week of November 4, 2002
Direct carbonylation of benzene
The first report:
OC
+
(solvent)
Soon afterwards:
O
CO
1 atm
P h3P
Rh(I)
O
PPh3
OC
H
Cl 7.2 mM
+
hv (295-420), rt, 40h
Eisenberg JACS 1986 (108) 535.
Postulated mechanism:
1 atm
(solvent)
3 tn
RhCl(CO)(PPh3)2 is
a
photochemical
decarbonylation
catalyst at rt.
CO
Rh(I)
PMe 3
PBu3
PEt3
P(i-Pr)3
P(p-tolyl)3
PPh3
P(OMe) 3
hv (295-420), rt, 33h
73 tn
1970
1955
1957
1947
1979
1982
2011
H
Ph
Me3P
Cl
OC
Rh(III)
H
PMe3
18 e-
Rh(I)
Me3P
PMe3
CO
hv
Cl
16 eCl
O
14 e-
Me3P
Cl
PMe3
PMe3
CO
OC
Rh(I)
Me3P
Rh(III)
H
PMe3
18 e-
Cl
CO
Rh (III)
H
PMe3
16 e-
TN
73
19
17
2
3
2
2
O
OC
H
Cl 0.21 mM
Me3P
CO (cm -1)
Phosphine
PMe3
PMe3 is thought to increase the
effectiveness of the Rh catalyst
both by increasing electron
density at the metal thereby
promote oxidative addition and
by decreasing tail-biting of the
complex.
Tanaka Chem. Lett. 1987 249.
Tanaka JACS 1990 (112) 7221.
M.C. White, Chem 153
OC
+
CO
PMe3
Rh(I)
Cl 0.21 mM
Me3P
1 atm
hv (295-420), rt, 33h
295-420
>325
aldehyde tn
(1-decanal, 2-, 3-, 4-)
nonene tn
610 (85:5:4:2:3)
126 (8:45:17:15:16)
319
0
R
Revised proposed catalytic cycle:
H
27 tn
Effects of irradiation wavelength: Flash photolysis revealed loss of CO
(thought to lead to the catalytically active 14e- species for C-H oxidative
addition) is the dominant photoreaction of RhCl(CO)(PPh3) 2 at >330
nm. Metal-to-ligand charge transfer band of Rh-CO @ 365 nm. Ford
JACS 1989 (111) 1932. Absorption of non-conjugated aldehydes appear
at ~285 nm. It was hypothesized by Tanaka that cutting of the
short-wavelength region capable of aldehyde excitation would improve
yields of the desired aldehyde.
wavelength (nm)
Week of November 4, 2002
Direct carbonylation of alkanes
Aliphatic hydrocarbons:
(solvent)
C-H Activation -253-
H
O
H
hv
285 nm
Photo-induced Norrish Type II Chemistry
H
O
Tanaka Chem. Comm. 1987 758.
+ CH3CHO
92 tn
H
While Norrish Type II reactions leading to dehomologated terminal alkenes
were suppressed by going to a longer wavelength, carbonylation selectivity
towards the 1o position of the alkane was lost and catalytic activity was
diminished. These results imply that photo-induced CO dissociation may not
be the major pathway in this system for generating the complex capable of
C-H activation of linear aliphatic alkanes.
Tanaka JACS 1990 7221.
OC
Rh (I)
PMe3
Cl
16 e-
R
The rate of benzene carbonylation
catalyzed
by
RhCl(CO)(PMe3)2
irradiated at >290 nm (ca. 314 nm, a
wavelength where Rh-CO does not
absorb) is proportional to CO pressure.
Goldman
proposes
a
photoelectronically excited intermediate
as the species effecting C-H activation.
Goldman JACS 1994 (116) 9498.
0.6 tn
O
Me3P
O
The carbonylation reaction is highly
regioselective towards primary C-H
bonds to give linear aldehydes with
high selectivities. Unfortunately, the
aldehydes formed readily undergo a
secondary photochemical reaction
(Norrish Type II) to give a
dehomologated terminal alkene and
acetaldehyde in large quantities.
+
* Irradation
Me3P
Cl
OC
Rh(III)
OC
O
Rh(I)
Me3P
H
PMe3
Cl
16 e-
PMe3
18 ePMe3
R
OC
Rh
CO
(III)
Cl
H
PMe3
18 e-
R
of a solution of
RhCl(CO)(PMe3)2 /C 6H6 in the
absence of CO at -40oC afforded
two isomers of the 18 ealkylhydrido complexes which
were fully characterized by NMR
(1H, 31P, 13C NMR). Fields JACS
1994 (116) 9492.
M.C. White, Chem 153
C-H Activation -254-
Week of November 4, 2002
Direct formation of aldimines
R
The first report:
N
OC
+
(solvent)
RNC
55 mM
Rh (I)
PMe3
Rh(I)
+ CyNC
H
Cl 0.7 mM
Me3P
OC
(solvent)
hv, rt, 36h
3 tn
R = cyclohexyl, 5 tn
Me, 38%/Rh
t-Bu, 3%/Rh
Cy
PMe3
N
Cl 0.7 mM
Me3P
hv, rt, 17h
6.0 mM
low conversions may be due in part to
the low solubility of the isocyanide
under the rxn conditions. Selectivities
not reflective of C-H activation via an
organometallic intermedaite.
H
6%/Rh
+
N
Cy
+
12%/Rh
12%/Rh
N
Tanaka Chem. Lett. 1987 2373.
