Current Organic Chemistry, 2010, 14, 0000-0000 1

1385-2728/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.

Cyclodextrins as Mass Transfer Additives in Aqueous Organometallic Catalysis

H. Bricout,a,b,c

F. Hapiot,a,b,c

A. Ponchel,a,b,c

S. Tilloya,b,c

and E. Monfliera,b,c

*

a Univ Lille Nord de France, F-59000 Lille, France

b UArtois, UCCS, Faculté des Sciences, Rue Jean Souvraz, SP 18, 62307 Lens, France

c CNRS, UMR 8181, F-59650 Villeneuve d’Ascq, France

Abstract: During the past fifteen years, the use of chemically modified cyclodextrins (CDs) in aqueous organometallic catalysis has sig-

nificantly contributed to enlarge the application field of biphasic processes in chemistry. In this paper, we describe how these su-

pramolecular receptors became one of the most efficient solutions to solve mass transfer problems in aqueous organometallic catalysis.

The scientific gaps that have been cleared to explain the exact role of the CDs in these biphasic systems are especially emphasized. In

particular, the impact of supramolecular interactions between chemically modified CDs and substrates, water soluble ligands or or-

ganometallic catalysts is addressed for a better understanding of the recognition processes involved in the catalytic reactions.

INTRODUCTION

Due to concerns about the environmental impact of chemical

transformations, chemists are challenged to develop clean processes

and promote waste recovery. Thus, catalytic routes are preferred to

stoichiometric ones and toxic solvents are replaced whenever pos-

sible by eco-friendly media such as liquid and supercritical CO2,

ionic liquids or water. In this context, the reactions catalyzed by

organometallic complexes in water appear particularly attractive.

Indeed, in addition to environmentally benign process conditions,

the aqueous/organic biphasic organometallic catalysis can also offer

advantages in terms of product/catalyst separation [1]. In fact, the

organometallic catalyst that is immobilized in the water by water-

soluble ligands such as the sodium salt of meta trisulfonated

triphenylphosphine (TPPTS – Scheme 1) can be easily separated

from products by decantation of the aqueous and organic phases at

the end of the reaction (Fig. (1)).

Fig. (1). Principle of aqueous/organic biphasic organometallic catalysis.

*Address correspondence to this author at the Univ. Artois, UCCS, Faculté des Sci-ences, Rue Jean Souvraz, SP 18, 62307 Lens Cedex, France; Tel: +33-321-791-772;

Fax: +33-321-791-755; E-mail: eric.monflier@univ-artois.fr

Although appropriate for partially water-soluble organic mole-

cules, this biphasic process does not allow the transformation of

highly hydrophobic substrates. To circumvent this crucial problem

and promote mass transfer between an organic phase and a catalyst-

containing aqueous compartment, the use of co-solvent [2], surfac-

tants [3,4], amphiphilic phosphines [5,6], dispersed particles [7] or

amphiphilic copolymers [8] has been reported. Nevertheless, the

reusability of these catalytic systems is not always guaranteed as

the formation of stable micro-emulsions or partition of the catalyst

in both phases can often occur.

During the past fifteen years, we developed the use of cyclo-

dextrins (CDs) as mass transfer promoters. A full description of

CDs is given in numerous reviews and papers [9]. Very concisely,

CDs are a class of naturally occurring receptors which are cyclic

oligosaccharides constituted of six ( -CD), seven ( -CD), or eight

( -CD) D-glucopyranose units. Their shape is a conical cylinder

whose inner surface is hydrophobic and outer surface hydrophilic

(Fig. (2)).

The aim of this paper is to gather all the data collected so far on

the use of CDs in aqueous organometallic catalysis. We will espe-

cially emphasize our contribution in the field and show how chemi-

cally modified CDs have been decisive to improve the catalytic

performances of many catalytic reactions.

1. 1986-1994: DIFFICULT BEGINNINGS

The 1986-1994 period saw the emergence of CDs as additives

in aqueous organometallic catalysis. The story began in 1986 when

H. Alper et al. successively published two papers on the use of

native CDs in palladium-catalyzed olefin oxidation and rhodium-

catalyzed conversion of carbonyl compounds to hydrocarbons

(Table (1)) [10,11].

In these papers, two main features of the CD-based catalytic

system already appeared. First, the activity of the system strongly

depended on the nature of the CD. Thus, in the oxidation reaction

of 1-decene by means of oxygen, palladium chloride and copper

chloride in water, the native -CD proved to be more efficient than

the native -CD, itself better than the native -CD. Adverse effects

were even evidenced with the native -CD in the rhodium-

catalyzed reduction of p-methoxyacetophenone. The yield was

lower than that obtained using -CD and was even less than in the

absence of a CD. Second, CDs modified the chemoselectivity of the

2 Current Organic Chemistry, 2010, Vol. 14, No. 13 Bricout et al.

reactions. Thus, when styrene underwent carbon-carbon bond

cleavage to benzaldehyde when oxidation was attempted using a

quaternary ammonium halides or PEG-400 as the phase transfer

catalyst, styrene was mainly converted to acetophenone when the

reaction was performed using native CDs. These pioneer works

were swiftly followed by Takahashi et al. who confirmed the effi-

ciency of native CDs as additives in palladium-catalyzed olefin

oxidation [12]. Conversely to what Alper previously observed,

similar selectivities were measured with - and -CDs. The authors

also noted that the reaction occurred in the bulk water phase but no

proof of this statement was given.

