Transmetalation from Tin toPalladium in the Stille Reaction

Peter J. YaoGroup Meeting

24 Jan 06

Classical Mechanism

Transmetalation

Mechanism of transmetalation is not as well known as oxidativeaddition and reductive elimination

Several important questions:- When is transmetalation rate-limiting?- Inversion or retention at α-carbon?- Which is displaced, X or L?- Associative or dissociative?

Echavarren, A. M. ACIEE 2004, 43, 4704-4734.

Early Mechanistic Studies

Coupling of organostannanes with acid chlorides

Stille, J. K. JACS 1983, 105, 6129-6137.

Hammett study, 5 mol% [Pd] in HMPA

ρ correlates with σ better than σ'

Positive ρ suggests C-Sn breakingprecedes C-Pd making in TS

RSnR'3Cl

OPhCH2(PPh3)2PdCl

+ R

O

SnR'3Cl+

R = X

Early Mechanistic Studies

Inversion at α-carbon

Starting from (S)-(+)-Benzyl-α-d alcohol, er 92/8 er 64/36

Taking racemization and deuterium isotope effect into account, estimated 65%stereospecificity – inversion

Postulated an open transition state SE2 electrophilic cleavage Prior dissociation of L?

SnBu3

H D

ClL2Pd

O

+HMPA, 65 °C

O

D H

Early Mechanistic Studies

Inversion at α-carbon

Starting from (S)-(+)-Benzyl-α-d alcohol, er 92/8 er 64/36

Retention at α-carbon

Falck, J. R. JACS 1994, 116, 1-5.

SnBu3

H D

ClL2Pd

O

+HMPA, 65 °C

O

D H

H3C(CH2)6 SnBu3

BzO H

Cl

O

+

Pd(PPh3)2Cl2CuCN

toluene75 °C, 18 h

H3C(CH2)6

BzO H

O

74% yield, 98% retention

Ligand Effects

Farina studied the effect of ligands on coupling of vinyltributylstannanewith various electrophiles

Good σ-donors are poor at promoting couplingExcess ligand inhibits the reaction

I SnBu3

Pd2dba3, L, THF50 °C

L

PPh3(2-MeC6H4)3PAsPh3(2-furyl)3P

rel. rate

1.035.21100105

yield (72 h)

15.219>95>95

Pd:L ratio = 1:4

PPh3(2-MeC6H4)3PAsPh3(2-furyl)3P

191193911480

15.225>95>95

Pd:L ratio = 1:2

Ligand Effects – Dissociative Mechanism

Farina suggested that ligand dissociation is key for transmetalation

(The 14-electron T-shaped complex is not explicitly shown in the text)

Solvent coordination is often shown rather than an empty coordination site.

Pd

L

L

I Pd

L

I Pd

L

I

SnBu3-L

SnBu3

+L

More Evidence for Dissociative Mechanism

Hartwig studied transmetalationto a dimeric complex

Hartwig, J. F. JACS 1995, 117, 11598-11599.

Assuming pre-equilibrium, then: rate = Kk2[dimer]1/2[PhSnMe3]

Integrated form: [dimer]1/2 = -kobs t

LPd

Ar

Br

BrPd

Ar

L

L = P(o-tol)3Ar = p-tol

L

Pd

Ar

Br

Br

Pd

Ar

L

L

Pd

Ar

BrK

k2

PhSnMe3

ArPh2

Transmetalation Kinetics

The data fits nicely… does that mean a 14-e T-shaped complex exists insolution? Espinet suggests an agostic interaction with a C-H bond in theo-methyl on P(o-tolyl)3.Is the pre-equilibrium model accurate?

Another Proposal

Espinet questioned the feasibility of a dissociative mechanism

Using K = k1/k-1 = 8.6 × 10-4 M (R = Ph, L = AsPh3) and [Pd]total = 3.2 × 10-3 M, hecalculated that [PdPhI(AsPh3)] = 1.3 × 10-3 M i.e. 40% dissociation.

He also argued against X-for-R' substitution in the classical mechanism because itnecessitates a fast trans-cis isomerization.

R Pd I

L

L

k1

k-1

R Pd I

[S]

L

SnBu3

k2R Pd

[S]

L

LR Pd

L

L

Another Proposal

Espinet's initial proposal Espinet, P. JACS 1998, 120, 8978-8985.

