chapter six synthetic applications of a novel...

Synthetic Applications of a Novel Pd(OAc)2/DABCO/Hydrotrope Combined Catalyst at Room Temperature

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Chapter Six

Synthetic Applications of a Novel Pd(OAc)2/DABCO/Hydrotrope

Combined Catalyst at Room Temperature

6.1 Introduction

Coupling reactions are widely used routes for the formation of carbon-

carbon bonds and carbon–hetero atom bonds particular for the synthesis of

biaryl compounds. For Suzuki–Miyaura cross coupling reaction, the most often

used polar aprotic solvents are DMF, toluene, acetonitrile, THF and dioxane

because they allow best solubility of both the substrates and the catalyst.

Therefore, high conversions can be obtained in short reaction times, under mild

conditions with higher selectivities. But many of these solvents are toxic or

they are not easy to remove from the product because of high boiling points.

These solvents are the main reason for a non satisfying E factor (environmental

factor) especially in the pharmaceutical industry. The results of their use are

emissions to atmosphere and water pollution. Now a days, new solvents like

ionic liquids, supercritical fluids, fluorous solvents as support for homogeneous

catalysts are widely used in organic synthesis [1]. However, these alternative

reaction media are currently of considerable interest due to increasing emphasis

on making organic processes ‘greener’ by minimizing organic waste in the

form of organic solvents. The most likely alternative among the various choices

available, in terms of potential generality, is reaction in water.

SM reaction is generally carried out at high reaction temperature, which

has its drawback in lower selectivity, deactivation of catalyst and mass transfer

limitations. These disadvantages limit the SM reaction at high temperature,

hence the reaction at room temperature is highly desirable. The reaction was

mostly carried out by homogeneous catalytic systems, because of their high

reactivity, high turnover numbers and milder reaction conditions. However, the

efficient separation and subsequent recycling of homogeneous Pd catalyst

remains a scientific challenge and an aspect of economical relevance. Research

on recycling of the catalyst attracts interest but is rarely established in industry.


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In a biphasic solvent mixture, substrates and product are, dissolved in one

solvent whereas the catalyst is dissolved in the other, and hence a catalyst

recycling can be accomplished by easy decantation.

1,4-Diazabicyclo [2.2.2] octane (DABCO), a cage-like compound (Fig.

6.1), is a small diazabicyclic molecule with medium-hindrance. It is used to

regulate the reaction rate in flexplay time-limited DVDs by adjusting pH.

Antioxidants, like DABCO, are used to improve the lifetime of dyes. This

makes DABCO useful in dye lasers and in mounting samples for fluorescence

microscopy [2].

Fig. 6.1 DABCO has received considerable attention as an inexpensive,

eco‐friendly, high reactive, easy to handle and non‐toxic base catalyst for

various organic transformations, affording the corresponding products in

excellent yields with high selectivity Fig. 6.2. The reactions are environmental

friendly and the catalyst can be recycled in some cases. Applications of

DABCO in synthetic chemistry have been reviewed by Bita Baghernejad [3].

Fig. 6.2


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Morita–Baylis–Hillman reaction (MBH) is an organic reaction of an

aldehyde and an α, β-unsaturated compound containing electron-withdrawing

group to give an allylic alcohol in presence of DABCO as a catalyst (Scheme

6.1). The MBH reaction, in the present day version, is an atom-economic

carbon-carbon bond formation reaction [4].

R1

CHO

+ EWG

DABCO

R1

OH

EWG

Scheme 6.1

Luque and Macquarrie [5] have developed a metal-free DABCO

catalyst for Sonogashira coupling with or without microwave (Scheme 6.2).

DABCO

I

F CF3

Ph +

F

F3C

Ph

n-decane, heat

Scheme 6.2 Choe and Lee [6] demonstrated stereoselective DABCO-catalyzed

synthesis of (E)-α-Ethynyl-α,β-unsaturated esters (Scheme 6.3) from allenyl

acetates.

R

OAc

COOEt

. R

COOEtDABCO

DMF, rt

Scheme 6.3

Sarlo and co-workers [7] demonstrated DABCO as an efficient reagent

for the synthesis of isoxazole derivatives (Scheme 6.4) from primary nitro

compounds and dipolarophiles.

