Chem 652 Spring 2013
C-H Activation and Functionalization
Prof. Donald Watson!
Read Hartwig Chapters 17
C-H Activation and Functionalization
C-H Activation:
+
R H
LnM
LnM R
C-H Functionalization:
R H
+
A
cat. LnM
R FG
+
B
FG = functional group
C-H Activation and Functionalization
Considerations:
•  C-H bonds typically have low dipole moments.
•  Low HOMO/ high LUMO.
•  C-H bonds are strong:
•  Alkyl-H: 90-100 kcal/mol
•  Ar-H: 100-110 kcal/mol
•  Arenes and alkanes are abundant (oil and gas) and
are therefore important potential feedstocks.
C-H Activation
Consider Oxidative Addition:
H
R H
+
LnM
BDEC-H ~ 90-100 kcal/mol
LnM
R
BDEM-H ~ 60 kcal/mol
BDEM-R ~ 25 kcal/mol
~ 85 kcal/mol
ΔH ~ + 15 kcal/mol
ΔS = negative
Therefor ENDOTHERMIC (in isolation)
Early Observations
Crabtree:
+
[H2Ir(PPh3)2(acetone)2]+ BF4– + 2
Ir
DCM, 40 °C
PF6–
PPh3
PPh3
+
•  As hydrogenation involves RE of M(C)(H), microscopic reverse
likely involved here.
•  COE can precoordinate to [Ir] (lowers entropy) and is driven by
formation of alkane.
+
tBu
[H2Ir(PPh3)2(acetone)2]+ BF4– +
DCM, 40 °C
Ph3P
Ph3P
PF6–
+
Ir
tBu
Me
H
Crabtree JACS, 1979, 101, 7738
Early Observations
Chatt:
Me
Me
Me
P
P
Me
Me
Cl
Ru
Cl
Na+
P
Me
P
Me
H
H
P
P
Nap
Ru
P
P
H2
C
Ru
+
P
P
P
P
Me
Me
C
H2
P
Me H
D
Cp2MH3 +
+ D2
Cp2MD3
D
+
+ H2/HD
D
M = Ta, Nb
D
D
P
Ru
Tebbe, Porshall:
D
P
P
M. L. H. Green:
Me
Me
+
Cp2W
H
Cp2W
hν, -H2
Cp2WH2
H
"Cp2W"
R H
Cp
H
W
W
H
Cp
First Systematic Study
Me
Me
Me
hν, -H2
Me
Me
Ir
Me
Me3P
Me
R H
Cp*Ir(PMe3)
Me
Ir
Me
Me3P
H
H
R-H
krel
4.0
Me
2.6
1.6
Me
Me
Me
Me
1.14
1.0
H
R
0.09
C6H12 vs. C6D12
kH/kD = 1.38
Bergman, JACS, 1982, 104, 352
Aromatic and Methane Activation
Me
Me
Me
Me
Me
Me
Me
H
Ir
Me
Me3P
Me
+
Me
Δ
R
Me
Me
Me
Ir
Me
Me3P
H
Ir
Me
Me3P
Me
Ph
Me
Me
CH4
H
Cy
150 °C
R H
+ Cy H
Me
Ir
Me
Me3P
H
Me
Primary C-H Bond Acitvation Kinetic and Thermodynamic
Me
Me
Me
Me
Me3P
Ir
Me
Me
Me
Me
Me
Me
hν, -H2
Me
H
H
Me
+
Me
Me
Me
Ir
Me
Me3P
H
Me
Me
Me
Ir
Me
Me3P
Me
+
Me
Me
H
kinetic
2.7 (1°)
Ir
Me
Me3P
1 (2°)
120 °C
Me
1°Ir-C > 2°Ir-C 5.5 kcal/mol
Me
Me
Me
Me
Me
Ir
Me
Me3P
Me
Me
H
thermodynamic
Note: 1° C-H bonds are considerably stronger than 2° and 3°.
Me
Me
H
C-H Difficult to Study Directly
Cp*Rh(CO)2
hν, -CO
Cp*Rh(CO)(Kr)
160K, Kr(liq)
k-1[Kr]
k1[CMe4]
C(CD3)4 vs. C(CH3)4
large inverse KIE for
binding observed
keq ~ 14
νCO = 1946 cm-1
Cp*Rh(CO)(CMe4)
σ-complex!
