122

CHAPTER 3

RESULTS AND DISCUSSION

3.1 ULLMANN CONDENSATION OF HALOTHIOPHENE -

CARBOXYLIC ACIDS WITH SODIUM BISULPHITE

3.1.1 Observation Against Literature Information

While studying the Ullmann type nucleophilic substitution reactions

of chloro- and bromothiophene carboxylic acids with sodium bisulphite under

aqueous conditions, it was observed that 3-bromothiophene-2-carboxylic acid

3b underwent a facile substitution compared to 3-chlorothiophene-2-

carboxylic acid 3a (Scheme 3.1).

S

X

COOH

X= Cl (3a)

X= Br (3b)

NaOH / NaHSO3

CuCl / Reflux

pH 7.5- 7.7

S

SO3Na

COONa HCl / KClS

SO3K

COOH

(5a)

100 °C

(4a)

Scheme 3.1 Ullmann condensation with sodium bisulphite

The cuprous chloride mediated substitution of bromo acid 3b was

completed in 2 h at 100°C under standard conditions (entry 3, Table 3.1).

Interestingly no ligand was employed for this reaction. The conversion in the

case of chloro acid 3a was only 3.5% at 100°C (entry 1, Table 3.1). The

chloro acid 3a required heating of the content to 140- 143°C under autoclave

condition for 16 h for the nucleophilic substitution (entry 2, Table 3.1). The

123

nucleophilic substitution did not take place without cuprous chloride catalyst

(entry 4, Table 3.1).

Table 3.1 HPLC monitoring results of substitution reactions of 3a and

3b with sodium bisulphite

Entry SM Catalyst Temperature

Monitoring results

HPLC area%

Time

(h)SM

Product

4a

1 3a CuCl 100 °C 3 95.4 (3a) 3.5

2 3a CuCl 140 °C 16 8.3 (3a) 81.7

3 3b CuCl 100 °C 2 Nil (3b) 89.2

4 3b Nil 100 °C 3 97.6 (3b) Nil

Although one would expect that bromo acid 3b can be used as the

starting material for the preparation of monopotassium salt of 3-

sulphothiopohene-2-carboxylic acid 5a, strangely the literature has

recommended only the use of corresponding chloro acid 3a (Dieter et al

1987). No specific reason has been cited for this preference of chloro

analogue over bromo analogue. Otto and Dieter (1979), in their patent work,

specifically stated that chloro acid 3a was the preferred starting material

compared to the bromo acid 3b without stating any reasons. Thus, the higher

reactivity of bromo acid 3b observed in this present work was in contradiction

to literature reports. A scalable, industrial and cost effective route towards the

synthesis of mono potassium salt of 3-sulfothiophene-2-carboxylic acid 5a

from 3-bromothiophene-2-carboxylic acid 3b was achieved. It is interesting to

note that there was no direct preparation of 5a from bromo acid 3b reported in

the literature. A comparison between the literature procedure and the current

research procedure is given in Table 3.2.

124

Table 3.2 Comparison of literature procedure vs. current research

process for the synthesis of 5a

Feature Literature procedure Current research procedure

Raw material Uses 3- chlorothiophene -2-

carboxylic acid 3a as the

starting material. This is

prepared from 3-

chlorothiophene 1a, which

costs Rs. 7000/ kg.

Uses 3-bromothiophene -2-

carboxylic acid 3b as the

starting material. This is

prepared from 3-

bromothiophene 1b, which

costs Rs 2600/ kg.

Capital cost The capital cost includes

basic requirement of a high

pressure kettle (Specialized

equipment).

Common stainless steel

reactors can be utilized which

are easy to maintain. No

specialized equipment is

required.

Experimental

conditions

Autoclave heated at

140 -143°C for 16 h.

Atmospheric pressure refluxing

at 100°C for 2 h.

Production

throughput

Limited to autoclave

equipment.

Utilizes common stainless Steel

reactor for reaction.

Yield 85% (taking in to account

about 10% unreacted starting

material)

85% (No starting material)

By product The liquid effluents from the

reaction contains sodium

chloride which is a common

chemical

The liquid waste contains

sodium bromide which is a

very useful chemical that can

be recovered in large scale

Energy saving Reaction conducted at 140-

143°C for 16 h in an

autoclave. The reaction did

not take place at 100°C.

Reaction conducted at 100°C,

in stainless steel reactor. The

reaction completed in 2 h.

125

The monopotassium salt of 3-sulphothiophene-2-carboxylic acid 5a

obtained from this research work was completely characterized by spectral

analysis (Section 2.5).

This procedure was scaled up successfully towards consistent

quality and yield of the monopotassium salt 5a (Table 3.3).

Table 3.3 Results of industrial scale preparation of 5a

EntryInput of 3b

(Kg)

Output 5a

(Kg)

HPLC Purity

(%)

1 175 165.6 99.4

2 177 165.8 99.6

3 175 160.1 99.7

3.1.2 Design of Experiments

In order to understand the higher reactivity of the bromo acid 3b

over that of chloro acid 3a and to study the mechanism of this nucleophilic

substitution, experiments were designed and conducted as shown in Table 3.4.

3-bromothiophene-2-carboxylic acid 3b was considered as the model

compound for the research studies under standard condition as given below.

Standard condition – The starting material (SM) was dissolved in one

equivalent of 10% aq. sodium hydroxide. Aqueous sodium bisulphite solution

(1.15 equiv. 37% aq.w/w), unless otherwise mentioned, was added and the pH

was adjusted to 7.5-7.7 using 30% aq. NaOH. Cuprous chloride (0.1 mol) was

added to the reaction mixture, unless otherwise mentioned, and the mixture

was heated to 100°C, unless otherwise mentioned.

126

Table 3.4 Design of experiments

S.No Experimental Design

1 Effect of different catalysts (AgNO3, ZnCl2, NiCl2, Lanthanum triflate,

Ytterbium triflate, Pd (OAc) 2, Pd (OAc) 2 with BINAP as ligand and

without catalyst).

2 Effect of different copper catalysts (CuCl, CuBr, CuI, CuO, Cu(OTf)2,

CuCl2, Cu(0), CuCl with TBAB as phase transfer catalyst)

3 Influence of temperature

4 Influence of pH

5 Optimal catalyst loading

6 Effect of co-solvents and additives (ethanol and 1,4-dioxan as co-

solvents and NaCl and 2,2’-bipyridyl as additives)

7 Different loading of nucleophile (sodium bisulphite)

8 Different nucleophiles (sodium sulphite , calcium bisulphite, cesium

bisulphite and no nucleophile)

9 Isomeric bromothiophenecarboxylic acids

10 Influence of different EWG substituent instead of carboxylic acid

( -COCH3 , -COOMe)

11 Effect of radical scavengers ( TEMPO, oxygen, p-dinitrobenzene,

THF, BHT)

12 Microwave conditions (microwave conditions, 80°C and 100W)

Samples were drawn at specified intervals from the reaction mixture

and analyzed by HPLC (mobile phase methanol: water: TFA:

TEA=1500:500:1:0.5 v/v; wavelength 254 nm and flow rate 1 mL per

minute.). The product was isolated wherever required, by acidification with

con. HCl followed by treatment with KCl as monopotassium salt of the

corresponding sulphothiophene carboxylic acid.

127

The required starting material viz., bromo acid 3b is known in the

literature (Tietze and Lohmann 2002, Kou-Yi and Ludwig 1975, Corral et al

1985, Masami Takahashi 1993 and Gol’dfarb and Vol’kenshteuin 1959). The

methods described in the literature for the preparation of bromo acid 3b either

employ chemicals that are hazardous and difficult to handle in large scale like

n-butyl lithium, grignard reagent or reagents like potassium permanganate,

potassium chlorate for oxidation of bromo ketone 2b. All these methods either

involve isolation issues or possess environment, safety and health (EHS)

concern. A simple two step route was envisaged for the synthesis of the

bromo acid 3b as outlined in Scheme 3.2.

S

Br(1b)

EDC/ AlCl3

S

Br(2b)

COCH3NaOCl

(oxidation)

S

Br(3b)

COOHCH3COCl

Scheme 3.2 Synthetic scheme for the preparation of 3-

bromothiophene-2-carboxylic acid 3b

Friedel-Crafts acetylation of commercially available

3-bromothiophene 1b, following a similar literature procedure (Pelly 2005)

afforded 3-bromo-2-acetylthiophene 2b, in 90% yield (Section 2.3). The

crude 2b as such was converted to the corresponding carboxylic acid 3b in

80% yield (Section 2.4) by haloform reaction using aqueous sodium

hypochlorite solution (10% w/w) following a similar literature reference

(Arnold, 1952). This simple and safe route which is amenable for large scale

manufacture of bromo acid 3b has not been exploited so for. This safe and

scalable process was successfully standardized to produce the bromo acid 3b

with consistent quality and yield in multi kilo levels (Table 3.5).

128

Table 3.5 Multi kilo level batches of 3b

Entry Input of 1b

(Kg)

Output of 3b

(Kg)

HPLC purity of 3b

(%)

1 100 97 99.5

2 100 98 99.5

3 100 97.8 99.5

3.1.3 Effect of Different Catalysts

It was observed that bromo acid 3b did not undergo substitution

with sodium bisulphite under standard conditions in the absence of cuprous

chloride, as monitored by HPLC. A number of Lewis acids as catalysts were

screened under standard conditions (Scheme 3.3) and the reaction was

monitored by HPLC.

S

Br

COOH

(3b)

NaOH / NaHSO3

CATALYST

S

SO3Na

(4a)

COONa

reflux. pH 7.5- 7.7

HCl / KClS

SO3K

COOH

(5a)

100 °C

Scheme 3.3 Ullmann condensation with sodium bisulphite with different

catalysts

Of the several Lewis acids and salts examined, viz. silver nitrate

(entry 1, Table 3.6), zinc chloride (entry 2, Table 3.6), nickel chloride (entry3,

Table 3.6), lanthanum triflate (entry 4, Table 3.6), ytterbium triflate (entry 5,

Table 3.6), copper (I) chloride (entry 6, Table 3.6), palladium (II) acetate

(entry 7, Table 3.6), palladium (II) acetate with ligand ± 2, 2’-bis

(diphenylphosphino)-1, 1’-binaphthyl (BINAP) (entry 8, Table 3.6) and

tetrakistriphenylphosphinepalladium(0) (entry 9, Table 3.6), only cuprous

chloride was found to exhibit the best catalytic activity in effecting the

nucleophilic substitution.

129

Table 3.6 Effect of Lewis acid catalysts and salts on substitution

reaction of 3b

Entry Catalyst

Monitoring results

HPLC area%Remarks

Time

(h)

SM

(3b)

Product

(4a)

1 AgNO3 3 88 10 little conversion.

2 ZnCl2 3 94 1 No reaction.

3 NiCl2 3 97.8 1.2 No reaction.

4 Lanthanum triflate 4. 98 1 No reaction.

5 Yiterbium triflate 4 98 1 No reaction.

6 CuCl 2 Nil 89.2 Neat reaction.

7 Pd(OAc)2 3 99 0.6 No reaction.

8 Pd(Oac)2 ± BINAP 3 99 0.6 No reaction.

9 Tetrakistriphenylphos

phinepalladium (0)

3 97.8 Nil No reaction.

3.1.4 Effect of Different Copper Salts as Catalysts

Various copper salts were tried as catalysts for this nucleophilic

substitution with sodium bisulphite under standard conditions (Scheme 3.4)

and the HPLC monitoring results are indicated in Table 3.7.

S

X

COOH

X= Cl (3a)

X= Br (3b)

COPPER SALT

reflux. pH 7.5- 7.7

S

SO3Na

(4a)

COONa HCl / KClS

SO3K

COOH

(5a)

100 °C

NaOH . NaHSO3

Scheme 3.4 Ullmann condensation with sodium bisulphite with different

copper salts as catalysts

130

Table 3.7 Effect of different copper salts as catalysts

Entry SMCopper salt as

catalyst

Monitoring results

HPLC area (%)

Time

(h)SM

Product

(4a)

1 3a CuCl 3 95.4 (3a) 3.5

2 3a CuBr 3 96.2 (3a) 2.8

3 3a CuI 3 97.2 (3a) 1.8

4 3a CuCl/ TBAI 3 97.9 (3a) 1.2

5 3a TBAI 3 97.8 (3a) 1.2

6 3b CuCl 2 Nil (3b) 89.2

7 3b CuBr 3 Nil (3b) 90.3

8 3b CuI 3 Nil (3b) 90.8

9 3b CuCl2 3 0.8 (3b) 87.8

10 3b Cu(OTf)2 3 9.5 (3b) 80.1

The chloro acid 3a did not undergo substitution with sodium

bisulphite under standard conditions with Cu (I) halides as catalyst (entries 1,

2 and 3, Table 3.7). As mentioned in the introduction chapter, prior exchange

(metathesis) between the substrate and the copper salt is known to take place

under the conditions of Ullmann condensation and has been reported by

Weingarten (1964). There was little difference in the rates of cuprous bromide

and cuprous iodide catalyzed reactions of chloro acid 3a at 100°C which

indicated that there was no prior fast halogen exchange between the copper

salt and substrate under these conditions. The addition of phase transfer

catalysts including tetrabutylammonium iodide also did not prove useful

(entry 4 and 5, Table 3.7). Various salts of copper viz.; copper (I) chloride

(entry 6, Table 3.7), copper (I) bromide (entry 7, Table 3.7), copper (I) iodide

131

(entry 8, Table 3.7), copper (II) chloride (entry 9, Table 3.7) and copper (II)

triflate (entry 10, Table 3.7) were examined as catalysts for this substitution

reaction. Though all these copper salts brought about the Ullmann cross

coupling of bromo acid 3b with sodium bisulphite, cuprous chloride was

found to exhibit the best catalytic activity in effecting the cross coupling.

3.1.5 Effect of Different Oxidation States of Copper

Since Cu (II) is an oxidizing agent and sodium bisulphite is a reducing

agent, a control experiment was carried out to check the compatibility of Cu (II)

in presence of sodium bisulphite. When a solution of cupric chloride was mixed

with a solution of sodium bisulphite at room temperature , evolution of sulphur

dioxide gas was observed ( a filter paper wetted with potassium permanganate

solution turned colorless in presence of this liberated gas), indicating that Cu(II)

was getting reduced to Cu(I) in solution, probably as outlined in Scheme 3.5.

