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Greener methods for Batch Sulfonation 2011

1 By Anuja Sawant

INSTITUTE OF CHEMICAL TECHNOLOGY

Greener methods for Batch Sulfonation

Project II Report submitted in Partial Fulfillment of the Requirements for the Award of the Degree of

Master of Green Technology

by

Anuja A. Sawant

Institute of Chemical Technology Mumbai-400019

Maharashtra, India

October 2011

GSS


2 By Anuja Sawant

TABLE OF CONTENTS

S.No. CONTENTS

Page No.

1. INTRODUCTION 5

1.1 General procedure for preparing sulfonates 6

1.2 Applications of sulfonates 7

1.3 Sulfonating agents 9

1.4 Commercial sulfonation methods 9

1.5 Batch processing 11

2 OBJECTIVES AND SCOPE 13

3 LITERATURE SURVEY 14

4 REFERENCES 38


3 By Anuja Sawant

List of Tables

Table

No.

Table Name Page

No.

1.1 Classification of sulfonates according to their chemical types 6

1.2 General procedures for preparing sulfonates 6

1.3 Types of Sulfonates and their applications 7

1.4 Sulfonating Agents 9

1.5 Comparison of Continuous and Batch Process 10

3.1 Comparison of conventional methods for preparing a sulphonated polymer

resin versus the newer greener method

15

3.2 Comparison of conventional methods for sulfonation of aromatic compounds

versus newer greener method

17

3.3 Newer greener method using silica sulfuric acid as compared to the

conventional method using sulfuric acid

19

3.4 Comparison of conventional method for sulfonation of aromatic compounds


20

3.5 Effect of MW Irradiation on Performance of 2-Naphthol Sulfonation 21

3.6 Comparison of sulfonation of aromatic compounds with concentrated H2SO4

with and without ultrasound

23

3.7 Sulfonation of aromatic compounds with concentrated H2SO4 with and

without ultrasound

25

3.8 Comparison of conventional methods for sulfonation of hydroxyaromatics


31

3.9 Comparison of conventional methods for sulfonating compounds having one

or more free hydroxyl functional groups and/or one or more optionally

substituted primary or secondary functional groups versus newer greener

method

34

3.10 Comparison of conventional methods for sulfonation of a zonisamide

intermediate versus newer greener method

37


4 By Anuja Sawant

List of Figures

Figure

No.

Figure Name Page

No.

1.1 Example of Aromatic Sulfonation Reaction 5

3.1 Reactions Occurring during 2- Naphthol Sulfonation 22

3.2 Sulfonation of aromatic compounds under sonication 24

3.3 Experimental setup for sulfonation of aromatic compounds under

sonication

25

3.4 General sulfonation reaction of polyhydroxyaromatics 28

3.5 Sulfonation of Catechol in Concentrated H2SO4 29

3.6 Sulfonation of Protocatechuic acid (PCA) with H2SO4 at 120˚C 30

3.7 Sulfonation of Pyrogallol (PG) with concentrated H2SO4 at RT 30

3.8 Sulfonation of pyrogallol (PG) with H2SO4 at 90˚C for 5h 31

3.9 Chemical Formula of Zonisamide 36


5 By Anuja Sawant

1. INTRODUCTION

Sulfonation may be defined as any chemical process by which the sulfonic acid group -

SO2OH, or the corresponding salt or sulfonyl halide group (e.g., -SO2Cl), is introduced into

an organic compound. These groups may be situated on either a carbon or a nitrogen atom.

Sulfonates of the second type (e.g., RNHSO2ONa) are termed N-sulfonates or sulfamates.

Figure 1: Example of Aromatic Sulfonation Reaction

Particular types of sulfonation include sulfochlorination (introduction of an –SO2Cl group

into an alkane using sulfur dioxide or chlorine), halosulfonation (reaction of a halosulfonic

acid –ClSO3H or FSO3H – with an aromatic or heterocyclic compound to introduce an –

SO2Cl or an –SO2F group), sulfoxidation (use of sulfur dioxide and oxygen to sulfonate an

alkane), sulfoalkylation, sulfoacylation, and sulfoarylation (introduction of sulfoalkyl,

sulfoacyl, or aulfoaryl groups). The first three types have the –SO2OH group on carbon, the

chemical nature of which determines the classification. Thus, C6H5OCH2SO2ONa (sodium

phenoxymethanesulfonate) would be considered an aliphatic sulfonate.