νCO = 1947 cm-1
k2
Cp*Rh(CO)(CH2CMe3)(H)
νCO = 2008 cm-1
k2 = RDS, but is VERY fast.
At 165 K k(CMe4) = 3.9 X 104 s-1
ΔH = 4.1 kcal/mol
ΔS = -11.2 e.u.
kH/kD = 16
Bergman, JACS, 1994, 116, 9585
Ultrafast IR Spectroscopy
!
ΔG‡(B→C) = 8.3 kcal/mol
Very similar to the ΔG‡ = 7.3 kcal/mol for Cp*(Rh)(CO)(RH) in Kr.
Bergman, Harris Science, 1997, 278, 260.
Ultrafast IR Spectroscopy
Bergman, Harris Science, 1997, 278, 260.
NMR Evidence for C-H Complexes
CpRe(CO)3
?
hν, − 78 °C
OC
OC
Ir
H
OC
H
OC
Ir
H
H
NMR: 𝛿 = -2.32 ppm (2H)
13C NMR: 𝛿 = -31.2 ppm (J
CH = 112.9 Hz)
(vs. JCH = 129.4 Hz for C5H10)
1H
Ball 1998, 120, 9953
X-Ray Evidence for C-H Complexes
Meyer, JACS, 2003, 125, 15734
X-Ray Evidence for C-H Complexes
Meyer, JACS, 2003, 125, 15734
Mechanisms of C-H Activation
IMPORTANT!
Not all C-H activations proceed via Oxidative Addition!
5 distinct mechanisms:
•  Oxidative Addition
•  Sigma-Bond Metathesis
•  Metalloradical Activation
•  1,2-Addition
•  Electrophilic Activation
•  For excellent discussion see:
Labinger and Bercaw, Nature, 2002, 417, 507
C-H Activation Via Oxidative Addition
H
R H
+
LxMn
LxMn+2
R
•  Typical for electron-rich, low valent “late” transition metal complexes
(Re, Fe, Ru, Os, Rh, Ir, Pt ).
•  Intermediates coordinatively unsaturated and almost always unstable.
•  Generated in situ by thermal or photochemical decomposition
precursor.
C-H Activation Via σ-Bond Metathesis
R
R'
M R
H
M
H
M R' + R H
R'
•  Typical of alkyl or hydride complexes of ‘early’ transition metals with d0
electronic configurations.
•  Most commonly from group 3 (Sc, lanthanides and actinides), but some
examples involving metals of groups 4 and 5 are known.
Example of C-H Activation Via σ-Bond Metathesis
Cp*2Lu
Me
Lu
Cp*
Cp*
Cp*2Lu Me
Me
Cp*2Lu Ph + MeH
13CH
X-Ray
4
Cp*2Lu 13CH3 + MeH
Note: Lu(IV) does not exist! Can not be oxidative addition.
13CH
3
Lu
H
CH3
C-H Activation Via Metalloradicals
Mes
N
Mes
N
Rh
N
H
Mes
= (TMP)Rh
Rh
N
C
H
Rh
H H
Mes
Rh(II), d7
[(TMP)Rh]2
2 (TMP)Rh
CH4
(TMP)Rh H + (TMP)Rh Me
Rate = [(TMP)Rh]2[CH4]
ΔH = -13.0±1.5 kcal/mol
ΔS = -19±5 e.u.
kH/kD = 8.6 (298 K)
Wayland, JACS, 1991, 113, 5305
C-H Activation Via 1,2-Activation
C
H
C
H
M
X
M
X
•  Early and middle metal imido
and carbene complexes.
Me
Zr
NHtBu
Me
Me
Zr
NHtBu
Me
Zr
NtBu
Zr
NHtBu
-MeH
Bergman JACS 2004, 126, 1018
N
Zr
NtBu
N
C-H Activation Via Electrophilic Activation
•
•
•
•
•
•
Late- or a post-transition metal.
Typically Pd(II), Pt(II) and/or Pt(IV), Hg(II), Tl(III).
Usually in a strongly polar medium such as water or an anhydrous acid.