2CuCl2 + 2 NaHSO3 NaHSO4 + + NaCl + HCl +SO22 CuCl

Scheme 3.5 Cupric chloride in presence of sodium bisulphite

Nevertheless, a few experiments were conducted with CuCl2 as

catalyst under the standard conditions. The order of catalytic activity of various

oxidation states of copper, i. e. Cu (I) as cuprous chloride, Cu (II) as cupric

chloride and copper as Cu (0) were investigated under standard conditions

(Scheme 3.6).

S

Br

COOH

(3b)

1. NaOH / NaHSO3

reflux. pH 7.5- 7.7

S

SO3Na

COONa

(4a)

HCl / KClS

SO3K

COOH

(5a)

100 °C

CATALYST

Scheme 3.6 Ullmann condensation with sodium bisulphite with different

oxidation states of copper catalysts

132

The order of catalytic activity was found to be Cu (I) Cu (II) > Cu

(Table 3.8).

Table 3.8 Different oxidation states of copper in Ullmann cross

coupling of bromo acid 3b with sodium bisulphite

EntrySM Catalyst

Monitoring results

HPLC area (%)

Time

(h)

SM

(3b)

Product

(4a)

1 3b CuCl 2 Nil 90.7

23b CuCl2

3

4

0.8

Nil

87.8

89.6

33b

Cu

(As copper bronze)

1 75.8 16.8

2 55.8 37.9

3 16.0 75.2

4 2.0 88.8

The substitution reaction was completed in about 2 h with Cu (I)

chloride as catalyst (entry 1, Table 3.8). When Cu (II) chloride was used for

the reaction, about 0.8% of the starting material 3b was present in 2 h and the

reaction was completed in 4 h (entry 2, Table 3.8) .When Cu (0) was used in

the form of copper-bronze as catalyst, the reaction went up to only 62%

conversion by HPLC in 2 h (entry 3, Table 3.8). This reaction however went

to completion in 4 h (Figure 3.1). The cuprous oxide present on the surface of

metal copper probably responsible for the observed catalytic activity (Paine

1987).

133

Figure 3.1 HPLC monitoring of bromo acid 3b using different

oxidation states of copper catalyst at 100°C

3.1.6 Influence of Temperature

It was observed that the reaction of bromo acid 3b with sodium

bisulphite was greatly influenced by temperature (Table 3.9). The reaction

was completed in 2 h at 100°C.

Table 3.9 Effect of temperature on Ullmann type coupling of 3b with

sodium bisulphite

SM Catalyst NucleophileTemp

(°C)

Monitoring results

HPLC area (%)

Time

(h)

SM

(3b)

Product

(4a)

3b CuCl NaHSO3

50 2 78 19

80 2 48 48

100 2 Nil 96

The reaction rate increased almost linearly with temperature

(Figure 3. 2).

134

Figure 3.2 Effect of temperature on conversion

3.1.7 Influence of pH

The effect of pH on the ease and course of this substitution reaction

was studied (Scheme 3.7)

S

Br

COOH

(3b)

NaOH / Nucleophile

CuCl

reflux. pH

S

SO3Na

(4a)

COONa HCl / KClS

SO3K

COOH

(5a)

100 °C

Scheme 3.7 Ullmann condensation with sodium bisulphite under

different pH

The reaction of bromo acid 3b with sodium bisolphite under different pH of

the medium was investigated. The progress of the reaction was followed by

HPLC and the results are tabulated in Table 3.10.

135

Table 3.10 Effect of pH on nucleophilic substitution reaction of 3b

Entry SM pH Nucleophile

Monitoring results

HPLC area %

Time

(h)

SM

(3b)

Product

(4a)

1 3b 4.5 NaHSO3

3 56.6 Nil

Side product 3c -21%

2 3b 7.5-7.7 NaHSO3 2 Nil 89.2

3 3b 10.5 Na2SO3 2 Nil 97.1

The nucleophilic substitution of bromo acid 3b with sodium

bisulphite was conducted at 100oC without adjusting the pH to 7.5-7.7. The

pH of the reaction mixture after addition of sodium bisulphite was 4.5. The

reaction was conducted under this pH condition in presence of CuCl. The

reaction was not completed even after 3 h as monitored by HPLC (entry 1,

Table 3.10). Starting material to the extent of 56.8% was present after 3 h at

100°C, while 21% of hydrodebromination product thiophene-2-carboxylic

acid 3c was observed. The formation of considerable amount of hydro

debromination product 3c in acidic pH conditions is similar to the finding

encountered by Cohen et al (1974) when they conducted their Ullmann cross

coupling reaction in presence of added benzoic acid. This clearly indicated the

importance of pH of reaction medium towards this substitution reaction and

also its role in controlling the formation of competing reduction product.

Interestingly, when the cross coupling reaction was performed with sodium

sulphite, instead of sodium bisulphite, the pH of the reaction mixture was

around 10.5. Under this reaction conditions, the reaction proceeded very well

in 2 h resulting in complete consumption of starting material with 97.1%

product formation (entry 3, Table 3.10), These observations indicate that the

136

actual nucleophile may be sulphite ion even in the case of reaction with

sodium bisulphite, when the reaction was conducted at pH 7.5-7.7 with

sodium bisulphite.

3.1.8 Optimal Catalyst Loading

Next, the nucleophilic substitution of bromo acid 3b with sodium

bisulphite was studied with respect to the catalyst loading (Scheme 3.8) under

standard conditions.

S

Br

COOH

(3b)

NaOH / NaHSO3

CATALYST

reflux. pH 7.5- 7.7

S

SO3Na

(4a)

COONa HCl / KClS

SO3K

COOH

(5a)

100 °C

Scheme 3.8 Ullmann condensation with sodium bisulphite under

different loading of CuCl

The reaction was monitored by HPLC and the results are shown in

Table 3.11. The optimal catalyst loading was found to be 0.1 mol with respect

to the substrate. Higher loadings resulted in the formation of more of

hydrodebromination product 3c viz., thiophene-2-carboxylic acid, though

complete conversion of the starting material 3b was observed even at the end

of 0.5 h (entry 2 and 3, Table 3.11). It was observed that excess catalyst make

the substitution reaction faster but the selectivity was reduced due to

competing side reactions such as the formation of more thiphene-2-

carboxylic acid .

137

Table 3.11 Different catalyst loading

Entry SMCatalyst

(CuCl)

Monitoring results

HPLC area %

Time

(h)

SM

(3b)

Product

4a

13b 0.1 mol

0.5 2.67 87.8

1 1.1 89.02

2 Nil 89.2

3 Nil 88.7

2 3b 0.50 mol

0.5 Nil 83.6

1 Nil 84.4

2 Nil 83.9

3 Nil 83.5

Side product RT 3.47 min- 9.13 (3c)

3 3b 1.0 mol

0.5 Nil 75.5

1 Nil 75.2

2 Nil 76.6

3 Nil 76.8

Side product RT 3.47 min- 9.13 (3c)

3.1.9 Effect of Co-solvents and Additives

Next the influence of co- solvents like ethanol, 1, 4-dioxan and also

the effect of additives like sodium chloride and ligand 2, 2’-bipyridyl on the

rate of this substitution reaction was examined (Scheme 3.9).

S

Br

COOH

( 3b)

NaOH / NaHSO3

CuCl / reflux

co-solvent / additive

pH 7.5- 7.7

S

SO3Na

(4a)

COONa HCl / KClS

SO3K

COOH

(5a)

100 °C

Scheme 3.9 Ullmann condensation in presence of co-solvents / additives

138

The HPLC monitoring results are given in Table 3.12.

Table 3.12 Effect of co-solvents and additives

Entry SM Condition

Monitoring results

HPLC area(%)Remarks

Time

(h)

SM

(3b)

Produce

(4a)

1 3b A* 3 22.6 62.3 EtOH as co solvent

(45%v/v aq. ethanol)

2 3b A* 3 14 69 1,4-Dioxan as co

solvent

(45% v/v aq. dioxan )

3 3b A** 3 Nil 83.8 NaCl as additive

4 3b A** 0.5 Nil 84.7 2-2’-bipyridyl as

additive

A*- Reaction conditions are similar to standard condition but 2 V of

water was replaced by indicated solvent

A**- Similar to standard condition with 0.2 equiv. of indicated additive.

It was observed earlier that the reaction in water medium was

completed in 2 h while the reaction did not go to completion even after 3 h in

presence of co-solvents (entries 1 and 2, Table 3.12). Hence, this study

revealed that the reaction was much faster in water compared to water- dioxan

and water- ethanol mixtures. The added sodium chloride (NaCl) also did not

have any noticeable effect on the rate of reaction (entry 3, Table 3.12).

Significantly, addition of ligand, 2, 2’- bipyridyl has a tremendous rate

accelerating effect (entry 4, Table 3.12). Only a few examples are known for

Ullmann type cross coupling reactions in aqueous medium and this reaction is

yet another addition to this short list.

139

3.1.10 Microwave Conditions

The copper mediated nucleophilic substitution of 3a and 3b with

sodium bisulphite was also performed under similar microwave conditions

(Scheme 3.10) using the same molar proportions of reagents.

S

X

COOH

X= Cl (3a)

X= Br (3b)

CuCl/ MicrowaveS

SO3Na

(4a)

COONa HCl / KClS

SO3K

COOH

(5a)

100 °C

pH 7.5- 7.7

NaOH . NaHSO3

Scheme 3.10 Ullmann condensation with sodium bisulphite under

microwave

It was observed that under microwave condition also the bromo acid

3b was more reactive than chloro acid 3a (Table 3.13).

Table 3.13 Monitoring results under microwave conditions.

Entry SM

Monitoring results

HPLC area(%)Remarks

Time

(min.)SM

Product

(4a)

1 3a 295.6

(3a)2.9

Microwave conditions, 80°C,

and 100W- No reaction

2 3b 24.9

(3b)68.8

Microwave conditions 80°C,

100W, Product formed. Better

conversion compared

to 3a

140

3.1.11 Effect of Concentration of Sodium Bisulphite

The Ullmann cross coupling of 3-bromothiophene-2-carboxylic acid

3b was studied with respect to different molar proportions of sodium

bisulphite with respect to the bromo acid 3b under standard conditions.

(Scheme 3.11)

S

Br

COOH

( 3b)

NaOH / Nucleophile

CuCl / reflux

pH 7.5- 7.7

S

SO3Na

(4a)

COOH HCl / KClS

SO3K

COOH

(5a)

100 °C

Scheme 3.11 Ullmann condensation with different concentrations of

sodium bisulphite

The reaction was monitored by HPLC (Table 3.14). Though there

was no appreciable difference between 1.15 equiv (entry 1, Table 3.14) and

1.5 equiv of sodium bisulphite (entry 2, Table 3.14), the optimal quantity of

the nucleophile would be 1.15 equiv. with respect to the substrate from the

raw material perspective. With increase in concentration of the nucleophile

(entry 3, Table 3.14), the selectivity was not affected though there was

sluggishness in the initial rate of reaction.

141

Table 3.14 Effect of different concentrations of sodium bisulphite

SMCatalyst

0.1 molNucleophile

Monitoring results

HPLC area (%)

Time

(h)

SM

(3b)

Product

(4a)

3bCuCl NaHSO3

1.15 eq.

0.5 2.67 87.8

1 1.1 89.0

2 Nil 89.2

3 Nil 90.7

3bCuCl NaHSO3

1.5 eq.

0.5 3.8 89.2

1 0.62 90/9

2 Nil 92.9

3 Nil 93.5

3bCuCl NaHSO3

2.0 eq.

0.5 64.1 33.4

1 41.7 54.9

2 5.65 89.2

3 Nil 94.6

3.1.12 Ullmann Cross Coupling of 3b with other Bisulphite Salts as

Nucleophiles

The nucleophilic substitution was studied with a few other metal

bisulphite salts under the standard reaction condition (Scheme 3.12).

S

Br

COOH

(3b)

1) NaOH / Nucleophile CuCl / reflux pH 7.5- 7.7

2) HCl / KCl

S

SO3K

COOH

(5a)

Scheme 3.12 Ullmann condensation of 3b with different metal bisulphite

salts

142

The substitution reaction was monitored by HPLC (Table 3.15).

Table 3.15 Reaction of 3b with different nucleophiles

EntrySM Nucleophile

Monitoring results

HPLC area (%)

Time

(h)

SM

(3b)

Product

(5a)

1 3b Calcium bisulphite 3 18.1 22.3

2 3b Cerium bisulphite 3 11.9 53.3

3 3b Sodium sulphite (pH 10.5) 2 Nil 97.1

4 3b Sodium sulphite (pH 7.5-7.7) 3 7.1 86.2

The substitution reaction of 3b was slow when calcium bisulphite

(entry 1, Table 3.15) or cerium bisulphite (entry 2, Table 3.15) was used as

nucleophile under standard condition. More of side product viz., thiophene-2-

carboxylic acid 3c was formed in these cases. Interestingly, when the cross

coupling reaction was performed with same equivalents of sodium sulphite

(pH of the reaction mixture was around 10.5) instead of sodium bisulphite,

the reaction proceeded very well in 2 h resulting complete consumption of

starting material with 97.1% product formation as monitored by HPLC

(entry 3, Table 3.15). When the same reaction with sodium sulphite was

performed at pH 7.5-7.7, by adjusting the pH from 10.5 using dilute HCl, it

was observed that even after 3 h, the reaction was incomplete and 7.1% of the

starting material 3b remained unreacted. Probably the addition of acid to

adjust the pH would have quenched some quantity of sodium sulphite

resulting in depletion of the nucleophile. These observations indicate that the

actual nucleophile may be the sulphite ion even in the case of the reaction

with sodium bisulphite as the reaction was done at pH 7.5-7.7 and that its

concentration might had been low at this pH.

143

3.1.13 Ullmann Condensation without Nucleophile

The Ullmann cross coupling of 3b was conducted without sodium

bisulphite under standard conditions (Scheme 3.13) to see the outcome. The

results are shown in Table 3.13.

