scope of gold n-heterocyclic carbenes (nhcs) mediated ... · carbenes to the n heterocyclic...

Universiteit Van Amsterdam

Scope of Gold N-Heterocyclic Carbenes (NHCs) mediated catalysis in a hexameric C- alkyl Resorcin[4]arene supramolecular cage.

A literature thesis

Monalisha Goswami (10230203)

02-Jul-12

Supramolecular cages can serve as selective reaction chambers for chemical transformations. This review is a survey of the scope of Gold- NHCs catalysed transformations in one such supramolecular cage.

3

Acknowledgement

I would like to extend my thanks and gratitude to my supervisor Professor Joost N H

Reek for guiding me through the progress of this literature thesis. Heartfelt thanks are

also due to Sander Oldenhof, my immediate supervisor, who saw me through the thick

and thin during the progress of this report and pointing out scope for improvements

which I couldn’t have seen on my own. I also wish to thank Dr. Jarl Ivar van der Vlugt

for giving his consent to be the second reviewer for this report albeit at a very short

notice.

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Table of Contents

CHAPTER 1 ............................................................................................................................................... 7

1.1 Carbenes- early works ...................................................................................................................................... 7

1.2- Carbenes- Electronic configuration and geometry .......................................................................................... 8

1.3 N Heterocyclic Carbenes ................................................................................................................................ 10

1.3.1 Fischer Carbene complexes ............................................................................................................................ 11

1.4 Organometallic Chemistry of NHCs ................................................................................................................ 13

1.4.1 A little comparison with Phosphines .............................................................................................................. 14

1.4.2 NHCs- Rapport with the metals ...................................................................................................................... 14

1.4.3 NHC complexes of transition metals- ............................................................................................................. 16

1.5 Closing remarks .............................................................................................................................................. 16

REFERENCES- CHAPTER 1 ..................................................................................................................................... 17

CHAPTER 2 ............................................................................................................................................. 19

2.1 Gold- special properties. ................................................................................................................................ 19

2.2 How gold paved its way as a catalyst ............................................................................................................. 20

2.3 Modes of reactivity of Gold in Gold catalysis ................................................................................................. 23


CHAPTER 3 ............................................................................................................................................. 26

3.1 Introduction ................................................................................................................................................... 26

3.2 Bonding in Au-NHCs ....................................................................................................................................... 26

3.2.1 Relativistic effects and back-bonding ............................................................................................................. 27

3.3 Synthesis of Gold-NHCs .................................................................................................................................. 28

3.3.1 The silver oxide route ..................................................................................................................................... 28

3.3.2 Ligand substitution reaction- The other is the free NHC in a simple ligand substitution reaction. ............... 28

3.3.3 In situ synthesis .............................................................................................................................................. 28

3.3.4 The silver free route ....................................................................................................................................... 29

3.3.5 The Gold Synthons ......................................................................................................................................... 30

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3.3.6 The piggyback synthesis ................................................................................................................................. 30

3.4 Reactions involving Gold NHCs ....................................................................................................................... 32

3.4.1 Enyne cycloisomerisation and the likes- ........................................................................................................ 32

3.4.2 Reactions involving propargylic esters ........................................................................................................... 33

3.4.3 Alkene activation- ........................................................................................................................................... 35

3.4.4 Hydration-type reactions ............................................................................................................................... 37

3.4.5 Gold catalysis in a supramolecular cage- a step further ahead...................................................................... 39


CHAPTER 4 ............................................................................................................................................. 44

4.1 Can issues of catalyst poisoning/decomposition be tackled? ......................................................................... 44

4.2 Can reactivity/ selectivity be altered? ............................................................................................................ 45

4.2.1 Conjugated enones from propargylic esters- a closer look ............................................................................ 45

4.3 Conclusion ..................................................................................................................................................... 49

4.4 Outlook .......................................................................................................................................................... 50


7

CHAPTER 1

From methylene carbenes to N -Heterocyclic Carbenes

1.1 Carbenes- early works Traditionally a carbene is defined as a two-coordinate carbon compound that has two nonbonding

electrons and no formal charge on the carbon; the non bonding electrons being either paired

(singlet) or unpaired (triplet). The possibility of such a species was first conceived in 1862 by A.

Geuther. 1 He suggested that the alkaline hydrolysis of chloroform proceeds though the formation of

a reaction intermediate with a divalent carbon called dichlorocarbene. Almost thirty years later in

1897, the reaction intermediate for the famous Reimer-Tiemann reaction (Nef, 1897) and the

transformation of pyrrol to β-chloropyridine in chloroform was thought to be the same carbenic

species, the dicholorocarbene, by J.Nef. 2 It was three years later that M. Gomberg (Gomberg, 1900)

characterized the first example of a free radical, the triphenylchloromethylene(1), through

elemental analysis and chemical reactivity (Scheme 1.1). 3

Scheme 1.1- generation of the first stable radical by M. Gomberg.

By the first three decades of the nineteen hundreds the existence of free radicals was finally well

recognized, and their use in organic chemistry as reaction intermediates was growing extremely

rapidly. In this regard, carbene moieties were also regarded as diradicals (Kimse, 1964). 4 A turning

point came in 1953 when W. Doering et al proposed an elegant synthesis of tropolones via an

addition of methylene to benzene (Scheme 1.2). 5

8

Scheme 1.2- synthesis of tropolane derivatives via a methylene intermediate.

However, it was a year later that the existence of dibromo methylene intermediate was confirmed

in the first synthesis of cycolpropane by the addition of bromoform to an alkene (Scheme 1.3). 6

Scheme 1.3- Olefin propanation via methylene intermediate.

Followed by this many more syntheses that involved the methylene intermediate were reported

which prompted chemists and physicists to take a closer look towards these reactive species.

1.2- Carbenes- Electronic configuration and geometry It was way back in 1951 that two scientists were using quantum mechanics to determine the

geometric structures and properties of small molecules. They were J. Lennard-Jones and J. Pole,

who hinted something towards the existence of two different ground states for the methylene

carbene but they could not determine the one with the lowest energy. 7 One of the ground states

they proposed was a singlet state with triangular geometry possessing three orbitals filled with two

paired electrons and an empty orbital. The other proposed ground state was a triplet state with a

linear geometry possessing two orbitals filled with paired electrons and two orbitals filled with

unpaired electrons.

Two years later, J. Duschenne and L. Burnelle (Duchesne et al, 1953) proved that :CF2 had a singlet

ground state with a sp2 hybridization and the orbital bearing the nonbonding pair of electrons being

nearly s. 8 In 1964, Zimmerman et al assumed that steric protection would enhance the stability of

9

carbenes. They succeeded in synthesizing dimesitylmethylene but no success in isolating the

carbene was achieved. 9 Analysis of the rearrangement products suggested that the carbene

involved was a triplet carbene with an unexpected non linear geometry (scheme 1.4).

Scheme 1.4- generation of triplet carbene and regeneration products.

In 1968, Hoffmann et al accurately determined the minimum splitting energy required between

both ground states to have a methylene with a singlet state (scheme 1.5). They also suggested that

the singlet state could be favored by π-overlap between the p-orbitals of the carbene and the α-

substituents. 10

Scheme 1.5- electronic states of a carbene

During the 1970s and 1980s, numerous theoretical works using ab initio quantum calculations

were published to rationalize the electronic structures and the geometries of methylene moieties

such as :CH2, :CHF, :CHBr, :CF2, :CCl2. It also became clearer that inductive and mesomeric effects

act synergistically to determine the energy gap between both ground states (Harrison et al, 1971;

10

Pauling et al, 1980). 11 In 1992, Goddard’s group was able to predict accurately the ground state

configuration of a series of carbenes :CXY (X, Y = H, F, Cl, Br, I, SiH3), with a method using only some

slight calculations and which is applicable to other arbitrary carbenes. 12

1.3 N Heterocyclic Carbenes Prior to 1960, there was a school of thought that carbenes were too reactive to be isolated. This

thwarted widespread efforts to investigate carbene chemistry. Perhaps true for the majority of

carbenes, this proved to be an inaccurate assessment of the N-heterocyclic carbenes. As can be seen

in the scheme 1.6 below, the carbenes go through an energy downhill from the simple methylene

carbenes to the N heterocyclic Carbenes (NHCs) making it possible for the NHCs to be isolated. 13

Scheme 1.6- Downhill energy pathway leading to isolable NHCs.