For practical reasons, it is also useful to refer to three other types of sulfonates, namely, those

derived from petroleum fractions, from lignin, and from fatty oils. These materials are

mixtures of indeterminate or variable composition, probably comprising one or more of the

main chemical types of sulfonates together with sulfates and other sulfur compounds, and are

made largely by empirical procedures. All three types are commercially important. It is

convenient to classify sulfonates into four main chemical types, they are tabulated as follows:


6 By Anuja Sawant

Table 1.1: Classification of sulfonates according to their chemical types

Sr. No. Main chemical types of Sulfonates

1 Aliphatic and alicyclic

2 Aromatic

3 Heterocylic

4 N-sulfonates or sulfamates

1.1 General procedures for preparing sulfonates:

Condensation procedures refer to the reaction of organic sulfonate “building blocks” (such as

HOCH2CH2SO3Na) with other organic compounds (such as long-chain acid chlorides) to

form new sulfonates with altered properties; these methods include sulfoalkylation,

sulfoacylation, and sulfoarylation. The general procedures for preparing sulfonates are

tabulated as follows:

Table 1.2: General procedures for preparing sulfonates

Sr. No. General procedures for preparing sulfonates

1 Treatment of an organic compound with SO3 or a compound thereof

2 Treatment with a compound of SO2

3 Condensation and polymerization methods

4 Oxidation of an organic already containing sulfur in a lower state of oxidation such

as RSH.


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1.2 Applications of sulfonates:

The applications of sulfonates are tabulated as follows:

Table 1.3: Types of Sulfonates and their applications

Sr.

No.

Types of Sulfonates Applications

1 Dyes Acid Dyes

Solvent Dyes

Basic Dyes

Disperse Dyes

Fiber-Active Dyes

Vat Dyes

2 Dye Intermediates Anthraquinone Sulfonic Acid

Naphthalene Sulfonic Acid

3 Naphthalene sulfonates Naphthalene Sulfonic Acid as naphthalenic

tanning material.

Alkyl Naphthalene Sulfonates for industrial

applications as nondetergent wetting agents and as

dye intermediates.

Use as surfactants.

Naphthalene sulfonate-formaldehyde condensates

as concrete additives.

4 Alkylated Aromatics Synthetic surfactant: Linear Alkylbenzene

Sulfonate (LAS)

Sulfonated toluene, xylene, and cumene,

neutralized to the corresponding ammonium or

sodium salts, are important industrially as

hydrotropes or coupling agents in the manufacture

of liquid cleaners and other surfactant

compositions. Also as crisping agents in drum and


8 By Anuja Sawant

spray drying operations.

5 Aliphatic Sulfonates or

Hydroxysulfonates

Intermediates in the synthesis of a variety of

organic compounds.

6 Sulfosuccinates and

Sulfosuccinamates

Household, toiletry, and cosmetic products.

7 Paraffin sulfonates

(sometimes referred to as

secondary alkanesulfonates

(SAS))

Liquid and heavy-duty solid detergents

8 Fatty acid ester sulfonates Sodium fatty acid easter sulfonates are known to

be highly attractive as surfactants, they can also

be used in the textile industry, emulsion

polymerization, cosmetics, and metal surface

fields.

9 Petroleum Sulfonates Lubricant additives

Emulsifiers

Floatation agents

Corrosion inhibitors

Enhanced oil recovery

Lube additives

10 Lignosulfonates Sacrificial adsorbate for reducing petroleum

sulfonate adsorption by 50% in enhanced oil

recovery.

Animal feed pellets

Concrete additives

Road dust control

Oil-Well drilling muds

Pesticide dispersant

11 Monomer and Polymer

Sulfonates

Ion-exchange resins for demineralization

Membranes for reverse osmosis or Donan dialysis

Separators in electrochemical cells

Selective membrane of many types


9 By Anuja Sawant

1.3 Sulfonating agents:

Sulfonating agents are of two types – inorganic and organic. In the following paragraphs a

survey is made of the principal sulfonating agents, with special reference to their properties

and major applications. These agents may be summarized as follows:

Table 1.4: Sulfonating Agents

Sr.