H
Cy
R
RNC
C
N
PPh3
Rh(I)
Cl 0.2 mM
Ph3P
+
N
H
hv, rt, 36h
4 tn
R= neopentyl
1.0 mM
Proposed mechanism:
RNC
Rh(I)
PPh3
-PMe3
Cl
+ PMe3
Ph3P
16 e-
RNC
N
Rh(I)
Jones notes that this system (unlike the one
reported by Tanaka) is completely
ineffective at aldimine formation from
aliphatic hydrocarbons.
PPh3
Cl
R
14 eH
R
H
N
H
CNR
Rh(III)
RNC
Rh(III)
PPh3
PPh3
Cl
Cl
16 e-
16 eCNR
Jones OM 1990 (9) 718.
M.C. White, Chem 153
C-H Activation -255-
Week of November 4, 2002
Direct Borylation of Alkanes: Stoichiometric
(solvent)
BCat'
83%/W
100% regioselectivity
Bcat'
OC
OC
WII B
Selectivity between activation/ functionalization
of 1o vs. 2o C-H bonds is high. Reactions of the
tungsten complex with cyclohexane resulted in
22% yield based on W. This system appears to
be highly sensitive to sterics as demonstrated in
it's ability to discriminate between the linear and
branched 1o C-H bonds of isopentane.
O
hv
(solvent)
BCat'
COO
+ Cat'B
55%/W
18 estoichiometric
BCat'
(solvent)
lesser reactivity was also
observed with the Ru
and Fe analogs
74%/W
The exact mechanism of C-H activation/functionalization is unclear. Two possibilities are
likely: 1. oxidative addition followed by reductive elimination, 2. σ-bond metathesis. The
first possibility would require loss of a second CO or Cp* slippage to create a site of
electronic unsaturation at the W to accomodaite both the alkyl and hydride substituents.
Alternatively, σ-bond methathesis could occur directly with the shown 16e- intermediate.
Alkane dehydrogenation followed by anti-Markovnikov hydroboration is excluded since
aliphatic alkenes result in vinylborates rather than the observed alkylborate esters.
Proposed mechanism:
II
O
OC W B
OC
COO
18 e-
2%/W
hv
CO
OC
W
II
O
R
B
O
OC
H
16 e-
?
II
OC W H
OC
+
Cat'B
R
16 e-
stoichiometric
Photolysis in the presence of PMe3 results in the
formation of Cp*W(CO) 2(PMe 3)Bcat'. This was
taken as evidence for the photo-induced loss of
CO to generate coordinatively unsaturated 16 eintermediate that may interact with the alkane.
Hartwig Science 1997 (277) 211.
M.C. White, Chem 153
C-H Activation -256-
Week of November 4, 2002
Direct Borylation of Alkanes: Catalytic
The first catalytic report:
note similarity w/ Bergman
stiochiometric C-H activation
complexes.
IrIII
Me3 P
O
+
H
BPin
17 mol%
HB
+ H2
150 oC, 5 d
O
1 eq
(solvent)
BPin
53% (based
on borane)
BPin = pinacolborane
Smith JACS 1999 (121) 7696.
Hartwig runs with it...
facile thermal alkene dissociation
forms coordinatively unsaturated
complexes
IrI
10 mol%
200 oC, 10 d
Bpin
2 C6H13
+
2 H2
58%/B
O
2 C6H13
(solvent)
+
O
B
O
The rate acceleration observed in going from a
3rd row metal complex to an analogous 2nd row
complex may be accounted for by a weakening
of M-C bonds which may promote turnover steps
in the catalytic cycle.
Rh I
B
O
(pinBBpin)
5 mol%
150 oC, 5 h
Bpin
2 C6H13
+
2 H2
85%/B
Rh I
Hartwig Science 2000 (287) 1996.
1 mol%
o
150 C, 80 h
Bpin
2 C6H13
72%/B
+
2 H2
100% regioselectivity for the terminal borane
was consistently observed. The linear borane is
thought to be the kinetic product. Exposure of
secondary alkyl boranes to reaction conditions
does
not
result
in
isomerization.
2-Methylheptane resulted exclusively in
products formed from primary C-H bond
activation with the less sterically hindered
terminal
methyl
group
becoming
functionalized selectively.
M.C. White, Chem 153
C-H Activation -257-
Week of November 4, 2002
Mechanism of direct borylation of alkanes
HBpin, generated under the
rxn conditions, is equally
effective as source of borane
Rh I
O
+
C6H13
O
B
B
O
(solvent)
5 mol%
O
C6H13
Bpin
Rh I
O
+
H
5 mol%
B
Bpin
C6H13
O
C6H13
(pinBBpin)
85%/B
150 oC, 5 h
Hartwig Science 2000 (287) 1996.
Hartwig's mechanistic proposal
Rh I
18 e-
∆
Rh I
14eRh I
To validate his mechanistic proposal that invokes high energy Rh(V)
intermediates, Hartwig synthesizes what he claims is an Ir(V)
dihydrido bisboryl species (the high reactivity of the Rh complex has
precluded its isolation/characterization). Although Hartwig argues
against a σ-complexed borane Ir(III) species, his evidence does not
conclusively eliminate it as a possibility. The independently
synthesized intermediate was an effective alkane borylation reagent,
resulting in similar yields and the same selectivities observed in the
catalytic system.
via RhIII intermediates
18 e-
R-Bpin
H
X = H, Bpin
H
X
Bpin
Bpin
X
Rh III
R-H
Rh V
H
R
18eRh(V) is a very high
energy
oxidation
state: controversial
intermediates.
X
III
Ir
H
Bpin
Bpin
H
200oC
Rh III
?
or
IrV
C6H13
(solvent)
Bpin
Bpin
C6H13
pinBX
Rh V
X
Bpin
H
X
45%/B
HX
Hartwig JACS 2001 (123) 8422.
