Catalytic Organometallic Carbon-Heteroatom Bond Formation
John F. Hartwig
Department of Chemistry, University of Illinois, 600 South Mathews Ave, Urbana, IL 61801
A. Introduction. Organometallic complexes contain organic groups attached to a central metal
through metal-carbon bonds.1 These complexes undergo a set of elementary reactions, many of
which form carbon-carbon or carbon-hydrogen bonds. In recent years, the linking of these
reactions to create catalytic processes to form carbon-carbon bonds has been a focus of synthetic
organic chemistry. Such organometallic catalysts are now used to form carbon-carbon bonds in
commodity chemicals and polymers produced on the scale of millions of tons per year, tailormade polymers produced in small quantities, and highly intricate pharmaceuticals and
biologically active natural products, often produced in milligram quantities for biological testing.
Although carbon-carbon bonds comprise the backbone of many organic structures, the function
of these organic molecules is often derived from the presence of “heteroatoms”, such as nitrogen,
oxygen, and sulfur held in these molecules by “carbon-heteroatom bonds.” For example,
pharmaceuticals and conductive polymers often contain amine C-N bonds, and almost all natural
products contain ether, ketone, or ester C-O bonds. Heterocyclic compounds in which C-N or CO bonds reside in the ring structure are found in all applications of chemistry. Some prominent
biologically active molecules – such as the multibillion-dollar drug Nexium – also contain
carbon-sulfur bonds. Moreover, useful synthetic intermediates often contain carbon-boron or
carbon-silicon bonds that are later converted into carbon-carbon, carbon-oxygen or carbonnitrogen bonds in the final products.
Thus, one can imagine that catalytic reactions to form these carbon-heteroatom bonds would
substantially impact the synthesis of molecules with important functions in chemistry and its
allied fields. Such catalytic reactions would most likely occur through intermediates containing
metal-heteroatom bonds that undergo elementary reactions akin to those of organometallic
compounds. Compounds with metal-heteroatom bonds that undergo these types of reactions are
referred to in this review as "heteroorganometallic" complexes. To tap the potential of these
compounds as intermediates in catalytic processes one needs to understand the principles that
govern their reactivity, and these principles are now being delineated.
This review describes catalytic organometallic carbon-heteroatom bond formation and its
underlying heteroorganometallic chemistry. Cross-coupling to form C-N, C-O, and C-S bonds,2,3
C-H bond functionalizations to form C-O,4 C-X,5,6 and C-B7 bonds, olefin oxidations8 and olefin
aminations9,10 to form C-O and C-N bonds are used as case studies; the principles of metalligand bonding will be used as a framework to explain the differences in reactivity between
organometallic and heteroorganometallic intermediates.
B. Background
B.1. Examples of classic catalytic organometallic reactions
A brief overview of some classic catalytic processes occurring through organometallic
intermediates, and the elementary reactions that comprise these catalytic processes, will be
1
helpful for readers less familiar with organometallic systems. Two of these processes – crosscouplings to form carbon-carbon bonds and hydrogenations to form carbon-hydrogen bonds –
are commonly used by synthetic chemists (A and B of Chart 1). A third process–
dehydrogenation of alkanes – has been highly sought-after and is under development (C of Chart
1).
Palladium-catalyzed cross-coupling (A of Chart 1) has become one of the most utilized catalytic
processes for synthesizing medicinally active compounds. The antihypertensive sartan drugs,11
the anti-asthma drug Singulair,12 and everyday products such as sunscreen,12 are often prepared
using palladium-catalyzed cross-coupling reactions. Cross-coupling is also used to make
conjugated polymers for advanced applications such as components of organic light-emitting
diodes and sensors used for the detection of the explosive TNT.13-16 The intermediates that form
the new carbon-carbon bond in the final product are classic organometallic species.
Additions to olefins are also important catalytic organometallic reactions conducted on both
large scales to prepare commodity chemicals, and smaller scales for the synthesis of fine
chemicals and advanced pharmaceutical intermediates. Hydrogenation (Chart 1) is one example
of an olefin addition reaction. Hydrogenation has been used to generate materials ranging from
margarine (partially hydrogenated vegetable oil)17 to the most structurally and stereochemically
intricate natural products.18 Another classic catalytic reaction of olefins, the cleavage and
reformation of carbon-carbon double bonds (olefin metathesis), was recently reviewed in this
journal.19
The conversion of typically unreactive C-H bonds to C=C and C-X (X=O, N, B, Si) bonds20,21
promises to eliminate some of today’s reliance on existing carbon-heteroatom bonds to install
functional groups. For the past twenty years one of the most intensively studied C-H
functionalizations that occurs through organometallic intermediates has been the cleavage of two
C-H bonds in an alkane to form the carbon-carbon -bonds in alkenes (C of Chart 1). This
dehydrogenation reaction, termed alkane metathesis, has recently been used, in tandem with
olefin metathesis, to develop a catalytic process for the cleavage and reformation of the C-C
bonds in alkanes termed “alkane metathesis.”22,23
Chart 1. Examples of Catalytic C-C and C-H
Bond-Forming Processes
A. Cross Coupling
R X + M-R'
B. Hydrogenation
R
catalyst
R R' + M X
catalyst
H
via LnM
+ H2
R'
C. Alkane Dehydrogenation
catalyst
R'
R
R'
R'
R'
H
via LnM
H
+ H2
B.2. The Organometallic Chemistry of Catalytic C-C and C-H Bond Formation
Advances in the syntheses of transition metal complexes, the discovery of individual
stoichiometric reactions of these complexes, and methods to stitch these steps together into
2
catalytic cycles has led to the development of many of the catalytic organometallic processes
used today. Typical reactions of organometallic complexes include – but are not limited to –
oxidative addition, reductive elimination, migratory insertion, and -hydrogen elimination.24,25
Some of these reactions also occur with main group compounds, but they occur under milder and
more controllable conditions with ligated, soluble transition metal complexes (Chart 2).