In the early 1960s it was the group of Wanzlick who first investigated the reactivity and stability of

N-heterocyclic carbenes. The complexes synthesized by his group are shown in scheme 1.7. The

first authentic metal-carbene complexes of type 2 were reported in 1960s (Wanzlick et al, 1968). 14

In 1968, two little-recognized reports by Ofele and Wanzlick et al appeared that described

complexes 3 and 4 with N heterocyclic carbenes as ligands. 15 These were perhaps the first

published reports of metal NHC complexes being synthesised in a lab. It started with the

mononuclear and dinuclear complexes of Chromium and Mercury respectively (scheme 1.7) but

today at least one such complex is known for almost every transition metal.

11

Scheme 1.7- earliest examples of carbenes

These complexes, which at that time were highly unusual compounds, were both obtained from

imidazolium salts and metal-containing precursors of sufficient basicity to deprotonate the organic

substrate. In the first case a carbonylmetalate was used, while the mercury complex resulted simply

from the metal acetate. (equation 1 and 2)

So what are these N -heterocyclic carbenes? Before we delve into that, first a brief introduction to

Fischer Carbene complexes seems to be necessary.

1.3.1 Fischer Carbene complexes

Well stabilized heteroatom singlet carbenes, such as aminocarbenes and alkoxycarbenes have a

significant gap between their singlet and triplet ground states. They form a metal-carbon bond

constituted by mutual donor-acceptor interaction of two closed-shell (singlet) fragments. The

dominant bonding arises from carbene-metal σ-donation and simultaneously from metalcarbene π-

back-donation (Scheme 1.8). 16

12

Scheme 1.8- Metal –carbene bonding in Fischer Carbene complexes

The π-electrons are usually polarized toward the metal and the carbon-metal bond has a partial

double bond character which diminishes with the stabilization of the carbene by its α-groups. 16

For instance, in diaminocarbenes, including NHCs, the metal-carbon bond is seen as a simple bond;

the π-back-donation is usually weak because the carbonic carbon is already well stabilized by π-

back donation from its amino groups. 17, 18 Fischer carbene complexes are electrophilic at the

carbon-metal bond and are susceptible to nucleophilic attack at the carbene center. They are

generally associated with low oxidation state metals. 16-18

Turning to the NHCs again, also called Arduengo carbenes, these are diaminocarbenes and form

Fischer-type complexes with transition metals. Since the seminal work of Wanzlick 14 during the

1960s, plenty of NHC-metal complexes have been synthesized following the traditional route to

Fischer complexes without the involvement of any free carbene ligand. Nevertheless, the real

breakthrough came in 1991, when Arduengo et al. synthesized and isolated the first stable N-

heterocyclic carbene: the 1,3-bis(adamantyl)imidazol-2-ylidene (equation 3). 19

Since then, a great variety of NHCs bearing different scaffolds have been synthesized and reacted

with transition metals leading to well-defined complexes. Today, these carbenes are recognized as

13

an exciting alternative to the limitations of phosphine ligands in the field of organometallic

chemistry. Scheme 1.9 shows NHC scaffolds that are commonly encountered in literature. 20

Scheme 1.9- Scaffolds of NHCs currently in literature

In the scheme 1.9, different substituents on the NHC scaffold can be seen. Slight changes to the NHC

architectures have a dramatic change on the electronic donor properties of the carbene moieties

and impose geometric constraints on the N-substituents, influencing their steric impact. These

different N-substituents allow for a modulation of the steric pressure on both the carbene and the

coordinated metal.

The ease of synthesis, functionalization, and isolation of NHCs, and the success in metallation with a

large variety of hard/soft metals make NHCs excellent ligands with similarities to phosphines. Two

reviews written by Bourissou and Hermann talk about the Metal NHC complexes in detail. Today,

the synthesis and use of NHCs have received great attention in the area of organometallic and

inorganic chemistry.

1.4 Organometallic Chemistry of NHCs The distance between the carbenic carbon and the metal in organometallic complexes gives an

insight on the ability of the carbene to accept any transfer of electronic density from the metal (π-

back donation). 21, 22 A short distance accounts for a partially metal−carbon double bond due to a π-

back donation. 23 It is well accepted that NHCs bind strongly metals by σ-bonding while the π-back-

bonding is negligible. 24 Only copper, silver and gold from Group 11 exhibit a significant π-back-

14

bonding from the metal to the NHC 25 (Termaten et al, 2003) although the case of Gold is highly

debated currently.

1.4.1 A little comparison with Phosphines

In metal complexes, NHCs share with phosphines the characteristics of being monodendate two-

electron ligands. 26 (Crabtree, 2005) Carbonyl-metal complexes bearing a CO group trans position to

an NHC or a phosphine ligand are of interest in determining bonding modes through infrared

spectroscopy. The vibrational frequency of C–O stretching is thought to be proportional to the π-

back donating ability of the NHC or phosphine ligand. In a totally symmetric vibrational mode more

basic ligands (σ donors) induce smaller vibrational frequencies. Studies of different complexes of

Ni(0) have shown that NHCs appear to be more electron-donating than most basic phosphines. 27

They bind more firmly to the metal center than phosphines ligands. Also, contrary to the

phosphines, NHCs bind with alkaline, lanthanides and high oxidation state metals in which π-back

donation is not possible. 28 So a greater variety of metal NHC complexes exist and they form more

stable complexes than the phosphines.

1.4.2 NHCs- Rapport with the metals

Complexes of NHCs with metals of almost every group have been encountered in literature. Next is

a summary of the known complexes of NHCs with main group metals. 29

Table 1.1- Metal complexes of NHCs

METAL REMARKS

Alkali metals-

4,5-dimethyl-1,3-diisopropylimidazolium salt

deprotonated by Li, Na and K

hexamethyldisilazide in THF to form

corresponding adducts

Bonding mostly electrostatic

slight shift upfield for the signals

of the carbenic carbon (13C

NMR) and can be suppressed by

trapping the alkali metals with

crown ethers.

Quite stable in air.

15

Alkaline Earth Metals-

Be- forms bis or tris adducts

Ca, Mg, Sr, Ba- only respective metallocenes

form carbenic adducts

Bonding is covalent for Calcium

Ionic for heavier metals

Use of excess carbene can lead to

formation of bis adducts

Group 13-

Al(III) & Ga(III)- 4-coordinate adducts

In(III) & Tl(III)- 5 coordinate bis adducts

possible

electronic structure of the

imidazole fragment intermediate

between free carbene and

imidazolium ion.

thermally stable in contrast to

phosphines.

Group 14 & 15-

under developed chemistry.

Tin(II) bis adduct reported; mono adduct with

sterically unencumbered carbenes

C-Sn bond highly polarized.

No Π back donation from Sn to

Carbene.

Lanthanides and Group 3 transition metals-

Metallocenes or tris(silylamido) complexes of

yt, sc, la, and of the lanthanides series bearing

at least one tetrahydrofuran ligand form some

NHC adducts by substitution of the

tetrahydrofuran

Bonding is electrostatic

M-C bond longer than sigma

bonded alkyl Lanthanide species

Actinides

In 2001, the first actinide NHC complexes

formed from two equivalents of 1,3-bis(2,4,6-

trimethylphenyl)imidazolylidene (IMes) with

uranyldichloride

NHC ligands are among the

weakest σ-donor for uranyl

complexes.