R NO2

R2R1

+

DABCO

CHCl3O

N

R1

R2

R

Scheme 6.4

Li and co-workers [8] have extensively studied the phosphine-free C-C

bond forming reactions using DABCO as a ligand under various reaction

conditions and are reviewed in Table 6.1.


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Table 6: Reported application of Pd(OAc)2/DABCO system in cross coupling

reactions.

X B(OH)2

R1 R2

+N

N

Pd-cat, base, solvent

R1

R2

Sr. No Reaction Solvent Temperature (ºC) Reference

1 Suzuki Acetone 110 [8a]

2 Suzuki DMF 110 [8b]

3 Suzuki PEG-400 110 [8c]

4 Stille Dioxane 100 [8d]

5 Sonogashira CH3CN MW [8e]

6 Sonogashira - Ball Milling [8f]

7 Sonogashira CH3CN RT [8g]

About many decades chemists began to retrieve the benefits of water as a

lovely substitute to the conventional organic solvents, not only due to the

availability and economical concern but also its greenness [9]. Traditionally

water is not proper solvent for organic transformations because of the limited

solubility of many organic substrates and reagents and functional group

tolerance, which causes the catalyst decomposition and deactivations.

Though recently effective methodologies are reported in literature for SM

reaction at room temperature in various organic solvents and in water with

heating, to the best of our knowledge very few data is available related to this

reaction in water at ambient temperature. Hence, to carry out SM reaction in

water at room temperature is highly desirable (Fig. 6.3).

Fig. 6.3


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In literature a variety of SM reactions has been carried out and outlined

bellow:

6.1.1 Suzuki-Miyaura reaction at room temperature in organic solvents.

6.1.2 Suzuki-Miyaura reaction at high temperature in water

6.1.3 Suzuki-Miyaura reaction at room temperature in water.

6.1.1 Suzuki-Miyaura reaction at room temperature in organic solvents:

Chun Liu et al. [10] developed a convenient, effective and mild protocol

for the palladium-catalyzed ligand-free Suzuki-Miyaura reaction in aqueous

DMF in presence of PdCl2 at room temperature.

Zhang and co-workers [11] developed a highly efficient

Pd(OAc)2/guanidine/ethanol:water system for the room temperature SM cross-

coupling reaction (Scheme 6.5).

Scheme 6.5

Saito and Fu [12] developed Ni-catalyzed SM cross-coupling of

unactivated alkyl electrophiles with alkylboranes at room temperature using

commercially available trans-N,N'-dimethyl-1,2-cyclohexanediamine ligand in

dioxane (Scheme 6.6).

R X

R1

NBB-9 NiCl2 glyme ligand

dioxane, rtR

R1

NH2

NH2

Ligand

+

Scheme 6.6

A versatile method was developed by Kirchhoff and co-workers [13]

for the cross-coupling of boronic acids with unactivated alkyl electrophiles at

room temperature using Pd(P(t-Bu)2Me)2 in t-amyl alcohol.

Rahimi and Schmidt [14] demonstrated 3,3'-[3,4-

Bis(dichloromethylene)cyclobut-1-ene-1,2-diyl]bis(1-methyl-1H-imidazolium)

bis(tetrafluoroborate), palladium(II)acetate catalyzed SM reactions (Scheme

6.7) in toluene.


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Scheme 6.7

Nolan et al. [15] developed (NHC)Pd(R-allyl)Cl complexes for Suzuki-

Miyaura reaction (Scheme 6.8) at room temperature in isopropanol.

Scheme 6.8

Yang, Li and Wang [16] introduced a recyclable Merrifield resin

immobilized phenanthroline-palladium(II) complex for SM reaction (Scheme

6.9) under mild reaction conditions.

Scheme 6.9

Zhang and co-workers [17] developed a highly active, air- and moisture-

stable and easily recoverable magnetic-nanoparticle-supported Pd catalyst

(Scheme 6.10) for SM reaction in ethanol.

