m.c. white, - harvard universitypeople.fas.harvard.edu/~chem253/notes/2004wk11-12.pdf · 2004. 12....
TRANSCRIPT
The Holy Grail of Catalysis
ARTHUR: Yes we seek the Holy Grail (clears throat very quietly). Our quest isto 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 253 C-H Activation -276- Week of December 6, 2004
R CH3
R 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 akinetic 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-Mintermediate under synthetically useful, mild conditions that enable functionalization and catalystrenewal.
M.C. White, Chem 253 C-H Activation -277- Week of December 6, 2004
Bergman:C-H Activation via Late, Nucleophilic Complexes
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).
These hydrido(alkyl)metal complexes areprone to non-productive reductive eliminationin the presence of oxidants and non-productive protonolysis in the presence of protic reagents
Relative rate constants for attack at a single C-H bond by 1 and 2 at -60oC.
C-H bond
benzenecyclopropanen-hexane (1o)
n-hexane (2o)propane (1o)
propane (2o) cyclopentanecyclohexane
krel (Rh, 2)
19.510.4
5.902.6
01.81.0
krel (Ir, 1)
3.92.12.7
0.21.5
0.31.11.0
arbitrarily set at 1
with acyclic substrates the Rh complex inserts only into 1o C-H bonds
regioselectivity: sp2 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 σ bond. Kinetic preference: activation barrier to σ-complex formation is lower for less sterically hindered C-H bonds and bonds withmore s character. Thermodynamic preference: stronger C-M bonds are formed (see Structure and Bonding, pg. 32).
MI
OC
CO
CO
MI
L
MIII
L
HMI
L
H
18 e-
hv or ∆∆∆∆
16 e- 18 e-proposedσ-complex
intermediate
ligand dissociation
M = Ir, 3 Rh, 4
MIII
Me3PH2
hv or ∆∆∆∆
M = Ir, 1 Rh, 2
oxidativeaddition
coordinatively and electronically unsaturated
intermediate
H
H
π-donor
low OS metals capable ofdonating electrons in σ-bondformation. Highly prone to air oxidation.
H
C
M M
H
C
π-backbonding>>σ-donation
oxidative addition
σ-complex
Hydrido(alkyl)metalcomplex
M.C. White, Q. Chen Chem 253 C-H Activation -278- Week of December 6, 2004
Evidence for intermolecular σ-complex formation
CO
D
D2C
CD3
D3C CD3
RhIII
OC CD2
D
CD3D3C
CD3
RhI [Kr]
OC
RhI
OC
CORhI
OC
CD3
D3C
CD3
CD3
18 e-
hv (flash), Kr (165K)
CO v (1946 cm-1)
CO v (1947 cm-1)
σ-complexCO v (2008 cm-1)
D
D2CCD3
D3C CD3
RhI
OC
RhI [Kr]
OC
Rh
OCCD2(C(CD3)3
D
+ (CD3)4C
to products
∆G
(kca
l/mol
)
‡
-3.2 kcal/mol
+ 6.9 kcal/mol
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.
Bergman JACS 1994 (116) 9585.
M.C. White, Chem 253 C-H Activation -279- Week of December 6, 2004
Evidence for concerted C-H oxidative addition
IrI
OC
CO
CO
IrI
OC
IrIII
OC
H
Bergman JACS 1983 (105) 3929.
IrI
OC
D
crossover experiment: evidence in support of a concerted mechanism.
18 e-
hv
σ-complexes
D12
IrII
OC
H IrII
OC
D
H2C
D11
H3C
+
IrI
OC
H
IrIII
OC
D
Less than 7% of the crossover products were observed by 1HNMR. This may be indicative of a minor radical pathway.
IrIII
OC
DIrIII
OC
H
D11 D11
D11
M.C. White, Chem 253 C-H Activation -280- Week of December 6, 2004
Dehydrogenation of alkanes to alkenes
R RH2
-H2
Catalyst requirements:
MLnx-3
"14e-"
RMLn
x
18e-
3 L H
MLn-2x-1
H
R
H
MLn-2x
R
H
H
β-hydride elimination
16e- 18e-
oxidative addition
H2, R
metal capable ofshuttling between Mn
and Mn-2 oxidation states
complex capable of accomodating 3 ligands from the substrate in itscoordination sphere mid-cycle
regeneration via olefin dissociation andelimination of H2. H2 must be rapidly and irreversibly removed to avoid olefinhydrogenation and isomerization
Ph3PIr(III)
PPh3
H
H
O
+(BF4
-)
recall: intermediate in cationic hydrogenation catalysts
10 eqO
CD2Cl2, -60oC
(coe)
Ph3PIr(III)
PPh3
H
H +(BF4
-)
observed to formquantitatively byNMR
-10oC->40oC Ir(I)PPh3
PPh3
+(BF4
-)
75%
recall: hydrogenation catalyst
The first report:
Crabtree JACS 1979 (101) 7738.
M.C. White, Chem 253 C-H Activation -281- Week of December 6, 2004
Crabtree:thermal dehydrogenation of alkanes to alkenes
Crabtree JACS 1987 (109) 8025.
solvent
HIr(III)
H O
O
P(p-FC6H4)3
P(p-FC6H4)3
CF3
+t-Bu
7.1 nM
355 mM
150oCt-Bu
2d, 1.4 tntn = turnover #
2d, 3 tn 2d, 9 tn
4% (3%)
+
56% (54%)
+
18% (17.5%)
+
trans-3-hexene 14% (18.5 %)cis-3-hexene 8% (7.5 %)
yields based on catalyst.
14 days
Product distributions of linear alkenesare thought to result from isomerization of the initial kinetic 1-ene product viaintermediate Ir hydride species.Subjecting 1-hexene to the reactionconditions gives similar olefindistributions (in parentheses).
sacrificial H2 acceptor with unusually high heat ofhydrogenation
HIr(III)
H O
O
P(p-FC6H4)3
P(p-FC6H4)3
CF3
HIr(III)
H OC(O)CF3
P(p-FC6H4)3
(p-FC6H4)3P t-Bu
t-Bu
Ir(III)H O
O
P(p-FC6H4)3
P(p-FC6H4)3
CF3
t-Bu
(C6H4p-F)3PIr(I)
(C6H4p-F)3P O
OCF3
(C6H4p-F)3PIr(I)
(C6H4p-F)3POC(O)CF3
HIr(III)
H OC(O)CF3
P(p-FC6H4)3
(p-FC6H4)3PR
HIr(III)
H OC(O)CF3
P(p-FC6H4)3
(p-FC6H4)3P R
R
t-BuR
HIr(III)
O
O
P(p-FC6H4)2
P(p-FC6H4)3
CF3
F
R
HIr(III)
H OC(O)CF3
P(p-FC6H4)3
(p-FC6H4)3P R
14 e-
oxidativeaddition
β-hydride elimination
"tail-biting" Ir(III)H OC(O)CF3
P(p-FC6H4)3
(p-FC6H4)3P
HR
isomerization pathway
hydrogenationpathway
R
isomerization
hydrogenation
Proposed Mechanism:
only trifluoroacetate complexeswere active in alkenedehydrogenations. Their greater lability with respect to acetatemay allow more facileinterconversion from η3 to η1
necessary to provide an opencoordination site for H2acceptor binding.