S

Br

COOH

( 3b)

1. NaOH / CuCl

pH 7.5- 7.7S

H

(3c)

COOH

2. HCl / KCl

+

S

OH

COOH

(5e)

Scheme 3.13 Ullmann condensation without nucleophile

In this event, the reaction resulted in the formation of more of

hydrodebromination product 3c in addition to unreacted starting material

(entry1, Table 3.16). Formation of hydrodebromination 3c, as the major

product under alkaline condition is noteworthy. The dehalogenation reaction

was more pronounced under drastic conditions viz., 140-143°C under

autoclave conditions (entry 2, Table 3.16). Another side product at RT 3.775

min was also observed in the HPLC trace of the monitoring sample

(Figure 3.3).

Table 3.16 Ullmann cross coupling of 3b without nuceophile

EntryCatalyst

10 mole%

Temp

( C)

Monitoring results

HPLC area (%)

Time

(h)

SM

(3b)(3c)

1CuCl 100

10 63.8 16.7

(RT 3.479 min)

2CuCl 140- 143

16 48.1 34.4

(RT 3.476 min)

144

This side product probably could arise from the nucleophilic

displacement of halogen by the hydroxyl anion (acting as nucleophile) from

the aqueous medium.

Figure 3.3 HPLC monitoring of 3b without nuceophile at 100°C

after 10 h

145

Figure 3.4 HPLC monitoring of 3b without nuceophile at 100°C

after 10 h co-eluted with thiophene-2-carboxylic acid 3c

146

Figure 3.5 HPLC monitoring of 3b without nucleophile at 140°C after

16 h

3.1.14 Isomeric Bromothiophenecarboxylic Acids

For the first time, the Ullmann type cross coupling reactions of

isomeric bromothiophene carboxylic acids, viz., 3-bromothiophene-2-

carboxylic acid 3b, 4-bromothiophene-2-carboxylic acid 3d, 5-

bromothiophene -2-carboxylic acid 3e and 2-bromothiophene -3-carboxylic

acid 3f with sodium bisulphite was studied under the standard condition in an

effort to understand the mechanism of the substitution reaction viz., the

147

relative importance of chelation and electronic effects like mesomeric

interactions (Scheme 3.14). The results are shown in Table 3.17.

S

1) NaOH / NaHSO3

CuCl / reflux

pH 7.5- 7.7S

2) HCl / KClBr

HOOC

2-COOH and 3-Br (3b)

2-COOH and 4-Br (3d)2-COOH and 5-Br (3e)

3-COOH and 2-Br (3f)(SM))

SO3K

2-COOH and 3-SO3K (5a)

2-COOH and 4-SO3K (5b)

2-COOH and 5-SO3K (5c)

3-COOH and 2-SO3K (5d)

(Product)

HOOC

Scheme 3.14 Ullmann condensation with isomeric bromothio

phenecarboxylic acids

Table 3.17 Ullmann cross coupling reaction of isomeric

bromothiophenecarboxylic acids with sodium bisulphite

Entry SM Structure

Monitoring results

HPLC area (%)Remarks

Time

(h)SM Product

1 3b SCOOH

Br

2 Nil (3b) 89.2 (5a) High

Conversion.

2 3d SCOOH

Br

3 73.6(3d) 22.4 (5b) Low

conversion

3 3e SCOOH

Br 321.1(3e) 73.6 (5c)

Faster than 3d

reaction.

16Nil (3e) 84.6 (5c)

Reaction at

140°C

4 3f SBr

COOH

0.5 2.1 (3f) 77.7 (5d) Very little SM

after 0.5 h.

148

The reaction of 4-bromo acid 3d with sodium bisulphite was significantly

slower compared to other isomers and only 22% conversion was observed

after 3 h under standard conditions (entry 2, Table 3.17). The conversion did

not improve even on drastic conditions, viz. heating in an autoclave 140°C. In

comparison, the 5- bromo acid 3e exhibited a better reactivity leading to 73%

conversion in 3 h under standard conditions. Complete conversion in this case

was observed at 140°C in an autoclave (entry 3, Table 3.17). In the case of 3f,

the reaction was fast and almost complete in 0.5 h (entry 4, Table 3.17). These

findings are similar to the results obtained by Tim et al (2000) in the case of

Pd catalyzed amination of electron deficient halothiophenes. The authors

prepared a series of functionalized aminothiophenes by palladium catalyzed

amination reactions. The authors observed that the reaction proceeded well in

these cases where the halide is adjacent to an electron withdrawing group

(Scheme 3.15). Thus the reactivity exhibited by 3-bromothiophene-2

carboxylic acid and 5-bromothiophene-2-carboxylic acid bring about the

importance of both the chelation and mesomeric interactions.

Between the two bromo acids, 3b (entry 1, Table 3.17) and 3f

(entry 4, Table 3.17), 3f displayed higher reactivity but at the same time led to

more hydrodebromination product 3h in comparison to that of 3b. The results

of this study indicated the following order of reactivity: 3f > 3b > 3e >> 3d.

This is an important finding towards understanding the mechanism of the

reaction. The mono potassium salt 5c obtained from 3e is not known in

literature. This salt was isolated and characterized by spectral data and HRMS

analysis (Section 2. 6.3). The reactivity of 3b and 3f parallels the observation

of Menno et al (1992) in the Ullmann coupling of 3-bromthiophene and 2-

bromothiophene with alkoxides.

149

SCOOMe

Br

SCOOMe

NHBu(Yield 94%) Methyl-3-n-butylaminothiophe

ne-2 carboxylate

+

n-butylamine1.2 equiv

2 equiv.Cs2CO3

5 mol% Pd(dba)2

Toluene/reflux

BuNH2

SCOOMe

SCOOMe

(Yield 76%%)Methyl-5-bromothiophene-2 carboxylate ( 1.0 equiv.)

+

N-(methyl) benzylamine, 1.2 equiv

2 equiv.Cs2CO3

5 mol% Pd(dba)2

Toluene/reflux

PhNHMe

Ph(Me)NBr

Methyl-4-N-(methyl)benzylamino-thiophene-2 carboxylate

SCN

Br

(Yield 86%)

n-butylamine1.2 equiv

2 equiv.Cs2CO3

5 mol% Pd(dba)2

Toluene/reflux

BuNH2+

3-bromo-2-cyanothiophene (1 equiv)

SCN

NHBu

3-n-butylamino-2-cyanot hiophene

SCN

(Yield 0%)

2 equiv.Cs2CO3

5 mol% Pd(dba)2

or 5 mol%Pd(OAc)2

Toluene/reflux+

4-bromo-2-cyanothiophene (1 equiv)

SCN

Br

PhNHMePh(Me)N

Methyl-5-N-(methyl)benzylamino-thiophene-2 carboxylate

Methyl-3-bromothiophene-2 carboxylate ( 1.0 equiv.)

N-(methyl) benzylamine, 1.2 equiv

Scheme 3.15 Pd catalyzed amination of electron deficient halothiophenes

They observed that the reaction in the case of 3-bromothiophne

afforded the expected ethers and no reduction product was observed whereas

the reaction in the case of 2 bromothiophene gave rise to more reduction

product. The following path way may be envisaged for the copper mediated

reduction process at C2 as shown in Scheme 3.16

S

Br

O Cu

HH

H

S

Br

CuOCH3S

H

+ CuBr + HCHO

2-bromothiophene

Scheme 3.16 Copper mediated reduction process

150

The delocalization of lone pairs of electrons on the sulphur atom

supports this path way for hydrodehalogenation. Probably the following

mechanistic pathway (Scheme 3.17) would account for a greater hydro

debromination in the case of 2-bromothiophene.

SBr

CuOCH3S

Br

Cu O

H

HH S

H + HCHO

2-bromothiophene

CuBr

Scheme 3.17 Possible pathway of reduction in 2-bromothiophene

3.1.15 Effect of Radical Scavengers

The copper mediated nucleophilic substitution of bromo acid 3b

with sodium bisulphite under standard condition was performed in the

presence of radical scavengers (Scheme 3.18).like molecular oxygen, 2, 2, 6,

6-tetramethylpiperidinyl-1-oxy (TEMPO), para di-nitrobenzene etc

(Bowman, et al 1987). The results are shown in Table 3.18

S

Br

COOH

(3b)

NaOH / NaHSO3

CuCl / T°CpH 7.5- 7.7

S

SO3K

(5a)

COOHS

SO3Na

(4a)

COOHHCl / KCl

Radical Scavenger

Scheme 3.18 Ullmann condensation in presence of radical scavengers

151

Table 3.18 Effect of radical scavengers

Entry Radical scavenger

Monitoring results

HPLC area (%)

Time

(h)

SM

(3b)

Product

(4a)

1 Oxygen 3 21.8 71.2

2 TEMPO 3 11.1 77.4

3 THF 3 Nil 96.1

4 BHT 3 Nil 89.2

It was observed that sodium bisulphite was partly destroyed by the

radical scavengers like oxygen (entry 1, Table 3.18), TEMPO (entry 2,

Table 3.18) and p-di-nitrobenzene resulting incomplete reaction but the

expected substitution product was also formed. It was clear that p-di-

nitrobenzene could not be used as radical anion scavenger in this reaction, as

the formation of para-nitro aniline was observed by TLC in comparison to

standard para-nitro aniline. Experiments were conducted separately in the

presence of butylated hydroxy toluene (BHT) and tetrahydrofuran (THF) as

radical quenchers (Cohen and Cristea 1976). The reaction was not inhibited

by these reagents and the expected product was formed in desired quality in

both cases (entries 3 & 4, Table 3.18). This useful information rules out SRN1

mechanistic path way for this copper mediated nucleophilic substitution

reaction.

3.1.16 Proposed Mechanism Based on the Experimental Data

The order of reactivity observed in nucleophilic substitution of

activated aromatic halides proceeding by addition-elimination mechanism via

SNAr is F> Cl> Br> I (Carey and Sundburg 2001). However in the cases of 3-

bromothiophene-2-carboxylic acid 3b and 3-chlorothiophene-2-carboxylic

152

acid 3a, which are activated hetero aromatic halides, a reversal in reactivity

was observed when they are subjected to Ullmann cross coupling reactions

with sodium bisulphite. The bromo acid 3b displayed a much higher reactivity

compared to the chloro acid 3a despite the patent literature recommending

chloro acid 3a over bromo acid 3b for this nucleophilic substitution reaction.

The ease of reduction of C-X bond in aromatic system under electrochemical

conditions has been found to parallel the leaving group ability (Gibson and

Spitzmesser 2003). In the case of aromatic compounds and the same aromatic

moiety, there is a rough correlation to electron transfer reactions (Denney, D.

E. and Denney, D. J. 1991 and Denney et al 1993). The ease of reductions

revealed by the reduction potential in liquid ammonia is PhI > PhBr > PhSPh

> PhCl > PhF > PhOPh (Amatore et al 1985) coincides with the reactivity

order determined under photo-initiation. Experiments carried out with pairs

of PhX in liquid ammonia under irradiation towards CH2COBut ions indicated

the following order of reactivity .PhCl / PhF= 29, PhBr / PhCl= 450 and PhI /

PhBr= 8.3. Therefore the increase in reactivity from PhF to PhI is almost

100000 (Amatore et al 1981). It was of interest to find out whether one could

expect a similar parallel between the cathodic reduction potential of C-X bond

and the ease of Ullmann cross coupling. This has been advanced as an

evidence in favour of the mechanism in the case of SRN1 reactions (Gibson

and Spitzmesser 2003). Since both the reduction of the C-X bond and

oxidative addition of a metal/metal ion into a C-X bond involve addition of 2

electrons, it was of interest to find out whether any correlation could be

observed between the reduction potentials and ease of the Ullmann cross

coupling of the various halothiophene carboxylic acids. More importantly,

whether the observed higher reactivity of 2-bromobenzoic acid 8a over 3-

bromothiophene-2-carboxylic acid 3b in the Ullmann cross coupling reaction

with sodium bisulphite could be correlated with the reduction potential of

these two bromo derivatives. So far no such study has been reported in

literature. In fact a comparative study of the electrochemical reduction of

153

various halothiophenecarboxylic acids or halobenzoic acids has not been

reported so far in literature. With a view to get some information regarding

this, the cathodic reduction potential of C- X bonds in the molecules of

interest were measured using cyclic voltammetry and the results are shown in

Table 3.19

Table 3.19 CV data of C-X bond reduction potentials.

Entry Structure Compounds Position

Cathodic

reduction

potential

(V)

1 S

Br

1b 3-Br - -2.745

2 S

Cl

COCH32a 3-Cl 2-Ac -1.957

3 S

Br

COCH32b 3-Br 2-Ac -1.882

4 S

Cl

COOH 3a 3-Cl 2-COOH -2.058

5 S

Br

COOH 3b 3-Br 2-COOH -1.995

6 S

COOH

Br 3f 2-Br 3-COOH -2.070

7 SCOOH

Br

3d 4-Br 2-COOH -1.980

8 SCOOH

Br 3e 5-Br 2-COOH -1.790

Semi differentiated voltammogram of 3a (entry 4, Table 3.19) and

3b (entry 5, Table 3.19) were considered at scan rate 0.5 Vs-1

, the supporting

electrolyte was TBAB (0.1M) at glassy carbon electrode. The cyclic

voltammetric data revealed that bromo derivatives were reduced at more

154

positive potential compared to the chloro analogs. A glance of the reduction

potential of the various bromo derivatives clearly revealed that the

introduction of a carboxyl group into the bromo thiophene ring facilitates the

reduction of the carbon-bromine bond (compared entry 1, Table 3.19) with

the rest). As could be expected, the bromo compounds were reduced at more

positive potentials compared to the chloro analogs (compared entries 3 and 2,

with entries 5 and 4, Table 3.19) The cathode peak potential for the C-Br

bond reduction of 3b was observed at -1.955V whereas the cathode peak

potential for the C-Cl bond reduction of 3a was observed at -2.058V (Figure

3.6). Similarly, the cathode peak potential for the C-Br bond reduction of the

bromo ketone 2b (entry 3, Table 3.19) was observed at -1.882V. The cathode

peak potential for the C-Cl bond reduction of 2a (entry 2, Table 3.19) was

observed at -1.957V exemplified in Figure 3.7.