H
Bpin
M.C. White, Chem 153
C-H Activation -258-
Week of November 4, 2002
Direct Arene borylation: Suzuki precursors
Towards synthetic utility...
In several examples the authors were able to achieve
intermolecular C-H activation/functionalization without
using the substrate as the solvent. Some substrates were
borylated under neat conditions while others employed
cyclohexane as solvent.
η5-indenyl complex capable
of rearranging to η3 and η1
IrI
Cl
Cl
Cl
Cl
O
B H
16h
Cl
1.5 eq
Ph2P
Cl
aryl-H: HBpin (1:2)
69% yield, 4h
Cl
PPh2
dppe
Recall that, in general, Ir complexes are less reactive than the
corresponding Rh complexes towards alkane borylation. Aryl
C-H bonds are more reactive towards C-H activation than alkyl
C-H. The factors favoring activation of aryl C-H bonds are the
high degree of s character in the Csp2-H bond which favors
σ-complexation to the metal and the strength of the resulting aryl
Csp2-M bond after oxidative addition.
Bpin
excellent regioselectivities for
functionalization of sterically
less hindered sites
1).HBpin, 2 mol% (Ind)Ir(COD), 2
mol% dppe, 100oC, 16 h
2). 3-bromotoluene, 2 mol%
Pd(PPh3)4, K3PO4, DME, 80oC, 17 h.
Cl
MeO2C
aryl-H: HBpin (1:2)
95% yield, 25h
89% based on arene
MeO
1 eq
Smith Science 2002 (295) 305.
A related study that uses the bpy ligand in conjunction with IrI: Hartwig JACS 2002 (124) 390.
BPin
MeO
aryl-H: HBpin (1:3)
62% yield, 95h, dmpe
Consecutive aryl borylation/Suzuki:
Cl
BPin
BPin
dppe 2mol%, 100oC
O
1 eq
N
2mol%
Cl
Cl
80% yield based
on dichlorobenzene
M.C. White, Chem 153
C-H Activation -259-
Week of November 4, 2002
Question 1: Catalytic Indole Production
Propose a catalytic cycle for the following Ru system that affords indoles in good yields
from 2,6-xylyl isocyanide.
PMe3
Me3 P
H
Ru II
Me3 P
PMe3
CN
20 mol%
benzene, 120oC, 94 h
HN
M.C. White, Chem 153
Q&A -260-
Week of November 4, 2002
Question 2
Provide a detailed mechanism for the following transformation.
O
3-5 eq.
O
Co 2(CO) 8 2 mol%
HSiEt 2Me (1.2 eq),
CO (50 atm)
MeEt2SiO
H
53%
M.C. White, Chem 153
Q&A -261-
Week of November 4, 2002
Question 3
PdL nI
PdL nI
cat. PdLn
I
cat. PdLn
I
CO
CO
PdL nI
PdL nI
O
O
When a competition exists between cyclic acylpalladation and cyclic carbopalladation, the preferred outcome is different for alkenyl and
alkynyl substrates. For alkenyl substrates, cyclic acylpalladation is favored over cyclic carbopalladation, and for alkynyl substrates, this
preference is reversed. Given these empirical observations, predict the products of the following transformations:
n-Bu
OH
E
E
I
OH
5% Cl2Pd(PPh3)2
NEt3 ( 2eq), CO (1 atm)
MeOH, 70oC
I
Me
5% Cl2Pd(PPh3)2
NEt3 ( 2eq), CO (1 atm)
MeOH, 70oC
I
Me
E
E
5% Cl2Pd(PPh3)2
NEt3 ( 2eq), CO (1 atm)
MeOH, 70oC
M.C. White,Q. Chen Chem 153
C-H Activation -262-
Week of November 4, 2002
Cyclometallation
Cyclometallation: intramolecular C-H activation of supporting metal ligands (a.k.a. "tail-biting")...
H
Ph3P
H
∆
C 6D 6
Ph2P
PPh3
IrI
P h3P
Cl
16 eagostic interaction
PtII
Ph3P
Ph2P
IrIII
P h3P
PPh3
H
-PPh3
P h3P
PPh3
H
Ph3P
PtII
OA
ligand dissociation
to create an open
coordination site
Cl
PtIV
rate-limiting
step: RE
Bennnett JACS (91) 1969 6983.
Chelate-assisted C-H activation:
Ph3P
Substrates with Lewis basic functionality can
temporarily become appended to a site of
coordinative unsaturation on a metal and undergo
chelate assisted C-H activation.
EtO
H
P h3P
RuII
Ph3P
H
O
PPh3
(excess)
PPh3
PPh3
H
Ph3P
hydrogenation
OEt
O
EtO
O
O
OA
RuII
PPh3
P h3P
PPh3
H
OEt
O
RuII
Ph3P
OEt
Ph3P
Whitesides OM 1982 (1) 13
H
Ibers JACS 1976 (98) 3874.
Ph3P
Ph3P
Ph3P
Ru0
H
PPh3
16 e-
Ph3P
Ru0
14 e-
PPh3
PtII
PPh3
Ph3P
-PPh3
PPh3
PtII
M.C. White, Chem 153
C-H Activation -263-
Week of November 4, 2002
Chelate assisted Csp2-H-olefin reductive coupling
Murai's breakthrough system...
metal chelating LB functionality
H
Ph3P
O
RuII
OC
R1
R2
H
+
Y
SiMe3
PPh3
O
PPh3
2 mol%
>99%
>99% yield
Si(OEt)3
R2
toluene, reflux
O
O
Si(OEt)3
R1
O
O
2-10 mmol
2 mmol
C sp2-H 4 atoms from LB
functionality results in
5-membered ring metal
chelate
Si(OEt)3
O
Y
Y = H (ethylene)
"privileged olefin"
Si(OEt)3
CH2SiMe3
t-Bu
>99%
>99%
100% regioselectivity
Murai Nature 1993 (366) 529.