No.

Sulfonating

Agents

Sub-types

1 Sulfur trioxide

and compounds

thereof

Sulfur trioxide, oleum, concentrated sulfuric acid (SO3 plus

water)

Chlorosulfonic acid (SO3 plus HCl)

Sulfur trioxide adducts with organic compounds

Sulfamic acid

2 The sulfur

dioxide group

Sulfurous acid, metallic sulfites

Sulfur dioxide with chlorine

Sulfur dioxide with oxygen

3 Sulfoalkylating

agents

Sulfomethylating agents (hydroxyl- and

aminomethanesulfonates)

Sulfoetylating agents (hydroxyl-, chloro-, and

methylaminoethanesulfonates; ethylenesulfonic acid)

Miscellaneous sulfoalkylating agents; sulfoacylation;

sulfoarylation; sulfatoalkylation

1.4 Commercial sulfonation methods:

There are two general types of industrial sulfonation procedures:

Batch (or discontinuous)

Continuous


10 By Anuja Sawant

Although batch methods were formerly used almost exclusively, and in fact still predominate,

interest in continuous operation has increased sharply since about 1945, paralleling the

rapidly growing production of phenol, synthetic detergents, lubricant additives, and synthetic

alcohols (ethanol and isopropanol), all of which involve either sulfonation or sulfation as

intermediate steps.

Batch Process is a process in which all the reactants are added together at the beginning of

the process and products removed at the termination of the reaction is called a batch process.

In this process, all the reagents are added at the commencement and no addition or

withdrawal is made while the reaction is progressing. Batch processes are suitable for small

production and for processes where a range of different products or grades is to be produced

in the same equipment for example, pigments, dye stuff and polymers.

Continuous Process is a process in which the reactants are fed to the reactor and the products

or byproducts are withdrawn in between while the reaction is still progressing. For example,

Haber Process for the manufacture of ammonia. Continuous production will normally give

lower production costs as compared to batch production, but it faces the limitation of lacking

the flexibility of batch production. Continuous reactors are usually preferred for large scale

production.

Table 1.5: Comparison of Continuous and Batch Process

Method Principle of working Advantages Disadvantages/

Limitations

Continuous Reactants are fed to

the reactor and the

products or byproducts

are withdrawn in

between while the

reaction is still

progressing

Improved process

control

Better product

quality

Substantially

lower production

cost

Continuous

operation is practical

only where the

reaction rate is high

and the volume of

production is large

and relatively

steady.

Higher process

development costs


11 By Anuja Sawant

More specialized

equipment required

Batch All reactants are added

at the commencement

and the product

withdrawn at the

completion of the

reaction. They are

conducted in tanks

attached with

impellers, gas bubbles

or pumps.

Suitable for small

scale production

Suitable for

processes where a

range of different

products or grades

is to be produced

in the same

equipment

Suitable for

reactions requiring

long reaction times

Suitable for

reactions with

superior selectivity

Not suitable for

large batch sizes

It is a closed system

in which once the

reactants are added

in the reactor, they

will come out as

products only after

the completion of

the reaction

1.5 Batch sulfonation process:

Batch sulfonations are conducted in reaction kettles or autoclaves of standard types, varying

in capacity from 30-2,500 gal. Two closely related design features are of major importance:

heat transfer and agitation. These factors usually require careful consideration since many

sulfonation reaction mixtures are viscous, which can result in inefficient heat exchange

leading to poor product quality and/or reduced productivity. Batch reactors are generally used

for the four general types of sulfonation procedures discussed in the introduction; special

equipment is required for a few reactions, however.

1.5.1 Problems:

Dilute sulfuric acid generated after sulphonation reaction is hazardous pollutant and its

disposal is very difficult process. The cause of generation in almost all cases is excess

addition of sulfuric acid for sulfonation. Excess sulfuric acid is added to facilitate mixing


12 By Anuja Sawant

due to low solubility of product in the reaction mixture and thereby completion of

reaction.

Neutralization of dilute sulfuric acid generated after sulfonation. Neutralization generates

large quantity of solid waste (gypsum).

