M.C. White,sites.fas.harvard.edu/~chem253/notes/2004wk11-12.pdfof Cp*R h(CO) 2 w ith neopentane-d 12...

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.


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.


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


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.


Crabtree:thermal dehydrogenation of alkanes to alkenes


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


"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.


Crabtree:photochemical dehydrogenation of alkanes to alkenes

Proposed Mechanism:


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


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).


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.


reductiveelimination


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.


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.


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-


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


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.


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.


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.


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.


Mechanism of direct borylation of alkanes


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.

?


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


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.


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


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


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


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...


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):


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


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


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.


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.


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


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


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.


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]

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