1. Gold-Catalyzed Reactions: A Treasure Trove of Reactivity
By: Nathalie Goulet
March 9, 2006

2. Overview Introduction Reactivity of gold with alkynes
Activation of allenes
- C-H bond activation
Enantioselectivity
Synthesis
Carene terpenoids
Jungianol
- Conclusions

3. Gold Preconceived notion that gold is expensive Complex Price for 1 g
$/mol
AuCl
197$
45 786
AuCl3
170$
51 566
PtCl2
260$
69 160
RhCl3
54 368
PdCl2
95$
11 144
RuCl3
97$
20 108
- Gold used to be thought of as chemically inert
Oxidation states of gold
-1 : auride compounds; e.g. CsAu, RbAu
1 : aurous compounds; e.g. AuCl
3 : auric compounds; e.g. AuCl3
5 : e.g. AuF5
Point 5 – explains why Au is so important in organic chemistry but not as dominant in the inorganic field
Point 6 – easy reduction and difficault oxidation of gold, a cross coupling chemistry seems to be difficult to reach due to the necessary change of oxidation states
Prices from Aldrich catalogue

4. Gold Au 79
196.97

5. Properties of Au: A Late Transition Metal
Pauling electronegativities of the transition elements Sc
1.3 Ti
1.5 V
1.6 Cr Mn Fe
1.8 Co
1.9 Ni Cu Y
1.2 Zr Nb Mo
2.1 Tc Ru
2.2 Rh
2.3 Pd Ag La
1.1 Hf Ta W Re Os Ir Pt Au
2.5
More electronegative metals tend to retain their valence electrons
Low oxidation states for late transition metals are more stable than higher ones
Back donation in late transition metals is not so marked compared to early transition metals
Gold is a soft transition metal and thus will prefer soft transition partners
Point 1 – because electrons are located in orbitals which are low in energy
Point 3 – any attached unsaturated ligand to the weak pi-donor will accumulate a positive charge making it subject to nucleophilic attack
Crabtree, R. H., The 0rganometallic Chemistry of the Transition Metals, John Wiley & Sons, Inc, New York, 2001, p.46

6. Crystal Field Theory
- d orbitals of a metal are affected by the presence of ligands where the ligands act as a negative charge
dx2-y2
dz2
Energy difference between dsigma and dpi is crystal field splitting
dyz
dxz
dxy
Octahedral geometry
Crabtree, R. H., The 0rganometallic Chemistry of the Transition Metals, John Wiley & Sons, Inc, New York, 2001, p.46

7. Why Are d8 Metals Square Planar?
dx2-y2
dx2-y2 dz2
dxy dyz dxz
dxy
dz2
dxy dyz dxz
dxz dxz
dx2-y2 dz2
Square Planar
Octahedral
Tetrahedral
The square planar geometry offers the electrons never to be placed in the highest energy orbital
d10 metals fill all the d orbitals
Conformation that offers less steric hinderance for the ligands
Au(III):
Au(I):
Crabtree, R. H., The 0rganometallic Chemistry of the Transition Metals, John Wiley & Sons, Inc, New York, 2001, p.46

8. Lewis Acid Activation
Hard Lewis acids:
- small
- high charge states
- weakly polarizable
- often activate reactions by coordination to the oxygen atom.
- e.g. Ti4+ and Fe3+
Soft Lewis acids:
- big
- low charge states
- strongly polarizable
- often activate the reaction through coordination with the π bond
- Cu+ and Pd2+
Au(III) is more oxophilic than Au(I) and so is a harder Lewis acid
Au(I) will have a higher affinity for alkynes

9. Reactivity of Alkynes
The LUMO of alkynes are low in energy and so will eagerly react with strong nucleophiles
Unless activated, alkynes will not react with weak nucleophiles
Using its d orbitals, gold can activate alkynes by interacting with both π orbitals of the alkyne
σ-type donation:
Π-type donation:
dxz
dx2-y2
Π-type
back-donation:
δ-type
back-donation:
dxy
dyz
Toreki, R. 20/11/2003
Hashmi, A. S. K. Gold Bulletin, 2003, 36, 3-9