1.5.2 Possible Solutions:

This acid can be utilized provided the salts, color and concentration (strength) of the acid

is in appropriate limit.

Use of appropriate quantity of sulfuric acid

Add suitable solvent to dissolve product rather than acid

Design a process for recyclization of the concentrated sulphuric aid

Gypsum formed can be used only after meeting standard criteria for color, organic

impurity and amount of salts present. If it doesn’t meet the criteria then disposal of this

waste becomes a very big problem.

Design a process where neutralization is not required.


13 By Anuja Sawant

2. OBJECTIVES AND SCOPE

The objective of this seminar is to discuss greener methods for batch sulfonation. For most

sulfonates, batch processing has always been, and probably will continue to be, the standard

preparative procedure. This is especially true of the many dye intermediates derived from

benzene, naphthalene, anthraquinone, and phthalocyanine which are prepared in relatively

small amounts by involved procedures from expensive raw materials. The sulfonated fatty

oils have also been studied, the batch methods predominates because of great variety of

products made, the variability in raw materials, and the time-consuming and empirical nature

of the working-up steps.

Greener methods for batch sulfonation will aim at the following:

Reactions that can be carried out at room temperature and consume less energy.

Reactions that use raw materials those are easily available.

Lowers waste stream issues.

Simplicity of the process.

Shorter reaction time.

Improved yields.

Improved conversions.

Improved selectivity.

Reduction or elimination of by-products such as sulfones.

Use of stoichiometric quantities of sulphonating agents.

Reactions that can be carried out at in solvent-free conditions.

Enhancement in reaction rates.


14 By Anuja Sawant

3. LITERATURE SURVEY

3.1 Sulphonated Polymer Resin and Preparation Thereof:

Conventional processes for preparing a sulphonated polymer resin use swelling agent, such

as a chlorohydrocarbon. This problem has been solved in the invention such that the

sulphonation of a polymer resin in a non-swollen state is performed by substantially pure

gaseous sulphur trioxide. Sulphonation is substantially performed on the shell layer of

polymer particles. Polystyrene-based resins are conventionally sulphonated for example by

concentrated sulphuric acid in a swelling agent (usually a chlorohydrocarbon). However, the

use of chlorohydrocarbons has been reduced for example due to environmental reasons.

Polystyrene-based resins have also been sulphonated directly by a gaseous sulphur trioxide. It

has been noted, however, that the obtained products where polymer particles are fully

sulphonated are not physically stable but they tend to break. The resins according to the

invention can be used for example as chromatographic resins, ion-exchange resins and

catalyst resins. They are typically ion-exchange resins and particularly strongly acidic cation-

exchange resins. The process enables the preparation of a partly sulphonated product, where

only the shell later of the polymer particles has been sulphonated. Such partly sulphonated

particles (less than one sulphone group per benzene ring) do not break when the sulphonated

product is being diluted during the after-treatment phase. Due to their stability, resins whose

shell layer has been sulphonated are useful for purposes which require resins in a spherical

form. Resin particles are also useful in the production of pulverized resins. A gel-type

polymer resin prepared has the following advantageous properties compared to a

conventional resin sulhonated with sulphuric acid:

It swells less than a conventional gel resin having the same cross-linking degree

It has better stability against oxidizing conditions

Corresponding stability

It has better resistance to osmotic shock

Better compression resistance

A higher degree of packing


15 By Anuja Sawant

Table 3.1: Comparison of conventional methods for preparing a sulphonated polymer

resin versus the newer greener method.

Conventional methods for preparing a

sulphonated polymer resin

Newer greener method

Uses swelling agent, such as

chlorohydrocarbon

Avoids the use of a swelling agent

Products obtained are not physically

stable but they tend to break

Products obtained are stable. Partly

sulphonated gel-type polymer resin

particles prepared according to the

invention do not break when the resin is

being used and processed.

Conventional resins sulphonated with

sulphuric acid have lesser activity

Macroporous resins prepared have been

found to have better activity

3.1.1 Advantages:

Avoids the use of a swelling agent, such as chlorohydrocarbon, which is harmful to the

environment.

Products obtained are stable.