Actinyl ions are hard Lewis acids;

coordination of the uranyl ion

with a soft σ-donor NHC

unprecedented.

However, the relation of NHCs with transition metals deserves a broader treatment and many

elaborate reviews have been written on it. 24 A short summary is presented here after.

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1.4.3 NHC complexes of transition metals-

There is an amazing diversity of transition metal NHC-complexes with a variety of other ligands and

oxidation states. All metals from groups 4 through 12 are covered, including the radioactive

technetium. 30 The motivation for such a large volume of work is the stability/availability of the

NHC ligands and the outstanding performances of their metal complexes in catalysis. Two detailed

reviews on the topic have been written by W. A. Hermann and G.Bertrand and it would be

impractical to include details of those complexes in this review. 24, 31

NHCs react with a broad range of organometallic precursors by direct addition or by replacement of

two-electron donor ligands. Nitriles, phosphines, tetrahydrofurane, carbonyl (CO),

tetrahydrothiophene (THT), pyridines, and dimethylsulfide (DMS) are among the most common

ligands displaced by the NHCs. Dinuclear precursors featuring halo or aceto bridges are also split by

the NHCs to form the corresponding monomeric complexes. Depending upon the metal and the

stoichiometry of reagent employed, complexes bearing up to three NHCs are commonly

synthesized.

1.5 Closing remarks In this chapter an attempt was made to understand the basic features of carbenes, especially N

Heterocyclic carbenes. This preliminary survey of corresponding literature should be essential to

understand the chemistry of Gold NHCs. N-heterocyclic carbenes have a very special place in the

carbene family thanks to their stability and their straightforward synthesis. They bind metals with

various oxidation states and generate organometallic complexes with enhanced stability and

unique properties in the field of catalysis. The complexes of NHCs have slowly emerged from

laboratory curiosities to powerful tools in organic, organometallic and material chemistry. They can

be reagents, reaction intermediates, or ligands for metal complexes. In this regard, NHC complexes

are outstanding catalysts for a broad array of organic transformations including cross-coupling

reactions, metathesis, hydrogenations, polymerizations and hydrosilylations for the most famous

ones.

17

REFERENCES- CHAPTER 1

1. Geuther, A.; Hermann, M. Ann. 1855, 95, 211-225.

2. Nef, J. U. Ann. 1897, 298, 202-374.

3. Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757-771

4. Kimse, W. Carbene Chemistry, Academic Press, New York & London, 1964, p:5.

5. Doering, W. v E.; Knox, L. H. J. Am. Chem. Soc. 1953, 75, 297-303.

6. Doering, W. v E.; Hoffmann, A. K. J. Am. Chem. Soc. 1954, 76, 6162-6165.

7. Lennard-Jones, J; Pople, J. A. Discus. Faraday. Soc. 1951, 10, 9-18.

8. Duchesne, J.; Burnelle, L. J. Chem. Phys. 1953, 21, 2005-2008.

9. Zimmerman, H. E.; Paskovich, D. H. J. Am. Chem. Soc. 1964, 86, 2149-2150.

10. a) Hoffmann, R. J. Am. Chem. Soc. 1968, 90, 1475-1485 b) Hoffmann, R.; Gleiter, R. J. Am.

Chem. Soc. 1968, 90, 5457-5460 c) Hoffmann, R.; Zeiss, G. D.; Van Dine, G. W. J. Am. Chem.

Soc. 1968, 90, 1485-1499.

11. a) Harrison, J. F. J. Am. Chem. Soc. 1971, 93, 4112-4119 b) Pauling, L. J. Chem. Soc., Chem.

Commun. 1980, 688-689.

12. Irikura, K. K.; Goddard III, W. A.; Beauchamp, J. L. J. Am. Chem. Soc. 1992, 114, 48-51.

13. Herrmann, J.; Köcher, C. Angew. Chem Int. Ed. 1997, 36, 2163-2187.

14. H.W. Wanzlick, H.J. Schonherr, Angew. Chem. 1968,80.154; Angew. Chem Inr. Ed. Engl. 1968,

7, 141.

15. K Ofele, J. Organomet. Chem. 1968, 12, P 42

16. Taylor, T. E.; Hall, M. B. J. Am. Chem. Soc. 1984, 106, 1576-1584.

17. Lappert, M. F. J. Organomet. Chem. 1988, 358, 185-214 and references therein.

18. Frenking, G.; Solà, M.; Vyboishchikov, S. F. J. Organomet. Chem. 2005, 690, 6178-6204.

19. Arduengo, A. J, Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361.

20. De Fremont, Pierre, "Synthesis of Well-Defined N-Heterocyclic Carbene (NHC) Complexes of

Late Transition Metals" (2008).University of New Orleans Theses and Dissertations. Paper

829.

21. a) Cardin, D. J.; Cetinkaya, B.; Lappert, M. F. Chem. Rev. 1972, 72, 545-574.

22. Bernasconi,C. F.; Ali, M. Organometallics 2004, 23, 6134-6139.

23. Lee, M.-T.; Hu, C.-H. Organometallics 2004, 23, 976-983 and references therein.

24. Herrmann, W. A. Angew. Chem Int. Ed. 2002, 41, 1290-1309.

18

25. Termaten, A. T.; Schakel, M.; Ehlers, A. W.; Lutz, M.; Spek, A. L.; Lammertsma, K. Chem. Eur. J.

2003, 9, 3577-3582.

26. Crabtree, R. H. J. Organomet. Chem. 2005, 690, 5451-5457.

27. Dorta, R.; Stevens, E. D.; Scott, N. M.; Costabile, C.; Cavallo, L.; Hoff, C. D.; Nolan, S. P. J. Am.

Chem. Soc. 2005, 127, 2485-2495.

28. Díez-González, S.; Nolan, S. P. Coord. Chem. Rev. 2007, 251, 874-883 and references therein.

29. N- Heterocyclic Carbenes in synthesis, edited by S.P Nolan, Wiley Vch, 2005.

30. Braband, H.; Kückmann, T. I.; Abram, U. J. Organomet. Chem. 2005, 690, 5421-5428 and

references therein.

31. Bourissou, D.; Guerret, O.; Gabbaï, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39-91.

19

CHAPTER 2

The Chemistry of Gold

2.1 Gold- special properties. Gold is unique in both its physical and chemical properties. This unique reactivity of gold compared

to its group analogues has been explained by the relativistic effects that come into play due to its

large size. Figure 2.1 shows the relative contraction of the 6s orbital of elemental Gold compared to

the other metals around the same atomic number. The differences between the 4d and 5d elements

and their compounds have been ascribed to the large stability of the 6s2 electron pair. Due to the

large size of its nucleus the relativistic effects become very important for Gold. 32, 33, 34 (Bond 2000,

2002; Pyykko 2002) Because of the increased mass of the nucleus, the s orbitals and to a lesser

extent the p orbitals are contracted, whereas the d and f orbitals are in fact expanded. 35 (Meyer et

al, 2004) As a result, the 6s2 pair is contracted and stabilized and Gold owes much of its chemistry

(including the catalytic properties is to the 5d band. 32,43

Fig2.1- Relativistic contraction of the 6s shell in Gold.

The yellow colour of Au, similar to that of Cu, but different from that of silver, caused by optical

absorption in the visible region, is due to the relativistic lowering gap between the 5d band and the

Fermi level. 32, 36 In the absence of this effect, gold would be white like Ag and have the same

propensity to tarnish and corrode. 32

20

The contraction of the 6s orbital also causes lengthening of the Au-Ligand bond in complexes or

compounds of Gold. A comparison of the Au-H and Ag-H bond strengths leads to the conclusion that

Gold has strong lewis acidity and at the same time forms a covalent like bond with the ligands while

sharing a bit of a positive charge with them (figure 2.2). So it overall acts a soft lewis acid. This in

turn causes it to highly and selectively activate ‘soft’ electrophiles such as the pi systems and as we

will see further, this is exactly what Gold catalysts do in the reactions that they take part in.