Many other examples follow:
O
H
O
O
Ph3P
RuII
OC
R
+
H
Y
O
PPh3
6 mol%
R
O
t-Bu
O
toluene, reflux
2-10 mmol
2 mmol
O
PPh3
O
C6H13
98%
t-Bu
73%
Internal alkynes also add...
Ph3P
RuII
OC
+ R
Murai Chem. Lett. 1995 681.
H
R
PPh3
CF3
R
Si(OEt)3
Aryl esters:
R
H
Si(OEt)3
>99%
O
Y
Murai Chem. Lett. 1995 679.
O
O
Et
O
PPh3
2 mol%
H
O
Ph3 P
OMe
+
toluene, reflux
R = Pr (72%), E/Z = 16/1
Ph (85%), E/Z = 9/1
Ru II
OC
H
Si(OEt)3
PPh3
PPh3
2 mol%
CF3
O
OMe
toluene, reflux
Si(OEt)3
Only aromatic esters substituted with CF 3 or F groups (m,p,and o) resulted in coupled
product. Other benzoates w/electron withdrawing substituents o-NO 2, p-NO 2, o-CN,
o-CO2Me failed to give coupled product.
Murai Chem. Lett. 1996 109.
M.C. White, Chem 153
C-H Activation -264-
Week of November 4, 2002
Oxygen chelate assisted Csp2-H-olefin reductive coupling
Cyclic and acylic vinyl esters :
Si(OEt)3
O
O
OR
H
OR
R1
Ph3P
OC
O
+
R2
RuII
H
R1
PPh 3
5 mol%
H
Si(OEt)3
OR
PPh 3
A high
degree
of
functional group tolerance
O
is demonstrated through
the substrates tested.
OEt
Si(OEt)3
A lack of reactivity is
observed when the β
Csp2-H bond is trans to
the ester carbonyl
O
O
NHCH3
80%
R = (CH2 )5CH 2 OAc, 85%
(CH2 )5CH2 OTBS, 91%
(CH2 )5CH2 Br, 54%
O
R2
toluene, reflux
Ph
Si(OEt)3
Si(OEt)3
O
O
Trost JACS 1995 (117) 5371.
H
RuII
OC
SiR 3
PPh3
SiR 3
OR
OR'
PPh3
O
CO
H
CO loss is supported by
the observation that the
reaction is inhibited in
the presence of CO.
70%
Hydrogenated product
is observed by GC
Proposed mechanism:
Ph3P
O
O
Ph3P
SiR3
OR'
H
Ru0
PPh3
OR'
Ph3P
P h3P
14 e-
reductive
elimination
O
O
Ph3P
RuII
SiR 3
Ph3P
Ru0
H
PPh3
PPh3
OR'
migratory
insertion
OR'
O
Ph3P
O
R3Si
RuII
SiR3 Ph3P
Ph3P
RuII
PPh3
P h3P
H
PPh3
H
M.C. White/Q.Chen Chem 153
C-H Activation -265-
Week of November 4, 2002
Nitrogen chelate assisted Csp2-H-olefin reductive coupling
t-Bu
t-Bu
N
H
t-Bu
N
N
Ru 3(CO) 12 (2 mol%)
+
Si(OEt)3
tol, 135 C, 24h
10%
RuH 2(CO)(PPh3) 3 26%
(2 mol%)
8%
Ru 3(CO) 12
130oC
heptane
N
H
Si(OEt)3
81%
N
(CO) 3 Ru
H
+
Si(OEt)3
Muria Chem. Lett. 1996 111.
2 CO
H
o
Ru(CO)3
Ru(CO)4
1
Ru3(µ-H)(m-C13H8N)(CO)10
Fish OM 1986 (5) 2193.
Some Ru-H is formed
via the dehydrogenative
coupling.
M.C. White, Chem 153
C-H Activation -266-
Week of November 4, 2002
Nitrogen chelate assisted Csp2-H/CO/olefin reductive coupling
Tolerates sensitive functionality:
Ph
Ph
Ph
N
N
+
O
O
Ru3(CO)12 (4 mol%)
O
N
+
N
N
CO (20 atm)
tol, 160oC, 24h
N
O
O
O
72% (linear:branched; 97:3)
Olefin isomerization occurs under the reaction conditions:
N
N
N
+
+
N
Ru 3(CO) 12 (4 mol%)
or
N
N
CO (20 atm)
tol, 160 oC, 24h
O
O
1-hexene; 68% (linear:branched; 94:6)
2-hexene; 41% (linear:branched; 94:6)
Proposed mechanism:
N
R
Ru3(CO)12
+
R
N
O
N
O
Ru(CO)3
N
Rux(CO)n
N
N
(CO)4
Ru
N
N
R
or
N
(OC)3Ru
CO
N
Ru(CO)3
H
H
Ru
(CO) 3
R
H
Ru(CO)n
R
N
N
N
N
Murai JACS 1996 (118) 493.
Rux(CO)n
O
O
M.C. White, Chem 153
C-H Activation -267-
Week of November 4, 2002
Indole synthesis via isonitrile chelation/ C-H bond activation
Propose a catalytic cycle for the following Ru system that affords indoles in good yields
from 2,6-xylyl isocyanide.