Rate Expressions

Associative

Steady-state assumption:

Pre-equilibrium assumption:

Pd + Sn

k1

k-1

C + L

C

k2

P

[ ]0=

dt

Cd

[ ][ ][ ]SnPd

kLk

kkrate

21

21

+=

!

[ ][ ][ ][ ]SnPd

LC

k

kK ==

!1

1

[ ][ ][ ] [ ]SnKL

SnPdKkrate

t

+= 2

Pd = RPdL2XSn = vinylSnBu3C = cyclic intermediateP = RPdL(vinyl)

Rate Expressions

Dissociative

Steady-state assumption:

Pre-equilibrium assumption:

[ ]0=

dt

Cd

k1

k-1

C + L

C + Sn

k2

P

Pd Pd = RPdL2XSn = vinylSnBu3C = RPdLXP = RPdL(vinyl)

[ ] [ ][ ][ ]SnPd

SnkLk

kkrate

21

21

+=

!

[ ][ ][ ] KL

SnPdKkrate

t

+= 2

[ ][ ][ ]Pd

LC

k

kK ==

!1

1

Kinetic Studies

Coupling monitored by 19F-NMR

Retardation by adding free ligand (for coupling with (vinyl)SnBu3)

Kinetic Studies

(a) Catalyst activity, showinga first order dependenceon [catalyst]

(b) Without addition of AsPh3

Eyring plots of ln(kobs/T) vs. 1/T give ΔH‡ and ΔS‡

negative ΔS‡ consistentwith associative rate-controlling step

Dissociative vs. Associative

Experimentally, the form of the rate equation is

DissociativeConsider both steady-state and pre-equilibrium models

- Steady-state

For small values of [L], rate ~ k' [Pd] i.e. zero-order in [Sn]

- Pre-equilibrium

This equation fits the empirical rate equation. However it gives a value ofKdissociation = 0.013 mM, 12% of [Pd]total which should be observable by NMR.

[ ] [ ][ ][ ]SnPd

SnkLk

kkrate

21

21

+=

!

[ ][ ][ ] KL

SnPdKkrate

t

+= 2

[ ][ ][ ]SnPdbL

arate

+=

Dissociative vs. Associative

Experimentally, the form of the rate equation is

AssociativeThe steady-state model has the correct form of the rate equation.

k1 = 0.034 M-1 s-1 k2/k-1 = 0.069 mM

However, this does not tell us about the structure of intermediate C.For example C can be a π-complex of the vinyl portion with Pd.

[ ][ ][ ]SnPdbL

arate

+=

[ ][ ][ ]SnPd

kLk

kkrate

21

21

+=

!

Geometry and Coordination at Palladium

Amatore claimed in a study on oxidative addition to have evidence of a14-e T-shaped Pd complex, observable by 1H-NMR and CV.

Espinet investigated this claim further by looking at the equilibrium:

In chloroform and THF, only the dimer is observed.However in DMF the monomer is observed.

Which is the active species for transmetalation? Espinet suggested it is always[PdPhI(AsPh3)2].

Amatore, C. Chem. Eur. J. 2001, 7, 2134-2142.Espinet, P. Chem. Eur. J. 2002, 8, 4843-4853.

LPdXR

XPdL

R

S

LPdXR

[S]2 R = F

Cl F

Cl F

L = AsPh3

Modified Proposal (Espinet)

Reinvestigating the Mechanism in DMF

Amatore reinvestigated the reaction in DMF using a clever technique tomonitor the reaction rate.

First, the reaction of dimer with 2 eq. (vinyl)SnBu3 was monitored:

Data fits the equation:1/x = kapp t + 1

Consistent with 1:1 reaction betweenreagents in stoichiometric amounts

Amatore, C. JACS 2003, 125, 4212-4222.

Pd

AsPh3

AsPh3

I SnBu3+

DMF

Pd(AsPh3)2

SnBu3I SnBu3I+_

Concentration can bemonitored by conductivity

Ph3As

Pd

IPh

I

Pd

AsPh3

Ph

SnBu3+

DMF

Ph

Mechanism in DMF

The dimer or the DMF-coordinated monomer can be the active species.