Fig 2.2- difference in Gold and Silver Hydrides.

2.2 How gold paved its way as a catalyst In the earliest examples of using Gold as a catalyst, in 1935, both AuCl and AuCl3 were found to act

as lewis acids for the chlorination of naphthalene to octachloronaphthalene. After almost four

decades in 1976 in a better experimentation H[AuCl4] was used (Thomas et al, 1976) to effect a

Markonikov addition to an alkyne with a TON of around 6 (scheme 2.1). 37

Scheme 2.1- early experimention with Gold

21

The Gold(III) was thus identified as a stochiometric oxidant of the likes of Fehlings and Toluene’s

reagent. The fact that Gold catalysis has drawn the attraction of chemists in the past two decades

can be seen from the fact that the same reaction was revisited by Utimoto et al in 1991. 38 The

power of gold catalysis was earlier demonstrated by the same group in 1987 in the hydroamination

reaction (scheme 2.2) which involved a 6-exo dig cyclisation when the reaction using a gold catalyst

was found to be way more facile than the one with the Palladium catalyst. 39

Scheme 2.2- Hydroamination reaction with Gold as a catalyst.

Similarly in 1986 the asymmetric aldol reaction (scheme 2.3) with isocyanides was shown to

proceed with excellent enantio and diastereoselectivity by Hayashi’s group. 40 This still remains the

quintessential and seminal example of ligand effects in homogeneous Au catalysis, and preceded

the current surge of interest in the field by over a decade. The selectivity of this reaction was also

found to be overwhelming. The enantioselectivity was over 99% and the trans selectivity about

97%.

Scheme 2.3- aldol reaction catalysed by Gold.

22

The other interesting aspect of homogenous gold catalysis is that the two different oxidation states

have different regioselectivities, in fact they are more often than not reversed. It is seen that in

Au(III) species the thermodynamic effects are more important while in Au(I) the reactivity is more

tunable by changing ligands. This was demonstrated by Gevorgyan, V. et al in 2005 wherein

selective 1,2- iodine, bromine and chlorine migration in haloallenyl ketones in the presence of Au

catalyst was attempted. 41 They found that depending on the Au catalyst used, either selective

bromine migration or hydrogen shift occurs, leading to the formation of 3- or 2- bromofurans

respectively (scheme 2.4).

Scheme 2.4- different oxidation of Gold leads to divergent products.

Although the Au(I) species has been researched upon extensively and broadly reviewed as well, the

Au(III) species is still in its early stages in the catalyst front probably because of the fact that its

reactivity can’t really be tuned by shuffling through a variety of ligands. Ligand effects in

homogenous gold catalysis have been extensively reviewed, the last one being published in 2008. 42

This review addressed ligand effects in homogeneous catalysis through December 2007 with

special emphasis on ligands and complexes enabling enantioselective catalysis. Instances where

catalyst choice, including ligand, counterion, or oxidation state of Au, enabled control over reaction

pathways were also comprehensively reviewed, including influence over diastereoselectivity,

regioselectivity, and chemoselectivity. The relationships between ligands and selectivity and the

developments of new catalysts and reactions still remain quite empirical and the only resolute

seems to be trial and error. However, from the review a few conclusions can be made which might

steer chemists to even design ligands for homogenous gold catalysis according to the need of the

reaction. The authors say that it is clear from observation and mechanistic studies that Biphenyl-

substituted phosphines and NHC ligands induce greater reactivity and modulate selectivity among

23

competing reaction pathways in carbophilic activation with Au(I) species. That the stability of

Au(III) catalysts may be greatly improved with N-donor ligands has also been established. In

addition such ligands have also been successfully employed with Au(I) precatalysts in oxidation and

group transfer reactions. Axially chiral, biaryl-based bisphosphine ligands with a 1:1 P:Au

stoichiometry have been successfully employed in the development of new catalytic, asymmetric

reactions. It has also been shown that chiral phosphoric acids are capable of inducing high levels of

enantioselectivity in additions of nucleophiles to allenes.

2.3 Modes of reactivity of Gold in Gold catalysis The relativistic effects that come into play in Gold also reflects in its reactivity and the modes it

adopts for the same. The two direct implications of the relativistic effects are the contraction of the

6s orbital and the expansion of the 5d orbital. These two effects translate to increased Π acidity and

also increased electron delocalization. This has been summarized in scheme 2.5

Scheme 2.5- Summary of modes of reactivity of Gold.

The increase in Π acidity makes reactions involving proto deauration facile and this has been used

for hetero functionalisation and cyclisation. This same Π acidity also helps it bind to aprotic

nucleophiles such as alkenes and alcohols and such systems have been used for ring expansion and

cyclo isomerisations. The products thus obtained can be regarded as lewis acid derived products.

24

The other aspect of gold’s reactivity is its coordination to systems like alkenes and ylides where

backdonation is possible. Its can either play a role as a cation or as a carbenoid. Some reactions

where this property is manifested are C-H bond functionalisation and cation cyclisation

rearrangements.

As far as the reactivity of the gold-NHC carbenes are concerned, it is obvious that the carbene gold

species is involved although there exists an ongoing debate on the carbene or cationic character of

the gold species. As mentioned earlier, it suggests a carbocationic-carbenoid continuum with

tunable reactivity. An entire literature review could be dedicated to that. But a carbocation-

carbenoid continuum best offers a helpful mnemonic to explain and predict many facets of gold

catalysis.

25


32. a) G. C. Bond, J. Mol. Catal. A 156, 2000, 1 b)G. C. Bond, Plat. Met. Rev. 44, 2000, 146.

33. G. C. Bond, Catal. Today 72, 2002, 5.

34. P. Pyykko, Angew. Chem. Int. Ed. 41, 2002, 3573.

35. R. Meyer, C. Lemire, S. K. Shaikhutdinov, H.-J. Freund, Gold Bull. 37, 2004, 72.

36. A. H. Guerrero, H. J. Fasoli, J. L. Costa, J. Chem. Educ. 76, 1999, 200.

37. Thomas, C.B et al. J. Chem. Soc. Perkin trans. 1, 1976. 1983.

38. Fukuda Y, Utimoto K, J. Org. Chem. 1991, 56, 3729.

39. Utimoto K et al Heterocycles 1987, 25, 297.

40. Ito, Y; Hayashi T, JACS 1986, 108, 6406.

41. Gevorgyan V et al JACS, 2005, 127, 10500-10501.

42. Gorin, Toste et al Chem Rev. 2008 August ; 108(8): 3351–3378.

43. P. Pyykko, Chem. Rev. 88, 1988, 563.

26

CHAPTER 3

Gold N- Heterocyclic Carbenes

3.1 Introduction After having presented a fair deal about the NHCs as ligands and Gold as a catalyst it is probably

expected by the reader that a Gold catalyst with NHCs as a ligand is worthy of attention. In fact

Gold- NHCs have attracted the attention of the chemists all around the world in the past decade.

Complexes of NHCs with metals, both transition and non transition, are well known now and have

been used in synthesis as catalysts very often (section 1. 4.2).