Chart 2. Elementary organometallic
comprising many catalytic cycles
reactions
A
LnM
reductive elimination
B
oxidative addition
LnM + A-B
Migratory insertion
LnM-R + X=Y
LnM
beta-elimination
via LnM R
X
Y
R
X=Y
Oxidative addition adds an organic reagent to a transition metal through insertion of the
transition metal into one of the bonds of the incoming reagent A-B. Reductive elimination
extrudes an organic product by coupling two ligands on the metal. The former process increases
the oxidation state of the metal, and the latter reduces it. Migratory insertion leads to the
incorporation of a bound, neutral (dative) ligand into a metal-ligand covalent bond, and elimination extrudes such a ligand.
Chart 3. Overview of the mechanisms of three catalytic organometallic processes
H
LnPd
Ar-R
Red.
Elim.
Ar-X
A
Cross-Coupling
Ar
LnPd
R
Ox.
Add'n
R
H
H
Red.
Elim.
Ar
LnPd
X
LnRh
R'
H-H
B
Hydrogenation
Ox.
Add'n
H
IrLn
H
H
LnIr
H
R
H
C
Transfer
LnIr
Dehydrogenation
R'
LnRh
LnRh
R
M-R
transmetalation
H
R
H
R'
LnIr
R
H
R
migratory insertion
These reactions (and a few others) have been used to create hundreds of catalytic processes,
including those noted in the introduction to this review. As shown in cycle A of Chart 3, crosscoupling occurs by a sequence of steps initiated by the oxidative addition of an organic halide
and finished by reductive elimination. These steps are linked by a transmetallation in which a
carbon nucleophile – typically an organoboron, organozinc, organotin, or organomagnesium
compound - replaces a metal-bound halogen to generate an intermediate containing two metalcarbon bonds.
Hydrogenation (cycle B of Chart 3) and related additions to olefins also occur by classic
organometallic reactions. Hydrogenation occurs by a combination of oxidative addition of the HH bond in dihydrogen, olefin insertion to form the first C-H bond, and reductive elimination to
form the second C-H bond.
3
Finally, many C-H bond functionalization processes begin with oxidative addition of a C-H
bond. The functionalization then occurs during subsequent reactions, such as -hydrogen
elimination, migratory insertion, reductive elimination, or a combination of these processes. For
example, alkane transfer dehydrogenation catalyzed by iridium complexes occurs through a
sequence of oxidative addition of an alkane C-H bond, -hydrogen elimination, and transfer of
the two hydrides to a “hydrogen acceptor” such as a second olefin.26
B.3. Organometallic Reactions of Metal-Amido, Alkoxo, and Thiolate Complexes.
Although the classic reactions of organometallic systems have been discovered and developed
for several decades, few examples of such reactions at the metal-nitrogen –oxygen, and –sulfur
bonds of metal-amido, alkoxo, and thiolato ligands were known until the last decade. These
reactions are shown generically in Chart 4. The absence of this reaction chemistry hampered
efforts to develop catalytic cross-couplings, additions to olefins, and C-H bond functionalizations
that form C-N, C-O, C-S or C-B bonds. Until recently, there were no isolated transition metal
complexes that underwent reductive elimination to form C-N, C-O, and C-S bonds in amines,
ethers, and sulfides,27,28 and few compounds reacted with the N-H bond in ammonia to form a
monomeric product.29,30 Isolated complexes that inserted simple alkenes into the M-N or M-O
bonds of metal-amido or metal-alkoxo complexes were also unknown.31-33 The lack of precedent
for these processes raised the question of whether it was even possible to develop organometallic
processes to form amines, ethers, and sulfides, or whether the metal-ligand combinations
necessary to trigger this reactivity had not yet been identified. Recent progress clearly indicates
the latter was true.