PMe3
Me3P
Ru
H
II
Me3 P
PMe3
CN
20 mol%
HN
benzene, 120 oC, 94 h
heat promoted
RE
HN
Me3 P
Ru
N
H
CN
Me3
P
Me3
P
H
Ru 0
P
Me3
P
Me3
II
Me3 P
PMe3
PMe3
NC
Ru 0
PMe3
PMe3
PMe3
isomerization
Me3 P
Me3 P
PMe3
Ru II
N
H
H
PMe3
H
Me3
P
PMe3
Me3 P
tautomerism
Ru II
N
PMe3
H
NC
PMe3
PMe3
Jones JACS 1986 (108) 5640.
NC
Me3 P
PMe3
migratory
insertion
Ru
II
Ru 0
P
Me3
Me3 P
H
OA
Me3 P
PMe3
PMe3
M.C. White, Chem 153
C-H Activation -268-
Week of November 4, 2002
Oxidative functionalization of alkanes
The methane to methanol challenge: Synthesizing "liquid gold":
Current industrial process consumes significant amounts of energy:
Ni/Al2O3
CO (g) + H2
∆Ho = 49.3 kcal/mol
CH4 (g) + H2O (g)
700oC
CO (g) + 2 H2 (g)
zeolite cat.
∆
CH3OH
Direct oxidation is thermodynamically favorable.
catalyst ?
CH4 (g) + 1/2 O 2 (g)
CH3OH ∆Ho = -30.7 kcal/mol
overoxidation to CO2 is
major problem w/methane
oxidation
o
∆H = -21.7 kcal/mol
Nature does it:
Methane Mono-Oxygenase (MMO):
Pseudomonos Oleovorans Mono-Oxygenase (POM):
MMO oxidizes methane to methanol with 100% chemoselectivity (no overoxidized
product results).
Oxidizes linear alkanes with 100% regio- and chemoselectivity
CH4 + O 2 + NADPH + H+
MMO
M. Capsulatus
12 min
CH3OH + NADP+ + H2O
84 tof
tof = nmol product/min/mg enzyme
n-alkanes + O2 + NADPH + H +
C6-C12
POM
1-alcohols
+ NADP+ + H2O
1-octanol, 590 tof
Higher hydrocarbons are oxidized with poor regioselectivities
MMO
M. Capsulatus
12 min
Coon Biochem. Biophys. Res. Comm. 1974 (57) 1011.
Munck PNAS 1997 (94) 2981.
+
OH
OH
1.3 : 1
Lipscomb J. Biol. Chem. 1992 (267) 17588.
A beginning...
The Shilov system:
Cl
Cl
CH4
+ H 2O
PtII
Cl
(K+) 2
Cl cat.
K2Pt(IV)Cl6 oxidant
120oC
Shilov Zh. Fiz. Khim. (Engl. Trans.) 1972 (46) 785.
regioselectivities: Bercaw JACS 1990 (112) 5628.
CH3OH
+ CH3Cl
In 1972 Shilov and coworkers demonstrated that a combination of chloroplatinum(II)
and (IV) salts in aqueous solutions at elevated temperatures effects the oxidation of
alkanes to mixtures of alcohols and alkyl chlorides. The regio- and chemoselectivity of
the Shilov system reflects those of other organometallic systems in that the stronger 1o
methyl hydrogens of propane and even ethanol are more reactive than the methylene
hydrogens. Unfortunately only modest selectivites are observed. Some overoxidized
products and regioisomeric mixtures of alcohols are observed because the product
alcohols are more soluble in the aqueous reaction media than the hydrocarbon.
M.C. White, Chem 153
C-H Activation -269-
Week of November 4, 2002
MMO
·Hydroxylase Active Site of MMO
OH 2
O
O
O
E114
Fe
H147
O
N
OH 2
O
O
O
Fe(II)
(II)
N
E243
O
E243
O
N
E144
N
E114
O
H246
H147
O
O
H2
O
E209
Fe (III)
O
N
N
O
H
O
Fe (III)
O
N
E144
N
E209
O
H246
MMOHox
MMOHred
o
Based on crystallographic studies of M. capsulatus(-160 C)
Proposed mechanism (thought to be operating for POM as well):
-
2e
(II)
Fe
H
O
(II)
Fe
·O O·
H
(III) O
(III)
Fe
Fe
H2O2 "peroxide
shunt"
-H+
ROH
H
O
(IV)
(III)
Fe
Fe
OH
R·
H
O
(IV)
(IV)
Fe
Fe
O
H
(III)
O
(III)
Fe
Fe
O O µ-1,2 peroxo
adduct
P
H+
H
O
(III)
(III)
Fe
Fe
O O+
H
Key piece of evidence supporting substrate radical
intermediate:
CH3
CH3
CH3
MMO
+
D
D
D
HO
OH
T
H
T
T
(R)-ethane
(S)-ethanol
RH
(IV)Fe
O· Q
Fe(III)
H+
-H2O
The second iron in MMO transiently stabilzes
intermediate Q by supplying an e- to fill the
oxygen atom's octet. This avoids energetically
unfavorable Fe(V) intermediates.
(R)-ethanol
35%
Lipscomb Chem. Reviews 1996 (96) 2625.
Attempts to mimic Nature's solution have failed. The key to chemo- and regioselectivity in
these radical systems may be MMO and POM's protein suprastructure which thus far have
not been mimicked in solution.
O
N
N
H
O
Lippard Nature 1993 (366) 537.
Fe III
N
2+
(ClO4-) 2
O
O
Cl Cl
Fe III
N
N
O
OH
N
cat.