The culmination of Gold and NHCs still remains a fairly new affair. In 2003, only one report

describing the catalytic activity of a NHC-Au complex had been published by Hermann co workers 44

(Schneider et al, 2003) titled ‘Synthesis of the First Gold(I) Carbene Complex with a Gold-Oxygen

Bond - First Catalytic Application of Gold(I) Complexes Bearing N-Heterocyclic Carbenes’. Also

worthy of attention is the fact that, prior to this date, Teles et al mentioned the use of NHCs for the

hydroalkoxylation of alkynes. Nevertheless, it was only the subject of a footnote and no

experimental details were given. 45 (Teles et al, 1998)

The earliest well documented example of synthesis came from Antonio M. Echavarren in 2005

(Nieto-Oberhuber, 2005) 46 which was shortly followed by the synthesis of similar and more

elaborate compounds by the group of S.P Nolan in the same year. 47 (De Fremont et al , 2005) From

then on a plethora of literature can be found on this topic.

3.2 Bonding in Au-NHCs In their article published in Nature in 2009, D Benitez et al presented their study of the Gold-

Carbene bonding (all carbenes) using experimental and computational techniques. 48 (Benitez et al,

2009) The results obtained were also tested on the cyclopropanation reaction using Gold Carbene

catalysts and they seemed to correlate. They suggest that the reactivity in gold(I)-coordinated

carbenes is best accounted for by a continuum ranging from a metal-stabilized singlet carbene to a

27

metal-coordinated carbocation. The position of a given gold species on this continuum is largely

determined by the carbene substituents and the ancillary ligand.

3.2.1 Relativistic effects and back-bonding

Another important aspect of Gold(I) is its credentials in backdonation in the Gold NHCs. Contrary to

the widely held view that back bonding in Au(I) species is not very significant as the anti bonding

orbital in Au(I) is too high in energy for any meaningful interaction 48 (Benitez et al, 2009) coupled

with the fact that Π accepting properties of NHCs are not commendable, a report in Chemistry- a

European journal by Salvi et al that appeared in 2010 argues otherwise. 49 (Salvi et al, 2010) They

provide a rigorous model-free definition and a detailed theoretical analysis of the electroncharge

displacements making up the donation and back-donation components of the Dewar–Chatt–

Duncanson model in some realistic catalytic intermediates of formula L–Au(I)–S in which L is an N-

heterocyclic carbene or Cl anion and S is an η-2-coordinated substrate containing a C- C multiple

bond. They showed that the gold-substrate bond is characterized by a large Π back-donation

component that is comparable to, and often as large as, the σ donation. The back-donation was

found to be a highly tunable bond component. They also analyzed its relationship with the nature of

the auxiliary ligand L and with structural (interdependent) factors such as metal–substrate bond

lengths and carbon pyramidalisation.

The commonly held view about the NHCs is that the ∏ acceptor properties are usually weak

because the carbonic carbon is already well stabilized by the ∏- back donation from its amino

groups. The metal – NHC bond is thus viewed as a simple sigma bond. However, in 2010 Alcarazo et

al published a paper in Angewandte Chemie where they report to have successfully steered the Π

acceptor properties of the N Heterocyclic Carbenes. 50 (Manuel Alcarazo et al, 2010) They further

probed into its implications towards Gold NHC catalysts. Herein they showed that the energy of the

Π acceptor orbital (LUMO) of the NHC can be modulated by ligand effects by about 0.6 eV without

changing its σ donating properties. They further conceived that this remarkable electronic leeway

should provide a handle to control the reactivity of metal–NHC based catalysts. Therefore, a set of

new NHC–gold complexes were prepared and applied to the cycloisomerization of eneallene. The

products obtained were in accordance with their expectation thus proving that that it can be much

easier to tune the p-acceptor properties of NHCs than to alter their s-donor qualities by similar

margins thus challenging the previously held view of the Π acidity of NHCs which was often

neglected or considered irrelevant.

28

3.3 Synthesis of Gold-NHCs An overview of different methods of synthesizing is presented in the following section.

3.3.1 The silver oxide route- It was developed by Lin and co-workers 51 to generate the

appropriate [Ag(NHC)Cl] complexes that are used as NHC transfer agents when reacted with the

[Au(DMS)Cl] precursor (DMS = dimethylsulfide).

3.3.2 Ligand substitution reaction- The other is the free NHC in a simple ligand substitution

reaction.

The above two routes are depicted in scheme 3.1

Scheme 3.1- free NHC and Ag route to synthesise Gold- NHCs

3.3.3 In situ synthesis- The third possible route to synthesise them is by adapting an insitu

method. 52 The metal NHCs are currently most often generated in situ by combining a [Au(L)Cl] (L =

phosphine or NHC) complex with a silver additive which acts as a halide abstractor. The approach is

really straightforward and it involves the simple use of a silver reagent acting on the NHC bearing

gold species, namely, [Au(IPr)Cl] (IPr = 1,3-bis(diisopropylphenyl) imidazol-2-ylidene)(Scheme

3.2).

29

Scheme 3.2- Insitu production of a stable cationic Gold NHC complex

Most other reported syntheses are based on these techniques except for two new methods with

advantages of their own which were very recently reported.

3.3.4 The silver free route- In December 2011 S Zhu et al reported a direct and practical

approach for the synthesis of Au(I)-NHC complexes from imidazolium salts and commercially

available aurate salt (MAuCl4.2H2O)(scheme 3.3). 53 Most syntheses of Au-NHCs proceed with the

sacrificial role of the Ag2O which don’t make such processes judicious. Such synthesis of well

defined Gold NHCs have not been reported except for the ‘Gold Synthons’ of course which will be

treated shortly here after. The beauty of this particular synthesis was that it proceeded without

sacrificing carbene transfer agent (Ag2O) or using highly sensitive free NHC.

Scheme 3.3- Silver free route to synthesise Gold NHCs

They described a direct and practical approach for the synthesis of Au(I)-NHC complexes from

imidazolium salts and commercially available Au(III) salts. Owing to the advantages of mild

reaction conditions, one step, one-pot and silver-free process, insensitiveness to the air and

30

moisture, this reaction will probably become the choice for the synthesis of Au(I)-NHC complexes

by chemists.

3.3.5 The Gold Synthons

Late transition metal (LTM) hydroxide complexes have been described as environmentally friendly

complexes that can act as versatile synthetic reagents.

However, such Hydroxide complexes of the coinage metals are not well known and as far as Gold is

concerned, only Au(III) hydroxides are known. To tackle the problem of synthesisng Au(I)

hydroxides, Nolan et al used the old and faithful NHCs as the ancillary ligands and very cleverly

exploited the stabilising effects of NHCs. 54 This in turn helped them synthesise the Gold-NHC

bearing a hydroxide which can be visualised as an intrinsic bronsted base and which on treatment

with a bronsted acid generates the cation which is known to be the intermediate in most Gold-NHC

catalysed reactions (scheme 3.4). Not only that, it undergoes a plethora of other reactions with

other reagents which show how versatile these synthons can synthetically be.

Scheme 3.4- synthesis of the Gold synthon.

A lot of follow up chemistry regarding the catalytic utility of these synthons has been done by the

same group and an excellent overview has been documented by Nolan, P et al.

3.3.6 The piggyback synthesis -In another research published in early 2012, an intriguing

synthesis of the lesser known anionic N-Heterocyclic Carbenes was reported by M Tamm et al. 55 In

what they call the piggyback ride, they describe such systems as Anionic N-heterocyclic carbenes

that bear their negative charge in the form of a weakly coordinating anionic borate moiety in the

backbone. In their quest to add to the small family of anionic NHCs they succeeded in deprotonating

31

the position 4 in the NHCs using n-butyl Lithium and then treating it with B(C6F5)3. (scheme 3.5)

This gave the Lithium salts of the so called frustrated carbene borane lewis pairs.

Scheme 3.5- synthesis of the Lithium salts and 3d structure depicting the piggy back ride.

The appropirately substituted lithium salts were then added in a toluene suspension of

[(THT)AuCl] (THT=tetrahydrothiophene) to give the neutral Au-NHC catalysts which were then

shown to have comparable reactivity in enyne rearrangements.

