Coordinative

Unsaturation

in Transition

Metal

Catalysis

++++

Curtis Seizert

9 July 2011

(!)

Revised: 16 September 2011

Zr [ ] ZrBu

Bu

whatis it?

ZrZr

Zr [ ] ZrBu

Bu

whatis it?

how tomake it

ZrZr

Zr [ ] ZrBu

Bu

whatis it?

how tomake it

Zr

ref iningdef initions

Zr

case studies

what is coordinative unsaturation?

stable precatalysts

active catalysts

the importance of coordinative unsaturation in catalysis

•Greater substrate scope

•Increased reaction rates

•Lower temperatures

“A vacant coordination site is perhaps the single m ost important property of a homogeneous catalyst”

-James P. Collman, Acc. Chem. Res., 1968, 1, 138.

then why isn’t everybody doing it?

There are considerable challenges associated with generating unsaturated catalysts, and these have often required creative solutions or serendipity to overcome

ligand dissociation from a precatalyst to generatea highly unsaturated complex is often times very slowand/or thermodynamically unfavorable

ligand dissociation from a precatalyst to generatea highly unsaturated complex is often times very slowand/or thermodynamically unfavorable

generating unsaturated species in solution often leadsto irreversible catalyst inactivation

how to generate coordinative unsaturation: Ligand Dissociation

Bulky ligands promote formation of monoligated palla dium

Strong donor ligands stabilize monoligated species

A ligand scavenger makes this process more efficien t

Christmann, U.; Vilar, R. Angew Chem Int Ed Engl2005, 44, 366.

PPh3: Less bulky, less donating Pt-Bu3: Bulkier, more donating

how to generate coordinative unsaturation: Forced Ligand Dissociation

Photochemical dissociation of H2 or CO can create very reactive intermediates, even at low temperatures

This principle has not been used in catalysis

Brown’s catalyst is activated by hydrogenation of the norbornadiene ligand to norbornane, which does not bind to the rhodium center

RhPh2P PPh2

H2

-

+

RhPh2P PPh2

+

Rh(I)16 e-

Rh(I)12 e-

Periana, R. A.; Bergman, R. G. J. Am. Chem. Soc.1986, 108, 7346.Drexler, H.-J.; Baumann, W.; Spannenberg, A.; Fischer, C.; Heller, D. J. Organometallic Chem.2001, 621, 89.

how to generate coordinative unsaturation:Reduction

Zr: Negishi, E., Holmes, S. J., Tour, J. M., Miller, J. A., Cederbaum, F. E., Swanson, D. R., Takahashi, T. J. Am. Chem. Soc. 1989, 111, 3336-3346.Pd: Amatore, C., Jutant, A., Amine M’Barki, M., Organometallics 1992, 11, 3009.

Reduction of (R3P)2Pd(OAc)2 complexes occurs spontaneously by internal oxidation of a phosphine, but the resulting reduction product product is not stable in the absence of an added ligand

Reduction via dialkylation

‘Virtual’ Coordinative Unsaturation

Solvent molecules perform the same function

An example from main group chemistry:

Coordinative unsaturation: It’s not real!

labileligand

using coordinative unsaturation as a focal point in viewing catalytic cycles

virtues

• often helps understanding of individual difference in catalytic activity based on ‘ancillary’ ligands

• key parameter in catalyst activation, catalyst deactivation, and substrate scope

caveats

• once you generate an unsaturated species, it still has to do the desired chemistry

• one species may behave as if it is coordinatively unsaturated, while a similar one with the same electron count will not

• not all active sites are created equal

ArX

ArX

RM

ArR

RAr

R

cross coupling

Heck reaction

hydrogenation

R XR

Nu

iridium catalyzedallylic substitution

olef in metathesis

ArX

ArX

RM

ArR

RAr

R

cross coupling

Heck reaction

hydrogenation

R XR

Nu

iridium catalyzedallylic substitution

olef in metathesis

olefin metathesis

Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L. J. Am. Chem. Soc.2004, 126, 16300.

This reaction is inefficient in the presence of Grubbs I or Grubbs II catalysts

O

O

O

PMBO

OO

O

H

PMBO

H

RuCl

Cl

O

SIMes

25 mol %

toluene, reflux76% yield

NNSIMes =

Hoveyda-Grubbs I

Ligands dramatically affect the behavior of metathesis catalysts

Ritter, T.; Hejl, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H. Organometallics2006, 25, 5740.

RuCl

Cl

PCy3

PCy3Ph

RuCl

Cl

SIMes

PCy3Ph

RuCl

Cl

SIMes

O

RuCl

Cl

PCy3

O

RuCl

Cl

L

Ph

PCy3-PGrubbs I

SIMes-PGrubbs II

PCy3-OHoveyda-Grubbs I

SIMes-OHoveyda-Grubbs II

ligands control metal’s affinity for substrate vs. phosphine

Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.2001, 123, 6543.

Rate of initiation is faster with PCy3

Rate of propagation is >104 times faster with SIMes

Faster overall with SIMes

What has olefin metathesis taught us?