H2O2, CH3CN, air
note: the same yields and selectivities were observed
when the reactions were run under an inert
atmosphere (Ar) or in air. This indicates that free
radicals, propagated with O2, are not acting as the
oxidant.
Nishida Chem. Lett. 1995 885.
+
4 tn
2 tn
M.C. White, Chem 153
C-H Activation -270-
Week of November 4, 2002
The Shilov System/C-H activation via late, electrophilic complexes
H
σ−donation>>
π-backbonding
M
M
heterolytic cleavage
+
C
H+
C
σ-complex
C-H activation processes that occur via heterolytic cleavage result in no oxidation state change at the metal. Generally,
electrophilic metal complexes are used that incorporate metals in their highest stable oxidation states. Unlike the Bergman
nucleophilic complexes, electrophilic complexes are compatable with oxidants and provide a route to oxidative
functionalization of hydrocarbons (the most desirable form of functionalization).
The Shilov system:
2 (K+)
2
Cl
Cl
PtII
Cl
Cl cat.
+ H 2O
CH4
CH3OH
K 2Pt(IV)Cl6 oxidant
Because Pt is a late "soft" metal,
the relatively diffuse alkane C-H
bond is able to intermolecularly
compete with the hard oxygen lone
pair of H2O for binding to the
metal.
+ CH3Cl
120oC
Proposed mechanism:
2 Cl -
2 H2O
PtII
Cl
II
Pt
CH4
OH 2
OH 2
OH 2
Cl
2
Cl
Cl
H
Cl (K+)2
Cl
Cl
Cl
OH 2
PtII H
MeOH
H 2O
Inversion of stereochemistry at
the platinum bound C using
deuteruim labeled substrates
provided strong evidence for
S N2 functionalization pathway
Bercaw ACIEE 1998 (37) 2180.
Cl
PtIV
OH 2
CH3
HCl soft deprotonation
CH3
IV
Cl
K+
Cl
Pt
Cl
Cl
or
Cl-
CH3
K+
Cl
Cl-
Cl
Cl
H 2O
PtIV
Cl
OH 2
CH3
Cl
Cl
Cl
PtII
OH 2
CH3
K+
note: no oxidation state
change to the metal
K2 Pt(IV)Cl6
K2 Pt(II)Cl4
Pt(II) catalyst is regenerated
M.C. White, Chem 153
C-H Activation -271-
Week of November 4, 2002
C-H activation via late, electrophilic complexes in highly acid media
Hg(II)(OSO 3H) 2 cat.
N
N
CH4 + 2 H2SO4
Cl
note that the product cannot
undergo further oxidation.
PtII
N
200oC
Periana Science 1993 (259) 340
Cl
N
500 tn
CH4 + 2 H2SO4
CH3OSO3H
50% yield (based on CH4)
H2SO4 (ox/solv)
H 2SO4 (ox/solv)
200oC
Periana Science 1998 (280) 560.
CH4 + CF3CO2H
CH3OSO3H
70% methyl bisulfate
(90% conversion/
80% selectivity) based
on methane.
Pd(OAc)2 stoic.
CH3O2CF3 + Pd (0)
CF3CO2H (solv)
Sen JACS 1987 (109) 8109
Heterolytic cleavage directly from the σ-complex is clearly operating for
Pd(II) and Hg(II) systems where the M(n+2) oxidation state of the
alkyl(hydrido)metal intermediate is prohibitively high in energy.
Proposed mechanism:
2+
+
-
N
N
N
OSO3 H
N
PtII
N
N
N
( OSO3 H)
PtII OSO3 H
OSO3 H
N
OSO3 H
(-OSO3 H)2
II
Pt
N
N
14 e- complex
CH3OSO3H
N
H
H
N
OSO3 H
The ligand may become protonated under
the reaction conditions. Protonation will
withdraw electron density from the Pt
through the σ-bonding framework of the
bidiazine ligand thereby enhancing its
electrophilicity.
CH4
-OSO3 H
+
OSO3 H
N
N
N
OSO3 H
N
PtIV
N
PtII H
CH 3
N
OSO3 H
N
N
OSO3 H
CH 3
+
(-OSO3 H)
-OSO3 H
N
N
H
OSO3 H
(-OSO3 H)
PtIV
or
N
N
CH 3
heterolytic cleavage
oxidation
N
SO2 + H2O
N
OSO3 H
PtII
SO3 + 2 H2SO4
N
N
CH 3
Although the Periana Pt system is unparalleled with
respect to its efficiency at oxidative functionalization of
methane, the high cost associated with platinum coupled
to the operational difficulty in seperating the product from
the solvent renders this route to methanol non-competitive
with traditional reforming.
M.C. White Chem 153
C-H Activation -272-
Week of November 4, 2002
Substrate-directed vinyl alkylation via electrophilic C-H activation
N
N
H
2+
H3 CCN
H3 CCN
Pd
II
NCCH3
NCCH3
1.PdCl 2(CH 3CN) 2/AgBF 4
NEt 3, CH3CN
2. NaBH 4
40-45%
N
N
H
(BF4 -)2
generated via in situ
metathesis
NaBH 4
NCCH3
2+
+
-
(BF4 )2
H3 CCN
(BF4 -)2
Pd II N
LnPd N
H
N
H
recall that Pd(IV) is a
prohibitively
high
energy oxidation state
+
NEt3
N
(BF4 -)2
Ln
Pd II
NEt3
migratory
insertion
N
H
Trost JACS 1978 (100) 3930.
MeO2 C
CO 2Me O
N
N
H
Corey JACS 2002 (124) 7904.