M.C. White, Chem 253 C-H Activation -282- Week of December 6, 2004
Crabtree:photochemical dehydrogenation of alkanes to alkenes
Proposed Mechanism:
Crabtree JACS 1987 (109) 8025.
Irradiation with light of the appropriatewavelength promotes reductive elimination ofthe dihydride catalyst leading directly to thecatalytically active 14e- complex. It's interestingto note that no reaction takes place with tbe inthe absence of 254 nm light. This implies thattbe acts as a H2 acceptor from a photochemically excited intermediate.
HIr(III)
H O
O
P(Cy)3
P(Cy)3
CF3
(Cy)3PIr(I)
(Cy)3P O
O
CF3
(Cy)3PIr(I)
(Cy)3POC(O)CF3
14 e-
HIr(III)
H OC(O)CF3
P(Cy)3
(Cy)3PR
HIr(III)
H OC(O)CF3
P(Cy)3
(Cy)3P R
R
t-Bu
R
oxidativeaddition
β-hydride elimination
Ir(III)H OC(O)CF3
P(Cy)3
(Cy)3P
HR
isomerization pathway
HIr(III)
H O
O
P(Cy)3
P(Cy)3
CF3
*
hv, 254nm
t-Bu
H2
H2 Some free H2is formed even in the presenceof tbe.
solvent
HIr(III)
H O
O
P(Cy)3
P(Cy)3
CF3
+t-Bu
7.1 nM
tbe355 mM
hv (254 nm)t-Bu 2.77tn (1.6)
+
2.19 tn (3.84)
+
7 days
Under conditions of hv and tbe,methylcyclohexane is the preferredproduct. This is thought to result from akinetic preference to form the sterically less hindered M-C bond.Methylenecyclohexane subjected to thereaction conditions results in only 25%conversion to the thermodynamically morestable 1-methylcyclohexene. Although thereaction proceeds w/out tbe, the productratios reflect more isomerization activity.
+
+ H20.85 tn (0.32) 1.26 tn (0.82)
tn w/out tbe present (in parentheses).
M.C. White, Chem 253 C-H Activation -283- Week of December 6, 2004
Tanaka: photochemical dehydrogenation
Proposed Mechanism:
0.7mM
hv, rt, N2138 tn, 17 h A theoretical amount of H2 was detectedin the gas phase.When a N2 streamwas used, tnincreased to 195 tn.
930 tn, 69hN2 stream
+
1:79:20
+
27 h, 155 tn
Me3P
Rh(I)OC PMe3
Cl
(solvent)
H2
+
PMe3/Rh
2551010
time (h)
1322322
hexenes1- 2- 3-
11262810
114443.4
21111
TN
5.44.018.70.67.2
Added phosphine ligand decreases the efficiency ofthe reaction but increases the regioselectivitytowards formation if 1-hexene. Within the samePMe3/Rh ratio, an erosion in regioselectivity isobserved upon prolonged reaction times. This isindicative of catalyst mediated alkene isomerization. Could this ratio also be reflective of the rates ofolefin hydrogenation? Exposure of 1-hexene to thereaction conditions results in 2-hexene (35%) andhexane (63%) after 22 h.
Me3P
Rh(I)OC PMe3
Cl
16 e-
hv
CO
Me3P Rh(I)PMe3
Cl14 e-
R
Rh(III)PMe3
Cl
H
PMe3R
H
Rh(III)PMe3
Cl
H
PMe3
R
H intermediate in Wilkinson hydrogenation
R
H2
light-promoted reductive elimination of H2 ??
Rh(III)PMe3
Cl
H
PMe3
HR
Added phosphine ligand may take up a vacant coordination site cis to theM-alkyl, preventing formation of theagostic interaction necessary to effectβ-hydride elimination. A decrease inboth alkane dehydrogenation andolefin isomerization results.
β-hydride elimination
reductiveelimination
M.C. White, Chem 253 C-H Activation -284- Week of December 6, 2004
Goldman: Wilkinson’s Catalyst Varient
Proposed Mechanism:
Goldman JACS 1992 (114) 9492.
Me3P
Rh(I)OC PMe3
Cl
16 e-
H2
Me3P
Rh(III)H PMe3
Cl
H
CO
Rh(III)PMe3
Cl
H
PMe3
18e-
H
CO
16 e-
Ph3P
Rh(III)H PPh3
Cl
H
Me3P Rh(I)PMe3
Cl
Tanaka's 14 e- intermediate
Rh(III)PMe3
Cl
H
PMe3
H
0.7mM
H2 (1000 psi), 60oC1.5 h, x tn
Me3P
Rh(I)OC PMe3
Cl
sacrificial alkene
++
alkane
, 59 tn
, 106 tn
, 53 tn
t-Bu, 4 tn
sacrificial alkenes
n-hexane gave hexenes in modesttn (9.6) with norbornene as the H2 acceptor. No mention was madeto the isomer distributions.
A variety of sacrificial alkenes work in thedehydrogenation of cyclooctane, anespecially reactive substrate. Cyclooctenehas a very low heat of hydrogenationprobably resulting from transannular steric repulsions in cyclooctane which are lesssevere in cyclooctene.
(solvent)
Formation of octahedral dihydride complex is thought toinitiate ligand dissociation. Wilkinson's hydrogenationcatalyst (see hydrogenation, pg. 142), known to dissociatePPh3 upon H2 oxidative addition, is cited as precedent forthis. There is no evidence that CO dissociates preferentiallyover PMe3. The authors invoke this to arrive at the same 14 e- intermediate proposed in Tanaka's photochemical system.
M.C. White, Chem 253 C-H Activation -285- Week of December 6, 2004
Substrate directed dehydrogenation via C-H activation
N
NO
H3CO
N
PtIICH3
N
NO
H3CO
N
Pt HN
NO
H3CO
OH
CF3CH2OHN
NO
H3CO
N
PtIVCH3
H
N
NO
H3CO
N
PtII
H
(OTf-)
+
(OTf-)
+
70oC, 60 h
Rhazinilam
(OTf-)
+
(OTf-)
+
CH4
Possible intermediates:
Sames constructs a ligand for the metal from the requisite functionality of the target that directsC-H activation towards only one of the 2 ethylsusbstituents. This results in selectivedehydrogenation to give the platinum hydride in>90% yield. The reaction is stiochiometric inplatinum and the metal must be removed viatreatment with aqueous potassium cyanide.
Sames JACS 2000 (122) 6321.
M.C. White, M.S. Taylor Chem 253 C-H Activation -286- Week of December 6, 2004
Dehydrogenation of n-alkanes to terminal olefins
A
(0.5 mol%)
150°C
Longerreaction
times
(norbornene, t-butylethylene, or 1-decene)sacrificial hydrogen acceptor
Ir
P
P
R R
R R
HH
R = t-Bu, i-Pr
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, olefinisomerization via sequential hydrometallation and β-hydride elimination erodes the kinetic selectivity, resulting in a mixture of olefin isomers.