Much of the literature on metal-alkoxo or -amido complexes was divided into two groups. In one
set of literature, the use of high-valent early metal alkoxo and amido complexes was commonly
described, but the amides and alkoxides were typically used as ancillary ligands because the MO and M-N bonds in these complexes were too strong to display extensive reactivity. In a
different body of literature, methods to prepare late metal amido and alkoxo complexes were
beginning to be developed, and their properties beginning to be explored.34 These complexes,
however, were often too unstable toward -hydrogen elimination to observe reactions that would
form C-N or C-O bonds.
Chart 4. Organometallic reactivity of transition
metal-heteroatom bonds.
Reductive Elimination to form C-N, C-O and
C-S Bonds in amines, ethers, and sulfides
YR
LnM
R-YR + LnM
R
Oxidative Addition of Amine N-H Bonds
NR2
R2N-H + LnM
LnM
H
Migratory Insertions of olefins into
M-NR2 and M-OR Bonds
YR
LnM YR +
LnM
4
In recent years, our understanding of the reactions of metal-amido, alkoxo and thiolate
complexes has changed dramatically. Many research groups are beginning to develop
synthetically valuable processes relying on heteroorganometallic intermediates. Thus, one
current issue is how the differences in properties between carbon and a heteroatom change the
course of these reactions. For example, does an increase in the electronegativity of the atom
bound to the metal increase or decrease the rate of addition, insertion, and elimination processes?
How does the presence of an electron pair on the heteroatom affect the rates of these reactions?
Does the presence of an unoccupied valence orbital on the heteroatom affect the rates of these
reactions?
Early ideas regarding the match or mismatch of a hard ligand with a soft or hard metal center35
predicted that the most reactive complexes would contain a mismatch of a hard ligand with a soft
metal. However, the examples in this review will show that a more complex set of guidelines is
needed to explain the patterns of reactivity reactivity. A few such guidelines will be presented in
the context of the emerging catalytic processes listed in the introduction that form carbonheteroatom bonds through the reactions of heteroorganometallic species.
C. Examples of Catalytic Reactions Occurring via Metal-Amido and Alkoxo Complexes
C.1. Palladium-Catalyzed Amination of Aryl Halides: Catalysis via Carbon-Heteroatom
Bond-Forming Reductive Elimination2,3
Cross-coupling reactions to form the C-N, C-O, and C-S bonds in amines, ethers and sulfides (A
of Chart 5) have become some of the most-practiced catalytic processes for the synthesis of
pharmaceutical candidates, fine chemicals, polymers, components of organic devices, and even
of ligands for other catalysts.2,3 The C-N coupling process evolved from an initial36 promising,
but relatively impractical, coupling of tin amides with aryl halides in the presence of a palladium
catalyst containing a sterically hindered, monodentate aromatic phosphine37 into a general
process that has been conducted with several successive generations of catalysts (B of Chart 5).
The initial process became more practical by replacing the tin amide reagents with a combination
of an amine and an alkoxide or silylamide base.38,39 The scope of the process became broader
with the use of bidentate aromatic phosphines that inhibited competing -hydrogen
elimination,40,41 followed by the use of sterically hindered alkyl monophosphines2,42-47 that
allowed the activation of less reactive haloarenes and accelerated reductive elimination to allow
the coupling to encompass formation of aryl ethers. Recent “fourth-generation” catalysts
containing sterically hindered alkyl bisphosphines fill some of the gaps in the scope left by the
“third-generation” catalysts and improve catalyst efficiency.48,49 Overall, the development of
these processes began to demonstrate the capability of late transition metal-amido, alkoxo, and
thiolato complexes to participate productively in catalytic cycles.
The basic steps of the mechanism of the amination process are shown in part C of Chart 5. Like
cross-coupling to form C-C bonds, this process is initiated by oxidative addition of a haloarene.
An arylpalladium amido, alkoxo, or thiolate complex is then formed from the oxidative addition
product by reaction of an amine, alcohol, or thiol and base. The catalytic cycle is then completed
by reductive elimination to form the C-N, C-O or C-S bond in the product amine, ether, or
sulfide.
5
Chart 5. Palladium-catalyzed amination of aryl halides
A
X X=Cl, Br, I, OTf, OTs
R
+ HYR'
Y=NR'', O, S
Pd / L
base
25-80 °C
C
Y
R'
R
base = NaO-t-Bu, Cs2CO3, K3PO4
B
First-generation catalyst: L=P(o-tolyl)3
Second-generation catalyst: chelating aromatic phosphines
DPPF, BINAP, Xantphos
Third-generation catalysts: Hindered alkylphosphines and carbenes:
P(t-Bu)3, Ph5FcP(t-Bu)2 (Fc=ferrpcenyl), N-Heterocyclic carbenes,
(Biaryl)PR2, (Heterobiaryl)PR2, caged P(NRR')3
Fourth-generation catalysts: a hindered ferrocenyl alkyl bisphosphine
D
Ph
25 °C
(DPPF)Pd
iBu
<30 min
N
Red.