Scheme 6.10

6.1.2 Suzuki-Miyaura reaction at high temperature in water:

Chao-Jun Li [18] demonstrated that Suzuki-Miyaura reaction in high-

temperature water without transition metals (Scheme 6.11).


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B(OH)2

+

Z

Br

TBAB, Na2CO3

Water, 150 oCZ

Z = Me, Ome, Cl, NH2, NO2 etc Scheme 6.11

Major modification is made available by use of soluble catalyst or

ligands [19] with this regard organoaqueous media which uses the water

soluble ligand has been emerged as a new way to carry out reactions in water.

As a part of a biphasic reaction mixture with the catalyst in the aqueous phase

and the product dissolved in the organic phase, easy product separation and

catalyst recycling is possible. This newly developed catalytic system that can

promote SM reaction in aqueous medium under mild reaction conditions using

a highly accessible and cheap ligand system would be extremely advantageous.

Liu and co-workers [20] developed oxygen-promoted PdCl2-catalyzed

ligand-free SM reaction in aqueous media.

Savignac et al. [21] described SM cross-coupling reactions between a

range of aryl bromides and boronic acids using a water-soluble Pd(0)/TPPTS

catalyst (Scheme 6.12) under mild conditions with high efficiency.

B(OH)2

+

R

Br

5 % Pd(OAc)2

15 %TPPTS

WaterR

Scheme 6.12

Shaughnessy and Booth [22] described sterically demanding, water-

soluble alkylphosphines (Fig. 6.4) in SM coupling in aqueous solvents.

3

SO3Na

P

1

2 3

Bu3P

NMe3

+

Cl-NMe3PR2

+

Cl-

Fig. 6.4


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Thermo regulated solvents, which are applied to enhance the

recyclability and because of environmental aspects, solvents, which are toxic or

non-volatile should be replaced with the aim of waste prevention rather than

waste treatment. Therefore, several research groups working in these areas

focused on different ideas. Liu et al. [23] developed an efficient and recyclable

protocol for the SM reaction in water based on the cloud point of thermo

regulated ligand Ph2P(CH2CH2O)nCH3 (Fig. 6.5).

Fig. 6.5

Jin and co-workers [24] introduced water-soluble imidazolium salts

bearing poly(ethylene glycol) moieties directly attached to N-atom of

imidazole which could be served as NHC precursors for the Pd-catalyzed SM

reaction in water (Fig. 6.6).

Fig. 6.6

Fleckenstein and Plenio [25] developed the highly active Pd complex of

the new disulfonated 9-(3-phenylpropyl)-9-PCy2-fluorene ligand (Fig. 6.7) in

aqueous SM coupling reactions.

Fig. 6.7


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The use of microwave ovens in organic synthesis is well acknowledged,

which is another alternative green technology in heating. The heating effect

utilized in microwave-assisted organic transformations is due to the dielectric

constant of the solvent. It is particularly convenient that, qualitatively, the

larger the dielectric constant of the reaction medium, greater is the absorption

of microwaves. With its high dielectric constant, water is also potentially a very

useful solvent for microwave-assisted organic synthesis.

There are various reports in literature [26] which uses MW assisted Pd

catalyzed reactions in water. Leadbeater and Marco [27] showed that the

Suzuki-type coupling of boronic acids and aryl halides is possible without the

need for a transition-metal catalyst under MW in water in presence of TBAB as

additive.

Yu and co-workers [28] demonstrated microwave-promoted SM

coupling reaction of aryl chlorides with boronic acids performed in an aqueous

media using air- and moisture-stable catalyst POPd2 (dihydrogen di-µ-

chlorodichlorobis(di-tert-butylphosphinito-κP)dipalladate) (Fig. 6.8).

Fig. 6.8

6.1.3 Suzuki-Miyaura reaction at room temperature in water (Use of

amphiphiles):

Peng and co-workers [29] disclosed an efficient catalytic system for the

ligand-free Suzuki–Miyaura reaction in water at room temperature, using

Stilbazo (Fig. 6.9) as a surfactant.

