Olefin Metathesis~Well-Defined Ru Catalysts~
3rd Literature Seminar
August 5, 2013
Soichi Ito (M2)1

~Topics~• Introduction• Evolution of Ruthenium Catalysts~from ill-defined catalysts to well-defined catalysts~
ill-defined Ruthenium catalysts
well-defined Ruthenium catalysts
First-Generation Grubbs Catalyst
Mechanistic Study(1997)
Second-Generation Grubbs Catalyst
Mechanistic Study(2001)2

Olefin Metathesis
A valuable Synthetic Tool for The Construction of Carbon-Carbon Bonds

3

“Olefin Metathesis”
by Calderon

4

Grubbs, R. H. et al., Acc. Chem. Res. 2001, 34, 18.

Yves ChauvinHe was born on October 10, 1930 in Menin.
He joined Institut Français du Pétrole in 1960.
Motto“If you want to find something new, look for something new!”• Dimersol Process (nickel-based catalyst): for gasoline
 Dimerization of propylene into isohexenes: additive in gasoline as octane numberbooster.
 One of the first examples of application of homogeneous catalysts in refining• Dimersol Process: for chemistry Dimerizing n-butenes to isooctenes
 Isooctenes are used as starting material for PVC plasticizer• Alphabutol process (titanium based catalyst)
 Dimerization of ethylene into 1-butene
 1-butene is used as comonomer for polyethylene manufacture• Difasol Process (improved Dimersol Process)5Non-Pair-Wise Mechanism

Chauvin,Y. et al. Makromol. Chem. 1971,6141, 161.
Chauvin,Y. Angew. Chem. Int. Ed. 2006, 45, 3740.

Consideration of the Mechanism of the Olefin
Metathesis Reaction

7

Grubbs, R. H. et al., J. Am. Chem. Soc. 1975, 97, 3265.

Pair-Wise Mechanism“Olefin Metathesis” was coined in this paper

WRONG TURNS
Unusual intermediates proposed initially haveSince been rejected

Calderon, N. et al. Tetrahedron Lett. 1967, 34, 3327

8Chauvin,Y. Angew. Chem. Int. Ed. 2006, 45, 3740.

Evidence for Chauvin’s Mechanism

2 :Chauvin,Y. et al. Makromol. Chem. 1971, 141, 161.

1:

1 (Statistical distribution )Chauvin,Y. Angew. Chem. Int. Ed. 2006, 45, 3740.

The first stable transition metal M=CHR species.
Schrock, R. R., J. Am. Chem. Soc. 1974, 96, 6796.

9Grubbs, R. H. et al., J. Am. Chem. Soc. 1975, 97, 3265. Grubbs, R. H. et al., Acc. Chem. Res. 2001, 34, 18.

~Topics~• Introduction• Evolution of Ruthenium Catalysts~from ill-defined catalysts to well-defined catalysts~
ill-defined Ruthenium catalysts
well-defined Ruthenium catalysts
First-Generation Grubbs Catalyst
Mechanistic Study(1997)
Second-Generation Grubbs Catalyst
Mechanistic Study(2001)
10

Ruthenium(Ⅲ) Salt for ROMPAt that time…
Oxophilic alkylidene ROMP catalyst

Heteroatoms

In an effort to further the development of the polymerization of heterocyclic monomers…

7-oxa-norbornene
derivative

Yield : 95%>
m.w. : 1 × 105

in dry organic solvents
RuCl3(hydrate) and OsCl3(hydrate) were successful.
Grubbs, R. H. et al., J. Am. Chem. Soc., 1988, 110, 960.

Lengthy initiation period (on the order of hours to days) limited their usefulness.
(Once initiated, the polymerization proceeded at a very high rate.)
Ⅱ was used as a monomer.
 Water dramatically decreased the initiation period. (yield was nearly quantitative)
22-24 h/organic solvents→30-35 min/aqeous solution
 The used aqueous Ru solution was recyclable and became more active.
37.5 min→10-12 s
11Grubbs, R. H. et al., J. Am. Chem. Soc. 1988, 110, 7452.

Ruthenium(Ⅱ) Complex for ROMP
first
recycled
Ru(H2O)6(tos)2 was far more active. (initiation time: 50-55 s→10-12 s)

 The active solution from Ru3+ salts (RuCl3, K2RuCl5) showed the identical olefin resonancesof adduct Ⅲ.
 Ru3+ does not form stable olefin complexes.
 Ru4+ (as Ru Red) and Ru2+ olefin complex are formed when Ⅱ was polymerized byRu(NH3)5(H2O)3+.
Proposed Mechanism
12

Grubbs, R. H. et al., J. Am. Chem. Soc. 1988, 110, 7452.

