Literature TalkUttam K. Tambar
March 1, 20048pm, Noyes 147
R R
N
N
R R
N
N
Rh Rh Rh Rh
R
R
N2
Rh Rh
R
R
reversible irreversible
N
N
carbenoid
Rh2L4
X
Y
H
A
D
B A
D
B
H
Y
X
H
A
D
B
Rh2L4
YX
H
A
D
B
Rh2L4
YX
or
1
2
Rhodium Carbenoids and C-H Insertion
I. What is a Carbene?
II. What is a Carbenoid?
III. Carbenoid Formation from Diazo Compounds
IV. C-H Insertion with Rhodium Carbenoids
V. Enantioselective C-H Insertion with Rhodium Carbenoids
Outline
General References:
Modern Catalytic Methods for Organic Synthesis with Diazo Compounds:From Cyclopropanes to Ylides (Doyle)
Chem Rev. 1986, 86, 919 (Doyle)
Chem Rev. 2003, 103, 2861 (Davies)
Advanced Organic Chemistry: Reactions and Mechanisms (Bernard Miller)
Carey & Sundberg, Part B, Chapter 10
Michael P. Doyle(University of Arizona)
Huw M. L. Davies(University at Buffalo - SUNY)
1
I. What is a Carbene:Structure
Carbenes are neutral molecules containing divalent carbon atoms with 2 unshared electrons:
H
C:
H
2 possible electronic structures: singlet and triplet
R
R
:
R
R
.
.
100°
137°
singlet
• resembles carbocation and carbanion united on same carbon
• "sp2" filled orbital with empty "p" oribtal
• many R groups (with unshared electrons) can stabilize singlet more than triplet
triplet• resembles diradical• R groups in "sp" orbital, 2 partially filled orthogonal "p" oribtals• usually more stable than singlet form (Hund's rule)
I. What is a Carbene:
Formation from Diazo Decomposition
O
O
NN
! or hƒN2 C O
O
H H
+
Driving force for decomposition of diazo compounds: formation of N2activation energy for diazoalkane decomposition = 30 kcal/mol (thermal or photochemical energy)
Usually it is difficult to know if a "carbene" reaction in solution involves a free carbeneor some pseudo-carbene species that behaves like a carbene
2
I. What is a Carbene:
Reactivity
Free carbenes undergo insertion reactions
singlet carbene
• Direct (one-step) insertion into C-H bonds, which leads to retention of stereochemistry at carbon• No selectivity between different types of C-H bonds in intermolecular reactions(only some selectivity in intramolecular reactions)
H
HCH2
+
H
H
H
+
1 : 6(statistical mixture)
"methylene must be classified as the most indiscriminate reagent known in organic chemistry."(JACS 1956, 78, 3224)
(a)
(b) photolysis of diazomethane in heptane:
CH2N2
hf
38%
25%
24%
13%
JACS 1956, 78, 3224
JACS 1961, 83, 1934
I. What is a Carbene:
Reactivity
Free carbenes undergo insertion reactions
triplet carbene
• Multi-step process (involving radical pairs), which can lead to scrambling of stereochemistry
Ph
Ph
N2
hƒ Ph
Ph
triplet
Ph-Me Ph
Ph
H + Ph CH2
radical pair
Ph
Ph
Ph
Ph
Ph
Ph
Ph
PhPhJACS 1969, 91, 4549 & 4554
3
II. What is a Carbenoid:
Structure and Formation
Carbenoid is a vague term used for a molecule in which all carbons are tetravalentbut still has properties resembling those of a carbene(usually the carbene-like carbon has multiple bonds with a metal)
R
C
R
MLn
Carbenoids can be formed by reacting salts of transition metals (eg. Cu, Pd, Rh) with diazo compounds
Initially the transition metal complexes used to decompose diazo compounds were heterogenous Cu complexes(JCS 1906, 89, 179)
EtO
O
N2
Copper dust
EtO
O
O
OEt
N2NH
N
O
EtO
O
EtO
OOEt
II. What is a Carbenoid:
Structure and Formation
In 1952 Yates postulated that the reaction of transition metal complexes with diazo compounds led tothe generation of transient electrophilic metal carbenes: "reaction of ROC:H (or of the RCOC:H-copper complex) probably involves an attack by the unshared pair of electrons on oxygen, nitrogen or sulfur at the electron-deficient methine carbon followed by a prototropic shift" (JACS 1952, 74, 5376)
Then homogeneous Cu complexes were utilized
O O
OOCu N2
Ph
Ph
+PhH
!