Fig. 6.9

Das and co-workers [30] described in situ generated catalytic system

based on PdCl2 and primary amine-based ligand (Fig. 6.10) in the SM reaction

of arylhalides in water, at room temperature, without any additive.


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Fig. 6.10

Suzuki-Miyaura reaction at room temperature in water has been

generally carried out in the presence of additives, which increases the solubility

of substrates in water. The diverse set of amphiphiles is reported in literature.

Yamamoto [31] has recently developed transition metal-catalyzed aryl

C–H bond activation reactions which provide an especially direct and atom

economical approach for functionalizing aromatic rings using Brij surfactant.

Zhang et al. [32] have shown that Pd(OAc)2, in combination with PEG,

can be used as a highly efficient catalyst for the SM coupling reaction in water.

Palladium-catalyzed Suzuki cross-coupling reaction in presence of

catalytic amount of quaternary ammonium salts Aliquat 336

(tricaprilylmethylammonium chloride) was described by Colobert and co-

workers [33].

Arcadi and his group [34] described palladium-catalyzed

Suzuki−Miyaura cross coupling reaction in various aqueous surfactants under

mild conditions.

Palladium on activated carbon (Pd/C) is also used as catalyst with the

advantages in recovery, refining of the palladium, the better performance at

higher temperatures without the need of expensive phosphine ligands and it

shows a low metal contamination of the products. The used carbon is

inexpensive and its large surface area (~1000 m2/g) allows Pd to disperse

widely on its surface. Carbon as support material is more stable to basic and

acidic conditions than alumina or silica. Recent reports have demonstrated the

applications of Pd/C for the Suzuki-Miyaura coupling as a convenient and

phosphine-free catalyst [35].

Lipshutz et al. [36] have published a series of papers demonstrating the

use of PTS (Polyoxyethanyl-α-Tocopheryl Succinate) surfactant derivative


176

(Fig. 6.11) in number of palladium- and ruthenium-catalyzed reactions in water

at room temperature.

Fig. 6.11

Unlike many amphiphile PTS is an unsymmetrical diester containing

three components: a dicarboxylic acid (Sebacic acid), a lipophilic portion in

vitamin E (or α-Tocopherol), and a hydrophilic subsection based on PEG-600

(Scheme 6.13).

B(OH)2

+

R2

Br

PTS

Water, RTR2

R1

R1

Scheme 6.13

Lipshutz and co-workers [37] have recently developed a second

generation surfactants based on the polyoxyethanyl-α-tocopheryl succinate

derivative, TPGS-750-M (Fig. 6.12).

Fig. 6.12

It is an effective nano micelle-forming diester species composed of

racemic α-tocopherol, MPEG- 750, and succinic acid, and has been readily

prepared and used in metal-catalyzed cross-coupling reactions like Heck,

Suzuki-Miyaura, Sonogashira, and Negishi, in water.

Hence, this chapter focuses on the application of Pd/DABCO catalyst, in

which a hydrpotrope enables the Nobel prize award-winning Suzuki-Miyaura

coupling reaction to be run in water at room temperature which is not been

reported in literature yet. Within the frame a parallel work of other coupling

reactions is processing in our laboratory.


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6.2. Present work

Recently highly effective methodologies are reported in literature for

Suzuki-Miyaura reaction at room temperature. Major modification is

forthcoming by use of soluble catalyst or ligands. Although these approaches

lead to water soluble catalysts, a sequence of steps is required in each

preparation. Hence very simple protocol for affecting the water solubilization

at room temperature in absence of co-solvent and without recourse to

alterations in substrate/commercial catalyst design is of prime importance.

To engender solubility most reactions in water were performed using a

co-solvent or some co-solutes such as PTC, surfactants etc [38]. Another

approach towards increasing the potential of water for organic synthesis to

compete with organic solvents is hydrotropism [39] similar to miceller catalysis

[40]. Thus hydrotropes are small amphiphilic molecules with hydrophilic

character having ability to increase solubility of organic compounds many fold

excess in water. As such hydrotropes are of great industrial interest, notably

their applications in drug solubilization in pharmaceuticals, separation sciences,

nanocarriers, and organic transformations.