N
H
OMe
NCO2 Me
Pd(OAc)2 (1 eq)
NaOAc (1 eq)
AcOH: H 2O (1:1)
25oC, 24h
31%
N
H
model system for key
cyclization
step in
(+)-Austamide synthesis
M.C. White, Chem 153
C-H Activation -273-
Week of November 4, 2002
Substrate-directed alkane arylation via electrophilic C-H activation
OMe
OMe
OMe
N
PdOAc 2 (4 mol%)
OMe
Cu(OAc)2 (2 eq.)
benzoquinone (4 mol%)
N
100oC
Ph 2Si(OH)Me (2 eq)
or
S
R
S
Si(OH)Me2
Ph
R = Ph, 73%
R= PhCH=CH, 64%
OMe
OMe
2 CuOAc
N
O
S
Pd II
O
O
OMe
O
+
(OAc -)
OMe
OMe
2 CuOAc2
N
Pd(0)Ln
Ph
OMe
OMe
OMe
N
AcO
Pd II
N
S
H
Pd II
S
pka ~ 50
-
Ph
OAc
OMe
OMe
base-assisted
heterolytic
cleavage
Sames JACS 2002 (124) 13372.
transmetalation
N
Pd II
S
AcO
Ph 2SiOHMe
S
M.C. White/M.W. Kanan Chem 153
C-H Activation -274-
Week of November 4, 2002
Intermolecular arene vinylation via electrophilic C-H activation
H
Pd(OAc)2 1mol%
+
CO2Et
O
CF3CO2H/CH2Cl 2 (4:1)
25oC
O
O
O
H
HO
O
O
+
O
O
O
O
CF 3 ( O2CCF3)
O
CO 2Et
O
O
protonolysis
HO
H
O
PdII
Reactions run in CF3CO2D yielded
products with vinyl deuterium
incorporation α to the ester.
+
CH3
O2CCF3
Pd II
O
61%
(-O2CCF3 )
CF 3
Reactions run in acetic acid failed.
TFA is thought to be necessary for
the formation of cationic Pd(II)
species. Reactions run with Pd(0)
sources gave only trace amounts
of product (<20%).
PdII
CO2Et
O
PdII
O
CF3
O
trans migratory
insertion
O
O
O
O
CO2Et
CO 2Et
CF3
O
?
Fujiwara Science 2000 (287) 1992.
Reaction exhibits excellent functional
group tolerance with unprotected OH,
CO2Et Br, and acetals tolerated in the arene.
Coupling to activated alkenes (vinyl
esters) was also effected in high yields
(65-96%).
O
CF 3
M.C. White, Chem 153
Q&A -275-
Week of November 4, 2002
Silylformylation
Provide a detailed mechanism for the following transformation reported in the literature.
O
O
Co 2(CO) 8 2 mol%
HSiEt 2Me (1.2 eq),
CO (50 atm)
3-5 eq.
MeEt2SiO
H
53%
Reaction works for 3,4, and 5 membered cyclic ethers. Ring strain may promote the
nucleophilic ring opening reaction. Neither tetrahydropyran or diethyl ether react under
these conditions. The high affinity of silicon for oxygen is used to account for the fact
that R3SiCo(CO)4 and not HCo(CO)4 interacts with the cyclic ether.
H
(OC)4Co
Co(CO)4
Co(CO)4
HSiR3
O
O
R3Si
MeEt2SiO
Co(CO)4
H
O
SiR 3
MeEt2SiO
Co(CO)3
HSiR3
H
O
SiR 3
O
Co(CO)4
MeEt2SiO
Co(CO)3
migratory
insertion
Murai ACIEE 1977 (16) 789.
Murai ACIEE 1979 (18) 837.
Co(CO)4
MeEt2SiO
nucleophilic ring
opening
M.C. White, Chem 153
Q&A -276-
Week of November 4, 2002
Carbonylation
PdLnI
PdLnI
cat. PdLn
cat. PdLn
I
I
CO
CO
PdLnI
PdLnI
O
O
When a competition exists between cyclic acylpalladation and cyclic carbopalladation, the preferred outcome is different for alkenyl and
alkynyl substrates. For alkenyl substrates, cyclic acylpalladation is favored over cyclic carbopalladation, and for alkynyl substrates, this
preference is reversed. Given these empirical observations, predict the products of the following transformations:
n-Bu
OH
E
I
E
I
Me
OH
I
Me
5% Cl2Pd(PPh3)2
NEt3 ( 2eq), CO (1 atm) 73%
MeOH, 70oC
E
E
5% Cl2Pd(PPh3)2
NEt3 ( 2eq), CO (1 atm) 66%
MeOH, 70oC
O
O
n-Bu
O
E
O
E = CO2Me
5% Cl2Pd(PPh3)2
NEt3 ( 2eq), CO (1 atm)
MeOH, 70oC
O
E
E
E
Negishi JACS 1994(116) 7923.
Negishi JACS 1985(107) 8289.
M.C. White/ M.W. Kanan, Chem 153
TESO
Q&A -277-
Week of November 4, 2002
O
TESO
O
Pd(PPh 3)4
800 psi CO
O
or
R
TESO
R
R
O
OTf
OH
OH
O
i-Pr 2NEt, PhCN
65 to 110°C
OTf
Leighton Org. Lett. 2000 (2) 2905.
Provide a mechanism for this one-pot transformation. Explain why both the E- and Z-tetrasubstituted enol
triflates react to form the desired product in comperable yields.