The authors claim that this has two advantages at least. First, examples in which a silver-free

activation of neutral gold(I) precursors was employed are rare, and such protocols still remain

highly desirable. Furthermore, the cationic nature of the active catalysts usually requires the

reactions to be carried out in polar solvents, such as dichloromethane or acetonitrile, which might

be regarded as a limitation. The Weakly Coordinated Anion-NHC systems, on the other hand, offer

the possibility of producing neutral, single-source, carbene-gold catalysts for application in less

polar solvents and without the use of silver salts in any of the reaction steps.

32

3.4 Reactions involving Gold NHCs Reactions of Gold NHCs have been thoroughly treated by Nolan in two reviews, one in 2008 and the

other in 2011. 52, 56 The most common reactions are discussed in short in the following few

paragraphs. (For all abbreviations in the following section refer to scheme 3.1.)

3.4.1 Enyne cycloisomerisation and the likes-

The skeletal rearrangement of enynes is the most popular reaction in Gold-NHC catalysed

transformations. The efficient use of [(IMes)AuCl] (IMes=N,N o-bis(2,4,6-trimethylphenyl)imidazol-

2-ylidene) (Scheme 3.6), in conjunction with AgSbF6, has been reported for the intermolecular bis-

cyclopropanation of 1,6-enynes with alkenes. 57

Scheme 3.6- Cyclopropanation catalysed by [(IMes)AuCl]

In this transformation, the first cyclopropanation occurs intramolecularly, leading to

cyclopropylcarbene intermediate 3, which is trapped by an external alkene to afford bis-

cyclopropyl compound 4. For this specific transformation, the NHC ligand on gold outperformed

tertiary phosphine and phosphite ligands both in terms of yield and selectivity. The scope of the

reaction was found to be broad, encompassing cyclic and acyclic alkenes. Intramolecular

transformations have also been reported and optimization studies suggest that the solvent and the

silver salt are of key importance in steering the selectivity between the tetra (6) and tricyclic (7)

products formed (scheme 3.7). In these reactions two subsequent intramolecular cyclpropanations

occur and in the presence of an unsymmetrical diene, the second cyclopropanation occurs at the

less hindered double bond. Highly strained compounds are obtained from the double propanations

of 1,6-enynes which possess a 1,4 cyclohexadiene core, via a cyclopropanecarbene.

33

Scheme 3.7- intramolecular cyclopropanation catalysed by [(IPr)AuCl}

Toste and coworkers have reported different types of enyne cycloisomerisations done in the

presence of diphenyl sulphoxide, (scheme 3.8) which is found to oxidise the carbenic intermediate.

58 This also served as a proof that the reaction did indeed proceed through the

cyclopropanecarbene. Also, the IPr (figure 3.1) containing catalyst turned out to be more active in

these oxidation type reactions compared to PPh3 or IMes ones.

Scheme 3.8- Enyne cycloisomarisation in presence of Diphenyl Sulfoxide.

3.4.2 Reactions involving propargylic esters

In propargylic the ester moiety usually performs a 1,2- or 1,3- shift upon electrophilic activation of

the alkyne. So it is logical to expect that this intramolecular attack inhibits their reactivity with

carbene based catalysts. But interestingly, far from inhibiting their reactivity it actually triggers

carbene- and allene- based transformations.(scheme 3.9)

34

Scheme 3.9- intramolecular transformations in propargylic esters

In this context, a theoretical study by Cavallo and coworkers demonstrated that the intermediates

14, 15 and 16 are in rapid equilibrium and the resting state was probably 16. 59 The good thing

was that they also considered the PPh3 ligands and that made room for a comparison of the NHCs

with the phosphine based Gold catalysts. It was concluded in their paper that in case of the

Phosphines two resting states were possible with lowest energies. This might explain the

selectivities that gold NHCs show in these kind of reactions compared to Phosphine based catalysts;

or to say when allene based versus carbene based reactivity is necessary. Thus it can be said that

NHCs outperform the Phosphines on selectivity grounds. This, however, is to be taken with a word

of caution. Nature of ligand, nature of substrate and notably substitution at the ester and the

acetylenic positions also have a serious role to play.

In the context of the propargylic esters a lot of success has been achieved by the Gold-NHCs,

specially with the selectivity issues. They have been showed to be highly selective for cyclisation of

1,5-enynes bearing a propargylic acetate. 60 When an aryl moiety is present in the 1,4-enyne

structure they form substituted indenes. This transformation is described as a tandem [3,3]

rearrangement-hydroarylation reaction and this is supposed to be selective over cyclisation of the

1,5-enyne framework (scheme 3.10). Pre-isolated allenyl esters have also been used to form these

indenes thus supporting the allene intermeditates.

35

Scheme 3.10- tandem [3,3] rearrangement-hydroarylation reaction of propargylic esters.

3.4.3 Alkene activation-

The activation of alkenes is one of the less famous reactions of these catalysts when compared to

the ones involving alkynes. A diboration of olefins was reported by Frenandes et al in 2006 and that

was the first report of Gold-NHC used in a reaction of alkenes. 61 The complexes used, however,

were bis-NHC complexes and that is unusual in itself (scheme 3.11). They efficiently catalysed the

diboration of styrene and vinyl cyclohexadiene at room temperature.

Scheme 3.11- bis –NHC complexes used for diboration.

Hydroamination of unactivated alkenes has also been reported using [(IPr)AuCl] and it was found

to be very effective (scheme 3.12). 62 The IPr containing species shows higher reactivity when

36

compared to sterically hindered and electron rich o-biphenylphosphine containing gold species. A

large array of N-alkyl Ureas was hence effectively synthesized.

Scheme 3.12- hydroamination of alkenes.

Following the isomerisation of the allylic esters, an allylic rearrangement reaction of alkenes has

also been reported (scheme 3.13) where Π-activation of the C-C double bond in the substrate

triggers an intramolecular attack by the carbonyl oxygen to form a stable 6-membered 1,3-

acetoxonium species. 63 The carbonyl bond then forms again to yield the isomerised olefin.

Scheme 3.13- allylic rearrangement of alkenes.

37

3.4.4 Hydration-type reactions

During the studies concerning the indene formation mentioned before, Nolan’s group continuously

isolated a small amount of side product. On being probed into, this side product unfolded a whole

new reaction and then the mechanistic studies involving it led to the formulation of the gold

synthons that have been mentioned in the previous chapter (section 3.3.5).

The reaction is the following-

Scheme 3.14- Cycloisomerisation reaction of propargylic esters.

On upscaling the above reaction, the by product was obtained in higher yield and they noticed that

increasing the temperature led to greater formation of the conjugated enone side product. 64

Strikingly, the indene product is not formed at all if water is present and the reaction is heated. A lot

of substrates were subjected to this hydration of propargylic esters and satisfactory to good results

were obtained.

This reaction was then extrapolated to the Meyer-Schuster reaction (scheme 3.15) and was found

to be successful for tertiary alcohols and sterically demanding substrates. 65 It, however, failed to

work for terminal alkynes and primary alcohols.

Scheme 3.15- Meyer Schuster reaction of propargylic alcohols.

38

Following this accidentally discovered hydration, Nolan’s group then turned to the simpler

hydration of alkynes (scheme 3.16). These proceeded smoothly and at low catalyst loadings. These

reactions again demonstrated the fact that these catalysts were extremely active and very tolerant

of thermal treatment.

Scheme 3.16- hydration of different alkynes.

The next reaction that they turned to, to increase the foray of hydration reactions was the hydration

of other sp hybridized systems. The nitrile bond was an obvious choice and till then every other

LTM was used for this reaction except for gold. 66 It was found that the nitriles weren’t just

spectator entities in catalysis but could also react to form amides (scheme 3.17).