10. Reactivity of Alkynes
- Terminal alkynes can interact through a second mode of action especially with AuI
Forms a gold(I)-alkynyl complex
stable
will not readily react with nucleophiles
η1-Au-η1:
η2-Au-η1:
Hashmi, A. S. K., Gold Bulletin, 2003, 36, 3
Mingos, D. M. P.; Yau, J.; Menzer, S.; Williams, D. J. Angew Chem. Int. Ed. 1995, 34, 1894

11. Reactivity of Alkynes A broad range of nucleophiles may be used
Carbon-carbon bond forming reactions:
Propargyl-Claisen rearrangement
- Carbon-oxygen bond forming reactions:
- Ketone or acetal formation
Carbon-nitrogen bond forming reactions:
Acetylenic Schmidt Reaction

12. Propargyl Claisen Rearrangement
Can be catalyzed by:
Hard Lewis acids by coordination to the oxygen atom
Soft Lewis acids by coordination to the π bond
e.g. Hg(II) and Pd(II)
Propargyl Claisen rearrangement
Typical soft Lewis acids cannot be used
Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,

13. Propargyl Claisen Rearrangement
Gold is so alkynophilic that it will prefer binding to the alkyne than to the vinyl ether
Entry R1 R2 R3
Yield 1
p-MeO-C6H4 H
n-C4H9
89% 2
p-CF3-C6H4 Me
86% 3
PhCH2CH2
91%
these catalysts are limited by the binding of the electrophilic metal to the strongly nucleophilic vinyl ether
C-C bond forming- Carbon nucleophile
Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,

14. Interaction of Gold with Alkynes
Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,

15. Active Catalyst: AuI or AuIII
- Many reactions can use either AuI or AuIII. Sometimes one is faster than the other, however the active catalyst remains unknown
- Reduction of high oxidation state pre-catalyst to catalyst is mandatory in several late transition state metal catalyzed reactions
- AuCl3-catalyzed benzannulation by Yamamoto was studied using B3LYP, a DFT calculation method
Due to high oxidation state of Au 3 , reduction in medium would be no surprise
Density functional theory (DFT)-energy of a molecule is calculated from an expression involving electron density distribution, the potential of the atomic nuclei, and a mathematical device called a functional. Internal electrons in each atom are not treated separatly but are replaced by a potential.Nuclear ositions are varied until energy of the molecule is minimized
Straub, B. F. Chem. Commun. 2004,
Asao, N.; Tokahashi, K.; Lee, L.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124,

16. Active Catalyst: AuI or AuIII
Yamamoto’s Proposal:
With both catalysts there is the same reaction energy barrier
Simultaneous catalysis cannot be ruled out
Computational results:
DFT reveals same predicted Gibbs activation energy of 115 kJ/mol for both AuI and AuIII
Catalytic activities of AuCl3 and AuCl were indistinguishable within the reliability of the chosen level of theory
Straub, B. F. Chem. Commun. 2004,
Asao, N.; Tokahashi, K.; Lee, L.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124,

17. Hydration of Alkynes
- Hydration of alkynes is well-known however only electron-rich acetylenes react satisfactorily
- Simple alkynes need toxic Hg(II) salts to enhance reactivity 1 2
Entry R1 R2
Adduct
Yield 1
n-C4H9 H
99% 2
NC(CH2)3
83% 3
n-C3H7
CH3
1/2 = 1.2:1
76%
Au has turnover frequencies of at least two orders of magnitude more than other catalysts
- The major product is Markovnikov adduct
Mizushima, E.; Sata, K.; Hayashi, T., Tanaka,M.; Angew. Chem. Int. Ed. 2002,41, 4563
Fukuda, Y., Utimoto, K.; J. Org. Chem. 1991, 56, 3729