Once again, coordinative unsaturation greatly affects catalyst efficiency

We must refine our notion of coordinative unsaturation to include not only the reactivity of ‘vacant’ sites in general, but their relative reactivities towards substrate versus excess ligand

NHCs do not act as π-acids, whereas phosphines act as weak π-acids. Coordination of a more strongly π-acidic ligand trans to an NHC is favored relative to the phosphine case

ArX

ArX

RM

ArR

RAr

R

cross coupling

Heck reaction

hydrogenation

R XR

Nu

iridium catalyzedallylic substitution

olef in metathesis

The Heck Reaction and Cross Coupling

PdPh3P

Ph3P PPh3

PPh3

PdPh3P PPh3

PPh3

PdPh3P PPh3

PdX

Ph3P PPh3

Ar

PdX

Ph3P PPh3

ArX

oxidativeaddition

migratoryinsertion

reductiveelimination

18 e-

16 e-

14 e-

16 e-

16 e-

R

PdPh3P PPh3

PPh3

PdPh3P PPh3

PdX

Ph3P PPh3

ArPd

R

Ph3P PPh3

Ar

ArX

RM

-ArR oxidativeaddition

transmetallation

reductiveelimination

ratelimitingstep

16 e-

14 e-

16 e-

16 e-

Ar

PdX

Ph3P PPh3

H

16 e-

-hydride

elimination

R

RAr

-HX

ratelimitingstep

-

ArX

RAr

R

Heck reactionAr

XR

MAr

R

cross coupling

where the art started

Precatalyts

Electrophiles

Temperatures

Catalyst Loading

Pd(PPh3)4Pd(OAc)2 + PPh3Pd(dba)2 or Pd2(dba)3 + PPh3

ArIArBrArOTf

Elevated temperatures often required

1 - 10 mol %

The active catalyst in homogeneous cross coupling reactions was usually L2Pd, but ligand dissociation to this species isn’t always easy...

excesses of strong ligands lead to inert catalysts

ligand

PPh3

(p-MeOC6H4)3P

(o-Tol)3P

(2-furyl)3P

AsPh3

krel-4(P:Pd = 4)

1.0

<.07

35.2

105

1100

krel-2(P:Pd = 2)

19

7.2

119

391

1480**

inhibition

factor*

19

>100

3.4

3.7

1.3

reactions using P:Pd = 2 had >95% yield

*krel-2 / krel-4**incomplete reaction because of catalyst decomp.,

94% yield

I SnBu3

1 mol %Pd2(dba)3•CHCl3

ligand, THF, 50 °C

Strongly binding ligands inhibit the reaction by quenching coordination sites

A negative correlation exists between reaction rates and inhibition factors

This information led to the widespread use of (2-furyl)2P and AsPh3 in cross coupling reactions –these seem to facilitate the formation of coordinatively unsaturated species in solution

Farina, V.; Krishnan, B. J. Am. Chem. Soc.1991, 113, 9585.Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org. Chem.1993, 58, 5434.

the rise of monoligated Pd

Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc.2002, 124, 6343.Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem. Int. Ed.2002, 41, 4746.Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4685.

Formation of L1Pd type species makes previously impossible couplings routine

Sources of monoligated Pd: not all precatalysts are created equal

Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem.2003, 68, 2861.Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem. Int. Ed.2002, 41, 4746.

some methods of generating L1Pd

Monoligated Pd via dissociation of ‘innocent’ ligands

The activity of these monophosphine-diene complexes depends on their ability to release the diene, liberating L1Pd

Activity: 1 > 2 > 3

Andreu, M. G.; Zapf, A.; Beller, M. Chem. Comm.2000, 2475.

the in situ formation of catalysts from palladium-dba complexes falls into this category.

in general, it seems that this method leads to less active catalysts than reduction or reductive elimination –no ligand is truly innocent

Monoligated Pd via reduction of Pd(OAc)2 – a new take on an old method

Activation in water using Pd(OAc)2 (0.01 mmol), L (0.03 mmol) and H2O (0.04 mmol) in 1 mL

dioxane at 80 °C

Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett.2008, 10, 3505.

Monoligated Pd via reductive elimination from Pd(II) complexes

Bedford, R. B.; Cazin, C. S. J. Chem. Comm.2001, 1540.

Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc.2010, 132,

14073.

Monoligated Pd via reductive elimination of Pd(II) complexes

Navarro, O.; Kelly, R. A.; Nolan, S. P.J. Am. Chem. Soc.2003, 125, 16194.

Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc.2006,

128, 4101.

Recap of reductive elimination methods:

homocoupling of organometallicspublic domain

palladacycle reductive elimination via β-hydride

eliminationNolan 2003

palladacycle - external nucleophile reductive elimination

Bedford 2001

base induced palladacycle reductive eliminationBuchwald 2008

nucleophilic attack on η3-allylthis example: Nolan 2006

Why choice of ligand is crucial

To promote L1Pd type reactivity, a ligand must not only promote formation of L1Pd but stabilize the species to prevent catalyst deactivation

large trialkylphosphines are the ligands of choice

Large size:

•drives ligand dissociation equilibrium to the right

•offers steric protection from nucleation and precipitation of metallic palladium

•promotes reductive elimination of strained Pd(II) intermediates

Strong basicity:

•stabilizes the electron poor monophosphine complex

•promotes oxidative addition

Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.Angew. Chem. Int. Ed.2004, 43, 1871.Stambuli, J. P.; Bühl, M.; Hartwig, J. F. J. Am. Chem. Soc.2002, 124, 9346.