Figure 3.6 Semi differential cyclic voltammogram of 3b (solid line) and

3a (broken line)

155

Figure 3.7 Semi differential cyclic voltammogram of 2b (solid line)

and 2a (broken line)

The cathode reduction potential of C-X bonds in 4-bromothiophene-

2-carboxylic acid 3d and 5-bromothiophene-2-carboxylic acid 3e were

measured to be – 1.980V and -1.790V respectively (Figure 3.8)

Figure 3.8 (Continued)

156

Figure 3.8 Semi differential cyclic voltammogram of 3d, 3e and 3f

The halo ketones undergo reduction more readily compared to the

halo acids, as one would anticipate (entry 2 vs entry 4, Table 3.19 and entry 3

vs entry 5, Table 3.19). The 2-bromothiophen-3-carboxylic acid 3f is reduced

at more negative potential (-2.070V) compared to the 3-bromo isomer 3b

(-1.995V). This could be attributed to the alpha hetero atom effect, viz.,

electron repulsion between the lone pair of electrons on the sulphur and the

developing negative charge on the C2. This parallels the ease of reduction of

bromothiophenes mediated by metals. It is known that the metal mediated

reduction of 2, 3, 4- tribromothiophenes leads first to 2,3-dibromo, then to 3-

bromo and finally to 2-bromothiophene (Gronowitz and Raznikiewicz 1973).

The reduction potential of 5-bromothioophene-2-carboxylic acid ( -1.790V) is

found to be lowest among all the bromothiophenes studied ( entry 8,

Table 3.19). This could be due to the mesomeric interaction involving

extended conjugation. One more factor may contribute for the easier

reduction of carbon-bromine bond in the case of this compound. In the case

of 3-bromothiophene-2-carboxylic acid 3b, the dipole repulsion between the

two functionalities may make the reduction process more difficult (alpha

haloketone effect and anomeric effect) whereas in the case of 5-

bromothiophene-2-carboxylic acid 3e, such a dipole repulsion does not exist.

157

While the results obtained from the above study did not throw much

light to understand the mechanism of the reaction, they provided new and

interesting information. Uncatalyzed pathway or Lewis acid promoted SNAr

mechanism proceeding through addition-elimination mechanism can be ruled

out on the basis of the following observations: (i) first of all, chloro analog

displayed very poor reactivity compared to the bromo analog (ii) Other Lewis

acids did not bring about coupling reaction and only Cu (I) was found to be

the effective catalyst (iii) In the absence of cuprous chloride, cross coupling

reaction was not observed (iv) high reactivity of ortho bromo carboxylic acid,

so called ‘ortho- carboxylate effect’ observed in the present case as well as

reported by James Paine (1985) and McKillop and Bruggink (1975) in related

halobenzoic acid salts. Our findings parallels the observations of Cirigotts et

al (1974) who noted that silver nitrate, zinc chloride, nickel chloride and Pd

(II) chloride were completely ineffective catalysts for condensation of 2-

bromobenzoic acid with benzoyl acetone in ethanolic sodium hydroxide. They

had observed that catalysis by some copper species was essential for this

reaction. Elimination-addition mechanism via an aryne intermediate (Terrier

1982 and Diliang Gua et al 2008) can also be ruled out as there was no scope

for formation of any hetero aryne intermediate in the case of 3b and 3f. Any

aryne intermediate generated by decarboxylative debromination cannot give

rise to the observed products viz., ortho- sulfocarboxylic acids.

Among the classes of mechanism that have been proposed in the

literature (Lindley 1984 and Nathan Kornblum 1978) there are two

conceivable ones involving (1) radical intermediates involving SRN1 pathway

and (2) oxidative addition-reduction elimination mechanism. Reactions that

proceed via SRN1 mechanism exhibit the following characteristics (i)

acceleration of reaction rate by addition of reducing agents like Sn (II), Fe

(II), Ti (III; II) (Cohen et al 1974), (ii) inhibition of the reaction by oxygen or

158

radical traps like TEMPO (Abdelouahab et al 2005) or di-t-butylniroxide

(Bowman 1982), galvanoxyl (Buegelmans et al 1982), (iii) quenching of the

reaction by added p-di-nitrobenzene or m-di-nitrobenzene (Bowman 1982)

and (iv) formation of oligomers when styrene was added (Todres 1978). Also,

there is a correlation between reduction potential and leaving group ability of

the halide (Todres 1978). The order of reactivity in SRN1 is ArI > ArBr>

ArCl.> ArF, which is opposite to that of SNAr ArF>> ArCl> ArBr> ArI

(Linley 1984, Carey and Sundburg 2001). In SRN1 reactions of aryl halides,

ortho substituent to the halide retards the rate due to steric factors while

electron withdrawing group at the para position marginally increases the rate

of the reaction (Linley 1984). When Ullmann cross coupling of bromo acid

3b with sodium bisulphite under standard condition was performed in the

presence of radical scavengers like BHT or THF (Cohen 1976), the reaction

was not inhibited and expected product was formed at the same rate and in

desired purity and yield (entry 3 and 4,Table 3.23). This observation clearly

ruled out SRN1 mechanistic pathway.

Bowman et al (1982) investigated the mechanism in the case of

CuI catalyzed reaction of 1-chloro-4-iodobenzene with phenyl thiolate which

yielded mono coupled product where as polymeric material was obtained

under SRN1 reaction conditions and this experimental observations led to the

inference that no aryl radicals are produced under copper (I) catalyzed

conditions. Further in contrast to the 3 bromothiophene-2-carboxylic acid 3b

and 5-bromothiophene-2-carboxylic acid 3e, the cuprous chloride catalyzed

cross coupling reaction of 4-bromothiophene-2-carboxylic acid 3d isomer

with sodium bisulphite was significantly very slow. The observed reactivity

3f 3b > 3e >>3d cannot be accounted by SRN1 mechanism. Also the ortho-

carboxylate effect observed in the case of 3b cannot be rationalized on the

basis of SRN1 mechanism. The experimental findings are consistent with an

159

intramolecular oxidative addition-reductive elimination mechanism operating

in the case of 3b as depicted is Scheme 3.19.

Scheme 3.19 Intramolecular oxidative addition - reductive elimination

mechanistic pathway

The intervention of oxidative addition-reductive elimination

mechanism in Ullmann condensation was first proposed by Cohen in 1974.

This mechanism was subsequently substantiated by several literature reports

(Cohen 1976, Bowman et al 1984 and Gary et al 1996) indicating Cu (I) and

Cu (III) intermediates. Oxidative addition of cuprous halides to aryl halides is

a reversible process according to literature (Cohen 1976). The well

documented copper catalyzed halogen exchange in aryl halides is a further

indication of the reversibility (Cohen 1976). Possible role of additional

ligands may be to stabilize copper (I) species, increase the solubility of the

catalytic species, to prevent aggregation of the metal and to promote the

oxidative addition to Cu (I) complex (Cohen 1976). In fact the exceptionally

high catalytic activity of copper (I) thiophene-2-carboxylate in Ullmann cross

S

B r

O

O

C u

S

N a 2S O 3

S C O O C u

S O 3N a

In tram o le cu la r o x id a t iv e

ad d itio n

R e d u c tiv ee lim in a t io n

L

C u

O

O

B r C l

S

C u

O

O

N a O 2 S O X

IIII I I

XI

IC l

S C O O

B r

S C O O

S O 3N aS C O O

B r

C u C l

N a XX = B r,C l.

N a +

N a +

N a +N a +

N a +N a +

N a +

160

coupling reactions has been ascribed to the stabilization of Cu(III) complex

formed in the oxidative addition step thereby driving the equilibrium to the

forward direction (Gary D. Allred et al 1996).

The proposed mechanism is

consistent with the observed findings.

1. The reactivity order ArBr > ArCl parallels the leaving group

ability of the halide ion.

2. Couplings are favored by electron withdrawing groups

3. Coupling did not take place in the absence of copper catalyst.

4. There is a correlation between cyclic voltametry data on

cathodic potential and the leaving group ability of the halide.

5. Free radical inhibitors like BHT or THF did not suppress the

reaction.

6. Bromo ketone 2b and the ester 3g did not exhibit high

reactivity when compared to that of bromo acid 3b towards

this copper catalyzed substitution reaction with sodium

bisulphite.

The HPLC in-process check profile of a sample of reaction mixture

of copper mediated nucleophilic substitution of 3b with sodium bisulphite

after 2 h under standard conditions is shown in Figure 3.9. There were two

impurities (side products) observed in the HPLC chromatogram. The impurity

at RT (Retention Time) 3.559 minutes corresponding to relative retention

time (RRT) 1.16 was due to the formation of thiophene-2-carboxylic acid 3c,

by hydrodebromination of 3b under reaction conditions. This was confirmed

by co-injecting a reference sample of 3c (Section 2.12) which got co-eluted

along with RRT 1.16 impurity.

161

Also the UV max absorption value (247. 66 nm) of RRT 1.16 peak

was same as the UV max absorption value (247. 48 nm) of a pure sample of

thiophene-2-carboxylic acid 3c (Figures 3.10, 3.11 and 3.12).

Figure 3.9 HPLC monitoring of 3b after 2 h under standard conditions

162

Figure 3.10 HPLC and UV profile of crude 5a

163

Figure 3.11 HPLC and UV profile of pure sample of 5a

164

Figure 3.12 HPLC and UV profile of pure sample of 3c

Another impurity ar RRT 1.19 was then investigated. The LC-MS

analysis of RRT 1.19 impurity did not reveal any mass for the corresponding

peak as this was not ionized under the analytical conditions. Since Ullmann

type reaction was known to give biaryls as minor product, a few experimental

trials were conducted towards the synthesis of [3,3’]bithiophenyl-2,2’-

dicarboxylic acid ( Figure 3.13)

165

S COOH

S

COOH

Figure 3.13 Possible structure of RRT 1.19 impurity

[3,3’] Bithiophenyl-2,2’-dicarboxylic acid is known in literature

with Chemical Abstracts Service (CAS) registry number 31493-17-5

(Leardini et al 1970). As per the literature information, the synthesis of this

compound was attempted from methyl 3-bromothiophene-2-carboxylate 3g as

indicated in Scheme 3.20.

SCOOMe

Br

(3g)

Copper-Bronze

DMF, reflux

S COOMe

S

COOMe

KOH

S COOH

S

COOH

(11b)(11a)

[3,3']Bithiophenyl-2,2'-

dicarboxylic acid dimethyl ester

[3,3']Bithiophenyl-2,2'-dicarboxylic acid

3-Bromo-thiophene-2-carboxylic acid methyl ester

Scheme 3.20 Literature route of synthesis of 11b

A few experimental trials were conducted towards the synthesis of

[3,3’]bithiophenyl-2,2’-dicarboxylic acid using the literature information.

Despite limited efforts this compound could not be prepared.

Attempts to characterize the copper salt of 3b (Gary et al 1996) by a

single crystal XRD was not successful as suitable crystal of the copper salt

could not be generated. The first direct observation of Cu (I)-Cu (III) redox

steps relevant to Ullmann type coupling reaction has very recently been

provided by Alicia et al (2010). Uncertainty remains as to whether

nucleophilic substitution step precedes or follow the oxidative addition step.

166

From the experimental data generated, the intramolecular oxidative

addition-reductive elimination mechanism with -complexation of the

carboxylate copper with aromatic cloud as the driving force for promoting

oxidative addition of copper from the carboxylate salt in to the Ar-X bond

(Zheng et.al 2009) can be discounted. The authors did not reveal any support

to their proposed mechanism. The mechanism requires planarity for the -

cloud of the aromatic system and the attacking nucleophile which is

debatable. More emphasis was given to the regio-selectivity of the

substitution. These authors indicated that the substitution was more facile

with o- bromo substituent compared to o- chloro substituent (entries 1 and 23

of Table 2) of Zheng et al (2009) based on the yields obtained and suggested

aromatic -complexation of the carboxylate copper. The role of halogens was

not defined to account for this reaction rate profile. More so, this mechanism,

may not justify the rate differences between isomeric bromothiophene

carboxylic acids that were generated in this present research work. Such a

comparative study of isomeric halocarboxylic acids was not described in

detail by Zheng et al in their published work. Hence, based on the

experimental data generated in this research work, halogen assisted

complexation with ortho- carboxylate copper providing the environment for

an intramolecular oxidative addition can be justified.

3.1.17 Influence of Different EWG Substituent

With a view to get additional evidence for the operation of ortho-

carboxylate effect, the Ullmann condensation reaction with sodium bisulphite

was performed with 3- brmothiophene-2-carboxylic acid 3b, 2-acetyl-3-

bromothiophene 2b and 3-bromo-2-carbomethoxy thiophene 3g under similar

reaction conditions (Scheme 3.21).

167

S

Br

EWG

NaOH / aq.EtOH

CuCl / reflux S

SO3Na

EWG

EWG = COCH3 (2b)

EWG = COOH (3b)

EWG-= COOMe (3g)

HCl / KCl S

SO3K

EWG

EWG = COCH3 (4b)

EWG = COOH (4a)

EWG-= COOMe (4c)

EWG = COOH (5a)

Scheme 3.21 Ullmann condensation with different EWG at 2-position

Under the same reaction conditions stated below, only bromo acid

3b (entry 1, Table 3.20) was found to be reactive while 3-bromo-2-

acetylthiophene 2b (entry 2, Table 3.20) and 3-bromo-2-carbomethoxy

thiophene 3g (entry 3, Table 3.20) were ineffective and did not undergo any

reaction, revealing the rate acceleration was solely due to the ortho-

carboxylate coordination effect operating in the case of 3b.

Table 3.20 Effect of different electron withdrawing groups

Entry SM EWG

Monitoring results

HPLC area (%)Remarks

Time

(h)SM Product

1 3b -COOH 3 22.6 (3b) 62.3 (4a) Slow reaction

2 2b -COCH3 3 96.1 (2b) Nil (4b) No reaction

3 3g -COOCH3 3 98.2 (3g) Nil (4c) No reaction

The reaction was performed under aqueous ethnolic conditions in

order to account for solubility. The substrates were taken in aqueous alcohol

(4 ml of 50% aq. ethanol/g of substrate) along with 1.15 equiv. of sodium

bisulphite as 40% aq. solution and 10 mole % cuprous chloride as catalyst.

168

The reaction mass was heated to 100°C and samples were drawn at regular

intervals and analyzed by HPLC.