3.1.2 Procedure:

1. The polymer is preferably sulphonated at a reduced pressure, and the reaction space

containing the polymer is subjected to a reduced pressure already before the sulphonation

in order to remove diluting gas components, such as air. The pressure produced in the

reaction space is typically lower than 10000 Pa, preferably less than 1000 Pa, and most

preferably between 50 and 100 Pa.

2. Sulphonation is carried out at a low temperature, typically from 20 to 120˚C, and

preferably 40 to 80˚C.


16 By Anuja Sawant

3. The polymer resin is typically sulphonated in a particle form, preferably in a spherical

form. It can also be in fibrous form, i.e. it can consist of either staple and/or long fibres. It

can also be in a pulverized form.

4. The process employs substantially pure gaseous sulphur trioxide as the sulphonating

agent. The source of sulphur trioxide can be pure sulphur trioxide per se or sulphur

dioxide, which is oxidized in situ into sulphur trioxide, or oleum (fuming sulphuric acid

which contains sulphur trioxide), in which case the sulphonating is typically carried out at

the vapour pressure of sulphur trioxide or at a lower pressure.

5. After the sulphonation reaction the sulphonated product is subjected to after-treatment to

prevent breakage of the resin structure for example by first diluting the reaction product

with sulphuric acid (50%) and thereafter washing it with water to a pH value of 5. The

reaction product can also be diluted directly into water. (Karki et al., 2003)

3.2 A novel method for sulfonation of aromatic rings with silica sulfuric acid:

A mild and efficient method for synthesis of arylsulfonic acids with silica sulfuric acid for

conversion of a variety of aromatic compounds in 1,2-dichloroethane or in excess of substrate

without using any solvent to the corresponding sulfonic acids. In sulfonation of aromatic

compounds, the sulfonic acids are often in equilibrium with sulfones as byproducts.

However, at lower temperatures the equilibrium is very slow and is favorable for the

formation of corresponding sulfonic acids. In this method since silica sulfuric acid is used for

sulfonation at moderate temperature and also as silica sulfuric acid is bulky, therefore this

reagent reacts with high selectivity and the reverse reaction is low and the sulfones are not

produced at all.

ArH + SIO2O-SO3H ArSO3H +SIO2-OH


17 By Anuja Sawant

Table 3.2: Comparison of conventional methods for sulfonation of aromatic compounds


Conventional methods for sulfonation of

aromatic compounds


In sulfonation of aromatic compounds

the sulfonic acids are often in

equilibrium with sulfones as a by-

product

Sulfones are not produced at all

Sulphuric acid causes destruction of

acid sensitive functional groups

Silica sulphuric acid does not cause

destruction of acid sensitive functional

groups

3.2.1 Advantages:

Availability of the starting materials

Simplicity of sulfonation procedure under heterogeneous system

Clean, and straightforward work-up

Short reaction time

High yields without formation of sulfones as by-products

The reaction proceeds under heterogeneous conditions and also the silica gel can be used

several times without losing its activity

Higher yield without solvent as compared to with solvent

3.2.2 Procedure:

Typical procedure for preparation of sulfonic acids in excess of substrate: Preparation of

mesitylene sulfonic acid:

1. A 25mL round bottomed flask was charged with silica sulfuric acid (1.9 g, 5mmol) and

mesitylene (5mL) and a magnetic stirrer.

2. The reaction mixture was stirred at 80˚C for 30min, the heterogeneous mixture then was

filtered, washed with 10mL of dichloromethane, and the solvent was removed under

reduced pressure.

3. The residue was washed with n-hexane (2 X 10mL) and dried in air to produce white

solid (0.75 g, 75% yield).


18 By Anuja Sawant

Typical procedure for preparation of sulfonic acids in 1,2- dicholoroethane: Preparation of

mesitylene sulfonic acid:

1. A 25mL round bottomed flask was charged with silica sulfuric acid (0.38 g, 1mmol),

mesitylene (0.13mL, 1mmol), and 1,2-dichloroethane (5mL) and a magnetic stirrer.

2. The reaction mixture was stirred at 80˚C for 30min, the heterogeneous mixture then was

filtered, washed with 10mL of dichloromethane, and the solvent was removed under

reduced pressure.