Additional weak interactions stabilize the L1Pd intermediate and provide sites of ‘virtual’ coordinative

unsaturation

*An agostic interaction is present in ArPd(Pt-Bu3)X intermediates, but (Pt-Bu3)Pd has

never been isolated

Cross coupling summary

Generating highly unsaturated catalysts can lead to great increases in reaction rate and substrate scope

P PdCy

Cy

MeO

MeO

Sterically bulky ligands can be used to bias an equilibrium in favor of dissociation, leading to a more reactive catalyst.

Ligand choice is important – good ligands both facilitate the formation of monoligated Pd from the precatalyst and stabilize the active catalyst

The precatalyst is very important – generally reductive elimination fro stable Pd(II) species makes more active catalysts than does simple ligand dissociation.

Low temp addition of PhCl: Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.2008, 130, 6686.

ArX

ArX

RM

ArR

RAr

R

cross coupling

Heck reaction

hydrogenation

R XR

Nu

iridium catalyzedallylic substitution

olef in metathesis

hydrogenation

RhPh3P

Ph3P PPh3

Cl

16 e-

RhPh3P

Ph3P PPh3

H

H

Cl

18 e-

R

RhPh3P

PPh3

H

H

Cl

R

RhPh3P

S PPh3

HCl

R

RhPh3P

S PPh3

Cl

RhPh3P

S PPh3

H

H

Cl

"16 e-"

"14 e-"18 e-

"16 e-"

H2

H2

substratecompetes with

PPh3 for abindingsite

Wilkinson'sprecatalyst

Wilkinson’s (pre)catalyst reacts with H2

to form a coordinatively saturated Rh(III) complex – ligand dissociation is

required!

differences in rates of hydrogenation are accounted for by decrease in ability of

more hindered olefins to bind to Rh

rates drop off to nearly 0 with tri- and tetrasubstituted olefins

Halpern, J.; Okamoto, T.; Zakhariev, A. J. Mol. Catal.1977, 2, 65.

cationic diene complexes as hydrogenation catalysts

Diene ligands are labile under the reaction conditions, allowing the formation of highly unsaturated species

virtual coordinative unsaturation and Crabtree’s catalyst

Non coordinating solvents are a must!

The highly unsaturated intermediates are prone to

form clusters in the absence ligands

Crabtree, R. H.; Felkin, H.; Morris, G. E.J. Organomet. Chem.1977, 141, 205.Chodosh, D. F.; Crabtree, R. H.; Felkin, H.; Morris, G. E.J. Organomet. Chem.1978, 161, C67.

the effect of unsaturation in hydrogenation catalysis

nearly any olefin can be hydrogenated with Crabtree’s catalyst, although tri- and tetrasubstituted olefins require slow addition of catalyst

Crabtree, R. Acc. Chem. Res.1979, 12, 331.

Initial rates of hydrogenation in

better anions, better catalysts

Even standard ‘non-coordinating’ anions such as PF6

- bind too strongly to the Ir center and extremely weakly coordinating anions such as BArF and AlORF are needed*

Smidt, S. P.; Zimmermann, N.; Studer, M.; Pfaltz, A. Chem.–Eur. J.2004, 10, 4685.*See also: Drago, D.; Pregosin, P. S.; Pfaltz, A. Chem. Comm.2002, 286-287.

unsaturation allows directing effects through metal-substrate coordination

cyclic substrates acyclic substrates

Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev.1993, 93, 1307.Crabtree, R. H.; Davis, M. W. J. Org. Chem.1986, 51, 2655.

R'R

OH

N

OH O

O

O

Ph

OTBS

OH

OTBS

OH

HBzO

Et

R = MeR' = Ph

R = PhR' = CO2Me

Rh+

2 mol %, 15 psi32:1

0.5 mol %, 15 psi99:1

17.5 mol %, 640 psi10:1

3 mol %, 15 psi19:1

20 mol %, 15 psi99:1

Ir+

N/A

N/A

2.5 mol %3:1

N/A

N/A

hydrogenation summary

highly unsaturated hydrogenation catalysts exhibit a larger substrate scope as well as a tendency to deactivate

the activity of cationic, unsaturated hydrogenation catalysts is remarkably dependent on both the nature

of the counterion and the solvent – strong coordination from either deactivates the catalyst

due to the open coordination site, the catalyst can complex the substrate, opening the door to directing effects

iridium catalyzed asymmetric allylic alkylation

Hartwig, J. F.; Stanley, L. M.Acc. Chem. Res. 2010, 43, 1461.

Ir

P

NRO

RO

Ph

Ph

[IrCl(cod)]2 + L

IrL

P

NRO

RO

Ph

Ph

HCl

Ir

P

NRO

RO

Ph

Ph

R'

OCO2Me

Ir

P

NRO

RO

Ph

Ph

R'

Ir

P

NRO

RO

Ph

Ph

R'

Nu

R'

Nu

R'

OCO2Me

BaseL

IrL

Cl

Nu-

Catalyst Activation

CatalystPrecursors

Substrate

Product

+

16 e-

18 e-

18 e-

18 e- 18 e-

18 e-

Yet another case of ligand inhibition

IrL

P

NRO

RO

Ph

Ph

Ir

PH

NRO

RO

Ph

Ph

R'

OCO2Me

R'

OCO2Me

+

+ L

substrate-ligandexchange equilibrium

18 e- 18 e-

Standard conditions with 2:1 P:Ir gives sluggish reactions and narrow scope

Substrate has to compete with ligand for a binding site on Ir!

The tempting solution doesn’t work

Solving this problem isn’t as easy as just lowering the P:Ir ratio!