Ox.
H
Elim.
Add'n
Ph
25 °C
(DPPF)Pd
1.5 h
NHPh
Ar
Ar
LnPd
LnPd
Ph
85 °C
(DPPF)Pd
NRR'
X
N(tolyl)2 1.5 h
Ph O
120 °C
HNRR' + base
(DPPF)Pd
N
29 h
Ph Me
DPPF=
Ph
PPh2
110 °C
(DPPF)Pd
Fe
10 h
OPh
PPh2
Ar-NRR'
LnPd
Ar-X
PhNH(iso-Bu)
64%
HNPh2
80%
PhN(tolyl)2
90%
O
Ph
N
Me
Ph
34%
Ph-O-Ar
0%
The scope of the final reductive elimination reaction in this catalytic cycle was striking.
Although no type of reductive elimination to form the C-N, C-O or C-S bond in an amine ether
or sulfide from an isolated amido, alkoxo, or thiolate complex was known when this reaction was
first discovered, catalytic couplings of aryl halides with amines, alcohols and thiols now imply
that these types of reductive eliminations can occur from complexes containing a diverse set of
aryl and heteroaryl groups, as well as a diverse set of amido, alkoxo and thiolato groups. In fact,
with the right ancillary ligands on the metal, these reactions are typically faster than competing
processes, such as -hydrogen eliminations that lead to undesired side products.
Electronic Effects on Carbon-Heteroatom Bond-Forming Reductive Elimination. Although
amido and alkoxo ligands have now been shown to participate in reductive elimination reactions
in a manner similar to aryl and alkyl ligands, the electronic properties of amido and alkoxo
ligands cause the rates and scope of the organometallic reactivity of amido and alkoxo
complexes to differ in synthetically important ways from those of alkyl complexes. A selection
of the mechanistic studies that revealed the influence of the electronic properties of the
heteroatom ligand on the rates of reductive elimination follows.28
The series of reactions50,51 in part D of Chart 5 show that the rate of reductive elimination from a
series of compounds containing the same ancillary ligand is faster when the covalent heteroatom
ligand has stronger electron donating properties. In addition to these data, comparisons of the
rates of reactions of arylamido complexes and phenoxo complexes,52 and the rates of reaction of
alkylamido versus alkoxo complexes,53 show that the rate of reductive elimination from the
amido complexes is faster than from the less electron-rich phenoxo and alkoxo complexes. Yet, a
comparison of the rates of these reactions to those of thiolate complexes shows that basicity
alone does not control the rate. Complexes containing the less basic, but more polarizable and
nucleophilic, thiolate ligand undergo reductive elimination much faster than do alkoxo
complexes, and at rates that are similar to or faster than those of the amido complexes.54
These relative rates clearly argue against explanations for relative reactivity based on hard-soft
matches and mismatches. The compounds containing the largest hard-soft mismatch are actually
the least reactive. (An amidate ligand is harder than an amide ligand, and a phenoxide is harder
than an arylamide.) Thus, another explanation for the relative rates must be used. Two possible
explanations could be based on participation of the electron pair on the heteroatom. In one case,
6
the compounds containing the most basic electron pairs would be the most reactive because these
electron pairs weaken the metal-ligand bond through filled-filled dp orbital interactions;55 in
a second case, the reaction would occur by attack of this electron pair on the palladium-bound
aryl group, and the most nucleophilic electron pair would lead to the fastest rate. These theories
can be tested. If one or the other of these theories is correct, then substantially smaller electronic
effects would be observed for analogous reactions of alkyl complexes because the alkyl
complexes lack the basic electron pair on the atom bound to the metal.
Studies have been conducted on reductive elimination from a series of closely related
arylpalladium alkyl complexes containing varied functional groups on the -carbon that alter the
electronic properties of the alkyl group.56 This study showed that the electronic effects on
reductive elimination from the alkyl complexes were similar to those on reductive elimination
from the amido complexes. Thus, explanations for the relative rates based on the electron pair
are not valid. Instead, the dominant electronic effect on reductive elimination appears to result
from differences in the electronegativity of the atom bound to the metal.57 Apparently, the more
covalent and less ionic the M-X bond, and the more polarizable the X atom, the faster the rate of
concerted reductive elimination from the intermediates in the catalytic coupling to form carbonheteroatom bonds.58,59
C.2. Catalytic C-H Bond Functionalization: Catalysis by Carbon-Heteroatom BondForming Reductive Elimination and a New Pathway for C-H Bond Cleavage. Catalytic C-H
bond functionalizations that occur via reductive eliminations to form carbon-heteroatom bonds
have also been developed. Two classes of systems for the functionalization of alkanes to form
carbon-heteroatom bonds through heteroorganometallic intermediates are shown in Charts 6 and
7. In one case, the hydrogen in a C-H bond of an arene or alkyl chain are converted to halide or
acetate with regioselectivity controlled by a ligating functionality. In a second case, a terminal CH in an alkane is functionalized by the use of a rhodium catalyst and boron reagents.