3. The residue was washed with n-hexane (2 X 10mL) and dried in air to produce white

solid (0.08 g, 40% yield). (Hajipour A. R. et al., 2004)

3.3 Chemical Recycling of Polystyrene. Sulfonation with Different Sulfonation Agents:

Up till now this solid sulfonating agent was mainly used in the sulfonation reaction of small

aromatic compounds. However using silica sulfuric acid for sulfonation of polystyrene we

yielded insoluble in water product with the cation-exchange properties. By using silica

sulfuric acid as the sulfonating agent for polystyrene modification it is possible to obtain a

product with ion-exchange properties. The sulfonation is relatively simple and the obtained

polystyrene derivatives can be used for purification of water. Ion exchange capacity of

sulfonated polystyrene is similar to commercial ion exchangers. In this method waste

polystyrene foam and virgin polystyrene as a reference materials were converted by chemical

reactions under heterogeneous conditions into useful products. Polymeric flocculants were

obtained from polystyrene during the sulfonation with sulfuric acid as the sulfonating agent

and Ag2SO4 as the catalyst. The products were successfully used as flocculants in the

treatment of the waste water. Solid silica sulfuric acid was also used to convert polystyrene.

In comparison with the conventional sulfonation methods this sulfonating agent simplifies

the reaction and makes easier separation of products from acid and solvent. (Sułkowski W.

W. et al., 2010)


19 By Anuja Sawant

Table 3.3: Newer greener method using silica sulfuric acid as compared to the

conventional method using sulfuric acid

Newer greener method using silica sulfuric acid as

compared to the conventional method using sulfuric acid

Reaction Simplified

Separation of products

from acid and solvent

Easier

3.4 Process for sulfonation of an aromatic compound:

A process for the sulfonation of an aromatic compound with an aryl sulfonating agent in the

presence of a catalyst, characterized in that the sulfonation reaction is carried out in the

presence of a catalytically effective amount of a mixture of bismuth tri-halide and of

perfluoroalkanesulfonic acid. A conventional process for the preparation of aromatic sulfones

consists in carrying out a sulfonation reaction of Friedel-Crafts type. The aromatic compound

and an aryl sulfonating agent are reacted in the presence of a catalyst, which is generally

aluminum chloride. However, the use of aluminum chloride exhibits numerous

disadvantages. Aluminum chloride is a corrosive and irritating product. Furthermore, it is

necessary to employ a large amount of aluminum chloride at least equal to stoichiometry, as a

result of the complexing of the sulfone formed. Consequently, aluminum chloride is thus not

a true catalyst. In addition, at the end of the reaction, it is necessary to remove the aluminum

chloride from the reaction mixture by carrying out an acidic or basic hydrolysis. The

hydrolysis technique results in the need to carry out a lengthy and expensive treatment

comprising, after the hydrolysis, extraction of the organic phase, separation of the aqueous

and organic phases, indeed drying of the latter. The separation of the aluminum chloride is

thus lengthy and expensive. Furthermore, the problem is posed of the saline aqueous

effluents which subsequently have to be neutralized, which requires an additional operation.

Furthermore, the aluminum chloride cannot be recycled because of its hydrolysis.


20 By Anuja Sawant

Table 1.4: Comparison of conventional method for sulfonation of aromatic compounds


Conventional method for sulfonation of

aromatic compounds


Uses aluminum chloride which is

Corrosive

Used in large amounts

Separation of AlCl3 is lengthy and

expensive

Cannot be recycled

Uses catalytically effective amount of a

mixture of bismuth tri-halide and of

perfluoroalkanesulfonic acid

3.4.1 Procedure:

1. In a first stage of the process of the invention, the sulfonation of the aromatic compound

is carried. In a following stage, the hydrolysis of the reaction mass obtained is carried out.

2. After bringing the reactants in contact, the reaction mixture is brought to the desired

temperature. The temperature is between 20˚C. and 200˚C., preferably between 100˚C.

and 140˚C. The reaction is carried out at atmospheric pressure but lower or higher

pressures may also be suitable.

3. In a following stage of the process of the invention, a hydrolysis treatment of the reaction

mass obtained is carried out. The catalytic mixture, a portion of which is then in the salt

form, is separated off, preferably by filtration. This salt can be recycled after drying.