3.1.18 Ullmann Condensation of 3b with other Nucleophiles

With a view to find out if the observed high reactivity exhibited by

the bromo acid 3b towards sodium bisulphite is a special case and restricted

only to sodium bisulphite, experiments were carried out with other

nucleophiles under standard conditions. The reaction of the bromo acid 3b

was investigated with a few phenols (Scheme 3.22) and amines (Scheme

3.23) as nucleophiles.

SCOOH

Br

Reflux 100C

aq. NaOH/ CuClphenol

No reaction

aq. NaOH/ CuCl

m-cresol No reaction(3b)

Reflux 100C

Scheme 3.22 Ullmann condensation of 3b with phenoxides under

standard conditions

The nucleophilic substitution reaction of 3b with phenol as

nucleophile under standard conditions did not take place as monitored by

TLC (mobile phase 40% chloroform in methanol). At the end of 3 h of reflux

under standard conditions, the isolated product showed only starting material

by1H NMR. The same trend was observed when m-cresol was used as

nucleophile for the substitution of 3b under standard conditions.

The substitution reaction of 3b with cyclohexyl amine did not take

place under standard conditions (Scheme 3.23) as monitored by TLC (mobile

phase 30% ethyl acetate in hexane). HPLC in process check analysis at the

169

end of 4 h indicated the presence of the starting material 77.4 area% in

addition to side products at RRT 1.16 (3c- 4.3 area%) and RRT 1.19 (16.5

area%)

SCOOH

Br

(3b)

aq. NaOH / CuClCyclohexyl amine

aq. NaOH / CuClBenzyl amine

No reaction

No reaction

Reflux 100oC

Reflux 100oC

Scheme 3.23 Ullmann condensation of 3b with amine nucleophiles under

standard conditions

The substitution reaction of 3b with benzyl amine as nucleophile

under standard conditions did not take place as monitored by TLC (Mobile

phase 30% ethyl acetate in hexane). Though it is difficult to predict the reason

at this juncture with limited studies, it appears that the copper mediated

nucleophilic substitution of 3b was specific to sodium bisulphite under these

reaction conditions (may be due to higher nucleophilicity coupled with

solubility factor in the case of sodium sulphite) as the reaction did not occur

with phenol and amine nucleophiles under the same standard reaction

conditions.

3.1.19 Practical Application of the Present Work

A scalable, industrial process for the preparation of methyl ester 7,

which is a key intermediate for synthesis of API’s like Tenoxicam (Dieter

et al 1987) and Sitaxsentan sodium (Raju et al 1997) was envisaged from this

research work based on the successful scalable process established for

monopotassium salt of 3-sulphothiophene-2-carboxylic acid 5a (Table 3.3)

from 3-bromothiophene-2-carboxylic acid 3b. The key pharma intermediate

170

viz. 2-carbomethoxythiophene-3-sulphonyl chloride 7 was obtained in two

steps from 5a (Scheme 3.24) as solid with m. p. 61-63°C (lit. value of 60-

62°C). The structure of the ester 7 was confirmed by HPLC, IR, NMR and

Mass spectra (Section 2.7).

SCOOH

SO3K

POCl3 / PCl5S

COCl

SO2Cl

(5a) (6)

MeOH

RefluxReflux

SCOOCH3

SO3Cl

(7)

Scheme 3.24 Reaction scheme for the synthesis of methyl ester 7

The process for the preparation of, ester 7 was scaled up

successfully .The product ester 7 was obtained with consistent yield and

purity from the monopotassium salt 5a (Table 3.21). Thus, a scalable,

industrial process for the preparation of methyl ester 7, which is a key

intermediate for synthesis of API’s has been realized.

Table 3.21 Consistent yield and purity of ester 7

EntryInput of 5a

(Kg)

Output 7

(Kg)

Purity

HPLC area(%)

1 100 73 99.9

2 100 73.5 99.9

3 100 72 99.9

3.2 IMPURITY FORMATION DURING SCALE UP OF 5a

3.2.1 Observation of an Impurity

The mono potassium salt of 3-sulphothiophene-2-carboxylic acid 5a

was prepared as given in section 2.5, starting from bromo acid 3b. The ester 7

171

was made in laboratory according to the literature procedure (Dieter, et al

1987) and the product was characterized completely by spectral data (Section

2.7). The process was considered for kilo-lab trials. During the scale up of the

process, unexpectedly, an impurity formation in the product was observed. In

one of the kilo-lab scale up batches, while converting the bis-acid chloride 6

to the ester 7 (Scheme 3.21), this impurity formation was noticed. This

impurity could not be removed by usual crystallization methods. Various

instrumental techniques including HPLC, NMR and Mass analysis were

carried out to investigate and understand the nature of the impurity. This

impurity eluted at a relative retention time (RRT) of 2.82 in HPLC. The1H-

NMR spectrum of the crude product from this scale up batch exhibited all the

signals expected for the ester 7. However, it also showed some additional

weak signals at ð-3.94 corresponding to methyl protons of another methyl

ester group and weak signals in the aromatic region at 7.3-7.4 (Figures 3.14

and 3.15).

Figure 3.141H NMR spectrum of impure sample of 3-chlorosulphonyl

thiphene-2-carboxylic acid methyl ester 7 in CDCl3

172

Figure 3.15 Expanded1H-NMR spectrum of the impure ester 7

3.2.2 Identification and Synthesis of Impurity

GC-MS analysis of this impure ester 7 indicated the presence of an

additional compound with a mass peak corresponding to a mass of 346. The

GC-MS spectrum revealed that this impurity could be a dimer type impurity

as the base peak was observed at 173, which is exactly half the value of 346

(Figure 3.16).

Figure 3.16 GC-MS spectrum of impure ester 7

173

A close scrutiny of the GC-MS data and1H NMR spectral data, coupled with

chemistry expertise, revealed that this impurity is likely to be bis-[2-

methoxycarbonyl-3-thienyl]-disulphide 11c. (Figure 3.17)

SS

S

MeOOCS

COOMe

11c

Figure 3.17 Proposed structure of impurity

The literature survey (Corral et al 1985) indicated that this disulphide is a

known compound and is prepared by the reduction of ester 7 using Zinc/Con.

HCl (Scheme 3.25).

SCOOMe

SO2Cl

7

SS

S

MeOOCS

COOMe

11c

Zn/HCl

Scheme 3.25 Preparation of bis-[2-methoxycarbonyl-3-thienyl]-disulphide

Accordingly, disulphide 11c was synthesised and characterized by

HPLC, NMR and Mass spectra (Section 2.11). The HPLC retention time (RT)

of the authentic disulphide 11c, under the same analytical conditions matched

with that of the impurity observed in scale up lot RT 12.27 (RRT 2.82). The

proton NMR spectral signals (Figure 3.18) also correspondingly matched with

that of extra signals seen in the NMR spectrum of the impure product. The

mass spectrum of synthesised disulphide 11c indicated a molecular mass of

346 with a base peak at 173. The impurity isolated by column

chromatography from the impure ester matched well in spectral data with that

of the synthesised disulphide. A sample of disulphide 11c co-injected with

174

the impure ester 7 in HPLC eluted at the same RT as that of the impurity

observed in ester. Thus this impurity observed during this particular scale-up

batch of methyl ester 7 was confirmed to be the disulphide 11c.

Figure 3.181H NMR spectrum of disulphide 11c

3.2.3 Origin of Impurity

It must be highlighted that this impurity was not observed in any of

the laboratory batches. The origin of this impurity was then investigated.

Sulphonyl chlorides are known to undergo reduction to disulphides (Zhang et

al 1996). It was noticed that in this particular kilo-lab batch reaction, the

selective methanolysis of bis-acid chloride 6 (Scheme 3.20) was performed in

a stainless steel reactor. A probe batch in laboratory with deliberate iron

contamination in the selective methanolysis step under the same reaction

conditions has clearly indicated the formation of disulphide impurity by

HPLC. It is evident that the metal contamination from the material of

construction (MOC) of the reactor under the prevailing acidic conditions, has

175

led to the reduction of methyl ester 7 resulting in formation the disulphide

impurity 11c. The knowledge derived from successful investigation of the

impurity originating from MOC of the reactor, during the preparation of the

ester 7 from the acid chloride 6 has thus paved way for a successful and

consistent process of very high quality material of ester 7, which is a key

pharmaceutical intermediate.

3.3 SYNTHESIS OF NEW ARYL ETHERS

The Ullmann cross coupling of aryl halides and heteroaryl halides

with phenoxides is one of the popular methods for the synthesis of diaryl

ethers and heteroaryl ethers (Marcoux et al 1997 and Torroca et al 2001) and

has been extensively investigated. This reaction continues to receive wide

attention (Cristau et al 2004). In this context, it was of interest to study the

Ullmann type cross coupling of 1a, 2b and 3b with a few phenoxides

(Scheme 3.26).

X = Br, R = H (1b)

X = Cl, R = COCH3 ( 2a )

X = Br, R = COCH3 (2b)

R = R1= H (10a)

R = COCH3, R1 = H (10b)

R = COCH3, R1 = CH3 (10c)

Pyridine / CuCl

118oC

S

R

X

S

O

R

OH

NaH/R1

R1

Scheme 3.26 Preparation of aryl ethers

3.3.1 Synthesis of 2-Acetyl-3-phenoxy thiophene and 2-Acetyl-3-(m-

tolyloxy) thiophene

Experiments were conducted in order to investigate the

reactivity pattern between chloro ketone 2a and bromo ketone 2b towards

nucleophilic substitution with phenol (Scheme 3.24). The results are shown in

176

Table 3.22. The Ullmann cross coupling of bromo ketone 2b with phenol

(entry 3, Table 3.22) was much faster than that of chloro ketone 2a (entry 2,

Table 3.22). After 8 h of reaction the bromo ketone 2b showed 94.9%

conversion with 3.9% of the starting material, while under identical

conditions, the reaction with 2a showed only 53.4% conversion, with 45.3%

of starting material. It must be stressed here that under these conditions, 3-

bromothiophene 1b, was hardly reactive (entry 1, Table 3.22).

Table 3.22 HPLC reaction monitoring data for phenyl ethers.

Entry SMCatalyst

0.1 mol

Monitoring results*

HPLC area (%) Remarks

Time (h) SM Product

11b CuCl

8 95

(1b)

3.2

(10a) Very slow

reaction16 57

(1b)

41

(10a)

22 16.2

(1b)

81.9

(10a) Slow reaction

22a CuCl

8 45.3

(2a)

53.4

(10b)

16 15.6

(2a)

82.8

(10b)

Enhanced

reaction rate

32b CuCl

8 3.9

(2b)

94

(10b)

16 0.2

(2b)

95

(10b)

* HPLC. reaction monitoring conditions - Mobile phase-methanol: water:

trifluoroacetic acid: triethylamine (1500:500:1:0.5). Flow rate 1 ml per minute,

pnjection volume 20 microlitres, wavelength-254 nm, elution mode Isocratic and

concentration 4mg per ml.

The order of reactivity was 2b >> 2a > 1b. The new aryl ethers 10b

and 10c were isolated and characterized completely by spectral data (Sections

2.9 and 2.10).

177

3.4 COMPARISON BETWEEN HALOBENZOIC ACIDS AND

HALOTHIOPHENECARBOXYLIC ACIDS IN ULLMANN

CONDENSATION

Halothiophenes are relatively inert to nucleophilic substitution while

that are conjugatively substituted with electron withdrawing groups are

comparatively more reactive to nucleophilic substitution (Kassmi, 1992).

SRN1 reactions occur with halogen derivatives of thiophene but less readily

compared to phenyl halides (Bunnet and Bernhard 1976, Miller 1968, Salo

Gronowitz 1991 and Bunnett 1983). The nucleophilic substitution of

unactivated halides are effected under harsh conditions compared to activated

halides. For the first time, a comparitive study on the Ullmann type

nucleophilic substitution with reference to ortho- carboxylic acid effect in 3-

halothiophene-2-carboxylic acids and 2-halobenzoic acids with sodium

bisulphite was undertaken. This study was also extended to a few other

nucleophiles like amines and phenols.

3.4.1 Ullmann Cross Coupling with Isomeric Bromobenzoic Acids

The cuprous chloride catalyzed Ullmann cross coupling of

halobenzoic acids with sodium bisulphite under the standard condition

(Scheme 3.27) was investigated and the experimental results are given in

Table 3.23. The o- bromobenzoic acid underwent very facile Ullmann type

coupling with sodium bisulphite under standard conditions (entry 1, Table

3.23). The meta isomer 8b (entry 2, Table 3.23) and para isomer 8c (entry 3,

Table 3.23) did not undergo substitution under standard conditions. Similarly

among the three isomeric chloro benzoic acids 8d, 8e and 8f (entries 4, 5 and

6, Table 3.23), only ortho chloro isomer 8d displayed some reactivity with

very low (23.% ) conversion compared to 8a (>94% conversion) and in the

case of 8e and 8f there was hardly any reaction.

178

1) NaOH / NaHSO3

CuCl/ reflux- 100oC

X= 2-Br, (8a)., X= 2-Cl, (8d)

X= 3-Br, (8b)., X= 3-Cl, (8e)X= 4-Br, (8c)., X= 4-Cl, (8f)

Y= 2-SO3K, (8g)

Y= 3-SO3K, (8h)

Y= 4-SO3K, (8i)

2) HCl / KCl

COOH

X

COOH

Y

Scheme 3.27 Ullmann cross coupling of isomeric halobenzoic acids

Table 3.23 Ullmann cross coupling reaction of halobenzoic acids

Entry SM Structure of

SM

Monitoring result

HPLC area (%)

Time

(h)

SM Product

1 8aBr

COOH

1 Nil (8a) 94.1 (8g)

2 8b

COOHBr

3 86.6 (8b) 3.2 (8h)

3 8c

COOH

Br 3 89.4 (8c) 10.3 (8i)

4 8d Cl

COOH

3 75.6 (8d) 22.7 (8g)

5 8e

COOHCl

3 99.7 (8e) Nil (8h)

6 8f

COOH

Cl 3 99.9 (8f) Nil (8i)

3.4.2 Sodium Bisulphite as Nucleophile

A comparison of Ullmann cross coupling reaction of sodium

bisulphite with halothiophenecarboxylic acids and halobenzoic acids is shown

in Table 3.24.