Note these are highly Lewis-acidic metals.
Often analogous to Friedel-Crafts mechanism.
Concerted mechanisms also have been demonstrated.
Pd(II)(OAc)2
HOAc
N
H
H
N
PdII OAc
OAc
N
PdII
OAc
OAc
-HOAc
N
PdII
OAc
C-H Functionalization
R H
+
A
cat. LnM
R FG
+
B
FG = functional group
•  C-H Functionalization is now a very broad and rapidly expanding
area.
•  What follows are vignettes of chemistry to give you a flavor for types
of chemistry begin developed.
•  Not nearly complete listing of all of the cool/important reactions that
have been investigated.
Directed Arylation
One of the first examples of a practical C-H functionalization.
Murai; Chatani Nature 1993, 366, 529
Substrate Scope
Murai; Chatani Nature 1993, 366, 529
Substrate Scope
Murai; Chatani Nature 1993, 366, 529
Intramolecular Reaction
•
•
•
•
Wilkinson's Catalyst
Imine directing group.
Broader Scope
Beta-hydrogen atoms in alkene.
Bergman; Ellman JACS 2001, 123, 9692.
Substrate Scope
Hydrolysis on
workup releases
ketone.
Generally, endo
selectivity for 5
and 6 membered
ring carbocycles.
Bergman; Ellman JACS 2001, 123, 9692.
Substrate Scope
Heterocycles –
exo selectivity.
Coordination?
Bergman; Ellman JACS 2001, 123, 9692.
Enantioselective Version
Bisphosphines ineffective.
Ellman; Bergman JACS 2004, 126, 7192.
Limited Substrate Scope
Note: Substrate/ligand
dependence.
Ellman; Bergman JACS 2004, 126, 7192.
Applications in Bioactive Molecule Synthesis
3 is a mescaline analog.
Bergman; Ellman OL 2003, 5, 1301.
Applications in Total Synthesis
(+)-Lithospermic Acid
(anti-HIV)
Bergman; Ellman JACS 2005, 127, 13496.
Hydroarylation Using Hetereoaromatic Directing Groups
Bergman; Ellman JACS 2001, 123, 2685.
Scope of Reaction
Limited to Intramolecular Reactions
Bergman; Ellman JACS 2001, 123, 2685.
Curious Observation
Bergman; Ellman JACS 2001, 123, 2685.
Intermolecular Reaction
Previous method did not allow for intermolecular reaction.
Bergman; Ellman JACS 2002, 124, 13964.
Model System Used to ID Additive
Me
Me
M PCy3
M
PCy3
N
H
Me
HPCy3
Bergman; Ellman JACS 2002, 124, 13964.
Heteroaromatic Scope
Bergman; Ellman JACS 2002, 124, 13964.
Alkene Scope
Bergman; Ellman JACS 2002, 124, 13964.
Application to Novel Kinase Inhibitors
Bergman; Ellman JACS 2007, 129, 490.
Mechanistic Surprise: Carbene
Proposed Mechanism:
X-ray
Ellman; Bergman JACS 2006, 128, 2452.
Details Likely Even More Complex
Computational Study
Ellman; Bergman JACS 2006, 128, 2452.
Directed Orthoarylation of Phenols
Idea: Exchange of alcohol on
phosphinite load phenol with
directing group.
Bedford ACIE 2003, 42, 112
Bedford Chem. Commun. 2008, 990
Optimization and Scope
Bedford Chem. Commun. 2008, 990
Detailed Mechanistic Study
Note: This model explains why chiral, bidentate ligands do not
work in asymmetric reactions.
Bergman; Ellman Organometallics 2005, 24, 5737.
Heterocycle Arylation
Phobanes
thought to avoid
dehydrogenation
of ligand.
Bergman; Ellman ACIE 2006, 45, 1589
Scope
Further Optimization
Bergman; Ellman JACS 2008, 130, 2493
Glovebox Free High Yielding Conditions
Bergman; Ellman JACS 2008, 130, 2493
Carbonylation Reactions
Note: Predated Murai studies.
Moore JACS 1992, 114, 5888
More Generalized Reaction Conditions
Chatani; Murai JACS 1996, 118, 493
Reviews
Reviews on directed hydroarylation and C-H functionalization:
(1) Alberico, D.; Scott, M. E.; Lautens, M. Chem Rev 2007, 107, 174–238.