Scheme 3.17- hydration of nitriles.

39

3.4.5 Gold catalysis in a supramolecular cage- a step further ahead

Enzymes are by far the best catalysts known by humans and they have been the inspiration for the

synthesis of entities where the supramolecular interactions between the catalyst and the substrate

give rise to great selectivities. With breakthroughs in the field of supramolecular chemistry it has

been possible to synthesize capsules where the secondary sphere environment gives a handle over

activities and selectivities in chemical reactions. Hydrogen bonded capsules serve as good

candidates for this task and particularly promising is the large hexamer called volleyball formed by

C-alkylresorcin[4]arenes subunits. The global structure of the hexameric form conforms to the

snub-cube (one of the 13 Archimedean solids) as depicted in scheme 3.18 and represents a viable

way to build spheroidal cages with octahedral symmetry by means of copies of the same subunit.

Scheme 3.18- synthesis and structure of the C-alkylresorcin[4]arene hexamer.

The 60 hydrogen bonds holding the pieces together like a seam provide an extraordinary example

of cooperativity, 67 imparting stability to this structure in the solid state as well as in solution of

suitable apolar solvents. J. Rebek Jr., whose group studied extensively this hexamer in solution and

used for the first time the term volleyball, 68 defines this structure “an example of a system on the

verge of assembly”. 69 The hexamer self assembles spontaneously in wet chloroform and benzene,

40

including eight water molecules to form the complete snub cube that is globally chiral. The

aggregate hosts preferentially cationic species, but neutral ones can also be included in the

electron-rich internal cavity if they demonstrate a high surface complementarity. Chirality at the

supramolecular level, a distinctive characteristic of biological assemblies, opens the possibility of

guest discrimination using the volleyball by means of diastereomers formation. In 1997, 70 when

the C-methylcalix[4]resorcinarene hexamer was described for the first time, a plethora of possible

future applications were suggested for this nanocapsule, including chiral catalysis, drug delivery

and separation media. The first one in particular was supported by the fact that the internal cavity

was large enough to include organometallic complexes, a very uncommon property among organic

supramolecular hosts. The large surface interaction between a hosted organometallic catalyst, the

capsule and the substrates, together with additional supramolecular interactions, would provide

something similar to an enzymatic catalyst.

It took more than 10 years for this idea to be actually realized.

The first example of a transition metal catalyst encapsulated in the hexameric capsule formed by C-

undecylcalix[4]resorcinarene subunits was reported by Reek et al in 2010. 71 Furthermore it was

demonstrated that, in the hydration reaction of terminal alkynes, an (NHC)-Au carbene complex

demonstrates chemo- and regio-selectivities that are strongly different from the same catalyst

when free in solution.

The progress of the reaction was not very gallant because as one might expect, the capsule being

hydrogen bonded itself provides a physical barrier towards the entry of the substrate and its

interaction with the catalyst. But what is intriguing and remarkable is the composition of the

products. Au catalysts are known to give Markovnikov addition of water to alkynes to yield the

methyl ketones and recent literature has shown that under anhydrous conditions the same catalyst

transforms this substrate into 1,2-dihydronaphthalene via an intramolecular rearrangement

(scheme 3.19). 72

41

Scheme 3.19- different products of hydration of alkyne highlighting the impact of the

supramolecular cage.

In the case of this encapsulated catalyst the keto product (12%) was obtained along with some

linear aldehyde (5%) which is unprecedented for gold catalyst mediated hydration reactions. What

is more striking is that the intramolecular rearrangement product that is obtained in the anhydrous

reaction with the free catalyst was also obtained in equal amounts as the ketone. This implies that

the ‘cramping’ of reactants and catalysts inside the supramolecular cages does have an effect in the

regioselectivity of the catalyst being encapsulated. It is of course difficult to ‘see’ and comment on

what exactly is going on inside the capsule during the course of the reaction but one thing that is

intuitive is that intramolecular reactions will seem to be favoured compared to the inter molecular

ones because of the size issue. Also the participation of the solvent molecules in the reactions

cannot always be taken for granted as the capsule itself provides a barrier for the entry of solvent

molecules once catalyst and substrate have been encapsulated as this involves breaking and

reforming of some important H- bonds. In the next chapter we will see what could be the future

applications of this novel supramolecular cage in the field of Gold- N Heterocyclic Carbenes

catalysed reactions.

42


44. Schneider, S. K.; Herrmann, W. A.; Herdtweck, E. Synthesis of the First Gold(I)

Carbene Complex with a Gold-Oxygen Bond - First Catalytic Application of Gold(I)

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44

CHAPTER 4

Supramolecular catalysis in Gold NHC - catalysed reactions

The report of gold catalysis in a supramolecular cage discussed in section 3.4.5 really triggers

interest towards the possibilities that these supramolecular self assembling cages have to offer.

Catalysis using Gold NHC carbenes has undertaken a long journey in the last one decade and so

have supramolecular assemblies and the possibility of the culmination of the two looks like a new

road to be taken in the field of catalysis. Of course there are issues of compatibility as the cages are

very sensitive to the reaction conditions and substrates.

4.1 Can issues of catalyst poisoning/decomposition be tackled? Hopeful of the possible applications of these cages in Gold-NHC catalysed reactions a thorough

survey of literature was done to look for cases of the gold catalyst being poisoned due to the

presence of a cationic or a neutral species. If yes, then these cationic species could be encapsulated

in the cage as the cages have an affinity for cations. On the other hand if the catalyst poisons are

anionic then they would not be encapsulated. The catalyst being inside the cage would be

unharmed by the anionic poison and hence issues of poisoning could be tackled. But such examples

of poisoning are scarce. The only real poison in Gold NHC catalysts is traces of Palladium because

no sample of Gold is 100% pure and there is always some unavoidable amount of Palladium

present. 73 In this context an example worth mentioning was the Gold catalysed Sonagashira

coupling which initially caused a lot of interest in the catalysis community but later was shown to

be actually catalysed by traces of Palladium which was present in the catalyst sample. 74

Next, a search to find reported pathways of catalyst decomposition was done. One possible pathway

of decomposition common to all metal NHC complexes was found. This was the decomposition to

the imidozolium salts. Although more relevant to the ‘abnormal’ carbenes (scheme), this is believed

to be operational in normal carbenes too (Scheme 4.1). 75

45

Scheme 4.1- catalyst decomposition in ‘abnormal’ carbenes.

But this is of not much relevance to these cages as the cages have an affinity towards cations and if

we manage to encapsulate the imidazolium cation, we only facilitate more decomposition of the

catalyst as the above equilibrium lies majorly in the favour of the decomposition.

4.2 Can reactivity/ selectivity be altered? There was another important aspect of these cages that could be explored to see if anything

worthwhile in the reactions catalysed by the Gold NHCs could be achieved. This was the fact that

the hexameric cage provides a confined environment to the substrates and hence it might be

interesting to see if the selectivity issues in reactions catalysed byGold NHCs could be altered or

bettered. Again two things had to be kept in mind. First that the capsules organize themselves in

water saturated solvents and so reactions which need non-aqueous mediums were not the ones of

choice.

4.2.1 Conjugated enones from propargylic esters- a closer look

Most extensively studied reactions of the Gold NHCs are the enyne cycloisomerisations,

cyclopropanations and other rearrangement reactions. These are done in non-aqueous mediums

and had to be ruled out at once. However, the second most extensively studied reactions are the

hydration type reactions and the hydration of alkynes has already been studied in the report

mentioned earlier (section 3.4.4). Another interesting hydration reaction is that of propargylic

esters. This was a chance discovery made by Nolan’s group when they tried to characterize a

byproduct and found that it was formed only in the presence of trace amounts of water but in

presence of sufficient water molecules, the byproduct was the only product (section 3.4.4). 64

46

Scheme 4.2- effect of water on rearrangements of proargylic esters.