Ph
Ph Ph
Ph
TL 1966, 59
EtO
O
N2+
(RO)3PCuCl
CO2Et CO2Et+
JACS 1969, 91, 1135 & 1141
R
O
N2
Cu
R
O
Hcomplexedwith Cu
X-H
X=RO, RS, R2N
Electrophile Nucleophile
R
O
X
4
III. Carbenoid Formation from Diazo Compounds:Lewis Acid Promoted Decomposition of Diazo Compounds
Diazo compounds are unstable to acid promoted decomposition:
H2C N2 + H+
H3C N2
H2C N + H+NH2C N N H H3C N N
Site of protonation:
kinetic product thermodynamic product
This instability of diazo compounds towards acids models their reactivity with lewis acidic transition metal complexes:
H2C N + LAN H2C N N
LA
III. Carbenoid Formation from Diazo Compounds:Mechanism of Transition Metal Promoted Decomposition of Diazo Compounds
R R
N
N
R R
N
N
Rh Rh Rh Rh
R
R
N2
Rh Rh
R
R
reversible irreversible
N
N
Lewis acidic transition metal complexes, like Rh(II) complexes, are effective catalysts for diazo decomposition.Activity of transition metal complexes depends on coordinative unsaturation at metal center,which allows them to react as "electrophiles" for diazo compound:
JACS 1996, 118, 8162
carbenoid
Some eccentric metal mediated diazo decomposition reactions do not yield carbenoids,and these reactions are often catalyzed by non-transition metal lewis acids as well:
NR
R'
O
N2
Cu(OTf)2
orBF3•OEt2
O
N
R'
R
NR MLn
R'
ONN O
N
R'
R
NN
MLn
Cu: J. Organomet. Chem. 1975, 88, 15
BF3: JOC 1980, 45, 3657
5
III. Carbenoid Formation from Diazo Compounds:Effect of Lewis Bases
An electron rich substrate (S:) can react withthe electrophilic metal carbenoid, whichresults in the regeneration of the transitionmetal complex (important for catalysis)
LnM LnM CR2
S:SCR2
R2C N2
Ln-M CR2
N2+
N2
Sometimes the reaction between the electrophiliccarbenoid and a Lewis basic substrate (S:) is desirable
But sometimes a Lewis base (B:) substrate can associate with the coordinatively usaturated transition metalcomplex and inhibits diazo decomposition:
MLn
-B:
+B:
B MLn
+R2C N2
-R2C N2
LnM CR2
N2
Effective inhibitors for diazo decomposition: amines, sulfides, nitriles, (sometimes alkenes, aromatics)(Inorg. Chem. 1982, 21, 2196)
Ineffective inhibitors for diazo decomposition: halogenated hydrocarbons, eg. DCM, DCE(great solvents for diazo decomposition)
III. Carbenoid Formation from Diazo Compounds:Rh(II) Catalysts
Carbene C-H insertions are highly non-selective
Carbenoid C-H insertions are much more selective because of the reduced reactivity of carbenoids
Rh Carbenoids (generated from Rh(II) dimer complexes) have become the most common catalystsfor C-H insertion reactions because of their selectivity and the ease with which ligands are modified
Dirhodium (II) carboxylates:
• First example of Rh carbenoid generation from diazo decomposition:(TL 1973, 2233)
• Complexes are air stable and easy to work with
• D4h symmetry with 4 bridging acetate ligands and 1 vacant
coordinate site per metal atom presents an octahedral geometry
resembling a circular wall with an electron rich circumference
and electron deficient core:
Rh Rh
O
O
O
O
O O
O O
O
Rh
O
OO
EtO
O
N2
Rh2(OAc)4
ROH+
EtO
O
OR+ N2
R = Et, i-Pr, t-Bu,H, MeO
!+
!-
!-
!-
!-
6
III. Carbenoid Formation from Diazo Compounds:Rh(II) Catalysts
Electron-withdrawing capabilities of carboxylate ligands affect properties of the catalyst(eg. Rh2(OAc)4 does not form olefin complexes in solution,but Rh2(TFA)4 does form olefin complexes in solution)Inorg. Chem. 1984, 23, 3684
Other ligands used in dirhodium (II) complexes:
carboxamidates phosphates andorthometallatedphosphines
CO
porphoryns
O
Rh
N
NO
Rh2(CO)16
Rh Rh
O
N
N
O
O N
N O
H
H
H
HRh Rh
O O
POO
Ar Ar
N
N N
N
Ar
Ar
Ar
Ar Rh
X
Inorg. Chem. 1986, 25, 260
TL 1992, 33, 5983TL 1992, 33, 5987
TL 1980, 21, 3489
TL 1981, 22, 1783
III. Carbenoid Formation from Diazo Compounds:Stability of Rh carbenoid complexes
The use of dirhodium (II) catalysts for intramolecular C-H insertion of diazo carbonyls hasdeveloped into a significant synthetic achievement because of the stability of these intermediates
Z Y
O O
N2
Z
O
N2
R R
N2
R
increasing stability
increasing reactivity
Y, Z = R, OR, NR2R = alkyl, aryl, H
NN + Rh2(t-BuCOO)4 Rh Rh
O
O
O
O
O O
O O
RR
R R
N
N
A stable dirhodium tetracarboxylate carbenoid was isolated recently by Padwa:
JACS 2001, 123, 11318
7
IV. C-H Insertion with Rh Carbenoids:
Introduction
Rh (II) complexes are used for C-H, Si-H, and Heteratom-H insertion reactions
C-H and Si-H insertions are unique because of the low polarity of the bonds,so their mechanisms are distinct from Heteroatom-H insertions
Different Types of Insertion Reactions:
C-H Insertion via Metal Carbenoids vs. C-H Activation via Oxidative Addition:
In metal carbenoid induced C-H activation the metal atom is not thought to interact directly with the alkane C-Hbond (this is different than most other C-H activation reactions, which involve oxidative addition of the metalacross the alkane C-H bond):
C MLn
X
Y
MLn
C MLn
H
MLn
C H
C
H
Y
X
N2
C N2
X
Y
vs.
C-H Insertion via Metal Carbenoids C-H Activation via Oxidative Addition
IV. C-H Insertion with Rh Carbenoids:
Mechanism of C-H Insertion
Rh2L4
X
Y
H
A
D
B A
D
B
H
Y
X
H
A
D
B
Rh2L4
YX
H
A
D
B
Rh2L4
YX
or
• Carbenoid's empty p-orbital overlaps with the !-orbital of the C-H bond
• C-C and C-H bond formation with carbenoid carbon proceeds as ligated metal dissociates (1)
1
2
• Taber prefers a transition state in which there is a more pronounced interaction/transfer of hydrogento rhodium (2), followed by a reductive elimination(JACS 1996, 118, 547)
8
IV. C-H Insertion with Rh Carbenoids:
General Characteristics of a Good Rh Complex for C-H Insertion
Proficient C-H insertion requires an appropriate level of electrophilic character at the metal center
• If the metal center is too electrophilic catalyst displays poor selectivity because of high reactivity,and it is susceptible to undesired competing reactions
• If the metal center is not electrophilic enough catalyst is not reactive enough to insert C-H bond
• Electron-withdrawing groups on metal or adjacent to carbenoid carbonincrease the electrophilicity of the carbenoid intermediate
• The best metal complexes bind to the carbenoid carbon through strong !-donationand weak "-back donation, which stabilizes the carbenoid carbon somewhat butstill ensures electrophilicity
Solutions:
IV. C-H Insertion with Rh Carbenoids:
Trends in Selectivity for Intermolecular C-H Insertion
Intermolecular C-H insertion has mechanistic value, but it is not always synthetically useful(because of low selectivity)
EtO
O
N2+
O
ORh2(OAc)4
O
O
O
OEt
k = 3.0 - 12 x 10-4 s-1
(reaction is first order in ethyl diazoacetate)
Tetrahedron 1989, 45, 69
9
IV. C-H Insertion with Rh Carbenoids:
Trends in Selectivity for Intramolecular C-H Insertion
C-H insertion occurs preferably at a carbon that can stabilize positive charge (electronic effects)