18. Acetylenic Schmidt Reaction
C-N bond forming, N nucleophile
Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260

19. Allene Activation 1 2 Entry Catalyst (1-2 mol%) Solvent (1M)
Temperature (ºC)
Ratio :2 1
AuCl3
Toluene
88:12 2 rt
95:5 3 70
98:2 4
THF
5:95 5
Au(PEt3)Cl
<1:99
C- O bond forming, Oxygen nucleophile
Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127,

20. Proposed Mechanism
Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127,

21. Carbene-Like Intermediates
Gold(I)-catalyzed cyclopropanation reaction tolerated a wide range of olefin substitution
The cis-cyclopropane is favored
Concerted carbene transfer from a gold(I) –carbenoid intermediate
Entry R R1 R2 R3 R4
Yield (cis:trans) 1
Pivaloate Me
67% 2
Acetate H
TMSCH2
62%(1.3:1) 3
Benzoate
Cyclohexyl
73%
Including mono, di, tri and tetra substituted
Compliments trans selectivity often observed in enantioselective olefin cyclopropanation using alpha-diazoacetates
Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,

22. Carbene-Like Intermediates
Identified DTBM-SEGPHOS-gold(I) ligand as the ligand of choice for enantioselective olefin cyclopropanation reaction
(R)-DTBM-SEGPHOS Ar
= Ph
70 %, 81% ee =
71%, 94% ee
>20:1 cis:trans
Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,

23. Insight Into Mechanism
Path A
A variety of common esters undergo the requisite 1,2-migration, including acetate, pivaloate and benzoate
Path B
- Large phosphine ligand increased selectivity for the cis cyclopropane
Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,

24. C-H Bond Activation
Not as common as alkyne activation though more examples have been emerging in the last few years
Activates C-H bonds to create a nucleophile which can interact with electrophiles
Often there is a dual role of Au in these transformations
Activates arenes
- Spectroscopic and isotope labelling experiments indicate the presence of the arene gold intermediate
Hoffmann-Roder, A.; Krause, N.; Org. Biomol. Chem. 2005, 3,
Shi, Z.; He, C.; J. Org. Chem. 2004, 69, 3669

25. Activation of β-Dicarbonyl Compounds
Yao, X.; Li, C. -J. J. Am. Chem. Soc. 2004, 126, 6884

26. 2,3-Indoline-Fused Cyclobutanes
- Tandem cationic Au(I)-catalyzed activations of both propargylic esters and the in situ generated allenylic esters
Product of first catalytic cycle
Zhang, L. J Am. Chem. Soc. 2005, 127, 16804

27. 2,3-Indoline-Fused Cyclobutanes
- Tandem cationic Au(I)-catalyzed activations of both propargylic esters and the in situ generated allenylic esters
Entry R R1 R2
Yield 1 Me
(CH2)4CH3
81% 2 H Ph Bu
98% 3
(CH2)3Br
95% 4
86%
Zhang, L. J Am. Chem. Soc. 2005, 127, 16804

28. Tandem Sequence
Zhang, L. J Am. Chem. Soc. 2005, 127, 16804

29. Tandem Sequence
Zhang, L. J Am. Chem. Soc. 2005, 127, 16804

30. First Enantioselective Example
Aldehyde
Ligand R=
Yield %
Ratio trans/cis
% ee of trans
PhCHO Et 98
89/11 96 Me 91
90/10 94
(E)-n-PrCH=CHCHO 83
81/19 84 97
80/20 87
t-BuCHO
100
100/0
Au better than metals in it’s group since it has a higher affinity with phosphorus atoms leaving the nitrogen atoms free to control the reaction. Ag and Cu coordinate with nitrogen instead of phosphorus
Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108,
Hayashi, T.; Sawamura, M.; Ito, Y. Tetrahedron 1992, 48, 1999

31. Control of Chirality
- When they created a catalyst with a longer side chain there was a loss of stereoselectivity
Without the terminal amino group there was a loss of stereoselectivity
Other chiral phosphines gave racemic products
Not really sure I understand second example
Cu and Ag were much less selective than Au
Medium size substituent on amino group gave higher trans/cis ratio
Hayashi, T.; Sawamura, M.; Ito, Y. Tetrahedron 1992, 48, 1999
Ito, Y.; Sawamura, M.; Hayashi, T.; J. Am. Chem. Soc. 1986, 108,