It then took four years to see other papers on the topic. In 1990,

the concept of CDs as additives to promote the mass transfer in a

biphasic system was extended to the deoxygenation of allylic alco-

hol [13], the hydrogenation of , -unsaturated acids and their de-

rivatives [14], and the hydrogenation of conjugated dienes [15]. At

this stage, the role of the CDs was not clear. Alper wrote about

cobalt-catalyzed deoxygenation of allylic alcohol: “Clearly, while

-cyclodextrin is not essential for this biphasic reaction, its pres-

ence is beneficial in promoting olefin formation”. The notion of

CD/substrate supramolecular complex even disappeared for the

benefit of the existence of adduct between the organometallic cata-

lyst and the CD. In hydrogenation of conjugated dienes, the CD was

believed to act as a supramolecular host but also as a second-sphere

ligand for the HCo(CN)53-

catalyst. Concurrently, the conclusions

of Joó about the reduction of aromatic and aliphatic aldehydes by

hydrogen transfer using CDs were not encouraging since the author

stated that “ -cyclodextrin resulted in inhibition of the metal com-

P

SO3Na

R

R

SO3Na

NaO3S

R

NN

N

P

ClN

NN

P

O

P P

NaO3S SO3Na

P SO3Na P

SO3Na

SO3Na

NaO3S

P

CO2Li

CO2Li

LiO2C

TPPMS TPPTS TPPTC

Sulfoxantphos

ortho-substituted TPPTS(R = -CH3 or -OCH3)

PTA (N-Bz-PTA)Cl

P (CH2)4 P

tetrasulfonated 1,4-bis(diphenylphosphino)butane

NaO3S

NaO3S

SO3Na

SO3Na

Scheme (1). Water-soluble ligands in CD-based aqueous catalysis.

Fig. (2). Chemical structure of native cyclodextrins.

Cyclodextrins as Mass Transfer Additives in Aqueous Organometallic Catalysis Current Organic Chemistry, 2010, Vol. 14, No. 13 3

plex-catalyzed transfer hydrogenation” [16]. The adverse effect of

the CDs in organometallic catalysis was also demonstrated by Jack-

son in hydroformylation of olefins [17]. In that case, a hydrogen-

bonding interaction between the -CD hydroxyls and the ligand

sulfonate groups of the HRh(CO)(TPPMS)3 complex (TPPMS:

sodium salt of mono sulfonated triphenylphosphine - Scheme (1))

was invoked to explain why the native -CD was not appropriate

for mass transfer in this biphasic system but no spectroscopic evi-

dence of such an interaction was given.

Finally, Lemaire et al. showed that, when -CD was added in a

MeOH/H2O mixture, similar enantiomeric excesses to those ob-

served in pure methanol were obtained in asymmetric hydrogena-

tion of -keto ester using a diamine as chiral inductor [18].

In the light of these results, the use of CDs did not appear a

very attractive approach to improve the mass transfer in aqueous

organometallic catalysis. Their impact on the activity and selectiv-

ity seemed to be very dependent on the reaction conditions, espe-

cially the nature of the catalyst and the substrate. Nevertheless, a

major advance was achieved in 1994 by our group with the use of

modified CDs.

2. 1994: A SIGNIFICANT BREAKTHROUGH

In 1994, we discovered that chemically modified CDs (Table

(2)) exhibited a better catalytic activity than native CDs in a

Wacker oxidation reaction of terminal alkenes catalyzed by a palla-

dium / heteropolyacids / copper system (Table (3)) [19-21]. The

best results were obtained with the randomly methylated -CD

(RAME- -CD – Table 2). RAME- -CD is a mixture of -CDs

partially O-methylated with statistically 12.6 OH groups modified

per CD. The OH groups in C-6 position are fully methylated

whereas those in C-2 and C-3 positions are partially methylated.

This CD allowed to oxidize in high yields a wide range of higher -

olefins. Furthermore, the 2-ketone selectivity was especially high as

isomerisation of the -olefins into internal olefins was not observed

in the presence of this CD [19,20]. Varying the substrate alkyl chain

length clearly indicated the requisite adequacy of the CD host cav-

ity with the substrate structure. An optimal length of 10 carbons

was found beyond which the oxidation yield decreased [20].