These processes require transition metal complexes that can both add a reagent by C-H bond
cleavage and eliminate the product by carbon-heteroatom bond formation. Some catalysts, such
as iron-oxo complexes, do so without formation of an intermediate containing a metal-carbon
bond.60 These complexes often abstract C-H bonds and deliver the resulting hydroxo group to an
alkyl radical. These reactions typically favor cleavage of the weaker of the available C-H bonds.
In contrast, organometallic systems preferentially cleave strong primary C-H bonds over weaker
secondary C-H bonds to form n-alkyl intermediates61-63 and even stronger aromatic C-H bonds to
form metal-aryl intermediates.62 Thus, a method to couple the resulting organometallic ligand
with an alkoxide, amide, or halide ligand would create methods for inner-sphere, organometallic
C-H bond “functionalization” that complement systems occurring by outer-sphere C-H
activation.
Two approaches to C-H bond functionalization by carbon-heteroatom bond-forming reductive
elimination have been developed recently. In one case, the barrier to reductive elimination was
reduced by generating high-valent intermediates. Although reductive eliminations to form
carbon-oxygen and carbon-halogen bonds from palladium(II) intermediates are slow and require
particular ligands,53 and reductive eliminations from Pt(IV) were limited to coupling with methyl
groups,58,59 reductive eliminations to form C-O and C-X bonds from palladium(IV) could be
7
more rapid and more general. Thus, oxidation of an alkylpalladium product of C-H activation
could generate a high-valent intermediate that would result in functionalization of the C-H bond
after reductive elimination to form C-O or C-halogen bonds.64,65 This approach, in combination
with the incorporation of a Lewis basic, coordinating functionality in the substrate, has been used
to develop directed functionalization of both aromatic (B of Chart 6),66 and aliphatic (C of Chart
6) C-H bonds.4,67
Chart 6. Organometallic oxidative C-O and Chalogen bond-forming functionalization of C-H
bonds
A.
X
R-X
reductive
elimination
step
X
HX
X
X
L2PdIV
R
X
X
L2PdII
R
X2 equivalent
oxidation step
B.
Ph Me
N
t-Bu
MeO
Ph Me
N
10 mol % Pd(OAc)2
PhI(OAc)2 (1 equiv)
I2 (1 equiv)
CH2Cl2, 24 °C, 13 h
O
C.
R-H C-H bond
cleavage step
L2PdII
N
5 mol % Pd(OAc)2
PhI(OAc)2 (1 equiv)
AcOH/Ac2O (1:1)
100 °C, 1.5-3.5 hh
t-Bu
O
I
99:1 dr
MeO
N
OAc
By a different approach, the functionalization of terminal alkyl C-H bonds and sterically
accessible aryl C-H bonds has been developed without the use of directing groups by exploiting
the electronic properties of intermediates containing metal-boron bonds. Stoichiometric
functionalization of arenes and alkanes with isolated metal-boryl compounds was observed first
(A of Chart 7),68-70 and these reactions were developed into catalytic processes by using diboron
reagents (B of Chart 7) to generate the reactive metal-boryl intermediate.7 The catalytic cycle for
this alkane functionalization (C of Chart 7) involves the reaction of rhodium-boryl intermediates
with alkyl C-H bonds to form organometallic intermediates that undergo B-C bond-forming
reductive elimination. Currently available mechanistic data imply that the C-H bond cleavage
and the B-C bond formation are facile due to participation of the unoccupied orbital on boron.
Part D of Chart 7 shows the mechanism and accompanying energetics of C-H borylation for one
of the original stoichiometric systems, as deduced from DFT calculations.71 These calculations
imply that the hydrogen atom is passed from the coordinated alkane to the unoccupied p-orbital
at boron to cleave the C-H bond. Similar calculations concerning the mechanism of cleavage of
the alkane C-H bond by rhodium intermediates in the catalytic borylation of alkanes imply that a
B-H bond is formed between a hydride and a boryl ligand during cleavage of the C-H bond to
form a hydride and an alkyl ligand.72 These modes of C-H bond cleavage are new and result
from the presence of an unoccupied p-orbital on boron.
8
Chart 7. Summary of the functionalization of alkanes with metal-boryl intermediates.