• tertiary carbon > secondary carbon > primary carbon(because of the availability of the electron density in the C-H bond)
O
N2
E
O
E
O
E
23 1
Rh2(OAc)4
JACS 1986, 108, 7686
• alkoxy groups activate adjacent C-H bonds:
O
N2
OBn
Rh2(OAc)4
O
OBn
O
OBn30% 0%
3e
2e
Tetrahedron 1991, 47, 1765
IV. C-H Insertion with Rh Carbenoids:
Trends in Selectivity for Intramolecular C-H Insertion
Sometimes electronic effects are outweighed by steric or conformational factors
• 5 membered rings > 6 membered rings
• electron-withdrawing groups (eg. CO2Me) inhibit adjacent C-H bonds (TL 1988, 29, 2283)
O
N2 CO2Me
Rh2(OAc)4
O
CO2Me
O
N2CO2Me
Rh2(OAc)4
O
CO2Me
64%
0%
O
N2 CO2Me
Rh2(OAc)4
CO2Me
O
0%
O
N2
E
O
ERh2(OAc)4
O
E
not observed
10
IV. C-H Insertion with Rh Carbenoids:
Diastereoselectivity in Intramolecular C-H Insertion
N2
Ph CO2Me Rh2(Oct)4
CH2Cl291%
CO2MePh
Me
N2 CO2Me
OO Rh2(Oct)4
CH2Cl285%
OO
CO2Me
OPhO2S
N2
OMe
O
SO2Ph
Ome
Rh2(Oct)4
CH2Cl260%
Model for explaining diastereoselectivity:pseudo-chair transition state(JACS 1996, 118, 547 &Tetrahedron 1996, 52, 3879)
HCO2Me
Me HRh2L4
H
Ph
CO2MePh
Meequitorial
V. Enantioselective C-H Insertion with Rh Carbenoids:
Classification of Carbenoid Intermediates
Although dirhodium (II) catalysts provide the highest levels of asymmetric induction for C-H insertion,there is no one class of chiral rhodium (II) complex that is effective for all C-H insertion reactions
This is because different types of carbenoid intermediates display very different reactivities
3 main categories of carbenoids:
acceptor substituted carbenoid
acceptor/acceptorsubstituted carbenoid
donor/acceptorsubstituted carbenoid
LnM
H
EWG
LnM
EWG
EWG
LnM
EDG
EWG11
V. Enantioselective C-H Insertion with Rh Carbenoids:
Acceptor Substitutd Carbenoids
acceptor substituted carbenoid LnM
H
EWG
Example of a catalyst for enantioselective intramolecular C-H activation:
N
O
Rh
Rh
MeO2C
4
O
RO
O
O
RO
OJACS 1991, 113, 8982
N2
catalyst
CH2Cl2
% Yield % eeR
Me
Et
Bn
73
64
64
91
89
87
CH3
O
O
H3C
Ph
O
O
H3C
Ph
catalyst
CH2Cl2
N230% yield, 76% ee
V. Enantioselective C-H Insertion with Rh Carbenoids:
Acceptor/Acceptor Substitutd Carbenoids
acceptor/acceptorsubstituted carbenoid LnM
EWG
EWG
Example of a catalyst for enantioselective intramolecular C-H activation:O
O
Rh
Rh
4
HN
O
O
TL 1990, 31, 5173
CO2MeR
O
N2
catalyst
CH2Cl2
R
CO2Me
O
aq. DMSO
120 °C
R
O
% Yield % eeR
Me
n-Pn
76
43
44
24
29
38
Ph 96 46
CH2=CH2
12
V. Enantioselective C-H Insertion with Rh Carbenoids:
Donor/Acceptor Substitutd Carbenoids
donor/acceptorsubstituted carbenoid LnM
EDG
EWG
Example of a catalyst for enantioselective intermolecular C-H activation:
O
O
Rh
Rh
4
N
SO2Ar
N2
MeO2C
JACS 1997, 119, 9075
R
+catalyst
81 °C
MeO2C H
R
% Yield % eeR
OMe 86
83
91
67
81
86
H
Cl
Outlook for the Future
• Rh (II) carbenoids have become the most widely used catalysts for selective C-H insertion reactions
• Both the catalyst design and carbenoid structure can affect reactivity and selectivity (chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity)
• C-H insertion with Rh carbenoids is now becoming a powerfuland widely applicable synthetic strategy for total synthesis(avoidance of functional group manipulations)
• A major area of future research will be to broaden the range ofcarbenoid systems that can undergo selective C-H insertion reactions
• Recent computational studies to study the mechanism mayhelp make the design of future systems more rational and predictable
13