Evolution of the solution

Problem: ligand deficient systems do not undergo ac tivation readily

Hartwig: perform cyclometallation in the presence of excess ligand, then add a ligand

scavenger

Helmchen: Use a stronger base and make both the excess ligand and the scavenger cheap

Alexakis: Use sterically bulky ligands to

promote activation through strain relief

OCO2Me

PhPh

CO2MeMeO2C

2 mol % [IrCl(cod)]24 mol % L

NaHC(CO2Me)2

8 mol % TBD20 mol % THT20 mol % CuI

N

N

NH

S

TBD = THT =

stronger base

cheap excess ligand

ligand scavenger

Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc.2003, 125, 14272.Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem. Int. Ed.2004, 43, 4595.Polet, D.; Alexakis, A. Org. Lett.2005, 7, 1621.

Another problem

Unsaturated catalysts can deactivate by retro-cyclo metallation

Continuing the evolution

Problem: Preactivated catalysts can still decyclomet allate and dimerize to release excess ligand

Hartwig: Use a single-component, preactivated catalyst with a weak ancillary

ligand (ethylene) to fill the remaining coordination site

Helmchen: Use a single-component, preactivatedIr(III) precatalyst that is activated by nucleophilic

attack on the η3-allyl ligand

Ir

P

NRO

RO

Ar

Ar

Ar = Ph, o-anisyl

Marković, D.; Hartwig, J. F. J. Am. Chem. Soc.2007, 129, 11680.Raskatov, J. A.; Spiess, S.; Gnamm, C.; Brödner, K.; Rominger, F.; Helmchen, G. Chem.–Eur. J.2010, 16, 6601.

Ir

P

NRO

RO

Ar

Ar

R'

+X-

X = ClO4, OTf, SbF6

Ar = Ph, o-anisyl

Summary of iridium catalyzed allylic substitution

The [IrCl(cod)(L)] precatalyst is coordinatively saturated at 16 electrons, but the complex strongly prefers an 18 electron configuration after cyclometallation

Ligand deficient systems can undergo disproportionation to coordinatively saturated species

The most efficient methods for keeping catalytically active complexes in the cycle involved preventing this disproportionation from occurring, thus preventing the release of free ligand into solution

Key points

Generating highly unsaturated catalysts can have profound effects on reaction rates and substrate scope.

Ligand dissociation is the ‘standard’ way of making an unsaturated catalyst, but other methods, such as reduction often give rise to more active systems.

Ligand choice is important – good ligands both facilitate the formation of unsaturated species from the precatalyst and stabilize the active catalyst

P PdCy

Cy

MeO

MeO

General Tolman, C. A.: The 16 and 18 electron rule in organometallic chemistry and homogeneous catalysis. Chemical Society Reviews 1972, 1, 337-353.

Krossing, I.; Raabe, I.: Noncoordinating Anions—Fact or Fiction? A Survey of Likely Candidates. Angewandte Chemie International Edition 2004, 43, 2066-2090.

Ligand Parameters Tolman, C. A.: Phosphorus ligand exchange equilibriums on zerovalent nickel. Dominant role for steric effects. Journal of the American Chemical Society 1970, 92, 2956-2965. Tolman, C. A.; Seidel, W. C.; Gerlach, D. H.: Triarylphosphine and ethylene complexes of zerovalent nickel, palladium, and platinum. Journal of the American Chemical Society 1972, 94, 2669-2676. Tolman, C. A.: Steric effects of phosphorus ligands in organometallic chemistry and homogeneous catalysis. Chemical Reviews 1977, 77, 313-348.

General Directing Effects Hoveyda, A. H.; Evans, D. A.; Fu, G. C.: Substrate-directable chemical reactions. Chemical Reviews 1993, 93, 1307-1370.

Light Induced Ligand Dissociation

Janowicz, A. H.; Bergman, R. G.: Carbon-hydrogen activation in completely saturated hydrocarbons: direct observation of M + R-H � M(R)(H). Journal of the American Chemical Society 1982, 104, 352-354. Janowicz, A. H.; Bergman, R. G.: Activation of carbon-hydrogen bonds in saturated hydrocarbons on photolysis of (η5-C5Me5)(PMe3)IrH2. Relative rates of reaction of the intermediate with different types of carbon-hydrogen bonds and functionalization of the metal-bound alkyl groups. Journal of the American Chemical Society 1983, 105, 3929-3939. Periana, R. A.; Bergman, R. G.: Rapid intramolecular rearrangement of a hydrido(cyclopropyl)rhodium complex to a rhodacyclobutane. Independent synthesis of the metallacycle by addition of hydride to the central carbon atom of a cationic rhodium π-allyl complex. Journal of the American Chemical Society 1984, 106, 7272-7273. Periana, R. A.; Bergman, R. G.: Carbon-carbon activation of organic small ring compounds by arrangement of cycloalkylhydridorhodium complexes to rhodacycloalkanes. Synthesis of metallacyclobutanes, including one with a tertiary metal-carbon bond, by nucleophilic addition to π-allyl complexes. Journal of the American Chemical Society 1986, 108, 7346-7355.

Olefin Metathesis Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H.: Synthesis and Activity of a New Generation of Ruthenium-Based Olefin Metathesis Catalysts Coordinated with 1,3-Dimesityl-4,5-dihydroimidazol-2-ylidene Ligands. Organic Letters 1999, 1, 953-956. Sanford, M. S.; Love, J. A.; Grubbs, R. H.: Mechanism and Activity of Ruthenium Olefin Metathesis Catalysts. Journal of the American Chemical Society 2001, 123, 6543-6554.