179

Table 3.24 Possible factors influencing the substitution reaction

Entry SM Compound

(SM)

Chelation

of

carboxylate

copper with

halogen

Chelation

of

carboxylate

copper with

sulphur

Mesomeric

Effevt

* HPLC

area%

(product)

**

Remarks

1 3a S

Cl

COOH

3.5 0.04

2 3b S

Br

COOH

89.2 1

3 3d SCOOH

Br x x22.4 0.25

4 3e SCOOH

Br

x73.6 0.82

5 3f S

COOH

Br

x77.7

(after 0.5h)>4

6 8aBr

COOH

x

94.1

(after 1 h)>2

7 8b

COOHBr x x x

3.2 0.036

8 8c

COOH

Br

x x

10.3 0.12

9 8dCl

COOH x

22.7 0.25

10 8e

COOHCl x x x

Nil No

reaction

11 8f

COOH

Cl

x x

Nil No

reaction

* Reaction rate based on the area% of the respective product formed after 3 h of

reaction, unless specified, under the same reaction conditions and HPLC

analytical conditions.

** Reaction rate with reference to the model compound 3-bromothiopherne-2-

carboxylic acid 3b.

180

Interestingly, the Ullmann cross coupling of sodium bisulphite with 2

bromobenzoic acid 8a (entry 1, Table 3.25), was faster (> 2 folds) compared

to that of 3-bromothiophene-2-carboxylic acid 3b.

Table 3.25 Comparison of Ullmann cross coupling of 8a and 3b with

sodium bisulphite under standard conditions

Entry SM Structure of SM

Monitoring result

HPLC area (%)

Time

(h)SM Product

1 8aBr

COOH

1 Nil

(8a)

94.1

(8g)

2 3b S

Br

COOH 2 Nil

(3b)

89.2

(5a)

The reaction in the case of acid 8a completed in 1h (entry 1, Table

3.25) as compared to 2 h in the case of 3b (entry 2, Table 3.25). It is to be

noted that the resulting product 8g has been described in literature (Anthony

1979, Kim 2010) from ortho chlorobenzoic acid 8d via Ullmann cross

coupling reaction with sodium sulphite under very harsh conditions viz., at

175°C, under pressure in an autoclave for 24 h (Scheme 3.28) and

surprisingly, there are no reports in the literature for the preparation of 8g

from bromobenzoic acid 8a.

COOH

Cl

NaOH,CuSO4.5H2O

H2O, Na2SO3 175°C, 24 h.,

6-7 Kg/cm2

pressure COOH

SO3K

(8d)2) HCl / KCl

(8g)

Scheme 3.28 Preparation of 8g reported in literature

181

The higher reactivity of 8a than that of 3b in Ullmann cross

coupling reaction with sodium bisulphite is an important finding towards

understanding the mechanism of this nucleophilic substitution. The reactivity

difference between 8a and 3b could be due to the possibility for formation of

one more intramolecular chelated complex involving copper thiophene-2-

carboxylate moiety with the sulphur atom in the thiophene ring as shown in

Figure 3.19.

SO

O

Cu

Br

S

O

Br Cu

O

example a example b

Figure 3.19 Possible chelations of carboxylate copper

An intramolecular oxidative addition-reductive elimination

mechanism involving o- copper carboxylate chelate (Figure 3.19 example a)

was proposed for the copper mediated nucleophilic substitution reaction of 3b

with sodium bisulphite based on the experimental data which is discussed in

detail under section 3.1.16. A possible competitive intramolecular chelation of

carboxylate copper with sulphur (Figure 3.19 example b) reduces the

possibility of the formation of required copper complex, thus resulting in a

slower reaction rate in the case of 3b compared to 8a where the scope for this

sort of competitive coordination does not exist. It is to be noted that

intramolecular oxidative addition of Cu+ to the C-Br bond is not possible in

the cases of 3d and 3e as there is no carboxylic group present ortho to the

bromine, unlike in the cases of 3b and 8a. The oxidative addition of Cu(I) in

the cases of 3d and 3e must involve only intermolecular process. Hence the

substitution reactions in the case of 3d and 3e are significantly slower

compared to 3b and 8a. A comparison of Ullmann condensation of 8b and

182

3d with sodium bisulphite under standard conditions is shown in Table 3.26,

while that of 8c and 3e is shown in Table 3.27.

Table 3.26 Comparison of Ullmann cross coupling of 8b and 3d with

sodium bisulphite under standard conditions

Entry SM Structure of

SM

Monitoring result

HPLC area (%)

Time

(h)

SM Product

1 8b

COOHBr

3 86.6

(8b)

3.2

(8h)

2 3d SCOOH

Br

3 73.6

(3d)

22.4

(5b)

Table 3.27 Comparison of Ullmann cross coupling of 8c and 3e with

sodium bisulphite under standard conditions

Entry SM Structure of

SM

Monitoring result

HPLC area (%)

Time

(h)

SM Product

1 8c

COOH

Br 3 89.4 (8c) 10.3 (8i)

23e

SCOOH

Br

3 21.1 (3e) 73.6 (5c)

Evidently, the comparatively higher reactivity of 3e than that of 3d

is due to the extended mesomeric interaction exerted by the carboxyl group

(Figure 3.20) which facilitates the oxidative addition of Cu+ to the Br-C bond.

183

SO

O

CuBr

SO

O

CuBr

ð

ð

Figure 3.20 Mesomeric interaction in 3e

In both ortho bromo and ortho chloro series, the halobenzoic acids

exhibited higher reactivity compared to 3-halothiophene carboxylic acids

towards cross coupling reaction with sodium bisulphite. Such a comparative

study of Ullmann cross coupling of halobenzoic acids and 3-halothiophene-3-

carboxylic acids with any nucleophile has not been reported in literature. The

rate spread in the case of 8a and 8c was approximately five fold greater

compared to that of 3b and 3e (Table 3. 28)

Table 3.28 Rate spread comparison in o and p isomers

Entry SM

Monitoring results –

HPLC area (%)*Rate

spread

based on

HPLCTime

(h)

SM Product

1Br

COOH

(8a)

1Nil

(8a)

94.1

(8g)

8a / 8c = 9.32

COOH

Br

(8c)

389.4

(8c)

10.3

(8i)

3 S

Br

COOH

(3b)

2Nil

(3b)

89.2

(5a)

3b / 3e = 1.84 S

COOH

Br

(3e)

321.1

(3e)

73.6

(5c)

* Reaction rate based on the area% of the respective product formed after 3 h of

reaction, unless specified, under the same reaction conditions and HPLC

analytical conditions

184

The bromides exhibited higher reactivity compared to the chlorides

both in the halobenzoic acids and halothiophenecarboxylic acids which

parallels the order of reactivity observed in Pd mediated cross coupling

reactions reported in the literature (Rina Singh and George Just 1989 and

Toshihiko 1980) as shown in Schemes 3.29 and 3.30.

O2N

X

+H C5H11

1-heptyne

2 mol% of Pd(PPh3)4

3 mol% Cu2Br2

N2 atmosphere

90°C

Boiling triethylamine

O2N

C5H11

When X= Cl, the reaction completed in 1440 minwhen X= Br, the reaction was over in < 3 minutes

4-halonitrobenzene

Scheme 3.29 Pd catalyzed ethynylation

X

+

HS 8 mol% Pd(PPh3)4

DMSO (20 ml)t-BuONa- 4 mmol, 100°C

S

Halo benzene2 mmol

Phenylthiol2 mmol

Diphenyl sulphide

When X= Cl, there was no reaction in 4 h.When X= Br, 82% of the product is obtained in 4 h.

Scheme 3.30 Pd catalyzed nucleophilic substitution

Although chloro acids 3a and 8d did not undergo Ullmann

condensation appreciably with sodium bisulphite under standard conditions

compared to bromo acids 3b and 8a, it is noteworthy to compare their relative

rates of Ullmann condensation reaction under standard conditions

(Table 3.29).

185

Table 3.29 Ullmann condensation of 3a and 8d with sodium bisulphite

Entry SM Structure of

SM

Monitoring result

HPLC area (%)

Time

(h)

SM Product

1 8d

Cl

COOH 3 75.6

(8d)

22.7

(8g)

2 3a SCOOH

Cl

3 95.4

(3a)

3.5

(5a)

The higher reactivity of 8d (entry 1, Table 3.29) compared to that of 3a (entry

2, Table 3.29) could be explained as discussed for bromo acids 8a and 3b

(Figure 3.21).

SO

O

Cu

Cl

Figure 3.21 Sulphur chelation in 3a

It is clear that when a carboxyl group is present ortho to the halide in the

aromatic ring (3a, 3b, 3f, 8a and 8d) the Ullmann condensation follows an

intramolecular oxidative addition-reductive elimination mechanism driven by

the chelation of the halogen with carboxylate copper. While in other cases

(3d, 3e, 8b, 8c, 8e, 8f) Ullmann condensation is favoured by intermolecular

oxidative addition of Cu+ to the Br-C bond.

With a view to find out if the observed higher reactivity exhibited

by the bromo acids 3b and 8a in these cross coupling reactions with sodium

bisullphite is a special case and restricted only to the sulphites, the reactivity

186

of bromo acids 3b and 8a were investigated with a few amines and phenols

and thereby compare their reactivity with these nucleophiles.

3.4.3 Amines as Nucleophiles

The Ullmann type cross coupling of aryl halides and heteroaryl

halides with amine nucleophiles is one of the popular methods for the

synthesis of aryl and heteroaryl substituted amines (Cohen and Tirpak 1975,

Sugaya et al 1994, Rottger et al 2007) and has been extensively investigated.

This reaction continues to receive wide attention (Cresteu et al 2004). In this

context, it is of interest to study the copper mediated cross coupling of 3b, 8a

with a few amine nucleophiles (cyclohexyl amine and benzyl amine) under

aqueous conditions and compare the relative reactivity under the same

reaction conditions (Scheme 3.31).

(3b)

+1 equiv. aq. NaOH

CuCl / refluxS

Br

COOH

(8a)

S

NHR

COOH

Br

COOH

+1 equiv. aq. NaOH

CuCl / reflux

NHR

COOH

R-NH2

R-NH2

R = cyclohexyl (12c)

R = benzyl (12d)

R = cyclohexyl (12a)

R = benzyl (12b)

Scheme 3.31 Ullmann condensation with amine nucleophiles

The Ullmann condensation reactions of 8a and 3b with cyclohexyl

amine were performed under standard conditions and the reactions were

monitored by HPLC. The results are tabulated in Table 3.30.

187

Table 3.30 Reaction monitoring by HPLC (cyclohexylamine)

EntryTime

(h)

HPLC monitoring results

area (%).

SM

(3b)

SM

(8a)

1 0.5 90 9.8

2 2 89 Nil

3 4 77.3 Nil.

2-Bromobenzoic acid 8a underwent substitution comparatively

better than 3-bromothiophene-2-carboxylic acid under the same reaction

conditions. The reaction was several times faster in the case of 2-

bromobenzoic acid and the product 12a was identified by1H-NMR (Zeng et

al 2009)

A similar reactivity profile was also observed in the case of benzyl

amine. The copper mediated coupling was faster in the case of 2-

bromobenzoic acid 8a as compared to 3-bromothiophene-2-carboxylic acid

3b . The reaction was monitored by TLC (mobile phase 30% ethyl acetate in

hexane) and the product 12b was isolated and identified by1H-NMR data

(Zeng et al 2009)..

3.4.4 Phenoxides as Nucleophiles

Ullmann type nucleophilic substitution in 2-acetyl-3-

bromothiophene 2b and 2-acetyl bromobenzene 9a with phenoxides were

conducted under non-aqueous conditions in order to understand the reactivity

pattern between the two (Scheme 3.32). The cross coupling of these halides

with sodium phenoxide and sodium 3-methylphenoxide were investigated in

pyridine as solvent and cuprous chloride as catalyst at 118oC (method B).

188

Method B: Phenol was dissolved in dry pyridine and one equivalent of NaH

(as 60% mineral oil suspension) was added under nitrogen atmosphere. The

starting material (0.33 equivalents) was added followed by addition of 0.33

equivalent of CuCl catalyst. The reaction mixture was heated to reflux

temperature under nitrogen and monitored by TLC.

S COCH3

Br

Ullmann cross coupling

Pyridine, CuCl, RefluxNucleophile

S COCH3

Nu

(2b)Nu = OPh (10b)Nu = m-tolyloxy (10c)

COCH3

Br

(9a)

Ullmann cross coupling

Pyridine, CuCl, RefluxNucleophile

COCH3

Nu

Nu = OPh (9b)

Nu = m-tolyloxy (9c)

Scheme 3.32 Comparitive study with phenoxides as nucleophile

The reaction of 2-acetyl bromobenzene 9a with phenoxide was

much faster compared to 2-acetyl-3-bromothiophene 2b by TLC in process

check analysis (30% ethyl acetate v/v in hexane). The reaction of 2-acetyl

bromobenzene 9a was completed in 2 h while in the case of 2-acetyl-3-

bromothiophene 2b the starting material was observed in TLC even after 8 h

of reaction. 2-Acetyldiphenyl ether 9b (Pellon et al 2003) was characterized

by NMR data. Following this procedure, new aryl ether 10b was prepared

from 2b and characterized by NMR spectral data and HRMS data (Section

2.9). A similar reactivity difference was observed between 2b and 9a, when

3-methyl phenol was used as the nucleophile under the same reaction

conditions. The reaction was monitored by TLC (mobile phase 30% ethyl

acetate v/v in hexane). The reaction of 2-acetyl bromobenzene 9a was

completed in 2 h while in the case of 2-acetyl-3-bromothiophene 2b the

starting material was observed in TLC even after 8 h of reaction and the

isolated products 10c (Section 2.10) and 9c (Pellon et al 2003) respectively,

189

were identified by NMR data. The cross coupling reactions of 3b and 8a with

p- chloro phenol were performed under aqueous conditions at 100°C using

cuprous chloride (0.1 mol) as catalyst (Scheme 3.33).

(3b)

+

Cl

OH 1 equi aq.NaOH

CuCl / refluxS

Br

COOH

(8a)

S

O

COOH

Cl

,(9d)

(10d)

Br

COOH

+

Cl

OH 1 equi aq.NaOH

CuCl / reflux

O

COOH

p-chlorophenol

p-chlorophenol

Cl

Scheme 3.33 Nucleophilic substitution with p-chlorophenol under

aqueous conditions

The reactions were monitored by HPLC using the standard

conditions (Table 3.31).