(2) Godula, K.; Sames, D. Science 2006, 312, 67–72.
(3) Daugulis, O.; Zaitsev, V.; Shabashov, D.; Pham, Q.-N.; Lazareva, A. Synlett
2006, 3382–3388.
(4) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem Rev 2002, 102, 1731–1770.
(5) Jun, C. H.; Moon, C. W.; Lee, D. Y. Chem. Eur. J. 2002, 8, 2422–2428.
(6) Kakiuchi, F.; Murai, S. Accounts of Chemical Research 2002, 35, 826–834.
Idea: Access to Pd(IV) Should Promote Reductive Elimination
Sanford JACS 2004, 126, 2300
Initial Studies
Formation of Pd(II) Intermediate Occurs Via Electrophilic Mechanism.
Sanford JACS 2004, 126, 2300
Scope
Sanford JACS 2004, 126, 2300
Arylation
[Mes–I–Ar]BF4
N
Pd(OAc)2 (5 mol%)
N
Ar
72%
Note both sp2 and sp3
centers are arylated.
Sanford JACS 2005, 127, 7330
Arylation
Sanford JACS 2005, 127, 7330
Fluoronation
Sanford JACS 2006, 128, 7134
Fluoronation
Aliphatic Substrates
Sanford JACS 2004, 126, 9542
Related Oxidative Reactions
Yu ACIE 2005, 44, 2112
Yu JACS 2006, 128, 12634
Yu JACS 2006, 128, 12634
Arylation of Weinreb Amides Using Boronic Acids
Yu JACS 2008, 130, 7190
Air As The Oxidant!
Yu JACS 2008, 130, 7190
Remote Directed C-H Activation
Yu Nature 2012, 486, 518
Some of the Examples
Yu Nature 2012, 486, 518
Reviews of Oxidative C-H Activation
(1)
(2)
(3)
(4)
(5)
Zhou, M.; Crabtree, R. H. Chem. Soc. Rev. 2011, 40, 1875–1884.
Boorman, T. C.; Larrosa, I. Chem. Soc. Rev. 2011, 40, 1910–1925.
Borovik, A. S. Chem. Soc. Rev. 2011, 40, 1870–1874.
Godula, K.; Sames, D. Science 2006, 312, 67–72.
Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439–2463.
Intermolecular Hydroacylation
Brookhart JACS 1998, 120, 6965
Mechanism
Intramolecular Alkene Hydroacylation
Bosnich Organometallics 1988, 7, 936
Competitive Decarbonylation
Note: Bidentate ligand (dppe) slows competitive decarbonylation
Bosnich Organometallics 1988, 7, 936
Hydroacylation
(1) Wu, X.-M.; Funakoshi, K.; Sakai, K.
Tetrahedron Letters 1992, 33, 6331–6334.
Ketone Hydroarylation
Dong JACS 2009, 131, 15608
Scope
Dong JACS 2009, 131, 15608
Direct Borylation of Aryl C-H Bonds
Catalytic Arene Borylation:
Smith JACS 1999, 121, 7696
Initial Photochemical Alkane Functionalization
Hartwig ACIE 1999, 38, 3391
Thermal Alkane Borylation
Note: both HBPin
and B2Pin2 work as
borylation
reagents.
Hartwig Science 2000, 287, 1995
General Arene Borylation
•
•
•
•
•
P2Ir catalyst
HBPin as borylation reagent.
Bisphosphine ligands.
High temperatures.
Controlled by steric interactions.
Maleczka; Smith Science 2002, 295, 305
Hartwig Version
•
•
•
•
•
N2Ir catalyst
B2Pin2 as borylation reagent.
bipyridine ligands.
Room temperature.
Controlled by steric interactions.
Ishiyama; Miyaura; Hartwig JACS 2002, 124, 390
Mechanism Alkane Functionalization
Note:
Computationally,
empty p-orbital on
B-atom assist
reductive
elimination.
Hartwig; Hall JACS 2005, 127, 2538
Mechanism Arene Functionalization
Ishiyama; Miyaura; Hartwig JACS 2005, 127, 14263