A. Original stoichiometric reaction
C. Catalytic cycle for alkane borylation
Me
OC
OC
W B
O
O
CO
Me
pinB Rh X
H
Bpin
85%, one isomer
B2pin2
B. Catalytic reaction of alkanes
R
n
+
O
O
B B
O
O
(pinB-Bpin)
2.5%[Cp*Rh(C6Me6)]
R
150 °C
R = H, O
O
O
R
N
R
Bpin + HBPin
n
70-88%
G0=0
OC
Fe B(OR)2
Fe B(OR) OC H
2
CH3
+ CH4
6.1 kcal/mol
Fe B(OR)2
OC
H
H3C
H
F
HBpin
X=H, Bpin
Cp*
Cp*
Rh
Rh
pinB
X
X
Cp*
RBpin
D. Calcaulated mechanisms on a model system
participation of the p-orbital in the
C-H bond cleavage step
Fe B(OR)2
OC
H 13.2 kcal/mol
H3C
3.6 kcal/mol
Cp*
Bcat* + Cp*W(CO)3H
h, 20 min
pinB Rh X
R
H
R-H
6.9 kcal/mol
Fe H
OC
B(OR)2-2.1 kcal/mol
H3C
OC
Fe H
+
H3C B(OR)2
However, this new pathway for C-H bond cleavage would not be useful without facile C-X bond
formation. Fortunately, a favorable match between the electrophilic properties of the boryl group
and the nucleophilic properties of the alkyl and aryl ligands causes B-C bond formation to occur
with little or no barrier. Thus, the electronic properties of boron are intimately involved in both
the activation and functionalization stages of this catalytic, organometallic alkane
functionalization.
C.3. Oxidation and Oxidative Amination of Olefins. Catalysis by Olefin Insertions into
Metal-Oxygen and Metal-Nitrogen Bonds. The catalytic oxidation and oxidative aminations of
olefins have been shown recently to occur by yet another elementary reaction of alkoxo and
amido ligands that parallels the elementary reactions of alkyl complexes: olefin insertions into
metal alkoxides and amides. These reactions include palladium-catalyzed oxidations of olefins to
form aldehydes, vinyl ethers, and vinyl acetates and related extensions of these oxidations
involving the oxidative aminations of olefins to form enamides. In addition, catalysts for olefin
hydroamination that are efficient enough for some synthetic applications have been developed
recently.10,73 Such catalysts had been sought for more than 30 years.
Organometallic Olefin Oxidation and Oxidative Amination.
Chart 8 shows a generic scheme for palladium-catalyzed olefin oxidation. Extensive mechanistic
studies on this process have led researchers to agree on the intermediacy and reactivity of
hydroxyalkyl, alkoxyalkyl, acetoxyalkyl, or aminoalkyl complexes (A of Chart 8). However,
there has been a longstanding debate about the mechanism for formation of this intermediate.74
Part B of Chart 8 depicts two likely pathways for formation of such an intermediate. By one
9
mechanism, the -functionalized alkyl intermediate is formed by coordination of an olefin and
subsequent nucleophilic attack of water, hydroxide, carboxylate, or amine onto the coordinated
olefin. By an alternative mechanism, the olefin coordinates and then inserts into an
accompanying hydroxo, alkoxo, carboxylate, or amido ligand. Several recent experiments have
shown that it is an insertion of the olefin into the M-O or M-N bond that leads to the
hydroxyalkyl, alkoxyalkyl, or aminoalkyl intermediate under some of the commonly used
reaction conditions.
Chart 8. Organometallic Oxidation and Oxidative Amination of Olefins
A. Overall catalytic process
R
+ R'YH
Y=O, NH
PdX2
oxidant
R
XPd
-H
elim.
YR'
+ HX
hydroxyalkyl, alkoxyalkyl,
acetoxyalkyl, or aminoalkyl
intermediate
B. Formation of the functionalized alkyl intermediate
R
R
or
X2Pd
+ R'YH
XPd
X2Pd
YR'
-HX
R
Pd(0) +
R
YR'
or
+ HX
O
for R'Y=OH
R
YR'
-HX
+ R'YH
XPd
+HX
YR'
R
XPd
R
These two pathways for formation of the -functionalized alkyl intermediate are differentiated
by the stereochemistry of certain oxidation products. External nucleophilic attack leads to an anti
arrangement of the metal and the nucleophile, while insertion leads to a syn arrangement of the
two. Reactions of deuterium-labeled terminal olefins or internal olefins with a source of
electrophilic chlorine (such as CuCl2) lead to different stereoisomeric products by the two
mechanisms. Alternatively, restrictions on the regiochemistry of the -hydrogen elimination step
in cyclic systems lead to allylic alcohols, ethers, or amides with stereochemistry that reveals the
mechanism of formation of the hydroxyalkyl, alkoxyalkyl, or aminoalkyl intermediate.
These studies have shown75-79 that reactions conducted in the absence of chloride form products
from a syn addition across the carbon-carbon double bond, while analogous reactions conducted
in the presence of chloride form products from anti addition across the carbon-carbon double
bond. The syn addition is a hallmark of a migratory insertion mechanism. Most likely, the two
mechanisms are different at different concentrations of chloride because coordination of chloride
to the metal discourages the generation of a hydroxo or alkoxo ligand cis to the olefin, while the
absence of added chloride allows for generation of these ligands cis to the olefin and subsequent
migratory insertion. Recent related experiments on the oxidative amination of olefins have also
provided stereochemical evidence for migratory insertion of an olefin into a palladium amidate
bond.9

Hydroaminations of Olefins through Lanthanide-Amido Complexes.