32. Enantioselective Hydrogenation
(R,R) Me-Duphos Au Pt Ir
Substrate
TOF
ee (%)
R=H
3942 20
10188 3
8088 1
R=Ph
906 80
926 90
1110 26
R=2-Nf
214 95
250 93
325 68
1005 75
1365 15
1118
Small Au-Au interaction: forces Au coordination to deviate from linearity P-Au-Cl are almost perpendicular
Ee increases with increased steric hinderance
Since high ee was obtained with bulky substrates opens the door to high ee to less bulky substrate by ligand modification
Gonzelez-Arrellano C.; Corma, A.; Iglesias, M.; Sanchez, F. Chem. Comm. 2005, 3451

33. Enantioselective hydrogenation
- Hydrogen activation by hydrogen splitting promoted by the electron-rich Au-complex bearing heteroatoms (Cl).
Should stabilize the H+ in a similar way than Pd-salen and Pd-Schiff
Gonzelez-Arrellano C.; Corma, A.; Iglesias, M.; Sanchez, F. Chem. Comm. 2005, 3451

34. Carene Terpenoids Synthesis
Plant essential oil
Is a pheromone
Component of terebentine
Is a [4.1.0] bicyclo compound that differs at the cyclopropane unit
What do carene do in life
2-carene
Sesquicarene
Isosesquicarene
Furstner, A.; Hannen, P. Chem. Commun. 2004,

35. Envisioned Strategy
This specific type of rearrangement was discovered as a side reaction mediated by ZnCl2
Obtained from a 3,3 sigmatropic rearrangement
Propargyl acetate in the presence of catalytic amounts of gold constitute a synthetic equivalents to alpha-diazoketones
- Although PtCl2 is normally the catalyst of choice it resulted in a significant amount of allenyl acetate
Furstner, A.; Hannen, P. Chem. Commun. 2004,

36. Sesquicarene Synthesis
Furstner, A.; Hannen, P. Chem. Commun. 2004,

37. Sesquicarene Synthesis
No cyclopropanation of the distal double bond thus showing that the cyclization of the conceivable 10-membered ring does not compete with kineticallt and thermodynamically more favorable 6 membered ring
Sesquicarene
Furstner, A.; Hannen, P. Chem. Commun. 2004,

38. Can Be Applied to the Other Carenes
Isosesquicarene
Furstner, A.; Hannen, P. Chem. Commun. 2004,

39. Jungianol - Sesquiterpene isolated from Jungia Malvaefolia
- Isolated and characterized by Bohlmann et al. in 1977
- Possesses a trisubstituted phenol substructure and has two side chains on the five membered, benzoannelated ring
Check phyto for more facts
Proposed structure of Jungianol
Hashmi, A. S. K.; Ding, L.; Bats, J. W.; Fischer, P.; Frey, W. Chem. Eur. J. 2003, 9,

40. Key Step
Furan undergoes a Diels-Alder with the alkyne activated by Au. Normally furan won’t undergo a DA but since dienophile is activated it is possible
AuIII act as a LA
Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Org. Lett. 2001, 3,
Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553

41. Synthesis Epi-Jungianol Jungianol (revised structure)
Hashmi, A.S.K.; Ding,L.; Bats, J.W.; Fischer, P.; Frey, W. Chem. Eur. J. 2003, 9,

42. Conclusions Gold can catalyze reactions through Lewis acid activation
- Au is able to activate C-H bonds to open a world of chemistry beyond alkynes
- Aurated species now becomes a nucleophile instead of an electrophile
- Development of ligands for enantioselective reactions
- Synthetically useful

43. Acknowledgements Dr. Louis Barriault Patrick Ang Steve Arns
Rachel Beingessner
Christiane Grisé
Mélina Girardin
Roch Lavigne
Louis Morency
Maxime Riou
Effie Sauer
Guillaume Tessier
Jeffrey Warrington