The high efficiency of chemically modified CDs in Wacker

oxidation was also later reported by Karakhanov et al. [22,23]. The

authors demonstrated that -CDs modified by polyoxoethylene

chains were more active in Wacker oxidation than surfactants- or

polymers-containing systems. They also showed that the presence

of polar modifying groups on the CD affected notably the molecu-

lar recognition ability of the CD. For instance, the presence of

oxyethyl groups substantially increased the formation constants for

substituted styrenes due to resulting enlarged CD cavity [23]. Their

works have been extended to other oxidation reactions such as hy-

droxylation of benzene or phenol by hydrogen peroxide [24] and

oxidation of alkyl aromatic compounds by hydrogen peroxide

[23,25].

Once the feasibility of a CD-based catalytic system was demon-

strated in Wacker oxidation, we extended the concept to many other

catalytic reactions [26]. Very interesting results were especially

Table 1. Catalytic Reactions Performed in the Presence of Native CDs

Catalytic Reaction Scheme References

Palladium-catalyzed olefins oxida-

tion (Wacker reaction) RR'

PdCl2 ; CuCl2

O2

RR'

O

[10, 12]

Rhodium-catalyzed reduction of

carbonyl compounds R

O

R'

Rh catalystR R'

H2

[11]

Cobalt-catalyzed deoxygenation of

allylic alcohols R R'

OH

R R'

H2, CoCl2

KOH, KCN, KCl

[13]

Cobalt-catalyzed hydrogenation of

a,b-unsaturated acids and deriva-

tives R R'

O H2, CoCl2

KOH, KCN, KClR R'

O

[14]

Cobalt-catalyzed hydrogenation of

conjugated dienes +

H2, CoCl2

Base

[15]

Transfer hydrogenation of alde-

hydes R

O

H

H2, catalyst

HCOONa R

OH

H

[16]

Rhodium-catalyzed hydroformyla-

tion of higher olefins R

Rh catalyst

CO + H2

RCHO +

R

CHO

[17]

Asymmetric hydrogenation of -

keto ester R

O

COOCH3

Catalyst

R

OH

COOCH3H2

[18]

Nickel-catalyzed alkylation of

aldehydes R

O

H

Ni(COD)2+ R'3B

P(t-Bu)3R

OH

R'

[68, 69]

4 Current Organic Chemistry, 2010, Vol. 14, No. 13 Bricout et al.

obtained in the biphasic rhodium-catalyzed hydroformylation of 1-

decene [27]. At 80°C under 50 bar CO/H2 with HRh(CO)(TPPTS)3

as catalyst, the reaction was completed within 6 h, the aldehydes

selectivity being 95%. The reaction was strongly dependent on the

nature of the CD substituents and the CD substitution degree. For

example, acetylated or hydroxypropylated -CD led to lower activ-

ity and selectivity. The permethylated -CD also gave poor results.

With RAME- -CD as an additive, the catalytic gains were all the

more remarkable that the substrate was water-insoluble, emphasiz-

ing the role of the CD on the mass transfer between both the aque-

ous and organic phases [28]. It was also demonstrated that the cata-

lytic system consisting of the metal, the water soluble ligand and

RAME- -CD can be quantitatively recovered. Indeed, with RAME-

-CD, the phase separation between the organic and aqueous

phases was fast and no increase in catalyst leaching into the organic

phase was observed. The rhodium and phosphorus content in the

organic phase were found to be less than 0.5 and 1.2 ppm, respec-

tively. Additionally, gravimetric analyses demonstrated the reus-

ability of the system as no trace of CD was found in the organic

phase at the end of the reaction. In a paper published in 1998, Kalck

et al. confirmed our results in higher olefin hydroformylation and

showed that the heptakis(2,6-di-O-methyl)- -CD exhibited better

catalytic performances than the native -CD for -olefins contain-

ing more than 8 carbons [29]. In another paper, they demonstrated

that the catalytic system can be recovered and that each new run

presented a slightly higher level of activity [30]. Finally, the behav-

ior of the chemically modified cyclodextrins during the cobalt-

catalyzed hydroformylation of higher olefins was found very simi-

lar to that observed during the rhodium-catalyzed hydroformylation

[31]. Here again, the results demonstrated that RAME- -CD gave

good conversion (>92%) and selectivity (>92%) for the hydro-

formylation of higher olefins without impeding the recovery of the

catalytic system.