TESO
TESO
TESO
PdLn
O
R
R
TfO
OH
OH
+ CO
O
O
R
- CO
4
Pd(OTf)Ln
OH
O
Pd(OTf)Ln
TESO
R
TESO
TESO
O
Pd(OTf)Ln
O
R
O
R
H
OH
5
OH
OH
+ CO
Ln(OTf)Pd
Pd(OTf)Ln
- CO
TESO
R
O
TESO
Pd(OTf)Ln
O
O
TESO
O
R
O
O
3,3-sigmatropic
rearrangement
O
O
R
OH
Oxidative addition into the Z-tetrasubstituted enol triflate leads directly to intermediate 5 which can continue on the path to the desired product.
Oxidative addition into the E-tetrasubstituted enol triflate leads to intermediate 4 which can isomerize to 5 via a ›-allenyl intermediate.
M.C. White, Chem 153
Q&A -278-
Week of November 4, 2002
Carbonylation
O
O
R
+
H 3C
H
N
H
N
H
CH3
O
CO, 0.25% PdBr2(PPh3)2
30% LiBr, 1% H2SO4
R
N CH3
N
H 3C
O
Substituted hydantoins can be prepared by the ureidocarbonylation of an aldehyde
in presence of LiBr and H2SO4. Propose a mechanism for this transformation.
O
H 3C
H 3C
Br
R
N
O
N
H
CH3
H 3C
R
N
N
R
+
H
H 3C
CH3
CO
H
R
Br
PdL2
CH3
Br
oxidative
addition
H
O
O
N
H
O
LiBr, H 2SO 4
N
O
H 3C
R
OC
PdL2
N
N
H
H
N
CH3
HBr
migratory
insertion
reductive
elimination
O
H 3C
L 2Pd(H)Br
N
N
H
R
PdL2Br
O
O
R
Beller ACIEE 1999 (38) 1454.
H 3C
N
N CH3
O
CH3
CH3
N
H
PdLn
Br
M.C. White/Q. Chen, Chem 153
Q&A -279-
Week of November 4, 2002
Hydrophosphinylation
n-Hex
H
O
PPh2
5% Pd(PPh3) 4
+
Ph 2P(O)H
n-Hex
1a) Hydrophosphinylation of internal and terminal alkynes with Ph2P(O)H can be catalyzed by a variety of palladium sources. Pd(PPh3)4 is selective
for the anti-Markovnikov product. Propose a mechanism for the hydrophosphinylation of 1-octyne below.
O
n-Hex
PPh2
O
Ph 2PH
Pd(PPh3)2
reductive
elimination
oxidative
addition
R
Ph3P
Ph3P
Pd
Ph3P
H
Pd
Ph3P
PPh2
PPh 2
O
O
hydropalladation
Ph3P
Ph3P
R
Tanaka, M. ACIEE 1998, 37, 94-96.
Tanaka, M. OM 1996, 15, 3259-3261.
R
H
Pd
PPh2
O
H
H
M.C. White/Q. Chen Chem 153
Q&A -280-
Week of November 4, 2002
Hydrophosphinylation
n-Hex
Ph2P(O)H
+
H
O
PPh2
5% PdMe 2(dmpe)
5% Ph2P(O)OH
n-Hex
b) The regioselectivity of the hydrophosphinylation can be completely reversed by using PdMe2(dmpe) (dmpe = dimethylphosphinoethane) and the phosphinic acid,
Ph 2P(O)OH. Propose a mechanism for the formation of the Markovnikov product under these conditions.
O
Ph 2POH
Me Me
P
Me
Pd
P
Me
Me
Me
To explain the observed reversal in regioselectivity in
the presence of diphenylphosphinic acid, Tanaka and
coworkers propose the formation of a new
catalytically active species under these conditions.
O
Ph2PH
O
PPh2
P
n-Hex
Pd
P
O
O
OPPh 2
R
H
PPh2
O
"protonolysis"
Ph 2P H
O
OPPh 2
P
P
Pd
Pd
P
P
Ph2P
R
R
O
Tanaka, M. ACIEE 1998, 37, 94-96.
Tanaka, M. OM 1996, 15, 3259-3261.
phosphinylpalladation
O
OPPh2
PPh2
O
H
M.W. Kanan/M.C. White, Chem 153
Q&A -281-
Week of November 4, 2002
Carbometallation
i
Pr
Since very little CH3D is observed,
oxidative addition of a C-H from the
ligand isopropyl group in intermediate
A must be much faster than oxidative
addition of C6D6 to A.
i
Pr-d7
i
Me
Me Pr
N
Me
Pt
Me
N
i
Me
N
C 6D 6 150°C
10 min.
+ C2H6, CH4
Pt
N
i
Pr
Me
Pr-d7
D
D D
Me
i
CD3
i
Pr
Pr-d7
1
2-d27
Provide a mechanism for the formation of 2-d27. Note that very little CH3D is
formed under the reaction conditions.
i
Goldberg JACS 2002 (124) 6804.
i
Pr
Me
N
Pt
Me
i
H Pr
N
Me
Pt
N
iPr
iPr
CD3
Me
iPr-d
7
D DD
Pt
N
i
CD3
Pr-d7
i
Pr
and/or
and/or
iPr
Pt
i
D Pr
N
C6D5
Pt
N
N
iPr
N
iPr
2
H
N
ox. add'n.
Pt
N
N
iPr
iPr
iPr
iPr
N
Pr-d7
7
- RH .......
iPr
A
H HH
Pt
Pr
- C 2H 6
iPr
iPr-d
i
1
Red. Elim.
N
iPr
Me
N
i
Pr-d7
iPr
iPr
Me
iPr
- CH4
N
Pt
Red. Elim.
C6D6
ox. add'n.
D
N
Pt
N
iPr
iPr
iPr
C6D5
iPr
Red. Elim.
N
Pt
N
N
iPr
i
Pr
C6D5
iPr-d
1