Although the nature and the concentration of the sacrificialhydrogen acceptor had little effect on the reaction rate, thesefactors had a large effect on the observed distribution ofdouble bond isomers in the product. The authors propose that the observed isomer distribution is largely determined by thecompetition between the sacrificial acceptor and the productolefin for insertion into the Ir-H bond of the dihydrideintermediate.
A
A
Ir
P
P
R R
R R
n-OctH
Ir
P
P
R R
R R
HH
Ir
P
P
R R
R R
H A
Ir
P
P
R R
R RGoldman, A. JACS 1999, 121, 4086.
M.C. White, Chem 253 C-H Activation -287- Week of December 6, 2004
Direct carbonylation of benzene
Postulated mechanism:
The first report:
(solvent)
+ CO
1 atm
Ph3P
Rh(I)OC PPh3
Cl 7.2 mM
hv (295-420), rt, 40h
O
H
3 tnRhCl(CO)(PPh3)2 is a photochemicaldecarbonylation catalyst at rt.
Eisenberg JACS 1986 (108) 535.
Soon afterwards:
(solvent)
+ CO
1 atm
Me3P
Rh(I)OC PMe3
Cl 0.21 mM
hv (295-420), rt, 33h
O
H
73 tn
Phosphine
PMe3PBu3PEt3P(i-Pr)3P(p-tolyl)3PPh3P(OMe)3
CO (cm-1)
1970195519571947197919822011
TN
7319172322
PMe3 is thought to increase theeffectiveness of the Rh catalystboth by increasing electrondensity at the metal therebypromote oxidative addition and by decreasing tail-biting of thecomplex.Tanaka Chem. Lett. 1987 249.Tanaka JACS 1990 (112) 7221.
Me3P
Rh(I)OC PMe3
Cl
16 e-Cl Rh(I)
PMe3
PMe3
14 e-
Cl Rh(III)
H
Me3P
PMe3
16 e-
Rh(III)
H
Me3P
PMe3
OC
Cl
ClRh(III)
H
Me3P
PMe3
O
Ph
18 e-
O
H
hv CO
CO
OC
CO
18 e-
M.C. White, Chem 253 C-H Activation -288- Week of December 6, 2004
Direct carbonylation of alkanesAliphatic hydrocarbons:
(solvent)
+ CO
1 atm
Me3P
Rh(I)OC PMe3
Cl 0.21 mM
hv (295-420), rt, 33hO
H
27 tn
+
0.6 tnO H
The carbonylation reaction is highlyregioselective towards primary C-Hbonds to give linear aldehydes withhigh selectivities. Unfortunately, the aldehydes formed readily undergo asecondary photochemical reaction(Norrish Type II) to give adehomologated terminal alkene andacetaldehyde in large quantities.
hv285 nm
O
H
H
CH3CHO+
92 tn
Tanaka Chem. Comm. 1987 758.
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 >330nm. Metal-to-ligand charge transfer band of Rh-CO @ 365 nm. FordJACS 1989 (111) 1932. Absorption of non-conjugated aldehydes appearat ~285 nm. It was hypothesized by Tanaka that cutting of theshort-wavelength region capable of aldehyde excitation would improveyields of the desired aldehyde.
wavelength (nm) aldehyde tn (1-decanal, 2-, 3-, 4-)
nonene tn
295-420>325
610 (85:5:4:2:3)126 (8:45:17:15:16)
3190
While Norrish Type II reactions leading to dehomologated terminal alkeneswere suppressed by going to a longer wavelength, carbonylation selectivitytowards the 1o position of the alkane was lost and catalytic activity wasdiminished. These results imply that photo-induced CO dissociation may not be the major pathway in this system for generating the complex capable ofC-H activation of linear aliphatic alkanes.
Tanaka JACS 1990 7221.
Photo-induced Norrish Type II Chemistry
Irradation of a solution ofRhCl(CO)(PMe3)2 /C6H6 in theabsence of CO at -40oC affordedtwo isomers of the 18 e-alkylhydrido complexes whichwere fully characterized by NMR(1H, 31P, 13C NMR). Fields JACS 1994 (116) 9492.
The rate of benzene carbonylationcatalyzed by RhCl(CO)(PMe3)2irradiated at >290 nm (ca. 314 nm, awavelength where Rh-CO does notabsorb) is proportional to CO pressure.Goldman proposes aphotoelectronically excited intermediate as the species effecting C-H activation.Goldman JACS 1994 (116) 9498.
Revised proposed catalytic cycle:
Me3P
Rh(I)OC PMe3
Cl
16 e-
Me3P
Rh(I)OC PMe3
Cl
16 e-
*
Rh(III)
H
PMe3
PMe3
OC
Cl
18 e-
R
ClRh(III)
H
Me3P
PMe3
18 e-
O
R
R
OC
CO
R H
O
M.C. White, Chem 253 C-H Activation -289- Week of December 6, 2004
Direct formation of aldimines
1.0 mM
+N
C
Ph3P
Rh(I)RNC PPh3
Cl 0.2 mM
hv, rt, 36h
N
H
R
R= neopentyl4 tn
Jones notes that this system (unlike the one reported by Tanaka) is completelyineffective at aldimine formation fromaliphatic hydrocarbons.
Jones OM 1990 (9) 718.
Ph3P
Rh(I)RNC PPh3
Cl
16 e-
-PMe3
+ PMe3
Rh(I)RNCPPh3
Cl
14 e-
Rh(III)RNC
PPh3
16 e-
Cl
H
Rh(III)CNR
PPh3
16 e-
Cl
HN
R
N
H
R
CNR
Proposed mechanism:
(solvent)
+ RNC
55 mM
Me3P
Rh(I)OC PMe3
Cl 0.7 mM
hv, rt, 36h
N
H
3 tn
R
R = cyclohexyl, 5 tn Me, 38%/Rh t-Bu, 3%/Rh
CyNC
6.0 mM(solvent)
+
low conversions may be due in part to the low solubility of the isocyanideunder the rxn conditions. Selectivitiesnot reflective of C-H activation via anorganometallic intermedaite.
Me3P
Rh(I)OC PMe3
Cl 0.7 mM
hv, rt, 17h
N
Cy
6%/Rh
H NCy
12%/Rh 12%/Rh
NH
Cy
+
+
The first report:
Tanaka Chem. Lett. 1987 2373.
M.C. White, Chem 253 C-H Activation -290- Week of December 6, 2004
Direct Borylation of Alkanes: Stoichiometric
Hartwig Science 1997 (277) 211.
Proposed mechanism:
WII
OC CO
OC B
O
O
BCat'
BCat'
BCat'
Selectivity between activation/ functionalizationof 1o vs. 2o C-H bonds is high. Reactions of thetungsten complex with cyclohexane resulted in22% yield based on W. This system appears tobe highly sensitive to sterics as demonstrated init's ability to discriminate between the linear and branched 1o C-H bonds of isopentane.