There is large number of reports available, which uses the phosphine

ligands, as they show high activity in Suzuki-Miyaura reaction. But major

obstacle by use of phosphines is their toxicity, air sensitivity and difficulty in

reusability due to the formation oxide having high environmental concern.

Hence, development of phosphine-free Pd catalysis is emerged as new catalytic

tool in transition metal catalyzed reactions [41]. In this regard amine ligands

are emerging as good alternatives in many Pd catalyzed reactions [42], because

of ease of tuning their electronic characters, less toxicity and easy availability.

Recently DABCO was found to act as useful ligand in many Pd catalyzed

phosphine-free cross coupling reactions.

Very recently, we have demonstrated hydrotrope as efficient, green,

recyclable reaction medium for various organic transformations. Hence we

expected that this medium might help to improve the Pd(OAC)2/DABCO

mediated cross-coupling reactions at ambient temperature. Here, we report the


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detail study of Pd(OAC)2/DABCO/Hydrotrope combined catalyst for SM

reaction in aqueous medium at room temperature. Our motivation is to develop

aqueous reaction medium for Pd catalyzed C-C bond forming reactions with

high activity to compete with the homogeneous catalysts.

6.3 Results and discussion

In search of more economically, commercially available, functionally

viable amphiphilic hydrotropic agents like Sodium p-Toluene Sulphonate

(NaPTS), Sodium Xylene Sulphonate (NaXS), Sodium Benzene Sulphonate

(NaBS) and Sodium Salicylate (NaS) found immense importance. At the

outset, 4-bromobenzophenone 1 and phenyl boronic acid 2 were employed as

the reaction partners to optimize the various reaction conditions in aqueous

hydrotropic solution (Scheme 6.14) at room temperature.

O

Br

BOHOH

+

O

K 2CO 3

aq.hydrotropic solution

Pd(OAc) 2 , DABCO

1 23

Scheme 6.14 Pd(OAc)2/DABCO/Hydrotrope combined catalyst for

Suzuki-Miyaura coupling reaction.

The key focus of the use of hydrotropes as a reaction media depends on

the nature of the hydrotrope used and its minimum hydrotropic concentration

(MHC). MHC of NaXS hydrotrope is 0.012 M aqueous solution [43], this

concentration was first chosen to study its effect for Suzuki-Miyaura reaction

in water. It was observed that only 50 % conversion was obtained at room

temperature after stirring the reaction mixture for prolonged reaction time

(Table 6.2, entry 1).


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Table 6.2: Optimization of hydrotrope concentration in Suzuki–Miyaura

coupling reactiona

Entry Concentration

(w/v %)

Time

(h)

Yieldb (%)

1 0.012M 25 50

2 10 20 50

3 20 16 60

4 30 5 97

5 40 2.5 96

6 50 4.0 96

7 60 1.0 96

8 70 1.25 97

9 80 5 90

aReaction conditions: arylhalide (1.0 mmol), arylboronic acid (1.1 mmol), Pd(OAc)2 (1 mol

%), DABCO (10 mol %), K2CO3 (2.0 mmol) and aq. hydrotropic solution (5.0 mL), room

temperature under air. bIsolated yields after purification.

With this result in hand, we have determined the optimum amount of

hydrotrope in water to obtain maximum conversion of substrates in minimum

time. Hence various wt % solutions from 10-80 % of NaXS were screened. It

was observed that 60 % NaXS concentration in water appeared to be more

effective. Reactivity maxima are frequently observed for many reactions

reported in hydrotrope aggregates, which leads to the conclusion that there

must be an optimal reaction site in aggregate where the rate of reaction is

maximum.


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Table 6.3: Optimization of catalyst and ligand loading in Suzuki–Miyaura

coupling reactiona

Entry Pd(OAc)2

(mol %)

DABCO

(mol %)

Time

(h)

Yieldb (%)

1 0.25 10 10 20

2 0.5 10 4.5 90

3 1.0 10 1.0 96

4 2.0 10 1.0 97

5 1.0 5 1.0 96

6 1.0 10 1.0 96

8 1.0 20 1.0 96

9 1.0 - 12 70

10 1.0 TPP

(10 mol%)

16 10

aReaction conditions: arylhalide (1.0 mmol), arylboronic acid (1.1 mmol), Pd(OAc)2 (0.25-

1mol %), DABCO (5-20 mol %), K2CO3 (2.0 mmol) and 60 % aq. hydrotropic solution (5.0

mL), rt under air. bIsolated yields after purification.