~Topics~• Introduction• Evolution of Ruthenium Catalysts~from ill-defined catalysts to well-defined catalysts~
ill-defined Ruthenium catalysts
well-defined Ruthenium catalysts
First-Generation Grubbs Catalyst
Mechanistic Study(1997)
Second-Generation Grubbs Catalyst
Mechanistic Study(2001)
13

ROMP by a Ruthenium Carbene Complex in Protic Media Complex 1 was stable under inert atmosphere and several minutes in air.
 1 was also stable for several days in C2Cl2/C6H6 in the presence ofFunctional-Groupwater, alcohol, or a diethyl ether solution of HCl.
Tolerance
 1 did not undergo Wittig-type reactions with either ketone or an aldehyde.
14Grubbs, R. H. et al., J. Am. Chem. Soc. 1992, 114, 3974.

ROMP by a Ruthenium Carbene Complex in Protic Media

low oxidation statelate transition metal
𝜋-accepter ligands
electrophilic

high oxidation state
early transition metal
nucleophilic＊酸化数はカルベンを4電子供与体と見なした場合“Typically, high oxidation state metallaolefins are called alkylidene complexes while lowoxidation state analogues are referred to as carbene complexes. The new complex described here
does not show all of the characteristics of either of these two classes of complexes.”
15

Grubbs, R. H. et al., J. Am. Chem. Soc. 1992, 114, 3974.

16

Chem. Rev. 2000, 100, 39

17Chem. Rev. 2000, 100, 39

New Catalysts with high metathesis activity
trans:cis=78:16 (2a)67:20 (2b)2a and 2b were moderately stable to air (≥1)

cone angle

the first metathesis of acyclic olefin with well-defined Ru carbene complexes
18

Grubbs, R. H. et al., J. Am. Chem. Soc. 1993, 115, 9858.

Application to RCM

 insensitivity to atmospheric oxygen and moisture functional-group tolerance

19

Grubbs, R. H. et al., J. Am. Chem. Soc. 1993, 115, 9856.

First-Generation Grubbs Catalyst

crystal structure of 8 3-6 decomposed in solution(3 and 4 faster than 5 and 6) in several hours.
 However, 3-6 were efficient catalysts of living ROMP.
(The initiation rate for 3 is about 1000 times greater than for 1).
 7 and 8 were air-stable.

20

Grubbs, R. H. et al., Angew. Chem. Int. Ed. 1995, 34, 2039.

Isolable Methylidene Complex
9 was the first isolable methylidene complex
which is an active metathesis catalyst.
thermodynamic product20 hquantitativekinetic products

21

Grubbs, R. H. et al., Angew. Chem. Int. Ed. 1995, 34, 2039.

~Topics~• Introduction• Evolution of Ruthenium Catalysts~from ill-defined catalysts to well-defined catalysts~
ill-defined Ruthenium catalysts
well-defined Ruthenium catalysts
First-Generation Grubbs Catalyst
Mechanistic Study(1997)
Second-Generation Grubbs Catalyst
Mechanistic Study(2001)
22

Ligand Effect on Activity
inactive

X=I＜Br＜Clactivity more electron withdrawing smaller

PR3=PPh3＜＜PiPr2Ph＜PCy2Ph＜PiPr3＜PCy3

activity more electron-donating larger
23

Grubbs, R. H. et al., J. Am. Chem. Soc. 1997, 119, 3887.

“Associative” vs “Dissociative”
18e
16e

18e

16e
16e

14e
16e

16e

16e
16e

24

Grubbs, R. H. et al., J. Am. Chem. Soc. 1997, 119, 3887.

Kinetics
addition of phosphine(0.25-1.0 equiv)

Kinetics did not exhibit first-order
behavior with respect to diene.

slower rate
pseudo first order

Dashed line: first order fit

25

Grubbs, R. H. et al., J. Am. Chem. Soc. 1997, 119, 3887.

Pseudo-First-Orderin the presence of additional PCy3
slope: (2.73 ± 0.01) × 10−5intercept:(5.27 ± 0.13) × 10−4

kobs = K0 + K1(1/[PCy3])

slope: 0.323 ± 0.005

intercept:(2.42 ± 0.72) × 10−4

kobs = K0’ + K1’([Ru]0)26

Grubbs, R. H. et al., J. Am. Chem. Soc. 1997, 119, 3887.