18 e-
stoichiometric
(solvent)
(solvent)
(solvent)
hv
Bcat' 83%/W100% regioselectivity
55%/W
74%/W
2%/W
+
lesser reactivity was also observed with the Ruand Fe analogs
Cat'B
WII
OC CO
OC B
O
O
18 e-
stoichiometric
hv
CO
Photolysis in the presence of PMe3 results in the formation of Cp*W(CO)2(PMe3)Bcat'. This wastaken as evidence for the photo-induced loss ofCO to generate coordinatively unsaturated 16 e-intermediate that may interact with the alkane.
WII
OC
OC B
O
O
16 e-
RH
?
WII
OC
OC H
16 e-
+R
Cat'B
The exact mechanism of C-H activation/functionalization is unclear. Two possibilities arelikely: 1. oxidative addition followed by reductive elimination, 2. σ-bond metathesis. Thefirst possibility would requires an increase in the oxidation state of the W to +4, a highenergy oxidation state for an organometallic W complex. Alternatively, σ-bondmethathesis could occur with no oxidation state change. Alkane dehydrogenation followed by anti-Markovnikov hydroboration is excluded since aliphatic alkenes result invinylborates rather than the observed alkylborate esters.
M.C. White, Chem 253 C-H Activation -291- Week of December 6, 2004
Direct Borylation of Alkanes: Catalytic
IrIII
Me3P
H
BPin
HB
O
O BPin17 mol%
150oC, 5 d+
BPin = pinacolborane
(solvent) 1 eq53% (basedon borane)
+ H2
The first catalytic report:
note similarity w/ Bergmanstiochiometric C-H activation complexes.
Smith JACS 1999 (121) 7696.
C6H13B
O
O
B
O
O
IrI
RhI
C6H13
Bpin 2 H2
C6H13
Bpin 2 H2
RhI
C6H13
Bpin 2 H2
Hartwig runs with it...
(pinBBpin)
+
(solvent)
10 mol%200oC, 10 d
2
2 +
58%/B
5 mol%
150oC, 5 h2 +
85%/B
facile thermal alkene dissociation forms coordinatively unsaturatedcomplexes
1 mol%
150oC, 80 h
2 +
72%/B
The rate acceleration observed in going from a3rd row metal complex to an analogous 2nd rowcomplex may be accounted for by a weakeningof M-C bonds which may promote turnover steps in the catalytic cycle.
Hartwig Science 2000 (287) 1996.
100% regioselectivity for the terminal boranewas consistently observed. The linear borane is thought to be the kinetic product. Exposure ofsecondary alkyl boranes to reaction conditionsdoes not result in isomerization.2-Methylheptane resulted exclusively inproducts formed from primary C-H bondactivation with the less sterically hinderedterminal methyl group becomingfunctionalized selectively.
M.C. White, Chem 253 C-H Activation -292- Week of December 6, 2004
Mechanism of direct borylation of alkanes
Hartwig Science 2000 (287) 1996.
HBpin, generated under therxn conditions, is equallyeffective as source of borane
C6H13B
O
O
B
O
O
RhI
C6H13
Bpin
(pinBBpin)
+
(solvent)
5 mol% +
85%/B
BO
OH
C6H13
150oC, 5 h
RhI
5 mol%C6H13
Bpin
RhI
RhI
18 e-
14e-
RhIII
X Bpin
RhV
18e-
X BpinH R
RhIII
H X
via RhIII intermediates
R-HR-Bpin
Rh(V) is a very high energy oxidationstate: controversialintermediates.
X = H, Bpin
RhV
X BpinH X
RhI
∆∆∆∆
18 e-
pinBX HX
Hartwig's mechanistic proposalTo 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 arguesagainst a σ-complexed borane Ir(III) species, his evidence does notconclusively eliminate it as a possibility. The independentlysynthesized intermediate was an effective alkane borylation reagent,resulting in similar yields and the same selectivities observed in thecatalytic system.
IrV
Bpin H
H Bpin
orIrIII
BpinH
H Bpin
C6H13
(solvent)
45%/B
C6H13
Bpin
200oC
Hartwig JACS 2001 (123) 8422.
?
M.C. White, Chem 253 C-H Activation -293- Week of December 6, 2004
Direct Arene borylation: Suzuki precursors
Cl
Cl
O
B
O
H
Cl
Cl
BPindppe 2mol%, 100oC
16h
1.5 eq1 eq89% based on arenePh2P PPh2
dppe
Towards synthetic utility...
IrI
η5-indenyl complex capable of rearranging to η3 and η1
2mol% N
Cl
Cl
Bpin
aryl-H: HBpin (1:2)69% yield, 4h
Cl
MeO2C
BPin
aryl-H: HBpin (1:2)95% yield, 25h
BPinMeO
MeO
aryl-H: HBpin (1:3)62% yield, 95h, dmpe
Recall that, in general, Ir complexes are less reactive than thecorresponding Rh complexes towards alkane borylation. ArylC-H bonds are more reactive towards C-H activation than alkyl
C-H. The factors favoring activation of aryl C-H bonds are thehigh degree of s character in the Csp2-H bond which favorsσ-complexation to the metal and the strength of the resulting aryl
Csp2-M bond after oxidative addition.
excellent regioselectivities for functionalization of stericallyless hindered sites
In several examples the authors were able to achieveintermolecular C-H activation/functionalization without using the substrate as the solvent. Some substrates wereborylated under neat conditions while others employedcyclohexane as solvent.
Consecutive aryl borylation/Suzuki:
Cl
Cl
1 eq
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
Cl80% yield based
on dichlorobenzene
Smith Science 2002 (295) 305.A related study that uses the bpy ligand in conjunction with IrI: Hartwig JACS 2002 (124) 390.
M.C. White,Q. Chen Chem 253 C-H Activation -294- Week of December 6, 2004
CyclometallationCyclometallation: intramolecular C-H activation of supporting metal ligands (a.k.a. "tail-biting")...
Ph3PIrI
Ph2P PPh3
Cl
H
agostic interaction
∆
C6D6
Ph3PIrIII
Ph2P PPh3
H
Cl
Bennnett JACS (91) 1969 6983.
Ph3PPtII
Ph3PPtII
Ph3P
HPtIV
Ph3P
H
PtIIPh3P
PtIIPh3P PPh3
-PPh3
PPh3
PPh3
-PPh3
rate-limitingstep: RE
ligand dissociation to create an opencoordination site
OA
Whitesides OM 1982 (1) 13
Chelate-assisted C-H activation:
Ibers JACS 1976 (98) 3874.
16 e-
16 e-
14 e-
Substrates with Lewis basic functionality cantemporarily become appended to a site ofcoordinative unsaturation on a metal and undergo chelate assisted C-H activation.