The use of hydrotrope is advantageous as it is commercially available,

very least expensive and can be recycled many times with simple reaction

workup.

As hydrotropes increase the solubility of reactants in many fold excess,

the product precipitates on dilution with water from hydrotropic solution,

which leads to the product formation in crystalline form with an improved

purity, and the mother liquor can be used to concentrate the hydrotrope for

recycling. After the completion of reaction as monitored by TLC, the reaction

mixture is quenched with water and the crude products were either filtered

directly or extracted with diethyl ether. The addition of diethyl ether facilitates

the phase separation, which makes the separation of product facile.

When model reaction was carried in absence of NaXS, under identical

conditions, gave trace amount of the product. This observation suggests that the


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hydrotrope is presumably providing micro-environment for substrate or reagent

or catalyst accumulation in which the coupling takes place.

Next, optimization of Pd catalyst and DABCO ligand was done. After

various experimentations 1 mol % Pd(OAc)2 and 10 mol % DABCO was found

to be best for maximum conversion in minimum time at ambient temperature

(Table 6.3). Without any ligand, only a 70 % yield of the corresponding

product 3 was obtained in the presence of 1 mol % Pd(OAc)2 and 2 equivalent

K2CO3 (Table 6.3, entry 9), whereas the yield was increased to 96 % when 10

mol % DABCO was added. No increase in yield was observed, with increase in

amount of DABCO (Table 6.3, entry 8). When same reaction was carried in

presence of 10 mol % TPP the yield decreased to 10 % in 16 h indicate that

DABCO is far more effective than phosphines (Table 6.3, entry 10).

After the optimization of Pd, DABCO and hydrotropic concentration, a

series of hydrotropes such as, NaPTS, NaBS, NaS were used along with

Pd(OAc)2 and DABCO for model reaction with 60 % concentration. Results

revealed that NaXS is more active as compared to NaPTS, NaBS and NaS

(Table 6.4).

Table 6.4: Screening of the various hydrotropes for Suzuki–Miyaura coupling

reactiona

Entry Hydrotrope Hydrotropic

concentration (% w/v)

Time

(min)

Yieldb

(%)

1 NaPTS 60 1.5 95

2 NaXS 60 1 96

3 NaBS 60 2.5 93

4 NaS 60 5 92

aReaction conditions: arylhalide (1.0 mmol), arylboronic acid (1.1 mmol), Pd(OAc)2 (0.25-

1mol %), DABCO (5-20 mol %), K2CO3 (2.0 mmol) and 60 % aq. hydrotropic solution (5.0

mL), rt under air. bIsolated yields after purification.

We next investigated the scope of this reaction using different bromo

compounds with various aryl boronic acids in 60 % aqueous NaXS solution


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with 1 mol% Pd(OAc)2 and 10 mol% DABCO (Table 6.5) at ambient

temperature.

Table 6.5: The Suzuki-Miyaura reaction of various aryl halides and

arylboronic acidsa

Entry Aryl halide Arylboronic

acid Product

b

Time

(h)

Yieldc

(%)

1

O

Br

BOH)2

O

1 96

2

BOH)2

F

O

F

1 96

3 B(OH) 2

O

1 93

4 CH3

O

Br

BOH)2

O

0.75 96

5 B(OH) 2

CH3

O

0.75 95

6 CH3

O

Cl

BOH)2

CH3

O 24 20

7 H

O

Br

BOH)2

H

O 1 95

8 B(OH) 2

H

O

1 94

9

Br

BOH)2

12 40


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10 NBr Br

BOH)2

N

0.5 96

11

B(OH)2

Et

N

CH3 CH3

1 95

12

Br

BOH)2

18 50

aReaction conditions: arylhalide (1.0 mmol), arylboronic acid (1.1 mmol), Pd(OAc)2 (1 mol

%), DABCO (10 mol %), K2CO3 (2.0 mmol) and 60 % aq. hydrotropic solution (5.0 mL),

room temperature under air. bAll products were analyzed by

1H NMR,

13C NMR, and Mass spectroscopy.

cIsolated yields after purification.