In the hydrocarboxylation of terminal alkenes using a

Pd/TPPTS system, RAME- -CD was found to be more efficient

than cosolvents to solve mass transfer limitation [32]. The unex-

pected high acid selectivities (up 90%) were attributed to the pro-

tective effect of the CD cavity. Noticeably, a high initial turnover

frequency of 400 h-1

was obtained with RAME- -CD as additive in

a ruthenium-catalyzed hydrogenation of water-insoluble aldehydes

[33]. The formation of inclusion complexes between CDs and vari-

ous components of the reaction medium (aldehyde, alcohol) was

evidenced by NMR and electrospray mass spectrometry [34]. Dur-

ing this work, it was also demonstrated that the dilution of substrate

in an organic phase affected the catalytic activity. Thus, from a

practical view point, if an organic phase is absolutely necessary to

dissolve the substrate (e.g. a solid aldehyde), the affinity between

organic phase and CD should be as low as possible. On the con-

trary, when the substrate is a liquid, the hydrogenation is advanta-

geously performed without any organic phase.

Thus, chemically modified CDs showed a very different behav-

ior in aqueous catalysis when compared to natives CDs. In particu-

lar, the partial substitution of the hydroxyl groups by methyl groups

Table 2. Chemically Modified CDs in Aqueous Organometallic Catalysis

O

O

OGGO

GO

1

2

3

4

5

6 n

G: H or R

n: 6 or 7

Abbreviation n Substituent (R) Carbon Bearing the OR

Group Number of R Group by CD

RAME- -CD 6 -CH3 2, 3 and 6 10.8

RAME- -CD 7 -CH3 2, 3 and 6 12.6

HTMAP- -CD 6 CH2 CH

OH

CH2 N+(CH3)3Cl-

2 1

3- -1 6

-(CH2)3-SO3K

-CH3

6

2 and 3

6

12

4- -1 6

-(CH2)4-SO3K

-CH3

6

2 and 3

6

12

3- -1 7

-(CH2)3-SO3K

-CH3

6

2 and 3

7

14

4- -1 7

-(CH2)4-SO3Na

-CH3

6

2 and 3

7

14

4- -2 7

-(CH2)4-SO3Na

-CH2-CH3

6

2 and 3

7

14

Cyclodextrins as Mass Transfer Additives in Aqueous Organometallic Catalysis Current Organic Chemistry, 2010, Vol. 14, No. 13 5

had a favourable effect on the CD mass transfer properties with

improvements of both activity and selectivity in many different

reactions. Nevertheless, some of the catalytic results remained un-

explained. For example, in the rhodium-catalyzed hydroformylation

of terminal alkenes, the linear/branched aldehydes ratio signifi-

cantly decreased in the presence of RAME- -CD but no clear ex-

planation could be given. Thus, at this stage, a better understanding

of the CD interactions with all the protagonists of the catalytic sys-

tem was necessary.

3. 1999: CDS TRAP TPPTS

In 1999, a spectroscopic study allowed us to make another ma-

jor advance in the comprehension of the recognition processes be-

tween the CDs and the components of the catalytic system. We

showed by UV-visible, circular dichroism, 1H and

31P NMR spec-

trometry that the water-soluble phosphine TPPTS could be included

in the -CD cavity with an association constant of 1,200 M-1

±10%

at 298 K [35,36]. T-ROESY experiments were especially indicative

of the existence of the -CD/TPPTS supramolecular complexes as

Table 3. Catalytic Reactions Performed with Chemically Modified CDs

Catalytic Reaction Scheme References

Palladium-catalyzed olefins oxida-

tion (Wacker reaction) RR'

PdCl2, CuCl2

RR'

O

O2

[19-23, 26]

Hydroxylation of benzene or phenol

R

Fe3+

/H2O2

R

R = H or OH OH

[23, 24]

Oxidation of alkyl aromatic com-

pounds R

Fe3+

/H2O2R

O

[23, 25]

Rhodium-catalyzed hydroformyla-

tion of higher olefins R

Rh catalyst

CO + H2

RCHO +

R

CHO

[26-31, 38, 39, 44, 45,

46, 48, 49, 50, 57, 58, 61, 62]

Aldehydes hydrogenation

R

Ru catalyst

R H

O

H

OHH

H2

[26, 33, 34]

Palladium-catalyzed hydrocar-

boxylation of higher olefins R

Rh catalyst

CO + H2OR

COOH +R

COOH

[26, 32]

Palladium-catalyzed cleavage of alkyl allyl carbonates

RO

O

O

Pd catalyst

HNEt2

R-OH + CO2

NEt2+

[40, 47, 56, 63, 64, 65, 66, 67]

Palladium-catalyzed telomeriza-

tion of butadiene with glycerol +

HO

HOOH

Pd(acac)2

TPPTS

O

ORRO

+

O

ORRO

[70]

Rhodium-catalyzed polymeriza-

tion of substituted acetylene monomers

Rh catalyst

HN

O

R

n

HN

O

R

[71]

6 Current Organic Chemistry, 2010, Vol. 14, No. 13 Bricout et al.

intense cross-peaks between the inner protons of the CD and some

of the sulfonated ligand protons were detected on the 2D spectrum.