Ph3P
RuIIPh3P PPh3
PPh3
H
H
O
EtO
(excess)
PPh3
Ph3P
RuIIPh3P PPh3
H
H
O
OEt
hydrogenation
O
EtO
Ph3P
Ru0Ph3P
PPh3
Ph3P
Ru0Ph3P
O
PPh3
H
OEt
Ph3P
RuIIPh3P
O
H
OEt
PPh3
OA
M.C. White, Chem 253 C-H Activation -295- Week of December 6, 2004
Chelate assisted Csp2-H-olefin reductive coupling
O
R1R2
2 mmol
Y+
OCRuII
Ph3P PPh3
PPh3
H
H 2 mol%
toluene, reflux
O
R1R2
Y2-10 mmol
Y = H (ethylene) Si(OEt)3 CH2SiMe3 t-Bu
O
SiMe3 OO
Si(OEt)3
"privileged olefin"
O
Si(OEt)3
O
Si(OEt)3
>99% yield >99%
>99% >99%100% regioselectivity
Murai's breakthrough system...
Murai Nature 1993 (366) 529.
Many other examples follow:
metal chelating LB functionality
Csp2-H 4 atoms from LB functionality results in5-membered ring metalchelate
O
O
R
2 mmol
Y+
2-10 mmol
OCRuII
Ph3P PPh3
PPh3
H
H 6 mol%
toluene, reflux
O
O
R
Y
O
O
t-Bu
C6H13
O
O
Et
Si(OEt)3
O
O
t-Bu
Si(OEt)3
98% >99%
73%Murai Chem. Lett. 1995 679.
OCRuII
Ph3P PPh3
PPh3
H
H 2 mol%
toluene, reflux
Internal alkynes also add...
O
RR+
OR
R
R = Pr (72%), E/Z = 16/1 Ph (85%), E/Z = 9/1Murai Chem. Lett. 1995 681.
Aryl esters:
CF3 O
OMe
Si(OEt)3
CF3 O
OMe
Si(OEt)3
OCRuII
Ph3P PPh3
PPh3
H
H
+2 mol%
toluene, reflux
Murai Chem. Lett. 1996 109.
Only aromatic esters substituted with CF3 or F groups (m,p,and o) resulted in coupled product. Other benzoates w/electron withdrawing substituents o-NO2, p-NO2, o-CN,o-CO2Me failed to give coupled product.
M.C. White, Chem 253 C-H Activation -296- Week of December 6, 2004
Cyclic and acylic vinyl esters :
O
OR
H
R1
R2
OCRuII
Ph3P PPh3
PPh3
H
H 5 mol%
toluene, reflux
O
OR
R1
R2 Si(OEt)3
+Si(OEt)3
A lack of reactivity isobserved when the βCsp2-H bond is trans to the ester carbonyl
O
OR
Si(OEt)3Ph
O
NHCH3
Si(OEt)3
O
OEt
O
OO
OO
Si(OEt)3
R = (CH2)5CH2OAc, 85% (CH2)5CH2OTBS, 91% (CH2)5CH2Br, 54%
80%
70%
A high degree offunctional group tolerance is demonstrated throughthe substrates tested.
Proposed mechanism:
Trost JACS 1995 (117) 5371.
Oxygen chelate assisted Csp2-H-olefin reductive coupling
OCRuII
Ph3P PPh3
PPh3
H
H
SiR3 SiR3
COCO loss is supported by the observation that thereaction is inhibited inthe presence of CO.
Hydrogenated product is observed by GC
Ph3P
Ru0Ph3P
PPh3
14 e-
Ph3P
Ru0Ph3P
O
PPh3
H
OR'
Ph3P
RuIIPh3P
O
H
OR'
PPh3Ph3P
RuIIPh3P
O
H
OR'
R3Si
PPh3
RuIIPh3P
O
OR'
SiR3
O
OR
H
SiR3
PPh3
migratory insertion
reductive elimination
O
OR'
SiR3
M.C. White/Q.Chen Chem 253 C-H Activation -297- Week of December 6, 2004
Nt-Bu
H
Si(OEt)3
N
t-Bu
H
Si(OEt)3
Ru3(CO)12 (2 mol%)
tol, 135oC, 24h+ +
Nt-Bu
H
Si(OEt)3
81% 10%
RuH2(CO)(PPh3)3 (2 mol%)
26% 8%
Muria Chem. Lett. 1996 111.
Some Ru-H is formedvia the dehydrogenative coupling.
Nitrogen chelate assisted Csp2-H-olefin reductive coupling
Fish OM 1986 (5) 2193.
Ru
Ru
Ru
(CO)4
(CO)3
(CO)3
N
H
N
Ru3(µ-H)(m-C13H8N)(CO)10
Ru3(CO)12
130oCheptane
1
2 CO
M.C. White, Chem 253 C-H Activation -298- Week of December 6, 2004
Nitrogen chelate assisted Csp2-H/CO/olefin reductive coupling
N
N
Ph
+O O
Ru3(CO)12 (4 mol%)
CO (20 atm)
tol, 160oC, 24h
N
N
Ph
O
72% (linear:branched; 97:3)
N
N
+ Ru3(CO)12 (4 mol%)
CO (20 atm)
tol, 160oC, 24h
N
N
O
1-hexene; 68% (linear:branched; 94:6)2-hexene; 41% (linear:branched; 94:6)
Tolerates sensitive functionality:
or
O O
Olefin isomerization occurs under the reaction conditions:
N
N
Ph
OO O
N
N
O
+
+
Proposed mechanism:
Murai JACS 1996 (118) 493.
N
N
Ru3(CO)12
N
N
(OC)3RuH
Ru(CO)3
(CO)4Ru
N
N
Ru(CO)3
Hor
NN
Ru(CO)n
H
R
NN
Rux(CO)n
R
NN
Rux(CO)n
O
R
Ru(CO)3
+
R
CO
N
N
O
R
M.C. White, Chem 253 C-H Activation -299- Week of December 6, 2004
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.
Jones JACS 1986 (108) 5640.
CN
RuII
PMe3
Me3P
PMe3
Me3P
H
20 mol%
benzene, 120oC, 94 h
HN
heat promoted RE
Ru0Me3P P
Me3
PMe3
Me3P
Me3P
Ru0NC
Me3P
PMe3
PMe3
Ru0NC PMe3
Me3P
Me3P
H
PMe3
RuII H
PMe3
PMe3
Me3P
PMe3
N
RuII PMe3
H
PMe3
Me3P
PMe3
NH
RuIINC H
PMe3
Me3P
Me3PPMe3
CN
OA
migratoryinsertion
isomerization
HN
RuII H
PMe3
PMe3
Me3P
PMe3
NH
tautomerism
M.C. White, Chem 253 C-H Activation -300- Week of December 15, 2004
Oxidative functionalization of alkanes
overoxidation to CO2 ismajor problem w/methane oxidation
The methane to methanol challenge: Synthesizing "liquid gold":
CH4 (g) + H2O (g) Ni/Al2O3
700oCCO (g) + H2 ∆Ho = 49.3 kcal/mol
CO (g) + 2 H2 (g) zeolite cat.∆
CH3OH ∆Ho = -21.7 kcal/mol
Current industrial process consumes significant amounts of energy:Direct oxidation is thermodynamically favorable.
CH4 (g) + 1/2 O2 (g) ∆Ho = -30.7 kcal/molcatalyst ? CH3OH
Nature does it:
Methane Mono-Oxygenase (MMO):
CH4 + O2 + NADPH + H+ MMOM. Capsulatus
12 min
CH3OH + NADP+ + H2O84 tof
tof = nmol product/min/mg enzyme
Higher hydrocarbons are oxidized with poor regioselectivities
MMO oxidizes methane to methanol with 100% chemoselectivity (no overoxidized product results).