4-Chloro acetophenone gave very less desired product even on

extending the reaction time to 24 h (Table 6.5, entry 6), as compared to aryl

bromides. Very less yield of the corresponding product was observed, when the

reaction of 2-bromofluorene, 4-bromobiphenyl, with phenyl boronic acid

(Table 6.5, entry 9 and 12), and this point indicated that the catalytic system is

highly selective towards the nature of the substrates used. In general

Pd(OAC)2/DABCO/Hydrotrope combined catalytic system was the carrier of

choice for a wide range of aryl boronic acids, but not good for range of aryl

halides.

Another striking feature of catalyst was easy recovery from the reaction

mixture. As hydrotrope are more soluble in water than in organic solvents,

almost 100 % of catalyst was quite easily recovered from the aqueous solution

after the reaction was completed. The reaction mixture was quenched with

water and the precipitated product was simply separated by extraction with

diethyl ether. The catalyst was in the aqueous layer and only removal of water

gave the catalyst which could be used in the next reaction. To assess the

reusability of catalyst, recycling experiments were carried out with 4-

bromobenzophenone and phenylboronic acid as substrates over the four

reaction cycles. After each experiment, the aqueous solution of catalyst was

recovered by extraction, washed thoroughly with diethyl ether, concentrated


184

and then subjected to a new run with fresh reactants under identical reaction

conditions. The results showed in Table. 6.6 indicated that catalyst could be

reused for at least five runs and yield of the product decreases continuously

with increasing reaction time.

Table 6.6: Recycling of Pd(OAC)2/DABCO/Hydrotrope combined catalyst in

Suzuki-Miyaura coupling reaction

Cycle Aryl halide Time (h) Yield (%)

1 1 96

2 26 90

3 48 50

4 48 30

5

O

Br

48 15

Characterization of products:

4-(naphthalen-5-yl)benzaldehyde (Table 6.5, entry 8): The 1H NMR

spectrum (Fig. 6.15) of the compound showed multiplet for four Hd protons

present on naphthalene ring at δ 7.42-7.57 ppm, while another multiplet at δ

7.89-7.93 ppm for two He protons (Fig. 6.13). One deshielded dd signal at δ

8.02 ppm is for two Ha protons of benzene ring and coupled to Hb proton of

same ring which showed doublet at 7.69 ppm. One Hc proton of naphthalene

ring resonated as doublet at 7.84 ppm having J = 8.4 Hz. Spectrum also showed

one sharp singlet at δ 10.13 ppm of aldehydes proton. 13

C NMR spectrum (Fig.

6.16) of same compound exhibited thirteen signals in the aromatic region from

δ 125.2 to 147.1 ppm, while signal at δ 191.1 ppm represent aldehyde carbon.


185

Fig. 6.13

6.4 Conclusion

The conclusion from this study was that hydrotrope was essential for

SM reaction in water at room temperature. The procedure is very simple like

‘dump and stir’ in water. The reagents and reaction medium (hydrotrope and

water) are readily available. No special precautions are needed in terms of

solvent degassing or protection of reactions from air. Isolation of products

involves simple filtration/extraction of reaction mixtures. No modifications of

catalyst/substrate were required to enhance their water solubility, nor any

special techniques involved. Easy recovery of product and possible reuse of

hydrotropic solutions makes this protocol the most attractive, particularly at

industrial levels. Hydrotropy technique is unique technique that eliminates the

costly organic solvents and energy normally involved in the conventional

organic transformations.

6.5 Experimental section

1H NMR and

13C NMR spectra were recorded on a Brucker AC (300

MHz for 1H NMR and 75 MHz for

13C NMR) spectrometer using CDCl3 as

solvent and tetramethylsilane (TMS) as an internal standard. Infrared spectra

were recorded on a Perkin-Elimer FTIR spectrometer. The samples were

examined as KBr discs ~ 5 % w/w. Melting points were determined with a

DBK melting point apparatus and are uncorrected. All the chemicals were


186

obtained from Aldrich, Spectrochem and were used without further

purification.