“Associative” vs “Dissociative”“associative”
pathway“dissociative”
pathway

A→ “dissociative” pathway
B→“associative” pathway
In the absence of excess phosphine,
A/[PCy3] ≫B (>90-95%, Figure 3)“dissociative” pathway ≫“associative” pathway

27

Grubbs, R. H. et al., J. Am. Chem. Soc. 1997, 119, 3887.

Low Concentration of Active Species

Catalyst Concentration●: 0.005 M◇: 0.010 M▲: 0.015 M□: 0.020 M

28

Grubbs, R. H. et al., J. Am. Chem. Soc. 1997, 119, 3887.

Stereochemistry of Intermediate

rotation29

Grubbs, R. H. et al., J. Am. Chem. Soc. 1997, 119, 3887.

Stereochemistry of Intermediateat the second step in RCM…
 Only cis coordination is possible. (small ring) trans coordination: strain energy

45°
degenerate metathesis reaction

Pathway 2 was more likely

30

Grubbs, R. H. et al., J. Am. Chem. Soc. 1997, 119, 3887.

Summary of First Mechanistic Studyrate determining step

16e

18e

14e

16e

“associative” pathway can be ignored

Effect of Halogens
 trans influence: Cl＜Br＜I
Ru-olefin bond strength: Cl＞Br＞I
K1: Cl＞Br＞I size: Cl＜Br＜I
steric repulsion(cis halogen): Cl＜Br＜I
K1: Cl＞Br＞I

Effect of Phosphines cone angle:
dissociation of phosphine:
K2:
K1:
K1K2:
 electron donating ability:trans influence:stabilization of I2 andmetallacyclobutane intermediate:

Halogen: smaller and more electron withdrawing
Phosphine: larger and more electron donating

31

Grubbs, R. H. et al., J. Am. Chem. Soc. 1997, 119, 3887.

~Topics~• Introduction• Evolution of Ruthenium Catalysts~from ill-defined catalysts to well-defined catalysts~
ill-defined Ruthenium catalysts
well-defined Ruthenium catalysts
First-Generation Grubbs Catalyst
Mechanistic Study(1997)
Second-Generation Grubbs Catalyst
Mechanistic Study(2001)32

Herrmann533Herrmann, W. A. et al., Angew. Chem. Int. Ed. 1998, 37, 2490.

Nolananaerobic solution calorimetry showed

Ru-L stability (−∆𝐻(kcal/mol):
IMes (15.6) > PCy3 (10.5)

2
RCM test
RCM activity: 3>2≅1
thermal stability (60℃): 2≫3>1
34Nolan, S. P. et al., J. Am. Chem. Soc. 1999, 121, 2674.

Grubbs

The complex 3 is less reactive thanthe parent 2 at rt for RCM.

35

Grubbs, R. H. et al., Tetrahedron Lett. 1999, 40, 2247.

Second-Generation Grubbs Catalyst

air- and water- tolerant

12

E=CO2Et, aE:Z=1.6:1, bE:Z=2.0:1
36
Grubbs, R. H. et al., Org. Lett. 1999, 1, 953.

First-Generation Hoveyda-Grubbs Catalyst

inactive17
 Excellent stability to air and moisture High recyclability

Kinetic Study
Complex 8 shows ca. 30 times slower initiation(less facile dissociation of the smaller ligand) 4 times faster propagation(without rate-retarding excess phosphine)

37

Hoveyda, A. H. et al., J. Am. Chem. Soc. 1999, 121, 791.

First-Generation Hoveyda-Grubbs Catalyst

38

Hoveyda, A. H. et al., J. Am. Chem. Soc. 1999, 121, 791.

Second-Generation Hoveyda-Grubbs Catalyst

Hoveyda, A. H. et al., J. Am. Chem. Soc. 2000, 122, 8168.
Publication Date: August 12, 2000

Received: September 8, 2000
39Blechert, S. et al., Tetrahedron. Lett. 2000, 41, 9973.

Second-Generation Hoveyda-Grubbs Catalyst

Complex 5 showed similar reactivity withComplex 3(high reactivity) in RCM.
Hoveyda, A. H. et al., J. Am. Chem. Soc. 2000, 122, 8168.