MMOM. Capsulatus
12 minOH
+
OH
1.3 : 1Lipscomb J. Biol. Chem. 1992 (267) 17588.
Pseudomonos Oleovorans Mono-Oxygenase (POM):
Oxidizes linear alkanes with 100% regio- and chemoselectivity
n-alkanes
C6-C12
+ O2 + NADPH + H+ 1-alcohols
+ NADP+ + H2O
1-octanol, 590 tof
POM
Coon Biochem. Biophys. Res. Comm. 1974 (57) 1011.Munck PNAS 1997 (94) 2981.
The Shilov system:
CH4 + H2O
ClPtII
Cl Cl
Cl
(K+)2
cat.
CH3OH + CH3Cl
120oC
K2Pt(IV)Cl6 oxidant
In 1972 Shilov and coworkers demonstrated that a combination of chloroplatinum(II)and (IV) salts in aqueous solutions at elevated temperatures effects the oxidation ofalkanes 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 methylenehydrogens. Unfortunately only modest selectivites are observed. Some overoxidizedproducts and regioisomeric mixtures of alcohols are observed because the productalcohols are more soluble in the aqueous reaction media than the hydrocarbon.
Shilov Zh. Fiz. Khim. (Engl. Trans.) 1972 (46) 785. regioselectivities: Bercaw JACS 1990 (112) 5628.
A beginning...
M.C. White, Chem 253 C-H Activation -301- Week of December 15, 2004
MMO
N
N
Fe(II)
OH2O
O OO
N
N
Fe(II)O
O
OO
N
N
Fe(III)
OH2O
O
H2O
N
N
Fe(III)
O
O
OO
OH
O
O·Hydroxylase Active Site of MMO
H147
E114
E243
H246
E209
E144
MMOHred
H147
E114
H246
E209
E144
MMOHox
E243
Based on crystallographic studies of M. capsulatus(-160oC) Lippard Nature 1993 (366) 537.
CH3
HTD
CH3
OHTD
CH3
HO TD
MMO
Key piece of evidence supporting substrate radical intermediate:
(R)-ethane (S)-ethanol (R)-ethanol
+
35%
Lipscomb Chem. Reviews 1996 (96) 2625.
FeIII
O
ON
N
N
FeIII
O
NN
N
Cl Cl
2+(ClO4
-)2
cat.
H2O2, CH3CN, airnote: the same yields and selectivities were observed when the reactions were run under an inertatmosphere (Ar) or in air. This indicates that freeradicals, propagated with O2, are not acting as theoxidant.
OH
+
O
4 tn 2 tn
Nishida Chem. Lett. 1995 885.
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 havenot been mimicked in solution.
Fe
HO
Fe
·O O·
Fe
HO
Fe
O O
Fe
HO
Fe
O O
H
Fe
HO
Fe
Fe
HO
FeO
Fe
HO
Fe
OH
Fe
HO
Fe
(II)(II)
(III)(III)
(III) (III)
O·
(III)(IV)
(IV) (IV)
(III)(III)
(III)(IV)
H2O2
-H+H+
H+
-H2OQ
µ-1,2 peroxoadduct
+R·
"peroxideshunt"
RH
P
2e-
ROH
The second iron in MMO transiently stabilzesintermediate Q by supplying an e- to fill theoxygen atom's octet. This avoids energetically unfavorable Fe(V) intermediates.
Proposed mechanism (thought to be operating for POM as well):
M.C. White, Chem 253 C-H Activation -302- Week of December 15, 2004
The Shilov System/C-H activation via late, electrophilic complexes
H
C
M M C
σ−donation>>π-backbonding
heterolytic cleavage
σ-complex
+ H+
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 oxidativefunctionalization of hydrocarbons (the most desirable form of functionalization).
Because Pt is a late "soft" metal,the relatively diffuse alkane C-Hbond is able to intermolecularlycompete with the hard oxygen lone pair of H2O for binding to themetal.
Inversion of stereochemistry at the platinum bound C usingdeuteruim labeled substratesprovided strong evidence forSN2 functionalization pathway
Proposed mechanism:
Bercaw ACIEE 1998 (37) 2180.
The Shilov system:
CH4 + H2O
ClPtII
Cl Cl
Cl
(K+)2
cat.
CH3OH + CH3Cl
120oC
K2Pt(IV)Cl6 oxidant
ClPtII
Cl OH2
OH2
ClPtII
Cl OH2
H
CH3
OH2
Cl-
soft deprotonation
ClPtII
Cl OH2
CH3
note: no oxidation state change to the metal
K+
K2Pt(IV)Cl6ClPtIV
Cl OH2
CH3
Cl
Cl
K+
HCl
ClPtIV
Cl Cl
Cl
CH3
H2O
K+
ClPtII
Cl Cl
Cl
2
(K+)2
2
H2O
2 H2O2 Cl -
K2Pt(II)Cl4 Pt(II) catalyst is regenerated
orCl
PtIVCl OH2
CH3
H Cl-
MeOH
CH4
M.C. White, Chem 253 C-H Activation -303- Week of December 15, 2004
C-H activation via late, electrophilic complexes in highly acid media
Although the Periana Pt system is unparalleled withrespect to its efficiency at oxidative functionalization ofmethane, the high cost associated with platinum coupledto the operational difficulty in seperating the product fromthe solvent renders this route to methanol non-competitive with traditional reforming.
Proposed mechanism:
N N
N N
PtIIOSO3H
OSO3H
N N
N N
PtII OSO3H
+
(-OSO3H)
14 e- complex
N N
N N
PtII
OSO3H
+
(-OSO3H)
H
CH3
or
N N
N N
PtIV
OSO3H
CH3
+
(-OSO3H)H
-OSO3H
-OSO3H
N N
N N
PtIIOSO3H
CH3
N N
N N
PtIVOSO3H
CH3
OSO3H
OSO3H
heterolytic cleavage
CH3OSO3H CH4
SO3 + 2 H2SO4
SO2 + H2O
oxidation
CH4 + 2 H2SO4
N N
N N
PtIICl
Cl
500 tn
H2SO4 (ox/solv)
200oC
CH3OSO3H
70% methyl bisulfate(90% conversion/80% selectivity) basedon methane.
note that the product cannot undergo further oxidation.
Periana Science 1998 (280) 560.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 thealkyl(hydrido)metal intermediate is prohibitively high in energy.
CH4 + 2 H2SO4
Hg(II)(OSO3H)2 cat.
H2SO4 (ox/solv)
200oC
CH3OSO3H
50% yield (based on CH4)
CH4 + Pd(OAc)2 stoic.CF3CO2H
CF3CO2H (solv)CH3O2CF3 + Pd (0)
Periana Science 1993 (259) 340
Sen JACS 1987 (109) 8109
N N
N N
PtIIOSO3H
OSO3H
HH
(-OSO3H)2
2+
The ligand may become protonated under the reaction conditions. Protonation willwithdraw electron density from the Ptthrough the σ-bonding framework of thebidiazine ligand thereby enhancing itselectrophilicity.