Sanford, M. S.; Ulman, M.; Grubbs, R. H.: New Insights into the Mechanism of Ruthenium-Catalyzed Olefin Metathesis Reactions. Journal of the American Chemical Society 2001, 123, 749-750. Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L.: Total Synthesis of Ingenol. Journal of the American Chemical Society 2004, 126, 16300-16301. Ritter, T.; Hejl, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H.: A Standard System of Characterization for Olefin Metathesis Catalysts. Organometallics 2006, 25, 5740-5745.

Cross Coupling Reviews Hartwig, J. F.: Transition Metal Catalyzed Synthesis of Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope and Mechanism. Angewandte Chemie International Edition 1998, 37, 2046-2067. Beletskaya, I. P.; Cheprakov, A. V.: The Heck Reaction as a Sharpening Stone of Palladium Catalysis. Chemical Reviews 2000, 100, 3009-3066. Littke, A. F.; Fu, G. C.: Palladium-Catalyzed Coupling Reactions of Aryl Chlorides. Angewandte Chemie International Edition 2002, 41, 4176-4211. Culkin, D. A.; Hartwig, J. F.: Palladium-Catalyzed α-Arylation of Carbonyl Compounds and Nitriles. Accounts of Chemical Research 2003, 36, 234-245. Christmann, U.; Vilar, R.: Monoligated palladium species as catalysts in cross-coupling reactions. Angew Chem Int Ed Engl 2005, 44, 366-74. Fu, G. C.: The Development of Versatile Methods for Palladium-Catalyzed Coupling Reactions of Aryl Electrophiles through the Use of P(t-Bu)3 and PCy3 as Ligands. Accounts of Chemical Research 2008, 41, 1555-1564. Marion, N.; Nolan, S. P.: Well-Defined N-Heterocyclic Carbenes−Palladium(II) Precatalysts for Cross-Coupling Reactions. Accounts of Chemical Research 2008, 41, 1440-1449. Surry, D. S.; Buchwald, S. L.: Dialkylbiaryl phosphines in Pd-catalyzed amination: a user's guide. Chemical Science 2011, 2, 27. Mechanism Kuran, W.; Musco, A.: Synthesis and characterization of tertiary phosphine Pd(0) complexes. Inorganica Chimica Acta 1975, 12, 187-193. Mann, B. E.; Musco, A.: Phosphorus-31 nuclear magnetic resonance spectroscopic characterisation of tertiary phosphine palladium(0) complexes: evidence for 14-electron complexes in solution. Journal of the Chemical Society, Dalton Transactions 1975, 1673-1677. Amatore, C.; Azzabi, M.; Jutand, A.: Role and effects of halide ions on the rates and mechanisms of oxidative addition of iodobenzene to low-ligated zerovalent palladium complexes Pd0(PPh3)2. Journal of the American Chemical Society 1991, 113, 8375-8384. Amatore, C.; Jutand, A.; Suarez, A.: Intimate mechanism of oxidative addition to zerovalent palladium complexes in the presence of halide ions and its relevance to the mechanism of palladium-catalyzed nucleophilic substitutions. Journal of the American Chemical Society 1993, 115, 9531-9541. Paul, F.; Patt, J.; Hartwig, J. F.: Palladium-catalyzed formation of carbon-nitrogen bonds. Reaction intermediates and catalyst improvements in the hetero cross-coupling of aryl halides and tin amides. Journal of the American Chemical Society 1994, 116, 5969-5970. Paul, F.; Patt, J.; Hartwig, J. F.: Structural Characterization and Simple Synthesis of {Pd[P(o-Tol)3]2}. Spectroscopic Study and Structural Characterization of the Dimeric Palladium(II) Complexes Obtained by Oxidative Addition of Aryl Bromides and Their Reactivity with Amines. Organometallics 1995, 14, 3030-3039.