15% with Complex 13

5
5 seems to be a promising catalyst
especially for CM.
4041, 9973.
Blechert, S. et al., Tetrahedron. Lett. 2000,

~Topics~• Introduction• Evolution of Ruthenium Catalysts~from ill-defined catalysts to well-defined catalysts~
ill-defined Ruthenium catalysts
well-defined Ruthenium catalysts
First-Generation Grubbs Catalyst
Mechanistic Study(1997)
Second-Generation Grubbs Catalyst
Mechanistic Study(2001)
41

14-Electron, Mono-Phosphine Intermediate
The rate of decomposition slowed significantlyin the presence of excess phosphine.

Grubbs, R. H. et al., J. Org. Chem. 1999, 64, 7202.

Simulations (Car-Parrinello dynamics simulations) reveal and lend support to the mechanism
proposed by Grubbs.
Their results showed that mono-phosphine complex was the active species.
42

Francesco Buda et al. J. Am. Chem. Soc. 1998, 120, 7174.

14-Electron, Mono-Phosphine Intermediate

Structure of 3

rotation of carbene moiety

was generated?

support43

Grubbs, R. H. et al., Angew. Chem. Int. Ed. 2000, 39, 3451.

Phosphine Exchange“associative” pathway
18e“dissociative” pathway
14eModel Study for the Phosphine/Olefin Substitution

exchange rate constants (kB) at 80℃(per coordinated phosphine ligand)9.6±0.2 s-1 ＞ 0.13±0.01 s-1 !!

44Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 749.

Eyring Plot kB is independent of [PCy3] ∆H‡ and ∆𝑆‡ are large and positive“dissociative” pathway• Eyring plot‡𝑙𝑛𝑘𝑘B ∆𝐻∆𝑆= 𝑙𝑛κ −+𝑇ℎ𝑅𝑇𝑅‡‡‡𝑘B ∆𝐻
∆𝑆= 𝑙𝑛 −+ℎ𝑅𝑇𝑅(∵κ ≅ 1)

A certain chemical reaction is performed at different
temperatures and the reaction rate is determined.
The plot of ln(k/T) versus 1/T gives a straight linewith slope -∆H‡/ R from which the enthalpy ofactivation can be derived andwith intercept ln(kB/h) + ∆S‡/ R from which theentropy of activation is derived.

*Here, kB is Boltzmann's constant

wikipedia
45

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 749.

Model for the Initial Eventkobs is dependent on
olefin concentration

kobs is independent ofolefin concentration.
kobs= (4.6±0.3)×10-4 s-1

46

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 749.

Complex 2even at low olefin concentration…

Observed Rate Constantsfor Phosphine Exchange

predicted kB at 35℃(4±3)×10-4 s-1 ≅ kobs (4.6±0.3)×10-4 s-1

Rate-determining step of the reaction is phosphine dissociation.
47

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 749.

Complex 1
at much higher olefin concentration…
1
Observed Rate Constantsfor Phosphine Exchange

predicted kB at 20℃
0.016±0.002 s-1 ≅ kobs 0.018±0.001 s-1
48

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 749.

Suggested Mechanism[Ru][Ru]≫[(4)]Steady-state approximation: k2 ≫k-2, [(4)] is constant, kobs[Ru]=k2[(4)][Olefin]

k1[Ru]=k2[(4)][Olefin]+k-1[(4)][PCy3]=[(4)](k2[Olefin]+k-1[PCy3])
𝑘1[Ru]
𝑘 −1[PCy3]∴=1+𝑘2[(4)][Olefin]
𝑘2[Olefin]
𝑘2 4 [Olefin]𝑘1
kobs== 𝑘−1 [PCy3][Ru]+1
𝑘2[Olefin]

k1 and k-1/k2 can be obtained fromkobs and [PCy3]/[Olefin].
49

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 749.

1/kobs versus [PCy3]/[Olefin]50

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 749.

What This Mechanistic Study IndicatedOlefin Metathesis Activity
Catalyst 2≫Catalyst 1
Catalyst 1: Relatively rapid initiation; Relatively few turnovers of 14-electron intermediate
Catalyst 2: Relatively slow initiation; Relatively many turnovers of 14-electron intermediate
Summary

14e

Dissociative pathway
14-electron intermediate

rate-determining step
The high activity of N-heterocyclic carbene-coordinated catalyst 2 is due to...
 Its improved selectivity for binding π-acidic olefinic substrates in the presence of phospnine→decreasing k-1/k2
 Not its ability to promote phosphine dissociation (increasing k1, previous assumption)
51

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 749.