Some of the catalysts for olefin hydroamination have also been shown to occur by insertion of an
olefin into a metal-amide linkage. Metallocene complexes containing lanthanide metals were
some of the first catalysts for intramolecular hydroaminations of alkenes to form nitrogen
heterocycles that occurred with substantial turnover numbers.80 This initial work has led to
hydroamination of alkenes with lanthanide complexes containing ancillary ligands besides
10
cyclopentadienyl derivatives. These complexes have catalyzed cyclizations with substantial
enantioselectivity in some cases.81-83 In all of these systems, the catalytic process, most likely,
occurs by insertion of the olefin into the metal-amide linkage.
Scheme 1
H
N
Cp2La
Cp2La
RH2N
alkene insertion
into a metal-amide
N
H
H
N
H
N
LaCp2
H 2N R
R=
The first lanthanide-catalyzed hydroaminations were important from the conceptual point of
view because they dispelled the notion that metal-nitrogen bonds involving high-valent
electrophilic metals are too strong to undergo processes that would parallel the reactions of highvalent organometallic complexes, such as olefin insertion. Measurements of lanthanide-amide
and lanthanide-alkyl bond strengths led to the prediction that insertions of alkenes into
lanthanide-amide bonds would be close to thermoneutral.84 Consistent with this prediction,
Marks showed that the hydroamination of aminoalkenes occurs by insertion of pendant olefins
into lanthanum-amido complexes.85 These reactions occur over the course of hours at room
temperature by rate-limiting insertion of the olefin into the La-N bond.
Comparisons between Insertions of Olefins into Metal-Amide and Metal-Alkyl Ligands
The conclusion that some oxidative aminations and hydroaminations of olefins occur by
insertion of an olefins into a metal-amide linkage begins to allow a comparison of the rates of
insertions into various metal alkyl and amido complexes and an understanding of the factors that
control these relative rates. Current data provide qualitative comparisons that can be used to
formulate preliminary theories about the effect of the non-bonded electron pair on rates of olefin
insertions into high-valent and low-valent amido complexes.
A comparison of lanthanide-catalyzed hydroamination and olefin polymerization reveals the
relative rates of insertions of olefins into lanthanide alkyl and lanthanide amide bonds. The
polymerizations of alkenes by lanthanide catalysts involves intermolecular, rate-limiting
insertions of ethylene into lanthanocene alkyl intermediates,86 whereas alkene hydroaminations
by lanthanide catalysts have been limited to reactions that occur by intramolecular insertions. 84,85
Because the lanthanide-catalyzed olefin hydroamination is slower than lanthanide-catalyzed
olefin polymerization, it appears that the rate of olefin insertions into lanthanide amides is slower
than that of olefin insertions into lanthanide alkyls. This slower rate of insertion into lanthanide
amides can be understood by the reaction's requirement to break an M-N bond that is stronger
than the M-C bond. The M-N bond is stronger in this case because of a favorable match of a hard
metal with a hard ligand and donation of the non-bonded electrons from the amido group into
unoccupied orbitals on the metal.
11
If the relative rates of insertions of olefins into lanthanide-amide and lanthanide-alkyl complexes
are affected by the hardness of the lanthanide metal and the ability of the metal to accept electron
density from the electron pair on nitrogen, then one might expect the relative rates for insertions
of olefins into amide and alkyl complexes of softer, more electron-rich late-metals to be
different. Although fast insertions of olefins into cationic or electrophilic neutral palladium alkyl
intermediates occur during palladium and nickel-catalyzed olefin oligomerization and
polymerization,87,88 two recent studies suggest that the insertions of olefins into more electronrich, late metal-amides and alkoxides can be even faster than olefin insertions into analogous
metal-alkyl complexes.
Chart 9. Data and basis for relative rates of olefin insertion into alkyl,
amide and alkoxo complexes.