Stambuli, J. P.; Bühl, M.; Hartwig, J. F.: Synthesis, Characterization, and Reactivity of Monomeric, Arylpalladium Halide Complexes with a Hindered Phosphine as the Only Dative Ligand. Journal of the American Chemical Society 2002, 124, 9346-9347. Shen, Q.; Ogata, T.; Hartwig, J. F.: Highly Reactive, General and Long-Lived Catalysts for Palladium-Catalyzed Amination of Heteroaryl and Aryl Chlorides, Bromides, and Iodides: Scope and Structure–Activity Relationships. Journal of the American Chemical Society 2008, 130, 6586-6596. Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F.: Effect of Ligand Steric Properties and Halide Identity on the Mechanism for Oxidative Addition of Haloarenes to Trialkylphosphine Pd(0) Complexes. Journal of the American Chemical Society 2009, 131, 8141-8154. Wen-jing Sun, W. C., Liang-jun Yu, Cheng-fa Jiang: Ligand Size Effect on PdLn Oxidative Addition with Aryl Bromide: A DFT Study. Huaxue wuli xuebao 2010, 23, 175-179. Carrow, B. P.; Hartwig, J. F.: Distinguishing Between Pathways for Transmetalation in Suzuki−Miyaura Reactions. Journal of the American Chemical Society 2011, 133, 2116-2119. Ligands – Pt-Bu3 Littke, A. F.; Fu, G. C.: A Convenient and General Method for Pd-Catalyzed Suzuki Cross-Couplings of Aryl Chlorides and Arylboronic Acids. Angewandte Chemie International Edition 1998, 37, 3387-3388. Littke, A. F.; Fu, G. C.: Heck Reactions in the Presence of P(t-Bu)3:  Expanded Scope and Milder Reaction Conditions for the Coupling of Aryl Chlorides. The Journal of Organic Chemistry 1998, 64, 10-11. Littke, A. F.; Fu, G. C.: The First General Method for Stille Cross-Couplings of Aryl Chlorides. Angewandte Chemie International Edition 1999, 38, 2411-2413. Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C.: Pd(PhCN)2Cl2/P(t-Bu)3:  A Versatile Catalyst for Sonogashira Reactions of Aryl Bromides at Room Temperature. Organic Letters 2000, 2, 1729-1731. Littke, A. F.; Dai, C.; Fu, G. C.: Versatile Catalysts for the Suzuki Cross-Coupling of Arylboronic Acids with Aryl and Vinyl Halides and Triflates under Mild Conditions. Journal of the American Chemical Society 2000, 122, 4020-4028. Dai, C.; Fu, G. C.: The First General Method for Palladium-Catalyzed Negishi Cross-Coupling of Aryl and Vinyl Chlorides:  Use of Commercially Available Pd(P(t-Bu)3)2 as a Catalyst. Journal of the American Chemical Society 2001, 123, 2719-2724. Littke, A. F.; Fu, G. C.: A Versatile Catalyst for Heck Reactions of Aryl Chlorides and Aryl Bromides under Mild Conditions. Journal of the American Chemical Society 2001, 123, 6989-7000. Netherton, M. R.; Fu, G. C.: Air-Stable Trialkylphosphonium Salts:  Simple, Practical, and Versatile Replacements for Air-Sensitive Trialkylphosphines. Applications in Stoichiometric and Catalytic Processes. Organic Letters 2001, 3, 4295-4298. Galardon, E.; Ramdeehul, S.; Brown, J. M.; Cowley, A.; Hii, K. K.; Jutand, A.: Profound Steric Control of Reactivity in Aryl Halide Addition to Bisphosphane Palladium(0) Complexes. Angewandte Chemie International Edition 2002, 41, 1760-1763. Littke, A. F.; Schwarz, L.; Fu, G. C.: Pd/P(t-Bu)3:  A Mild and General Catalyst for Stille Reactions of Aryl Chlorides and Aryl Bromides. Journal of the American Chemical Society 2002, 124, 6343-6348. Stambuli, J. P.; Kuwano, R.; Hartwig, J. F.: Unparalleled Rates for the Activation of Aryl Chlorides and Bromides: Coupling with Amines and Boronic Acids in Minutes at Room Temperature. Angewandte Chemie International Edition 2002, 41, 4746-4748. Ligands – AsPh3 Farina, V.; Krishnan, B.: Large rate accelerations in the stille reaction with tri-2-furylphosphine and triphenylarsine as palladium ligands: mechanistic and synthetic implications. Journal of the American Chemical Society 1991, 113, 9585-9595.

Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P.: Palladium-catalyzed coupling of arylstannanes with organic sulfonates: a comprehensive study. The Journal of Organic Chemistry 1993, 58, 5434-5444. Amatore, C.; Bahsoun, A. A.; Jutand, A.; Meyer, G.; Ndedi, N.; Ricard, L.: Mechanism of the Stille Reaction Catalyzed by Palladium Ligated to Arsine Ligand:  PhPdI(AsPh3)(DMF) Is the Species Reacting with Vinylstannane in DMF. Journal of the American Chemical Society 2003, 125, 4212-4222. Ligands – Dialkyl Biarylphosphines Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L.: A Highly Active Suzuki Catalyst for the Synthesis of Sterically Hindered Biaryls:  Novel Ligand Coordination. Journal of the American Chemical Society 2002, 124, 1162-1163. Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.: A Rationally Designed Universal Catalyst for Suzuki–Miyaura Coupling Processes. Angewandte Chemie International Edition 2004, 43, 1871-1876. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.: Catalysts for Suzuki−Miyaura Coupling Processes:  Scope and Studies of the Effect of Ligand Structure. Journal of the American Chemical Society 2005, 127, 4685-4696. 3-Coordinate Oxidative Addition Products Stambuli, J. P.; Incarvito, C. D.; Bühl, M.; Hartwig, J. F.: Synthesis, Structure, Theoretical Studies, and Ligand Exchange Reactions of Monomeric, T-Shaped Arylpalladium(II) Halide Complexes with an Additional, Weak Agostic Interaction. Journal of the American Chemical Society 2004, 126, 1184-1194. Yamashita, M.; Hartwig, J. F.: Synthesis, Structure, and Reductive Elimination Chemistry of Three-Coordinate Arylpalladium Amido Complexes. Journal of the American Chemical Society 2004, 126, 5344-5345. Methods: Reduction of Pd(II) Catalyst Precursors Amatore, C.; Jutand, A.; M'Barki, M. A.: Evidence of the formation of zerovalent palladium from Pd(OAc)2 and triphenylphosphine. Organometallics 1992, 11, 3009-3013. Amatore, C.; Carre, E.; Jutand, A.; M'Barki, M. A.: Rates and Mechanism of the Formation of Zerovalent Palladium Complexes from Mixtures of Pd(OAc)2 and Tertiary Phosphines and Their Reactivity in Oxidative Additions. Organometallics 1995, 14, 1818-1826. Amatore, C.; Carre, E.; Jutand, A.; M'Barki, M. A.; Meyer, G.: Evidence for the Ligation of Palladium(0) Complexes by Acetate Ions: Consequences on the Mechanism of Their Oxidative Addition with Phenyl Iodide and PhPd(OAc)(PPh3)2 as Intermediate in the Heck Reaction. Organometallics 1995, 14, 5605-5614. Amatore, C.; Jutand, A.: Anionic Pd(0) and Pd(II) Intermediates in Palladium-Catalyzed Heck and Cross-Coupling Reactions. Accounts of Chemical Research 2000, 33, 314-321. Bedford, R. B.; Cazin, C. S. J.: Highly active catalysts for the Suzuki coupling of aryl chlorides. Chemical Communications 2001, 1540-1541. Viciu, M. S.; Germaneau, R. F.; Navarro-Fernandez, O.; Stevens, E. D.; Nolan, S. P.: Activation and Reactivity of (NHC)Pd(allyl)Cl (NHC = N-Heterocyclic Carbene) Complexes in Cross-Coupling Reactions. Organometallics 2002, 21, 5470-5472. Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Horton, P. N.; Hursthouse, M. B.; Light, M. E.: High-Activity Catalysts for Suzuki Coupling and Amination Reactions with Deactivated Aryl Chloride Substrates:  Importance of the Palladium Source. Organometallics 2003, 22, 987-999. Bedford, R. B.; Hazelwood, S. L.; Horton, P. N.; Hursthouse, M. B.: Orthopalladated phosphinite complexes as high-activity catalysts for the Suzuki reaction. Dalton Transactions 2003, 4164-4174.

Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L.: Expanding Pd-Catalyzed C−N Bond-Forming Processes:  The First Amidation of Aryl Sulfonates, Aqueous Amination, and Complementarity with Cu-Catalyzed Reactions. Journal of the American Chemical Society 2003, 125, 6653-6655. Navarro, O.; Kelly, R. A.; Nolan, S. P.: A General Method for the Suzuki−Miyaura Cross-Coupling of Sterically Hindered Aryl Chlorides:  Synthesis of Di- and Tri-ortho-substituted Biaryls in 2-Propanol at Room Temperature. Journal of the American Chemical Society 2003, 125, 16194-16195. Viciu, M. S.; Kelly, R. A.; Stevens, E. D.; Naud, F.; Studer, M.; Nolan, S. P.: Synthesis, Characterization, and Catalytic Activity of N-Heterocyclic Carbene (NHC) Palladacycle Complexes. Organic Letters 2003, 5, 1479-1482. Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F.: Sterically Demanding, Bioxazoline-Derived N-Heterocyclic Carbene Ligands with Restricted Flexibility for Catalysis. Journal of the American Chemical Society 2004, 126, 15195-15201. Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P.: Modified (NHC)Pd(allyl)Cl (NHC = N-Heterocyclic Carbene) Complexes for Room-Temperature Suzuki−Miyaura and Buchwald−Hartwig Reactions. Journal of the American Chemical Society 2006, 128, 4101-4111. Biscoe, M. R.; Fors, B. P.; Buchwald, S. L.: A New Class of Easily Activated Palladium Precatalysts for Facile C−N Cross-Coupling Reactions and the Low Temperature Oxidative Addition of Aryl Chlorides. Journal of the American Chemical Society 2008, 130, 6686-6687. Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L.: Water-Mediated Catalyst Preactivation: An Efficient Protocol for C−N Cross-Coupling Reactions. Organic Letters 2008, 10, 3505-3508. Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L.: A Highly Active Catalyst for Pd-Catalyzed Amination Reactions: Cross-Coupling Reactions Using Aryl Mesylates and the Highly Selective Monoarylation of Primary Amines Using Aryl Chlorides. Journal of the American Chemical Society 2008, 130, 13552-13554. Norton, D. M.; Mitchell, E. A.; Botros, N. R.; Jessop, P. G.; Baird, M. C.: A Superior Precursor for Palladium(0)-Based Cross-Coupling and Other Catalytic Reactions. The Journal of Organic Chemistry 2009, 74, 6674-6680. Kinzel, T.; Zhang, Y.; Buchwald, S. L.: A New Palladium Precatalyst Allows for the Fast Suzuki−Miyaura Coupling Reactions of Unstable Polyfluorophenyl and 2-Heteroaryl Boronic Acids. Journal of the American Chemical Society 2010, 132, 14073-14075. Li, H.; Grasa, G. A.; Colacot, T. J.: A Highly Efficient, Practical, and General Route for the Synthesis of (R3P)2Pd(0): Structural Evidence on the Reduction Mechanism of Pd(II) to Pd(0). Organic Letters 2010, 12, 3332-3335. Methods: Precatalysts employing innocent ligands (including dba) Amatore, C.; Jutand, A.; Khalil, F.; M'Barki, M. A.; Mottier, L.: Rates and mechanisms of oxidative addition to zerovalent palladium complexes generated in situ from mixtures of Pd0(dba)2 and triphenylphosphine. Organometallics 1993, 12, 3168-3178. Andreu, M. G.; Zapf, A.; Beller, M.: Molecularly defined palladium() monophosphine complexes as catalysts for efficient cross-coupling of aryl chlorides and phenylboronic acid. Chemical Communications 2000, 2475-2476. Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F.: Scope and Mechanism of Palladium-Catalyzed Amination of Five-Membered Heterocyclic Halides. The Journal of Organic Chemistry 2003, 68, 2861-2873.