Phospnine Exchange

52

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 6543.

Initiation Kinetics (Reaction with Ethyl Vinyl Ether)at low [ethyl vinyl ether],
1,2,3,5 and 7 showedkB∝[ethyl vinyl ether] (approximately)

saturation

53

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 6543.

1/kobs=k-1[PR3]k1k2[Olefin]+1/k1

mistake?

(3.1 x 10-3)(3.2 x 10-3)(50℃: 4.2 x 10-1)

54

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 6543.

Solvent Effects on Initiation

 kInt ∝ dielectric constant Increased stabilization of the 4-coordinate B intermediate and/or free PCy3?
(Both are expected to be more polar than the Ru starting material.) The stabilization of B may involve coordination of solvent to the electron-deficient Ru(Ⅱ)
center. (THF, diethyl ether, however no evidence)
55Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 6543.

Relative Catalyst Activities

COD: serve as a benchmark for comparing the relative activities
Initiation (k1): 8<9<10 (10 initiates almost quantitatively)
Propagation (k-1/k2): 8>9>10
Comparison of 8 and11 showed that
11 initiates more than 50 times faster than 8. (8 and 11 generate the same propagating species)→The loading of catalyst can be reduced significantly.
13 reacts especially slowly because of the slow rate of phosphine dissociation.
(13 is a crucial intermediate during RCM and CM…)

56

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 6543.

Mechanism of Ru-Catalyzed Olefin Metathesis

 Bis-phosphine system (1-7): k1 is large, but k-1/k2≫1 (few catalytic turnover) NHC-complex (8-14): k1 is small, but k-1/k2~1 (many catalytic turnover)57

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 6543.

Ligand Effects• L-Type Ligand
 Selectivity for binding 𝜋-acidic olefinic substrates over 𝜎-donating phosphine (k2/k-1)

NHC-substituted Ru center ≫ phosphine-substituted Ru center As a electron donor ligand
NHC(IMesH2 > IMes) ≫ P(alkyl)3
 Electron donation of NHC’s is expected to…
stabilize the olefin complex C
accelerate the oxidative addition for matallacyclobutane formation• Phosphine Ligand

pKa’s of the conjugate acids
PCy3: 9.7
PPh3: 2.73
→the lower basicity, the higher k1((12)PBn3: 6.0, k1(rel)=~102)???
58

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 6543.

Phosphine Ligand

Hammett constant

the more electron-poor,
the faster dissociation59

Grubbs, R. H. et al., J. Am. Chem. Soc. 2003, 125, 10103.

Ligand Effects• Halide Ligand
 Cl→I: 250-fold increase in initiation (1→3, 8→10)
 This would be due to the increase in steric bulk.
Ionic radii: Cl- 167pm, I- 206pm, Covalent radii: Cl- 99pm, I- 133pm
the larger size of I- →steric crowding→promotion of PR3 dissociation
 Electronics may play a role, but cis electronic effect on dissociative ligand substitution isgenerally relatively small.
 Cl→I: 100-fold increase in k-1/k2 (poorly understood) Olefin metathesis activities: Cl→I, comparable or even lower• Carbene Ligand
 k1: H (4)<CHCHC(Me)2 (6) <Ph (1) <CH2CH3 (5) sterically bulky and electron-donating→effective promotion of phosphine dissociation

 Complex 4 and especially 13 are extremely poor initiators.
 Phosphine-free 13 is an active olefin metathesis catalyst.
→The formation of these complex should be avoided.(substrate design)60

Grubbs, R. H. et al., J. Am. Chem. Soc. 2001, 123, 6543.

Improved Catalysts Rush

Activity in RCM>2nd generationGrubbs catalyst

Activity in RCM>complex Abulky
A

Blechert, S. et al., Angew. Chem. Int. Ed. 2002, 41, 794.

kint (at 5℃)[× 10−3 s−1 ]4000(2nd generation Grubbs cat.
0.0032)

Blechert, S. et al., Angew. Chem. Int. Ed. 2002, 41, 2403.

Activity in RCM>2nd generation
Hoveyda-Grubbs
catalyst
61

Grubbs, R. H. et al., Angew. Chem. Int. Ed. 2002, 41, 4035.

Grela, K. et al., Angew. Chem. Int. Ed. 2002, 41, 4038.