M.C. White Chem 253 C-H Activation -304- Week of December 15, 2004
Corey JACS 2002 (124) 7904.
Substrate-directed vinyl alkylation via electrophilic C-H activation
NH
N
CO2Me
Pd(OAc)2 (1 eq)
NaOAc (1 eq)
AcOH: H2O (1:1)
25oC, 24h
O
OMe
31%
NH
NCO2Me
MeO2C
model system for keycyclization step in(+)-Austamide synthesis
NH
N 1.PdCl2(CH3CN)2/AgBF4 NEt3, CH3CN2. NaBH4
40-45%NH
N
H3CCNPdII
H3CCN NCCH3
NCCH3
(BF4-)2
2+
NH
NPdII
H
NCCH3
H3CCN (BF4-)2
2+
NEt3
NH
N
PdII
Ln
(BF4-)2
+
NH
NLnPd
(BF4-)2
+
generated via in situmetathesis
NaBH4
NEt3
recall that Pd(IV) is aprohibitively highenergy oxidation state
Trost JACS 1978 (100) 3930.migratory insertion
M.C. White, Chem 253 C-H Activation -305- Week of December 15, 2004
OMe
N
OMe
S
PdOAc2 (4 mol%)
Cu(OAc)2 (2 eq.)
benzoquinone (4 mol%)
100oCPh2Si(OH)Me (2 eq)or
PhSi(OH)Me2
OMe
N
OMe
SR
R = Ph, 73%R= PhCH=CH, 64%
OMe
N
OMe
SH
PdIIAcO
+(OAc-)
-OAc
pka ~ 50
OMe
N
OMe
SPdII
AcO
OMe
N
OMe
SPdII
Ph
OPdII
O O
O
Ph2SiOHMe
2 CuOAc2
2 CuOAc
OMe
N
OMe
S
Pd(0)Ln
OMe
N
OMe
SPh
transmetalationbase-assistedheterolyticcleavage
Sames JACS 2002 (124) 13372.
Substrate-directed alkane arylation via electrophilic C-H activation
M.C. White/M.W. Kanan Chem 253 C-H Activation -306- Week of December 15, 2004
Intermolecular arene vinylation via electrophilic C-H activation
PdIIO
OCF3
Fujiwara Science 2000 (287) 1992.
Pd(OAc)2 1mol%
CF3CO2H/CH2Cl2 (4:1)
25oC+ CO2Et
O
O
CO2Et
61%
+(-O2CCF3)
H
O
O
H
O
O
PdIIO
OCF3
?
+(-O2CCF3)
O
O
PdIIO
OCF3
CO2Et
PdIIO
OCF3
OHO
CH3
CO2Et
O O
O
HOCF3
H
O
O
O2CCF3
CO2Et
O
O
CO2Et
trans migratory insertion
protonolysis
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 amountsof product (<20%).
Reactions run in CF3CO2D yielded products with vinyl deuteriumincorporation α to the ester.
Reaction exhibits excellent functional group tolerance with unprotected OH, Br, and acetals tolerated in the arene. Coupling to activated alkenes (vinyl esters) was also effected in high yields (65-96%).
M.C. White, Chem 253 Olefin Oxidation -307- Week of December 15, 2004
Directed epoxidations
VV
OO
OR
O
O
t-Bu
VO
OOR
O
t-Bu
O
Sharpless Aldrichimica Acta 1979 (12), 63.
VIV
O
OO
OO
VO
OOR
Ot-Bu
O
OH
t-BuOOH (TBHP)
OHO
t-BuOH
O
OM
R
planar orientation: the planedefined by the lone pair of theoxygen of the η2-peroxo isperpendicular to the planedefined by the olefin π-orbital. This orientation avoidsunfavorable lone pair-πinteractions
O
OM
R
spiro orientation favored: theplane defined by the lone pair ofthe oxygen of the η2-peroxo isparallel to the plane defined by the olefin π-orbital. This orientationaligns the lone pair-π* orbitalsthereby facillitating C-O bondformation.
HOMO
O
O LUMO
LUMO
O
O
M
R
M
R
Formation of covalent, intramolecular allyloxide intermediates leads to large rate accelerations in the V catalyzed epoxidation of allylic alcohols. Methyl ethersundergo epoxidation 1000 times slower than the corresponding alcohols.
VO
OOR
O
t-Bu
O
vs. VO
OOR
O
t-Bu
OR
OMe1000 x faster
Sharpless Chem. Br. 1986 (22) 38.
Stereoelectronic factors lead to a highly ordered TS. Perfect for asymmetric induction....
Ph
PhOH
V
O
RO OROR 1 mol%
N
F3C O
O
N OH
PhH
3 mol%
TBHP (2 eq)
2 open coordination sites required foreffective catalysis. Appending a chiral ligand occupies these sites and resultsin ligand-decelerated catalysis.
Ph
PhOH
O
optimal substrate90%, 80% ee
tol, -20oC, 4 days
Bystander oxo ligands arepresent in many early d0 metals capable of oxidation. Theyoccupy potentially usefulbinding sites for appendingchiral ligands.
M.C. White, Chem 253 Olefin oxidation -308- Week of December 15, 2004
OHMn+(OR)n cat.
TBHP OH
O
For all metals capable of effecting catalytic epoxidation of allylic alcohols with TBHP, only Ti displayed ligand accelerated catalysis. All other systems were strongly inhibited or entirely deactivated with addedtartrate ligand.
Sharpless ACIEE 2002 (41) 2024.
The Sharpless epoxidation
"For years, right up until January of 1980, when the asymmetric epoxidation was discovered, every expert in asymmetric synthesis and catalysis advised me that what we sought- a catalyst that was both selective and versatile- was simply impossible." K.B. Sharpless Chem. Br. 1986 (22) 38.
R OH
Oi-Pr
Oi-PrTiIV
i-PrOi-PrO
(+)-DET or (+)-DIPT
TBHP, 3 Å MS,
CH2Cl2, -20oC
R OHO
Uniformly >90% ee, 60-70% yields
HO
HO
O
OR'
O
OR'R' = Et : (+)-DET i-Pr: (+)-DIPT
C2-symmetric ligand
note: no bystander oxo ligand
H15C7
OHAll olefin substitution patterns result in high ee's and good yields, with theexception of cis-disubstituted olefinsthat generally react slowly and givemoderate ee's (80's)
C7H15
OH
95% ee88% yield
Unsymmetrical disubstituted Trisubstituted
Ph
Me
OH
>98% ee79% yield
Tetrasubstituted
94% ee90% yield
86% ee74% yield
cis-disubstituted
OH
Sharpless JACS 1987 (109) 5765.Sharpless In Asymmetric Synthesis, Morrison, Ed.; Academic Press: New York, 1986 (5) 247.