Hydrogenation Iridium Crabtree, R. H.; Felkin, H.; Morris, G. E.: Cationic iridium diolefin complexes as alkene hydrogenation catalysts and the isolation of some related hydrido complexes. Journal of Organometallic Chemistry 1977, 141, 205-215.

Chodosh, D. F.; Crabtree, R. H.; Felkin, H.; Morris, G. E.: A tri-coordinate hydrogen ligand in a trinuclear iridium cluster. Journal of Organometallic Chemistry 1978, 161, C67-C70. Crabtree, R.: Iridium compounds in catalysis. Accounts of Chemical Research 1979, 12, 331-337. Crabtree, R. H.; Davis, M. W.: Directing effects in homogeneous hydrogenation with [Ir(cod)(PCy3)(py)]PF6. The Journal of Organic Chemistry 1986, 51, 2655-2661. Drago, D.; Pregosin, P. S.; Pfaltz, A.: Selective anion effects in chiral complexes of iridium via diffusion and HOESY data: relevance to catalysis. Chemical Communications 2002, 286-287. Martínez-Viviente, E.; Pregosin, P. S.: 1H and 19F PGSE Diffusion Studies on Iridium PHOX Complexes:  Counterion and Solvent Dependences. Inorganic Chemistry 2003, 42, 2209-2214. Smidt, S. P.; Zimmermann, N.; Studer, M.; Pfaltz, A.: Enantioselective Hydrogenation of Alkenes with Iridium–PHOX Catalysts: A Kinetic Study of Anion Effects. Chemistry – A European Journal 2004, 10, 4685-4693. Vazquez-Serrano, L. D.; Owens, B. T.; Buriak, J. M.: The search for new hydrogenation catalyst motifs based on N-heterocyclic carbene ligands. Inorganica Chimica Acta 2006, 359, 2786-2797. Roseblade, S. J.; Pfaltz, A.: Iridium-Catalyzed Asymmetric Hydrogenation of Olefins. Accounts of Chemical Research 2007, 40, 1402-1411. Wüstenberg, B.; Pfaltz, A.: Homogeneous Hydrogenation of Tri- and Tetrasubstituted Olefins: Comparison of Iridium-Phospinooxazoline [Ir-PHOX] Complexes and Crabtree Catalysts with Hexafluorophosphate (PF6) and Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BArF) as Counterions. Advanced Synthesis & Catalysis 2008, 350, 174-178. Mantilli, L.; Mazet, C.: Iridium-catalyzed isomerization of primary allylic alcohols under mild reaction conditions. Tetrahedron Letters 2009, 50, 4141-4144. Suzuki, T.: Organic Synthesis Involving Iridium-Catalyzed Oxidation. Chemical Reviews 2011, 111, 1825-1845. Rhodium Halpern, J.; Okamoto, T.; Zakhariev, A.: Mechanism of the chlorotris(triphenylphosphine) rhodium(I)-catalyzed hydrogenation of alkenes. The reaction of chlorodihydridotris(triphenyl-phosphine)rhodium(III) with cyclohexene. Journal of Molecular Catalysis 1977, 2, 65-68. Drexler, H.-J.; Baumann, W.; Spannenberg, A.; Fischer, C.; Heller, D.: Part III. COD versus NBD precatalysts. Dramatic difference in the asymmetric hydrogenation of prochiral olefins with five-membered diphosphine Rh-hydrogenation catalysts. Journal of Organometallic Chemistry 2001, 621, 89-102.

Iridium Catalyzed Allylic Substitution Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F.: Identification of an Activated Catalyst in the Iridium-Catalyzed Allylic Amination and Etherification. Increased Rates, Scope, and Selectivity. Journal of the American Chemical Society 2003, 125, 14272-14273. Lipowsky, G.; Miller, N.; Helmchen, G.: Regio- and Enantioselective Iridium-Catalyzed Allylic Alkylation with In Situ Activated P,C-Chelate Complexes. Angewandte Chemie International Edition 2004, 43, 4595-4597. Polet, D.; Alexakis, A.: Kinetic Study of Various Phosphoramidite Ligands in the Iridium-Catalyzed Allylic Substitution. Organic Letters 2005, 7, 1621-1624. Marković, D.; Hartwig, J. F.: Resting State and Kinetic Studies on the Asymmetric Allylic Substitutions Catalyzed by Iridium−Phosphoramidite Complexes. Journal of the American Chemical Society 2007, 129, 11680-11681. Hartwig, J. F.; Stanley, L. M.: Mechanistically Driven Development of Iridium Catalysts for Asymmetric Allylic Substitution. Accounts of Chemical Research 2010, 43, 1461-1475.

Raskatov, J. A.; Spiess, S.; Gnamm, C.; Brödner, K.; Rominger, F.; Helmchen, G.: Ir-Catalysed Asymmetric Allylic Substitutions with Cyclometalated (Phosphoramidite)Ir Complexes—Resting States, Catalytically Active (π-Allyl)Ir Complexes and Computational Exploration. Chemistry – A European Journal 2010, 16, 6601-6615.