The TPPTS inclusion in the CD cavity was also evidenced by scan-

ning tunnelling microscopy [37]. Structurally speaking, it clearly

appeared that the TPPTS phosphorus atom was located near the CD

secondary hydroxyl side, suggesting that the phosphorus was not

able to complex a metal anymore (Fig. (3)).

The impact of this study on our research was tremendous since

it allowed understanding the variation of l/b aldehyde ratio in the

CD mediated hydroformylation reactions. Actually, by trapping the

ligand, the CDs were strongly suspected to affect the equilibrium

between the different catalytic species [38]. The experimental proof

of this phenomenon was established three years later by High Pres-

sure NMR experiments [39]. In the presence of RAME- -CD under

CO/H2 pressure at 80°C, the 31

P NMR spectra of the

HRh(CO)(TPPTS)3 rhodium precursor showed chemical shift varia-

tions indicative of the formation of phosphine low-coordinated

rhodium species (Figs. (4) and (5)).

Fig. (3). Side view and top view of -CD/TPPTS inclusion complex.

Fig. (4). 31P{1H} NMR spectra at room temperature in D2O of a) [RhH(CO)(TPPTS)3] (1) under 50 atm (CO/H2) after 1h at 80 ºC; b) 1 + 3 equiv RAME- -

CD under 50 atm (CO/H2) after 1h at 80 ºC; c) 1 + 9 equiv RAME- -CD under 50 atm (CO/H2) after 1h at 80 ºC. [RhH(CO)2(TPPTS)2] (2);

[Rh2(CO)5(TPPTS)3] (3); [Rh2(CO)6(TPPTS)2] (4); [Rh2(CO)7(TPPTS)] (5) (Reproduced with permission from ref 39. Copyright Wiley-VCH Verlag GmbH &

Co. KGaA).

Cyclodextrins as Mass Transfer Additives in Aqueous Organometallic Catalysis Current Organic Chemistry, 2010, Vol. 14, No. 13 7

Knowing that HRh(CO)(TPPTS)2 and HRh(CO)2(TPPTS) con-

stitute the active species responsible for the formation of the linear

and branched aldehydes respectively, the inclusion of TPPTS in the

RAME- -CD cavity led to a decrease in the concentration of the

former and an increase in the concentration of the latter. As a con-

sequence, the linear/branched aldehyde ratio significantly dropped

from 2.7 without CD to 1.8 when RAME- -CD was used as addi-

tive. Detrimental effects of the CD/phosphine interaction have also

been demonstrated in the palladium-catalyzed cleavage of water-

insoluble alkyl allyl carbonates (Tsuji-Trost reaction) [40]. Indeed,

when the TPPTS/RAME- -CD ratio was too high, the CD was

poisoned by the sulfonated ligand and the substrate transfer signifi-

cantly decreased. Thus, the TPPTS/RAME- -CD ratio has to be

accurately controlled. Note that one and two-dimensional NMR

investigations showed that the mono sulfonated triphenylphosphine

(TPPMS) could also form 1:1 inclusion complexes with -CD, 2-

hydroxypropylated- -CD, RAME- -CD and (2-hydroxy-3-

trimethylammoniopropyl)- -CD chloride [41,42]. The obtained

supramolecular complexes were more stable than those obtained

with TPPTS. A thermodynamic study realized on three monosul-

fonated isomers of triphenylphosphine and -CD also demonstrated

that all inclusion complexes were enthalpy stabilized but highly

entropy destabilized [43]. Studies have also been carried out with

the carboxylated analogue of TPPTS, namely the meta tricarboxy-

lated triphenylphosphine (TPPTC - Scheme (1)). As TPPTS,

TPPTC also proved to interact with CDs. NMR measurements

(Job’s plots) were consistent with a mixture of 1:1 and 1:2 -

CD/TPPTC complexes. The existence of 1:2 complexes resulted

from the natural tendency of carboxylates to form dimeric species

[44].

4. 2000-2009: TOWARDS A BETTER UNDERSTANDING OF

THE CATALYTIC PROCESS

During this period, considerable efforts have been performed to

avoid the phosphine/cyclodextrin interaction and to get a better

insight into the role of CD in the rhodium-catalyzed hydroformyla-

tion of higher olefins.

4.1. How to Avoid the CD/Phosphine Interaction

The interaction between the RAME- -CD cavity and the ligand

used to dissolve the organometallic catalyst in the aqueous phase

can be prevented by using hydrophilic bulky phosphines. For ex-

ample, sulfoxantphos (Scheme (1)) weakly interacted with RAME-

-CD (Ka < 450 M-1

), resulting in very impressive catalytic results

in hydroformylation of 1-octene and 1-decene [45]. The chemose-

lectivity was over 99% and the high l/b aldehyde ratio of 33 was a

consequence of a steric congestion generated by both the bulky

sulfoxantphos ligand and the CD which forced the substrate to react

by its terminal carbon to give preferentially the linear aldehyde.