Typical experimental procedure for the Suzuki-Miyaura reaction

Arylbromide (1.0 mmol) and aryl boronic acid (1.1 mmol) was added to

a round bottom flask containing aqueous hydrotropic solution (5 mL). The

reaction mixture was stirred at room temperature and Pd(OAc)2 (1 mol %),

DABCO (10 mol %), and K2CO3 (2.0 mmol) were added to a flask and allowed

to stir until completion of reaction as determined by TLC. The resulting

reaction mixture was poured into water (15 mL), extracted with diethyl ether

(3×10 mL), and dried over anhydrous Na2SO4. Crude product was isolated and

purified by column chromatography from n-hexane-ethyl acetate.

Spectral data for representative compounds:

Biphenyl-4-carboxaldehyde (Table 6.5, entry 8): Low melting solid. IR

(KBr): υ = 3039, 2900, 2842, 1706 (C=O), 1608, 1390, 1200, 1166, 1018, 837,

805, 775, 689 cm-1

. 1H NMR (CDCl3, 300 MHz): δH (ppm): 7.30-7.35 (m, 3H),

7.60 (d, 2H, J = 7.6 Hz), 7.72 (d, 2H, J = 8.2 Hz), 7.89-7.91 (m, 2H), 10.00, (s,

1H). 13

C NMR (CDCl3, 75 MHz): δC (ppm) 191.3, 147.5, 141.0, 135.6, 130.7,

130.0, 128.9, 128.0, 127.8.

2,6-diphenylpyridine (Table 6.5, entry 10): White solid, observed mp 73–75

°C. IR (KBr): υ = 3055, 3030, 1585, 1485, 1421, 1389, 1333, 1242, 1071,

1010, 927, 818 cm-1

. 1H NMR (CDCl3, 300 MHz): δH (ppm): 7.50–7.59 (m,

6H), 7.70–7.86 (m, 3H), 8.19-8.25 (m, 4H). 13

C NMR (CDCl3, 75 MHz): δC

(ppm) 118.4, 127.0, 128.5, 128.9, 137.2, 139.4, 156.8.

2,6-bis(4-ethylphenyl)pyridine (Table 6.5, entry 11): White solid, observed

mp 106-108 °C. IR (KBr): υ = 2963, 2923, 2868, 1651, 1572, 1412, 1187,

1163, 1120, 1042, 1015, 802, 743 cm-1

. 1H NMR (CDCl3, 300 MHz): δH

(ppm): 1.30 (6H, t), 2.71 (4H, q), 7.27-7.54 (4H, m), 7.64-7.94 (4H, m), 8.06-

8.10 (3H, m). 13

C NMR (CDCl3, 75 MHz): δC (ppm) 15.5, 28.7, 118.0, 126.9,

128.2, 128.3, 137.3, 139.0, 145.2, 157.0.

Synthetic Applications of a Novel Pd(OAc)2/DABCO/Hydrotrope Combined Catalyst at Room

Temperature

194

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187

6.6 Spectra

Fig. 6.14 IR spectrum of 4-(naphthalen-5-yl)benzaldehyde

188

Fig. 6.15 1H NMR spectrum of 4-(naphthalen-5-yl)benzaldehyde

189

Fig. 6.16 13

C NMR spectrum of 4-(naphthalen-5-yl)benzaldehyde

190

Fig. 6.17 1H NMR spectrum of (4-(naphthalen-4-yl)phenyl)(phenyl)methanone

191

Fig. 6.18 13

C NMR spectrum of (4-(naphthalen-4-yl)phenyl)(phenyl)methanone

192

Fig. 6.19 1H NMR spectrum of 1-(4-(naphthalen-5-yl)phenyl)ethanone

193

Fig. 6.20 13

C NMR spectrum of 1-(4-(naphthalen-5-yl)phenyl)ethanone

chapter six synthetic applications of a novel...

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