L
LnPd
A
OH + Br
L
O Pd
Pd
O
L
B
R
85-105 °C
PEt3
2 Et3P Rh NHAr
PEt3
O
Et3P
Rh
R1
R2
Et3P
R1, R2 =Me, Ph
C6D6
2h
H Ar
N
PEt3
Rh
Rh
Et3P
H
PEt3
Et3P
+
R
O
L
Ar
N
Me
via:
LnRh XR
LnRh XR
R
R
RX
PEt3
20 oC-50 oC
C6D6
O
(PEt3)4RhH +
R1
R2
R
+ LnRh H
-stabilization for high-valent metals
stronger dative
-repulsion for low-valent metals
bond
‡
LnM XR
LnM XR
LnM XR
C
weaker dative
bond
no -stabilization or destabilization
H
‡
LnM CH2R
LnM CH2R
LnM CHR
First, studies of certain catalytic amidoarylations and alkoxyarylations of olefins begin to reveal
the relative rates of insertion into metal-amido and metal-aryl linkages.89-91 These reactions occur
through arylpalladium amido and arylpalladium alkoxo complexes, and in each case the product
from insertion of the olefin into the metal-amido or metal-alkoxo bond is formed. In one
particularly revealing experiment, depicted as part A of Chart 9, the selectivity from a catalytic
alkoxyarylation process involving a neutral phosphine-ligated palladium center bound by one
alkoxo and one aryl ligand, each containing a pendant olefin, showed that insertion into the
metal-alkoxo bond was faster than insertion into the palladium-aryl bond.91
A second set of data shown as part B of Chart 9 reveal the relative rates for these types of
insertions into discrete rhodium alkoxo and amido complexes.32,33 In one section of these studies,
intermolecular insertion of an olefin into a rhodium amido complex occurs. This reaction forms a
rhodium hydride and an enamine as the final products after -hydrogen elimination from the
initially formed aminoalkyl species.32 In a closely related study, intramolecular insertion of a
coordinated olefin into a rhodium alkoxide occurs. The resulting alkoxyalkyl intermediate
12
undergoes -hydrogen elimination to form a cyclic vinyl ether as the final product. 33 The
corresponding rhodium methyl complex does not insert alkenes. Thus, the rates for insertions of
olefins into these rhodium alkoxides and amides appear to be faster than insertions into the
analogous alkyls, and the relative rates for insertions of alkenes into these rhodium amido,
alkoxo, and alkyl species follow the trend CH2R < OR < NRR’.
Rates of reactions that follow such a trend are typically controlled by the effect of an electron
pair on the three types of ligands, not by the strengths of the M-X bonds or by the
electronegativities of the atom bound to the metal. Such an effect of the electron pair on the rates
of these insertions can be explained as summarized in part C of Chart 9. First, the bonds in the
starting, low-valent alkoxide or amide would likely be destabilized, relative to the analogous
alkyl complexes, by repulsion between the filled metal d-orbital and the filled amide or alkoxide
p-orbital. Second, because of the effect of the electron pair on the heteroatom, the metalheteroatom bond need not be fully cleaved during insertions into metal alkoxides and amides.
Instead, these insertions can be envisioned as converting the covalent M-X bond of an amido or
alkoxo complex into an M-X dative bond in an amine or ether complex. Because the degree of
metal-ligand bond-breaking in the overall process would be reduced by the formation of the
metal-ligand dative bond in the final product, the barrier for insertion should be reduced. Thus,
several differences in the properties of organometallic and heteroorganometallic complexes can
make the reactivity of amido and alkoxo complexes even greater than that of metal alkyl
complexes toward insertion reactions.
D. Summary and Further Consequences.
This review has provided a sampling of catalytic and related stoichiometric reactions that begin
to uncover the relationships between reactivities of organometallic and heteroorganometallic
systems. Three types of catalytic reactions reveal three different origins of the control of the rates
of carbon-heteroatom bond-formation within heterooorganometallic intermediates. Data on
cross-coupling implied that electronegativity and polarizability of the atom bound to the metal
influence the rates of reductive elimination more than the donating ability of the electron-pair.
Data on C-H activation showed that an unoccupied orbital on an electropositive heteroatom can
open new pathways for C-H bond cleavage and functionalization. Data on olefin oxidation and
oxidative amination showed that insertions of olefins into M-N and M-O bonds can occur and
that the rates of these reactions, relative to insertions into metal-alkyl bonds, depend on the
relative ability of the electron pair on oxygen and nitrogen to stabilize the reactants and products
of the insertion process.
Electronegativity, polarizability, and basicity of the atom bound to the metal also affect the
relative rates of other reactions of organometallic and heteroorganometallic species. For
example, -hydrogen elimination from alkoxo and amido complexes has now been shown to be
much slower than -hydrogen elimination from a directly analogous alkyl complex.92 Moreover,
recent studies have illustrated how the oxidative addition of ammonia can be more challenging
than the oxidative addition of methane because the basicity of ammonia’s electron pair can cause
formation of a stable Lewis acid-base complex.30,93 Thus, one rule, such as hard-soft mismatches
lead to higher reactivity, cannot explain the diverse reactivity of these complexes. Yet a set of
13
rules should be accessible that will generate predictive power, and these rules are beginning to be
established.
Ultimately, these reactions should allow for the creation of a diverse set of catalytic processes
that will significantly increase the power of chemical synthesis. Although a few of these process
have been developed to the point of being synthetically valuable, other processes need further
development and yet others remain to be discovered. Such discoveries should fuel one branch of
research at the interface between organic and inorganic chemistry that has already affected the
synthesis of molecules that influence the future of our health and the quality of our lives.
Summary
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