Note that the affinity of bidentate phosphines for -CDs was found

to be dependent on the nature of linker between the phosphorous

atoms. Thus, 1, -bis(diarylphosphino)alkanes such as tetrasul-

fonated 1,4-bis(diphenylphosphino)butane (Scheme (1)) interacted

more strongly with -CDs than sulfoxantphos [46]. The difference

of affinity was attributed to the great flexibility of the alkyl chain

compared to the xanthene skeleton. Recently, we showed that re-

placement of TPPTS by its ortho-trimethylated or ortho-

trimethoxylated meta-trisulfonated triphenylphosphine derivatives

(Scheme (1)) prevented the inclusion process to occur [47]. Benefi-

cial effects of this absence of interaction were observed in the pal-

[RhH(CO)(TPPTS)3]+ CO

[RhH(CO)2(TPPTS)2] + TPPTS

TPPTS

TPPTS + [RhH(CO)(TPPTS)2]

-CO

TPPTS + [RhH(CO)2(TPPTS)]

TPPTS

linear aldehyde

branched aldehyde

[Rh2(CO)5(TPPTS)3] + TPPTS

+ CO

TPPTS + [Rh2(CO)6(TPPTS)2]

TPPTS

TPPTS

(4)

(1) (2)

(3)

+ CO

[Rh2(CO)7(TPPTS)] + TPPTS

(5)

TPPTS

-H2TPPTS

+CO

Fig. (5). Shift of the equilibra towards phosphine low-coordinated rhodium species in the presence of RAME- -CD.

8 Current Organic Chemistry, 2010, Vol. 14, No. 13 Bricout et al.

ladium-catalyzed cleavage reaction of allyl undecyl carbonate.

1,3,5-triaza-7-phosphaadamantane (PTA) or its N-benzylated de-

rivative (N-Bz-PTA)Cl (Scheme (1)) could also be considered as

non-interacting phosphines as no alteration of the catalytic per-

formances was detected with these phosphines in the presence of

RAME- -CD [48]. This can be easily rationalized by invoking the

more hydrophilic character of PTA or (N-Bz-PTA)Cl resulting from

the presence of highly solvated atoms (three nitrogen and one phos-

phorus atoms). Their ability to form hydrogen bonds with water

disfavoured the enthalpic loss upon desolvation and prevented in-

clusion of PTA or (N-Bz- PTA)Cl in the hydrophobic CD cavity.

When TPPTS is used as ligand, the interaction between the

ligand and the CD can be suppressed by changing the size of the

CD cavity or by chemically modifying the -CD. In fact, the -

cyclodextrin cavity was too small to include one of the TPPTS sul-

fonated aromatic ring [40]. Thus, RAME- -CD led to good cata-

lytic performances in a palladium-catalyzed cleavage reaction of

alkyl allyl carbonates [40] and in rhodium-catalyzed hydroformyla-

tion [49]. In rhodium catalyzed hydroformylation of 1-octene, the

conversion with 1-octene was even higher than the one observed

with RAME- -CD and reached 96% after 6 hours with an excellent

aldehyde selectivity of 99% and a l/b aldehyde ratio was 3.0 [49].

Improvements in the l/b aldehyde ratio can also be realized by

means of cationic -CDs. Indeed, -CDs bearing 2-hydroxy-3-

trimethylammoniopropyl groups (HTMAP) (Table (2)) greatly in-

creased the reaction rate, the chemoselectivity and above all the

regioselectivity [50]. Thus, l/b aldehyde ratios up to 3.6 were meas-

ured, indicative of the in situ formation of new catalytic su-

pramolecular species obtained by ion-exchange between the cata-

lyst ligand and HTMAP- -CD. Contrary to supramolecular cata-

lysts where the CD was coordinated to the catalysts [51-55], ionic

bonding of CD to the organometallic catalyst offered the advantage

of a reversible interaction with the catalyst. Consequently, when the

CD was used in large excess with respect to the catalyst, the bind-

ing of the substrate/CD inclusion complex to the catalyst was tran-

sient and CD could behave as a supramolecular shuttle between the

catalytically active centre and the bulk or interface (Fig. (6)).

Another solution to avoid interaction between TPPTS and -CD

consisted in chemically modifying a -CD by sulfonated arms to

generate steric and electrostatic repulsions with the sulfonate

groups of TPPTS. Thus, grafting a sulfoalkyl group on the secon-

dary face of a native -CD resulted in a significant decrease in the

interaction with TPPTS [56]. Nevertheless, the catalytic activity of

these mono-substituted CDs remained low because they showed

poor adsorption ability at the aqueous/organic interface. More

elaborated CDs have then been designed. In particular, modified

CDs sulfoalkylated on their primary face and alkylated on their

secondary face (n- -n’ or n- -n') have been synthesized by Green

and co-workers (Table (2)) [57,58]. In addition to the absence of

interaction with TPPTS, these CDs have a strong amphiphilic char-

acter which means that they can adsorb very easily at an or-

ganic/water interface to improve the mass transfer between both

phases. The catalytic activities obtained with these CDs were higher

to those measured with partially methylated or hydroxypropylated

CDs. Note that the best activities in rhodium-catalyzed hydroformy-

lation of 1-decene were measured with 4- -n' (more than 250-fold

increase in relative reaction rate over that measured without CD).