Table 3.31 HPLC monitoring of 3b and 8a with p-chlorophenol

EntryTime

(h)

HPLVC monitoring results

area (%)

SM

(3b)

SM

(8a)

1 0.5 92.7 21.1

2 2 89.3 19.9

3 4 86.4 19.3

Under aqueous conditions at 100°C, the substitution was faster in 2-

bromobenzoic acid 8a compared to 3-bromothiophene-2-carboxylic acid 3b

where there was no significant reaction. The crude product 9d obtained from

8a was isolated and identified by proton NMR (Pellon et al 2003) . Hence it

was observed that the Ullmann condensation with phenoxide was faster in 2-

190

bromobenzoic acid compared to 3-bromothiophene-2-carboxylic acid. The

findings from this study clearly revealed that ortho- carboxylate effect is

mainly responsible for the high reactivity in the case of 3-bromothiophene-2-

carboxylic acid and 2-bromobenzoic acid in Ullmann cross coupling reactions

irrespective of the nature of the nucleophile, whether it is S or N or O. It is

also clear that the cross coupling reactions are several fold faster in the case

of 2-bromobenzoic acid compared to that of 3-bromothiophene-2-carboxylic

acid. The difference in the reactivity can be rationalized as explained below.

3.4.5 Plausible Mechanism for Higher Reactivity of 8a Compared to

3b in Ullmann Condensation

A competitive intramolecular chelation involving coordination of

sulphur atom of the thiophene moiety with the carboxylate copper

(Figure 3.22) reduces the probability for the oxidative addition of the metal to

the carbon halogen bond at C3 of thiophene moiety. This type of competitive

coordination does not exist in the case of benzene system. This may be the

reason for the higher reaction rate of 2-bromothiophene-3-carboxylic acid 3f

compared to 3-bromothiophene-2-carboxylic acid 3b in nucleophilic

substitution with sodium bisulphite under standard conditions.

Figure 3.22 Coordination with sulphur atom

S

Br

OS

Br

O

OCu

O Cu

191

3.5 CORRELATION OF CYCLIC VOLTAMMETRY DATA

WITH THE PROPOSED MECHANISM

Electrochemical techniques are concerned with the interplay

between the electricity and chemistry, namely the measurements of electrical

quantities such as current, potential or charge and their relationship to

chemical parameters. Such use of electrical measurements for analytical

purposes has found a vast range of applications including environmental

monitoring, industrial quality control and bio-medical analysis (Joseph Wang,

2001). Cyclic Voltammetry (CV) is the most widely used technique for

acquiring qualitative as well as quantitative information about electrochemical

reactions (Wang et al 2012, Plana et al 2009, Iotov et al 2009, Barnes et al

2011). The potential is linearly scanned using a triangular waveform from an

initial potential to a final potential. The current is measured corresponding to

the potential scanning. The peak current corresponds to the concentration of

the electro active species present. The three electrode assembly is used in

studying them which consist of a working electrode (glassy carbon electrode),

counter electrode (platinum wire) and reference electrode (Ag/AgCl).

Normally Tetra butyl ammonium bromide is used as supporting electrode in

solvents such as acetonitrile and DMF.

The reductive cleavage of organic compounds continues to be a

fascinating topic of research on account of diverse mechanistic pathways

mediated by the solvent characteristic and magnitude of the driving force.

Among various organic substrates, aromatic halides are especially interesting

in view of the difficulty in their reduction as one passes from carbon-iodine to

carbon-fluorine bond. It is customary to anticipate that these reductions lead

to the neutral radical and the corresponding halide anions. The stabilization of

these radicals can be controlled by (i) carbon-halogen bond energy (ii)

presence of electron withdrawing group in aromatic moiety and (iii) polarity

192

of the solvent. Cyclic voltammetry is the customary technique for studying

kinetics and mechanism of electro-organic reactions. For the first time,

attempts were made to correlate the reduction potentials of the C-X bond

obtained from cyclic voltammogram of halothiophenes and halothiophene

carboxylic acids with their reactivity towards Ullmann cross coupling reaction

with bisulphite and more specifically, the ortho- carboxylate effect (Scheme

3.34) observed in the Ullmann coupling is reflected in the cathodic reduction

potentials of these substrates.

+

1. 1 equiv. aq.NaOHCuCl / reflux

S

X

COOH S

SO3K

COOH

X

COOH

+

SO3K

COOH

NaHSO3

NaHSO3

2. HCl / KCl

(5a)

(8g)

(X= Cl, Br)

(X= Cl, Br)

1. 1 equiv. aq.NaOHCuCl / reflux

2. HCl / KCl

Scheme 3.34 General scheme for Ullmann type nucleophilc substitution

It was also felt worthwhile to compare the reduction potentials of

bromothiophene-2-carboxylic acids with those of bromobenzoic acids and see

if any correlation could be found between this comparison and the reactivity

of these two aromatic systems towards Ullmann cross coupling with

nucleophiles with reference to ortho- carboxylate effect.

3.5.1 CV of thiophene and benzene halides

The cyclic voltammetry data of halothiophenes and halobenzene

compounds are indicated in Table 3.32. It was observed that 2-

bromothiophene 1d, 3-bromothiophene 1b and 3,4-dibromothiophene 1e, all

underwent reduction at more or less in the same potential region viz., -2.72 to

-2.75V (Figure 3.23, examples a, b and c). It was surprising to note that there

193

was no significant difference between the reduction potential of 3-

bromothiophene, 1b (-2.745 V; entry 1 Table 3.32) and 2-bromothiophene, 1d

(-2.724 V; entry 2, Table 3.32) though 1d exhibited higher reactivity than 1b

in metal mediated or butyl lithium mediated chemical reduction.

Table 3.32 CV data of halothiophenes and halobenzene compounds

Entry StructureCompound

number

Cathodic reduction

potential

(V)

1S

Br

1b -2.745

2S

Br 1d -2.728

3S

BrBr

1e -2.724

4S

BrBr

Br

1f-2.113

-2.759

5Cl

1g-2.78

(Andrieux et al 1978)

6

Br

1h-2.44

(Andrieux et al 1978)

7S

Cl

COCH3

2a -1.957

8S

Br

COCH3

2b -1.882

9

Br

COCH3

9a -2.078

194

The cyclic voltammograms are given in Figure 3.23.

(example a) (example b)

(example c)

(example d) (example e)

Figure 3.23 (Continued)

195

(example f) (example g)

Figure 3.23 CV of halothiophene and halobenzene compounds

It is interesting to note that 3,4-dibromothiophene 1e exhibited only

one peak, a rather broad one at -2.724V (Figure 3.23, example c) in the same

potential region of 2 and 3-bromothiphenes, indicating that the presence of a

vicinal bromine atom does not have much influence on the cathodic reduction

of this dibromothiophene compound. In contrast 2, 3, 4-tribromothiophene,

1f, exhibited a different behavior. It showed two cathodic peaks with a

significant difference of 640 millivolts, one at -2.113V and the second at -

2.754V (Figure 3.23, example d). The first cathodic peak was observed at

unusually low potential (-2.113V) since all the bromothiophenes, not carrying

any electron withdrawing groups, studied in this work, were reduced at much

higher potential. The ratio of the current values for the first peak and second

peak is almost 1:2. From the current values, it can be inferred that the first

peak is due to reduction of one bromine atom and the second peak is due to

the reduction of the remaining 2 bromine atoms. Since the CV of 3,4-

dibromothiophene exhibits only one cathodic peak around 2.75V, the first

cathodic peak at -2.114V observed in the case of 1f can be assigned to the

reduction of the bromine at 2 position, which would result in the formation of

the 3,4-dibromothiophene. The second peak at -2.764V can be assigned to the

reduction of the bromine atoms at 3 and 4 positions. This is in accordance

196

with the regio-selectivity observed in the metal mediated reduction of 2,3,4-

tribromothiophenes (Gronowitz and Raznikiewicz 1973). Why the first

reduction should occur at such a low potential is difficult to comprehend at

this stage. This could be confirmed if the data on the reduction potentials of

2,3-dibromothiophene 1i and 2,4-dibromothiophene 1j were available.

Unfortunately, these two compounds could not be accessed during the course

of this investigation and hence their cyclic voltammograms could not be

taken. Among all the bromo compounds studied, the reduction potential of 3-

bromothiophene 1b was most negative (-2.745 V, entry 1, Table 3.32).

3.5.2 Halothiophene carbonyl compounds and halobenzene carbonyl

compounds - Mechanistic study with reference to CV data

The cyclic voltammogram of all halothiophene carbonyl compounds

and halobenzene carbonyl compounds studied in the present work are shown

in Figure 3.24.

(example a)

Figure 3.24 (Continued)

197

(example b)

(example c) (example d)

Figure 3.24 (Continued)

198

(example e)

(example f) (example g)

Figure 3.24 (Continued)

199

(example h) (example i)

Figure 3.24 CV of halothiophene carbonyl compounds and halobenzene

carbonyl compounds

2-aceyl-3-bromothiophene, ketone 2b and bromothiophenecarboxylic acids

3b and 3d showed two cathodic peaks, one corresponding to the reduction of

C-Br bond (first wave and less negative) and another due to the reduction of

the carbonyl group/H+ (second wave, more negative potential). This was

evident by comparing the cyclic voltammogram of 3-bromothiophene 1b

(Figure 3.23, example a) with that of 3-bromothiophene-2-carboxylic acid 3b

(Figure 3.24, example b) and also with those of 4-bromo and 5-bromo

thiophene-2-carboxylic acids 3d and 3e (Figure 3.24, example c) respectively.

The other two bromothiophene carboxylic acids 3f (Figure 3.24, example c)

and 3e (Figure 3.24, example d) showed only one broad peak.

The reduction potentials of all these compounds are listed in Table 3.33.

200

Table 3.33 CV of Halothiophene carbonyl compounds and halobenzene

carbonyl compounds.

Entry StructureCompound

number

Cathodic reduction potential

(V)

1S

Cl

COCH3

2a -1.957

2S

Br

COCH3

2b -1.882

3 S

Cl

COOH 3a -2.058

4S

Br

COOH 3b -1.995

5S

COOH

Br 3f -2.070

6S

COOH

Br

3d -1.980

7 SCOOH

Br 3e -1.790

8S

Br

COOCH3 3g -1.779

9 SCOOCH3

Br

3i -1.878

10 SCOOCH3

Br3j -1.472

11Br

COOH

8a -0.967

12Br

COCH3

9a -2.078

13 BrHOOC8b -0.999

14Br

HOOC

8c -0.958

201

The reduction potentials of the C-Br bond of bromothiophene

carboxylic acids were more positive compared to those of bromothiophenes

by as much as 750 millivolts or more (entries 4, 5, 6 and 7, Table 3.33

compared with entries 1,2 and 3, Table 3.32). Even when the bromine and

COOH are not conjugated as in the case of the acid 3d the C-Br bond

reduction occurs remarkably at a lower potential viz., - 1.980V (entry 6, Table

3.33) compared to 2/3-bromothiophene (-2.74V). Surprisingly there is a

marginal difference of 15 millivolts only between the reduction potentials of

acid 3b (-1.995V) and 3d (-1.980V) in spite of the fact that in the case of acid

3b, the bromine atom is conjugated with the -COOH group. When the

bromine is conjugated with the -COOH group as in the case of acid 3e but not

vicinally located, the reduction potential is further shifted to more positive

direction with a significant difference of 205 millivolts (-1.79V, entry 7,

Table 3.33). One may advance the following tentative explanation as to why

the 2 or 3-bromo acids (3f and 3b) is reduced at more negative potential

compared to the 5- bromo acid 3e. While resonance is present in both the

compounds 3b/3f and 3e, the developing negative charge on the carbon will

experience dipole-dipole repulsion in the case of 3b/3f due to the adjoining

CO group rendering the reduction process energetically more difficult. In the

case of 5-bromoacid 3e, the C-Br bond and -COOH are farther away from

each other and there is no dipole-dipole repulsion due to the developing

negative charge. -Haloketones and anomeric effects are well known

examples for the effect of dipole repulsion in influencing the physical /

chemical properties of a molecule (Carey and Sundburg 2003). The easier

reduction of 5-bromoacid 3e compared to that of the 4-bromoacid 3d can be

attributed to mesomeric interaction. Resonance involving the bromine and the

carboxyl in the case of 5-bromoacid 3e would facilitate the reduction of C-Br

bond whereas in 3d, the bromine is not in conjugation with the COOH group.

202

In the case of bromo and the corresponding chloro thiophene carbonyl

compounds, the bromo isomers were reduced at a more positive potential

compared to the corresponding chloro isomers as would be expected (Figure

3.24, examples a and b). This trend parallels their reactivity in the Ullmann

cross coupling reaction. The bromo ketone 2b and bromo ester 3g are reduced

at more positive potential when compared to the corresponding bromo acid 3b

(entries 2, 8 and 4, Table 3.33). It is interesting to note that while bromo

ketone 2b (entry 1, Table 3.33) is reduced at a more positive potential

compared to bromo acid 3b (entry 4, Table 3.33), the trend is reversed in

corresponding benzene system i.e. bromo acid 8a (entry 11, Table 3.33) is

reduced at a more positive potential compared to bromo ketone 9a (entry 12,

Table 3.33).

The order of ease of reduction of C-Br bond in bromothiophene

carboxylic acids as revealed by cyclic voltammetry data is 3e>3d=3b>3f. 2,

3, 4, 5-tetrabromothiophene 1k could be regio-selectively reduced stepwise

by zinc or n-butyl lithium to 2, 3, 4-tribromothiophene, 1f then to 3, 4-

dibromothiophene, 1e and then to 3-bromothiophene 3b (Gronowitz and

Raznikiewicz 1973). In fact this property has been used for the synthesis of 3-

bromothiophene. However this trend is not reflected in the case of Ullmann

cross coupling reactions which exhibited the following order of reactivity

3f>3b>3e>3d even though the reduction potentials of 2-bromo acid, 3f (-

2.070V) and 3-bromo acid 3b (-1.995 V) were very close but more negative

compared to that of 5-bromo acid 3e (-1.79V). The 2-bromo acid 3f is more

reactive compared to 3-bromo acid 3b. The observed order of reactivity

towards Ullmann cross coupling reaction is in contrast to the reduction

potentials which follows the order 3e>3d=3b>3f. Thus it is clear that factors

other than ease of reduction of the C-Br play a significant role in determining

the reactivity in Ullmann cross coupling reactions. The higher reactivity

exhibited by the bromo acids 3b and 3f in the Ullmann cross coupling with

203

sodium bisulphite is attributed to chelation and the availability of an

intramolecular oxidative addition pathway in these compounds (Figure 3.25).