If k2 > k1 (steady-state) then rate law has the same form as the 1:1 reaction.They cannot be distinguished by kinetics.Fortunately as shown by UV-vis, the dimer in DMF is quantitatively convertedto monomer.

Ph3As

Pd

IPh

I

Pd

AsPh3

PhSnBu3

k1

Ph3As

Pd

I

Ph

I

Pd

AsPh3

Ph

SnBu3

SnBu3

k2

Ph Pd I

AsPh3

SnBu3

2

Rate ExpressionsDimer does not participate, but DMFand AsPh3 can exchange to give twopossible reactive species.

[ ][ ][ ]

[ ][ ]LKL

kLk

Snkkrate

L+

!+

="

+

54

54

'

1'

[ ][ ][ ]

L

tL

KL

SnPdKkrate

+= 4

A (steady-state in 4)

B (pre-equilibrium)

Rate Expressions[AsPh3] was varied from 2-10 mM.

Data is consistent with B over wholerange of [AsPh3].

Note that rate A and rate B have thesame form for large [L]; at high ligandconcentrations they are not kineticallydistinguishable.

Modified Proposal (Amatore)

Coupling with Triflates - Even More Complex

Espinet used 19F-NMR to study coupling of fluoroaryl triflates withvinyltributylstannane, with and without addition of LiCl.

Espinet, P. JACS 2000, 122, 11771-11782.

Excess ligand or coordinating solvents can ionize triflate.

OTf

FF

F

F F

OTf

FCl

F

Cl F

It Gets Worse

The cationic species can undergo transmetalation as well.

Substitution: L-for-R or L'-for-R?

Iodide nucleophile:

What happens when the nucleophile is (vinyl)SnBu3?

Pd

FCl

F

Cl F

L

L

L' OTf

+

-

8:9 ca 1:5

Coupling with Cationic Species

SE2(open-cis) gives 12 which can undergo rapid reductive elimination.

SE2(open-trans) gives 10 which can undergo slow isomerizationand then reductive elimination.

Effect of LiCl

In some cases LiCl acceleratesthe reaction (1 vs. 2, 7 vs. 8),while in others it has a retardingeffect.

R-OTf R Pd

L

L

OTf R Pd

L

L

L OTf

+

-PdL4

+L LiCl

R Pd

L

L

Cl + LiOTf

Less electrophilic

Rate deceleration

Rate acceleration occurs when oxidative addition is rate-limiting, by generationof [PdCln(AsPh3)4-n]n-, a more nucleophilic species

Transmetalation - Cyclic vs. Open

SE2(cyclic) favored in nonpolar solvents with bridging groups present.

Stereochemistry: SE2(open) is invertive while SE2(cyclic) is retentive.

In polar coordinating solvents SE2(open) is favored.

This essentially completes Espinet's proposed mechanism.

Inversion from the SE2(open) TS in Stille'searly report

Another Intepretation

Lo Sterzo has used palladium to catalyze metal-carbon bond formation,forming metal acetylides (Fe, Ru, W, Mo) from trialkyltinacetylides.

Lo Sterzo, C. JACS 2002, 124, 1060-1071.

DFT Analysis

Farina isn't finished with the Stille reaction yet…

Tetraethynyltin and bromoethynyl Pd complex chosen to reduce number of rotamers insearch for transition states.

NH3 used as a nucleophile to coordinate to Sn and assist transmetalation.

No energy minima or transition states with five-coordinate Pd were found. Globalminimum energy TS is open with no Sn-Br interaction.

Napolitano, E.; Farina, V.; Persico, M. Organometallics 2003, 22, 4030-4037.

DFT Analysis

Another DFT Analysis

The cyclic associative transition state TSv-viii has the largest ΔG‡ of the cycle.

However the transmetalation is not concerted. First η2-coordination helpsdisplace a ligand. Then transmetalationand BrSnMe3 elimination.

Alvarez, R. OL 2006, 8, 35-38.

Conclusions

Espinet's proposed cycle with thekey associative transmetalation is animportant advance from the classicalmechanism.

There are still many importantissues that need to be resolved.

Pitifully, neglect of the coordination sphere ofthe metal is quite common in the literature ofmetal-catalyzed organic transformations. Wehope that this paper will serve to draw attentionon its mechanistic relevance in some cases.

Espinet in a footnote in his JACS 1998 paper.