However, an unconsidered lengthening of the alkyl chain grafted on

the secondary face of the CD had detrimental effect on the phase

separation. Thus, stable micro-emulsions were obtained with 4- -2

( -CD sulfobutylated on its primary face and ethylated on its sec-

ondary face) in rhodium-catalyzed hydroformylation of 1-decene

and the system was not valid in terms on reusability.

4.2. 2006-2007: The Role of Modified CDs Finally Elucidated

In 2006, the role of chemically modified CDs as mass transfer

promoters was finally elucidated. Indeed, the adsorption of CDs and

their complexes at the aqueous/organic interface has been demon-

strated by Wipff et al. [59,60]. A molecular dynamics study helped

explain which of the supramolecular complexes and/or catalytic

species were adsorbed at the interface. Their findings indicated that

the catalytic pathway was initiated by the adsorption of the CD to

the liquid interface. Once the CD adsorbed, the substrate was in-

cluded in the cavity with the double-bond preferentially oriented

towards the aqueous phase. Contrary to native CDs, methylated

CDs adopted specific amphiphilic orientations upon adsorption at

the liquid interface, the wider opening of the CD cavity pointed to

the water phase. This orientation facilitated further reaction with the

organometallic catalyst. When the inactive HRh(CO)(TPPTS)3 was

solubilised in water, the “active” forms of the catalyst

Fig. (6). Transient formation of organometallic complexes in the presence of a -CD bearing a cationic group. S represents a substrate included into the CD

cavity.

Cyclodextrins as Mass Transfer Additives in Aqueous Organometallic Catalysis Current Organic Chemistry, 2010, Vol. 14, No. 13 9

HRh(CO)(TPPTS)2 and HRh(CO)(TPPTS)2(decene) preferred the

interface over the bulk aqueous phase. In fact, CDs did not act as

“shuttles” transferring the hydrophobic olefin into the aqueous

phase but formed inclusion complexes pre-organized for the reac-

tion at the aqueous/organic interface (Fig. (7)).

CDs were considered as promoters, increasing the local concen-

tration of interacting species at the interface. The CD adsorption at

the liquid interface reduced the interfacial pressure and increased

the interfacial area, leading to enhanced contacts between species.

Conversely to the inverse phase transfer catalysis observed for

lower olefins, the catalytic process for higher olefin was truly an

interfacial phenomenon. As a conclusion, for higher olefins, the

reaction did not take place in the bulk water but right at the liquid-

liquid interface where all partners of the catalytic process were

concentrated (Fig. (8)).

The above molecular dynamics study has been confirmed by

surface tension measurements. Indeed, the surface tension meas-

urements demonstrated that chemically modified CDs such as

RAME- -CD adsorbed at the air-water interface. Furthermore, a

good correlation between surface excess (i.e. the CD concentration

adsorbed at the interface) and catalytic activity was obtained in the

case of hydroformylation of 1-decene [61]. The higher the CD con-

centration at the interface, the higher the catalytic activity.

Additionally, it has very recently been demonstrated that the

RAME- -CD efficiency was dependent on the CD methylation

degree [62]. A crude mixture of RAME- -CD has been fractionated

by chromatographic column to evaluate the influence of the methy-

lation degree on activity and selectivity of a rhodium/TPPTS cata-

lytic system in hydroformylation of 1-decene. Each sample of

methylated -CD was carefully analyzed by matrix-assisted laser

desorption/ionization time-of-flight mass spectrometry (MALDI-

TOF-MS) and electrospray ionization mass spectrometry (ESI-MS).

The catalytic activity was found to gradually increase with the

number of methyl groups on the methylated -CD whereas the

chemoselectivity and regioselectivity remained unchanged.

5. WHAT ELSE WITH CHEMICALLY MODIFIED CDS?

Not only behave modified CDs as mass transfer promoters but

also as multi-functional compounds. We detail below four examples

where the CD cannot be considered as a simple mass transfer addi-

tive.

The first example concerned catalytic discriminating processes

where chemically modified CDs behaved as enzyme mimics. In

fact, when the organic phase contained an isomers mixture, the

water soluble catalyst reacted with the isomer that preferentially

interacted with the CD cavity, inducing substrate selectivity (Fig.

(9)) [63,64].

