Rhodium Carbenoids and C-H InsertionRhodium 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

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


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


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


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


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:


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


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


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


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


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


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


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

Documents

Rhodium Carbenoids and C-H InsertionRhodium 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