Figure 3.25 Chelation supporting the oxidative addition

The lower reactivity of the acid 3b compared to that of 3f may be due

to the chelation of the copper carboxylate with sulphur atom in the case of 3b

thus reducing the probability for the oxidative addition of copper in to C-Br

bond. This sort of chelation is not possible in the case of 2-bromothiophene-3

carboxylic acid 3f and hence its enhanced reactivity. The higher reactivity of

3f over 3e may be due to the effect of chelation of Cu+ with the thiophene

ring sulphur. One may speculate the following explanation to account for the

higher reactivity of 3e over 3d. The chelation of Cu+ with thiophene ring

sulphur atom will bring down the charge density on sulphur and the effect of

this will be transmitted to the ring. The carbon C2 nearer to S atom will

experience this effect more than C3 or C4 of the thiophene moiety and as a

result of this lowering of electron density at this centre, the oxidative addition

(intermolecular) of Cu+ to the C-Br bond is facilitated. The present study

brings out the role and importance of chelation factor and lends support to the

proposed mechanism involving the intramolecular oxidative addition. In the

light of the interesting findings from the CV studies, it will be worthwhile to

examine the cyclic voltammetry behavior of thiophene compounds viz., 2, 3,

4, 5-tetrabromothiophene, 1k, 3-bromothiophene-4-carboxylic acid 3k and 2-

bromothiophene-4-carboxylic acid, 3l and compare the ease of reduction of

C-Br bonds in these compounds with their reactivity towards Ullmann cross

coupling reaction with sodium bisulphite.

S

Br

OS

Br

O

OCu

O Cu

204

S

Br1k

Br

Br

BrS

COOH3k

Br

S

COOH3l

Br

Figure 3.26 Thiophene compounds

In the case of 3-bromothiophene-4-carboxylic acid 3k, while

intramolecular oxidative addition can take place, there is no scope for

alternate chelation of copper carboxylate with the sulphur atom. Hence it

should exhibit high reactivity similar to that of 3f. With regard to 2-bromo-

thiophene-4-carboxylic acid, 3l, intramolecular oxidative pathway is not

possible. At the same time, chelation of Cu+

salt with ring sulphur is also not

possible. It remains to be seen how its reactivity would compare with that of

3d. The bromine atom is not conjugated with the -COOH group in both these

acids, 3k and 3l and also there is no dipole-dipole repulsion factor due to

developing negative charge in the case of the reduction of 3l. Based on this

reasoning, one could expect its reduction potential (C-Br bond) should be

lower (more positive) than that of 3k and also higher than that of 3e. Hence it

will be worthwhile to investigate the electrochemical reduction and Ullmann

cross coupling reactions of these acids.

The rate profile for Ullmann cross coupling reaction of halothiophenes

with phenol is 3-bromo-2-acetyl-thiophene (2b) > 3-chloro-2-acetyl thiophene

(2a) > 3-bromothiophene (1b). This is in accordance with the corresponding

CV data for the C-X bond reduction potentials (2b -1.882V, 2a -1.957V and

1b -2.745V).

205

3.5.3 Comparison of Thiophene and Benzene Halocarboxylic Acid

Systems in Ullmann Condensation Based on their CV Data

Nucleophilic substitutions of aromatic halides and heteroaroamtic

halides have been extensively investigated (Bunnet 1951, 1974 amd 1976,

Lindley 1984, Denney and Denney 1991, Diederich and Stang 1998, Carey

and Sundburg 2001, Gibson and Spitzmesser 2003, Laszlo and Barbara 2005,

Naohiko and Eiichi 2012). It is known that haloaromatics exhibit higher

reactivity compared to halothiophenes towards nucleophiles (Bunnet and

Bernhard 1976, Miller 1968, Salo Gronowitz 1991 and Bunnett 1983).

Different physical methods (X-ray, electron diffusion and microwave studies)

reveal a high double bond character of the C-S bond in thiophene (Figure

3.18).

SS S S S S

C2

C1

C3

C4

Figure 3.27 Canonical structures for thiophene molecule

In excessive heteroaromatics which contain a five membered ring

and contain only one heteroatom, the electron density is higher on the ring

carbon. This implies low reactivity towards nucleophiles. The C(2)-C(3) and

C(3)-C(4) bonds in thiophene molecule are respectively shorter and longer

than C-C bond of in a benzene ring and therefore have a correspondingly

higher and lower bond order. This fact causes the occurrence of different

ortho-relations corresponding to 2, 3 and 3, 4 di-substituted thiophenes. Many

kinetic, spectroscopic and reactivity data support this difference and lead to

distinguish the two molecules as hyper-ortho and hypo-ortho respectively.

Moreover, in the five membered ring of thiophene the values of internal

angles S-C1-C2 (111°28’) and C1-C2-C3 (112 °27’) are not far from those of

206

sp3 hybridized carbon atom (109°5’). This is similar to those represent the

reaction centre in the complexes for both SNAr and SEAr. At the same time

the high values of external angle makes the distance between the two ortho-

like substituents larger than in benzene derivatives, affecting both the

interactions between these substituents and their geometry with respect to the

ring. Theoretical and experimental studies indicate that thiophene is less

aromatic than benzene (resonance energy of thiophene 130 KJmol-1

and that

of benzene 151 KJmol-1

). The geometric structure and the aromaticity surely

affect the reactivity of thiophene derivatives with nucleophiles. Under

analogous reaction conditions, the reactivity of thiophene in SEAr is higher

than that of the corresponding benzene derivatives, for example, the nitration

and acetoxymercuration of thiophene are faster than benzene respectively by a

factor 850 (at 10°C) and 105 at 25C°. The piperidinodechlorination in ethanol

at 25° C of 2-chloro-3,5-dinitrothiophene is faster by a factor 500 than that of

2,4-dinitrochlorobenzene. This is in contrast to the nucleophilic substitution

occurring through addition-elimination SNAr mechanism.

SCl

NO2

O2N

Cl

NO2O2N

ethanol

ethanol

NH

NH

SN

NO2

O2N

N

NO2O2N

k thiophene / k benzene > 500

25° C

25° C

Scheme: 3.35 Piperidinodechlorination reaction

The high electron density on the ring carbon, characteristic of

excessive heteroaromatics causes a stabilization of the transition state for

207

SEAr reaction in thioiphene, where as the high electron delocalization ability

of the electron withdrawing aromatic residues favors SNAr reaction in

thiophene derivatives (Bunnet 1978). The intrinsic ability of the thiophene

ring to transit the electronic effect of the substituent is greater than the ability

of the benzene ring (a factor that can also be enhanced by hyper-ortho or

quasi-para relations and also can be enhanced by involving the transition of

electronic effects through sulphur heteroatom).

Unactivated halothiophenes are relatively inert to nucleophilic

substitution while those conjugatively substituted with electron withdrawing

groups are comparatively more reactive to nucleophilic substitution (Kassmi

1992). In unactivated systems, SRN1 reactions occur with halogen derivatives

of thiophene but less readily compared to phenyl halides (Bunnet and

Bernhard 1976, Miller 1968, Salo Gronowitz 1991, Bunnett 1983). This

order of reactivity is reversed in the case of activated substrates containing

highly electron withdrawing groups. The nucleophilic substitutions of

unactivated halides are effected under harsh conditions when compared to

activated halides.

It has been observed in literature that there is a parallel between the

reduction potentials of C-X bond of halides and the leaving group ability of

the halides (Gibson and Spitzmesser 2003). The order of reduction potential

of halobenzenes in liquid ammonia is PhI > PhBr > PhSPh > PhCl > PhF >

PhOPh (Amatore et al 1985) which coincides with the reactivity order

determined under photo initiation. Experiments carried out in liquid ammonia

under irradiation, with pair of PhX towards-CH2COBu

t, the following

reactivity order was found: PhCl / PhF= 29, PhBr / PhCl= 450. PhI / PhBr=

8.3. Therefore the increase in reactivity from PhF to PhI is almost 100000

(Amatore et al 1981). One could expect a similar parallel between the

cathodic reduction potential of C-X bond and the ease of Ullmann cross

208

coupling. With a view to get some insight into mechanism of this reaction, the

cathodic reduction potential of C- X bonds in the molecules of interest were

measured using cyclic voltammetry analysis. The CV data of aromatic halides

has been advanced as evidence in support of the mechanism in the case of

SRN1 reactions (Bunnet 1978). Since both the reduction of the C-X bond and

oxidative addition of a metal/metal ion into a C-X bond involve addition of 2

electrons, it was of interest to find out whether any correlation could be

observed between the reduction potentials and ease of the Ullmann cross

coupling of the various halothiophene carboxylic acids. More importantly, it

was our interest to check if the observed higher reactivity of 2-bromobenzoic

acid 8a over 3-bromo-thiophene-2-carboxylicacid 3b in the Ullmann cross

coupling reaction with sodium bisulphite could be correlated with the

reduction potential of these two bromo derivatives. So far no such study has

been reported in literature. In fact a comparative study of the electrochemical

reduction of various halothiophenecarboxylic acids or halobenzoic acids has

not been reported so far in literature. In view of this, cyclic voltammograms

of several halothiophene carboxylic acids and halobenzoic acids were

measured and the cathodic peak potentials are given in Table 3.33.

The Ullmann cross coupling of 2-bromobenzoic acid 8a with

sodium bisulphite was much faster compared to that of 2-chlorobenzoic acid

8d. The relative reactivity was similar to that observed in the case of 3-

bromothiphene-2-carboxlic acid 3b and 3-chloro-thiophebne-2-carboxylic

acid 3a. Harsh conditions have been employed in literature (Anthony 1979,

Kim 2010) for the Ullmann cross coupling of 2-chlorobenzoic acid 8d with

sodium bisulphite (175°C, autoclave, 7 kg/cm2 pressure for 24 h). It

interesting to note that 2-bomobenzoic acid 8a was several folds more

reactive than 3-bromothiophene-2-carboxylic acid 3b. The conversion profile

is tabulated in Table 3.25. Likewise, 5-bromo-thiophene-2-carboxylic acid 3e

was found to be more reactive than 4-bromobenzoic acid 8c (Table 3.27). One

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could advance the following explanation to account for the observed higher

reactivity of 2- bromobenzoic acid 8a compared to that of 3-bromothiophene-

2-carboxylic acid 3b. In the case of the thiophene acid 3b, the copper

carboxylate can form two chelates (Figure 3.19) i.e. one involving ring

sulphur and another involving the bromine. Of these only one can participate

in intramolecular oxidative addition and lead to product (Figure 3.19, example

a), whereas the other copper chelate cannot (Figure 3.19, example b). Thus,

the probability for the intramolecular oxidative addition involving the copper

complex which is the crucial step in this nucleophilic substitution reaction is

reduced in 3b. In the case of 2- bromobenzoic acid 8a such a situation does

not prevail and only one chelate involving the copper carboxylate is possible

and thus the probability factor is in favour of 2-bomobenzoic acid 8a

compared to 3-bromothiophene-2-carboxylic acid 3b. In addition to the rate

accelerating ortho carboxylate effect, some other electronic factor involving

the ring sulphur may also play a role.

A comparative study of the electronchemical reduction of various

halothiophenecarboxylic acids or halobenzoic acids has not been reported so

far in literature. The cathodic reduction potential of bromobenzene 1h (-2.44

V) was less negative (difference of 290-310 millivolts) compared to that of 3-

bromothiophene 3b and 2-bromothiophene 1d ( -2.72 V and -2.75 V)

indicating the significant influence of sulphur on the ease of reduction of the

C-Br bond in bromothiophenes. Since the thiophene ring is an activated

heteroaromatic system compared to benzene (super aromatic) for electrophilic

substitution reactions and vice versa for nucleophilic substitution reactions, it

is evident that the addition of electrons to such a system will be unfavourable

compared to that of simple benzene ring. This is reflected in the cathodic

reduction potential values of bromothiophene and bromobenzene. Based on

dipole-dipole repulsion consideration discussed earlier, and based on a

comparison of the cathodic potentials of bromothiophenecarboxylic acids, one

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would expect that 4-bromobenzoic acid 8d would exhibit a more positive

cathodic potential compared to that of 2-bromobenzoic acid, 8a. Though this

trend is observed, the difference (50 to 60 millivolts) is only marginal and not

as big as that observed in the case of thiophene acids 3b and 3e (205

millivolts). 2-bromobenzoic acid 8a is reduced only at a slightly more

negative potential (-0.967V) compared to the 4-isomer 8c (-0.958V). As a

follow up of this study, the cyclic voltammograms of 3-bromo-2- acetyl

thiophene 2b and 2-acetyl bromobenzene 9a were measured and compared

with their relativities towards Ullmann cross coupling reaction with

phenoxides as nucleophiles. It is interesting to note that a rather huge

difference (-1.111V) in the reduction potential between 2-bromobenzoic acid

8a and 2-bromoacetophenone 9a (bromo acid and bromo ketone of benzene

system) was observed compared to the difference of + 0.113V in the case of

3-bromothiophene-2-carboxylic acid and 2-acetyl-3-bromohiophene (bromo

acid and bromo ketone of thiophene system). The cathodic reduction potential

of C-X bond in 3-bromo-2- acetylthiophene 2b and 2-acetylbromobenzene 9a

are -1.882 V and -2.078V respectively. Based on these CV data, one may

expect that bromo ketone of thiophene system viz., 2b should manifest higher

reactivity compared to bromo ketone of benzene system viz., 9b towards

Ullmann cross coupling reaction. However 9b was found to be more reactive

than 2b, pointing to some role played the sulphur atom.

The present study has shown that the cathodic reduction potential

values of halobenzoic acids, haloacetophenones, halothiophene carboxylic

acids and ketones cannot be correlated in all cases to their respective

reactivity towards Ullmann cross coupling reactions, though a good

correlation has been observed in literature in the case of SRN1 reactions. The

present cyclic voltammetry investigation has led to some very interesting

findings which are worthy of further exploration.