This type of catalytic system clearly exhibited enzyme-like

properties. By using different pairs of structural isomers, it was

found that the substrate selectivity strongly depends on the water

solubility and the isomers structure. Thus, high substrate selectivity

could only be observed with highly water-insoluble isomers that

present pronounced structural differences. For example, alkyl or

(a) Inverse phase transfer catalysis (b) Interfacial catalysis

Fig. (8). Principle of aqueous biphasic organometallic catalysis mediated by modified CDs.

Fig. (7). [RhH(CO)(TPPTS)2(decene)]/2,6-dimethyl- -CD complex ad-

sorbed at the decene/water interface. This structure was generated by a

molecular dynamics simulation. (Reproduced with permission from ref 60. Copyright Wiley-VCH Verlag GmbH & Co. KGaA).

10 Current Organic Chemistry, 2010, Vol. 14, No. 13 Bricout et al.

arylalkyl allyl carbonates with a linear structure were more easily

transformed than branched ones. Moreover, the substrate-selectivity

effect was all the more marked that the substrates were hydropho-

bic. The size-fit concept which postulates the highest reactivity for

the best size-matched host–guest pair provided a very useful tool

for predicting the values of substrate selectivity [65,66]. However,

it was noteworthy that the presence of small organic water-soluble

molecules such as amine or alcohol derivatives appeared to be cru-

cial in the discriminating process. Indeed, the presence of such ad-

ditives greatly enhanced the substrate selectivity [67]. For instance,

the addition of triethylamine to the reaction medium improved the

discriminating power of methylated- -CD by a factor of 7. These

unexpected results were explained by considering the formation of

ternary CD/substrate/additive complexes.

The second example shows that modified CDs can increase the

reactivity of the substrate towards the catalyst. Thus, H. Yorimitsu

and K. Oshima reported that the reaction of benzaldehyde with a

trialkylborane having a benzyl ether moiety can be greatly im-

proved by adding native -CD into the reaction medium [68]. The

authors assumed that the CD suppresses an unfavourable interaction

between the nickel catalyst and the substrate by including the aro-

matic ring of substrate into its cavity [69].

The third example concerns the stability of the organometallic

catalyst in the aqueous phase. So, it has recently been shown that

RAME- -CD could reduce leaching of organometallic catalyst into

organic phases [70]. Indeed, A. Behr et al. demonstrated that addi-

tion of RAME- -CD in a palladium-catalyzed telomerization of

butadiene with glycerol significantly decreased the amount of cata-

lyst in the organic phase. The authors suggested that the catalyst

could attach itself to the polar CD and was retained in the aqueous

phase owing to the low solubility of RAME- -CD in the organic

phase.

Finally, the last example shows that stoichiometric amounts of

CD relative to the substrate can also be used. Thus, the inclusion

ability of hydroxypropylated -CD (HP- -CD) towards hydropho-

bic, substituted, acetylene monomers has very recently been turned

to good account in a polymerization reaction. Actually, D. Yang et

al. showed that Rh-based polymerizations of acetylene deriva-

tives/HP- -CD inclusion complex provided high-yield (>90%)

polymers with a nearly quantitative cis content [71]. The resulting

polymers could take an ordered helical conformation, as observed

with their counterparts obtained in organic solvents.

CONCLUSION

Throughout this paper, the reader should have noticed the pro-

gresses that have been made during the past twenty years in the

understanding of the role of CDs in aqueous organometallic cataly-

sis. From non-convincing results obtained with native CDs to the

high catalytic performances of RAMECDs, an effective solution is

now at hand to solve mass transfer problems between an organic

and aqueous phase. Our current knowledge on chemically modified

CDs not only allowed us to optimize aqueous biphasic systems but

also stimulated our research in many others fields such as heteroge-

neous catalysis [72,73] design of new supramolecular catalysts [74]

or synthesis of catalytic active species by CD-induced decoordina-

tion of ligand [75]. Thereby, the common ground of knowledge

acquired until now on chemically modified CDs constitute the

source of the future gains to be harvested at the interface of su-

pramolecular chemistry, organometallic, surface science and cataly-

sis.

ACKNOWLEDGEMENTS

This work was supported by the Centre National de la Recher-

che Scientifique (CNRS), the Ministère de l’Enseignement Supé-

rieur et de la Recherche and the Agence Nationale de la Recherche.

Roquette Frères (Lestrem, France) is gratefully acknowledged for

generous gifts of cyclodextrins. The authors are grateful to G.

Crowyn for his technical contribution.

ABBREVIATIONS

CD = cyclodextrin

RAME- -CD = randomly methylated -cyclodextrin

RAME- -CD = randomly methylated -cyclodextrin

HTMAP- -CD = 2-hydroxy-3-trimethylammoniopropyl -

cyclodextrin chloride

HP- -CD = hydroxypropyl -cyclodextrin

TPPTS = sodium salt of the meta trisulfonated

triphenylphosphine

TPPMS = sodium salt of the meta monosulfonated

triphenylphosphine

TPPTC = lithium salt of the meta tricarboxylated

triphenylphosphine

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