M.C. White, Chem 253 Olefin Oxidation -309- Week of December 15, 2004
Mechanism
R OH
Oi-Pr
Oi-PrTiIV
i-PrOi-PrO
(+)-DET or (+)-DIPT
TBHP, 3 Å MS,
CH2Cl2, -20oC
R OHO
Uniformly >90% ee, 60-70% yields
HO
HO
O
OR'
O
OR'R' = Et : (+)-DET i-Pr: (+)-DIPT
C2-symmetric ligand
note: no bystander oxo ligand
OTiIV
RO
RO
OTiIV
O O
O
R'(O)C
R'OR
OR'
OR
C(O)R'
The catalyst self-assembles under the reaction conditions to give predominantly a dimeric species that epoxidizesallylic alcohols with high levels of ee. The dimericspecies is significantly more active than Ti tetraalkoxidealone or Ti-tartrates of other than 1:1 stoichiometrywhich lead to zero or low ee products (respectively).
Oi-Pr
Oi-PrTiIV
i-PrOi-PrO
OTiIV
RO
RO
OTiIV(OR)3
O
OR' C(O)R'
Major species in solution and kinetically most active. Leads to high ee products.
R OHO
high ee's
rel. rate: 1.0
R OHO
low ee's
rel. rate: 0.28rel. rate: 0.38
R OHO
0 ee
OTiIV
RO
OR
OTiIV
O O
R'(O)C
CO2R
O
OR'
O
O
t-Bu
R
C(O)R'
proposed intermediate
Sharpless JACS 1991 (113) 106, 113.
M.C. White, Chem 253 Olefin Oxidation -310- Week of December 15, 2004
Non-directed epoxidations: transferable metal oxo
N N
N N
CO2HHO2C
FeII
S-Cys
P-450 catalyzed epoxidations
O O
N N
N N
CO2HHO2C
FeIII
S-Cys
OO
N N
N N
CO2HHO2C
FeIII
S-Cys
OO
N N
N N
CO2HHO2C
FeIII
S-Cys
OON N
N N
CO2HHO2C
FeV
S-Cys
O
N N
N N
CO2HHO2C
FeIII
S-Cys
H2O
R
N N
N N
CO2HHO2C
FeIV
S-Cys
O
FeV
O LUMO
RHOMO
Stereoelectronically favored side-on approach:
R
R
N N
N NFeIII
Cl
1 e-
2H+
1 e-
O O
OO
O
O
O O
O
O
O
catalyst
PhIO
85% yield84% ee
Collman JACS 1993 (115) 3834.
Chiral P-450 mimics
M.C. White, Chem 253 Olefin Oxidation -311- Week of December 15, 2004
Jacobsen epoxidation
The Jacobsen epoxidation
Ph Me
N N
O O
MnIII
0.1-4 mol%t-Bu t-Bu
t-But-Bu
NaOCl, CH2Cl2, pyridine N-Oxide (20 mol%)
Cl
cis-disubstituted substratesgive optimal yields and ee's
Ph Me
O
84% yieldcis: trans (11.5:1)
92% ee
O
Jacobsen JACS 1990 (112) 2801.Jacobsen JACS 1991 (113) 6703.Jacobsen JOC 1991 (56) 2296.Jacobsen TL 1996 (37) 3271.
PhO
O
BrO
88% ee90% yield
93% ee69% yield
TrisubstitutedCis-disubstituted
96% ee84% yield
Jacobsen TL 1995 (36) 5123.
Tetrasubstituted Cis-enynes give trans-epoxides :TMS
Cy
TMS
Cy
O
Jacobsen JACS 1991 (113) 7063.
N N
O O
MnIII
PF6
4 mol%OMe MeO
The first report of epoxidation activity:
PhIO (1 eq), CH3CN
2 eq limiting reagent
O
56% based on iodosylbenzene (PhIO)
Kochi JACS 1986 (108) 2309.
Bleach as a terminal oxidant:
N N
O O
NiII
catNaOCl (pH 13)/CH2Cl2
Bu3NBz+Br-
O
Radical intermediate envoke toaccount for exclusive formation of the E-epoxide from the Z.
84%
N N
O O
NiIV
ON N
O O
NiIII
O
Ph
NaCl
Burrows JACS 1988 (110) 4087.
N N
O O
MnV
PF6
OMe MeO
O
PhI
M.C. White, Chem 253 Olefin Oxidation -312- Week of December 15, 2004
MechanismProposed mechanism:
Ph Me
N N
O O
MnIII
0.1-4 mol%t-Bu t-Bu
t-But-Bu
NaOCl, CH2Cl2, pyridine N-Oxide (20 mol%)
Cl
cis-disubstituted substratesgive optimal yields and ee's
Ph Me
O
84% yieldcis: trans (11.5:1)
92% ee
N N
O O
MnV
t-Bu t-Bu
RR
t-But-BuL
ON N
O O
MnIV
t-Bu t-Bu
R
t-But-BuL
O
Ph
R
Me
N N
O O
MnIV
t-Bu t-Bu
R
t-But-BuL
O
R
Me
Ph
Me
OPh+
Rationale for enantioselection:
All trajectories to Mn oxoare sterically blocked except the one over the chiraldiimine backbone.
NN
O
OMnV
OH
H
Me
Ph
Jacobsen JOC 1991 (56) 6497.
M.C. White, Chem 253 Olefin Oxidation -313- Week of December 15, 2004
Sharpless dihydroxylation
OH
OH
OsVI
O
O
HO OHHO OH
2- +K2
0.2 mol%
(DHQD)2-PHAL (1 mol%)K3Fe(CN)6 (3 eq)
K2CO3 (3 eq)t-BuOH: H2O (1:1)
98% ee>90% yield
Commercially available as a mix:AD-mix-α uses the ligand (DHQ)2-PHALAD-mix-β uses the ligand (DHQD)2-PHAL
N
H
N
MeO
O
NN
O
N
H
N
OMe
(DHQD)2-PHAL
N
MeO
N
Et
HO
NN
O
N
Et
N
OMe
H
(DHQ)2-PHAL
pseudo-enantiomericWorks well for all olefin substitution
patterns with the exception ofcis-disubstituted and tetrasubstituted.
OsVI
O
O
HO OHHO OH
+K22-
General mechanism: Sharpless Chem. Rev. 1994 (94) 2483.
OsVIII
O
O
O OHO OH
+K22-
Sharpless JOC 1992 (57) 2768.
2 K3Fe(CN)62 OH-
2 K4Fe(CN)62 H2O
OsVIII
O
O
O
OOsVI
O
O
R
R
L
O
O
OsVIII
L
O
OO
O
2 OH-2 H2O
R
R
HO OH
R R
Evidence favors the [3+2] mechanism vs. [2+2]:Corey TL 1996 (28) 4899.Houk, Sharpless, Singleton JACS 1997 (119) 9907.
The enzyme-like binding cleft is especially well suited for π-stacking with aromatic substrates. Large rate accelarations are observed for aromatic substrates with the phalazine class of ligands.
ligand accelarated catalysis:although OsO4 is capable ofdihydroxylating olefins, the ligand bound complex does so at a muchgreater rate. Corey JACS 1993 (115) 2861, 12579.
Sharpless JACS 1994 (116) 1278.
Os
O
OO
L
O RR
[3+2]