We have seen this reaction in the previous section but it might be interesting to zoom a little more

into the comprehensive paper that described it. A lot of substrates were screened and a lot of

mechanistic studies were undertaken too.

Many mechanisms were envisaged (scheme 4.3). First was a tandem [3,3] rearrangement followed

by hydrolysis. The second was a SN2’ type reaction where nucleophilic attack of water took place at

the center created by the Au+ interacting with the sp orbitals of the alkyne.

Scheme 4.3- suggested mechanisms for hydration of propargylic esters.

47

The substrate scope of this reaction was extensively studied and a variety of them proved to be

successful with great selectivities. Amongst these were propargylic acetates substituted at the

acetylynic position to study the effect of substitution. A variety of Cinnamaldehydes and

unactivated acetates were experimented with to study the importance of conjugation. The following

is a table of the formation of conjugated enones from the unactivated propargylic esters.

Table 4.1- hydration products of unactivated propargylic esters.

As can be seen from the table the trans alkene is the dominant product in most of these reactions as

these are the thermodynamically most favoured ones.

48

The reaction mechanism which was finally computed is as follows. (scheme 4.4)

Scheme 4.4- computed reaction mechanism for hydration of propargylic esters.

Between the trans and the cis products one product is kinetic and the other is thermodynamic. The

water addition in the penultimate step can go either re or si face but the final product stability is

dictated by sterics. Now if we turn to the table 4.1 and look at entry 6, we see that the

diastereoselectivity is rather poor. The E:Z ratio is only 1.2:1. This is due the ‘small’ difference in

bulk between the ethyl and the butyl groups which the incoming nucleophile, that is, the water

molecule is not able to distinguish between. Now, when the same reaction is carried out inside the

supramolecular cage where everything is ‘cramped’ it might be possible for the incoming

nucleophile, that is, the water molecule, to be able to distinguish between the two faces depending

49

upon the bulk of the substituent on each. If that was to actually happen then the product obtained

would be the one which is thermodynamically most favoured thus favouring higher ratios of the E

diastereomer.

This way of amplifying diastereoselectivity in the formation of these conjugated enones is posed

with a few problems though. A side product of this reaction is formic acid (scheme 4.4). The cage

might be affected if a molecule of acid is produced in each catalytic cycle leading to decomposition

of the cage itself. Next, the product itself is an enone. It will be in equilibrium with its enolate (in

presence of base). If the product somehow equilibrates on being released from the cage then we are

back to square one and all selectivity is lost again.

4.3 Conclusion After spending a good deal of time trying to explore all types of reactions catalysed by the Gold

NHCs and trying to find reactions compatible with the resorcinearene hexamer what could be

concluded was that maybe Gold catalysis in a supramolecular cage is not the way to go after all. The

idea that looked promising at the outset seems to be crippled with some practical issues.

The supramolecular cage described in the research article of Reek et al 71 is a good choice for the

hydration reaction catalysed by the Gold NHC carbene. It is enormous in volume and the catalyst

when encapsulated occupies about 30% of the volume of the cage still leaving room for the

substrate to be encapsulated according to the 55% occupancy rule. 76 Secondly, the catalyst is a

cationic species and the cage is known to have affinity towards cations. This makes encapsulation

favoured. Even then, the product formation is not very gallant. Both intra and inter molecular

pathways seem to be operating. Most reactions catalysed by Gold NHCs are based on Π systems and

in almost all of them rearrangement pathways are a possibility. So, on one hand if we try to exploit

the spatial constraints offered by a supramolecular cage to enhance selectivities we end up

promoting intramolecular paths. While on the other, most candidates for intramolecular

rearrangements like alkynes or allenes or any substrate containing Π systems, in general, will react

with water, when present. The supramolecular cages are held together with water molecules; that

is the glue that keeps the six molecules of the resorcinarenes in place and the hexamers form only

in the presence of water. So in reality neither intramolecular reactions nor the intermolecular ones

can be achieved in totality.

50

4.4 Outlook There is no denial to the fact that Gold NHC catalysed reactions in a supramolecular cage is

probably not a fruitful area of research. But gold is only one of the so many elements that have been

exploited for catalysis. There is an array of transition metal catalysed reactions out there and so this

survey of Gold- NHC catalysed reactions can be considered as a good starting point. There is

definitely a long way to go. Even the cages can be tuned according to needs of the reaction. It was

reported that cages made of pyrogallol arene sub units have a better affinity for neutral molecules

compared to the resorcine[n]arenes. 77 So for a neutral catalyst these cages could be preferred.

Another interesting supramolecular entity that was stumbled upon during this survey was the so

called ‘pumpkins’. In 1981, the macrocyclic methylene-bridged glycoluril hexamer (CB[6]) was

dubbed “cucurbituril” by Mock and co-workers because of its resemblance to the most prominent

member of the cucurbitaceae family of plants—the pumpkin. 78 The beauty of supramolecular

entities lies in the fact that with changes in shape and size what also accompanies is the change in

chemical properties. This is true for these glycouril hexamers too. These aren’t supramolecular

cages but are cavitands. Below is a picture of the structural formula, the top and the front view

(figure 4.1) and also of the electrostatic potential of the cucurbit[6]uril compared to a cyclodextrin

(figure 4.2).

Figure 4.1- structural formula, front and top view of (CB [6]).

51

Figure 4.2- electrostatic potential of a) cyclodextrin b) (CB [6]).

The more negative electrostatic potential of the cucurbit[n]urils means that they have better

affinities for cations. The preparation, host guest chemistry and applications of cucurbit[n]urils

have not yet reached the stage of advancement that the resorcinarenes or cyclodextrins have but

these pumpkin shaped entities look very promising. Two elaborate reviews are available, the latter

being published in 2011. 79,80 Not many applications of cucurbit[n]urils have been exploited in the

field of organometallic catalysis. This seemed obvious to start with because the cavities of these

cucurbit[n]urils aren’t large enough to host incoming organometallic catalyst, substrate and a

reactant.

However, a research published in 2010 81 looks really fascinating. In an attempt to mimic what the

p53 protein does in the body 82 , its various targets, its effects on apoptosis regulation, its role in

metabolism, and the various strategies to design p53- binding drugs a group at Ohio sought to

design a small organic guest, which could interact with different targets and which could undergo

chemical alteration by a third partner upon such an interaction. They sought to desilylate an alkenyl

species using a Silver catalyst in the presence of supramolecular hosts. The rates of desilylation

were enhanced under these conditions.

52

The following picture summarises what they achieved in terms of host guest interactions.

Scheme 4. 5- host guest chemistry of (CB[n])s.

So, depending on the size of the cavitand different specific parts of the substrate were enclosed and

not only that, the entry of one caused the exit of the other. This shows the excellent selectivities that

can be achieved by changing the number of glycouril units in the cavitand. The mechanism that they

propose is as shown in scheme 4.6.

Scheme 4.6- suggested mechanism for desilylation by Ag+

53

Here the Ag+ complexed with the alkyne is further stabilized by the Oxygen atom in the side

portfolio of the cavitand. The authors argue that contrary to their expectation that the cavitand

would slow the reaction due to the bulkiness, the observed enhancement in rate is due to the

stabilization of the transition state by the Oxygen atom. Thus, here is an example where a

supramolecular cavitand causes rate enhancement of a reaction by stabilizing the transition state.

The small sizes of the cavity of these cavitands don’t seem to be an obstacle because their selectivity

and affinity is high enough to host only the reactive part of the molecule.

So, maybe the resorcinarene and Gold NHCs aren’t a remarkable alliance but supramolecular

catalysis is overall an exciting field and hopefully more and more examples in practice will arise in

the future where the unique properties of these cages will be fruitfully exploited.

54


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