4. At the end of the reaction, the desired product, namely the aromatic sulfonation, is

recovered in the organic phase. The aqueous and organic phases are separated. The

organic phase is washed one or more times with water. The sulfonated aromatic product

is subsequently recovered from the organic phase according to known techniques, by

removing the organic solvent, by distillation or by crystallization. (Dubac et al., 2002)

3.5 Microwave Assisted Sulfonation of 2-Naphthol by Sulfuric Acid: Cleaner

Production of Schaeffer’s Acid:

Use of large excess of solvents required for providing a medium for chemical reaction causes

ecological and economic concerns. One of the most accepted and reported advances in recent


21 By Anuja Sawant

years is the use of microwave (MW) assisted chemistry. The effects usually observed with

microwave activation in organic reactions are decreasing reaction times, increased product

yields, cleaner reaction with easier workup, and reduced effluent load. The MW dielectric

heating effect uses the ability of some liquids and solids to transform electromagnetic energy

into heat and thereby drive chemical reactions. It has been found that Schaeffer’s acid can be

produced from sulfonation of 2-N with high values of conversion (87%) and selectivity

(90%) at 90 °C and 200 W power in much less time, 4-5 min, compared to the conventional

process. This again utilizes only a stoichiometric quantity of sulfuric acid leading to

minimum effluent generation. Benefits of MW process include precise and controlled

volumetric heating, faster heating rates, lower energy consumption, and improved quality and

properties of the processed materials. Kinetics of the reaction showed that the overall order of

reaction in 2-N concentration varies from 1.6 to 1.7 and activation energy varies from about 5

to 10 kJ/mol. This activation energy is much less than that observed in the reaction in the

absence of MW irradiation.

Table 3.5: Effect of MW Irradiation on Performance of 2-Naphthol Sulfonationa

Molar ratio 2-N conversion, % Selectivity to Schaeffer’s

acid,%

S:2-N = 1:1 87 91

S:2-N = 2:1 81 81

O:2-N = 2:1 54 62 a 90˚C, 200 W, reaction time 5 min.


22 By Anuja Sawant

Figure 3.1: Reactions Occurring during 2- Naphthol Sulfonation


23 By Anuja Sawant

Table 3.6: Comparison of sulfonation of aromatic compounds with concentrated H2SO4

with and without ultrasound

Sr.

No.

Sulfonation of aromatic compounds with

concentrated H2SO4 without ultrasound

Sulfonation of aromatic compounds

with concentrated H2SO4 without

ultrasound

1 At least 200 times excess sulfuric acid is

employed for monosulfonation

Effect of MW irradiation on Performance

of 2-Naphthol sulfonation

Molar Ratio 2-N Conversion % Molar Ratio 2-N Conversion

%

S:2-N = 1.5:1 did not achieve

specified conversion

S:2-N = 1:1 87

S:2-N =2.5:1 73 S:2-N = 2:1 81

O:2-N = 2:1 54

2 Requires more time

Requires lesser time

3 Activation energy required is more Activation energy required is lesser

3.5.1 Advantages:

Efficient and rapid transformation of energy and heating throughout the volume

Reduction in reaction time

Utilizes only a stoichiometric quantity of sulfuric acid leading to minimum effluent

generation

Increase in conversion

Enhanced selectivity

3.5.2 Procedure:

1. Reactions in batch mode were carried out in a thermostated microwave assisted glass

reactor equipped with a magnetic stirrer.


24 By Anuja Sawant

2. The frequency of the microwave was 2450 MHz. The oven has power levels in five

stages and an eight -stage stirring facility.

3. A thermocouple was provided for measuring the reaction- mixture temperature in a

specially designed glass flask with a reflux condenser.

4. The oven has a blower on the back for venting and cooling the glass reactor after

completion of reaction.

5. For each run, sulfuric acid (S) or oleum (O) and 2-naphthol (2-N) in desired proportions

(totaling 30-50 mL volume) were mixed to prepare a homogeneous slurry by maintaining

the temperature around 15-20°C during addition of sulfuric acid into the 2-N powder with

continuous stirring.

6. The oven can accommodate a glass reactor with a maximum capacity of 250 mL.

7. Reactions were carried out at different temperatures and powers.

8. Samples of about 10 mL were withdrawn from the reactor at different intervals of time

and analyzed. (Umrigar V. M. et al., 2007)

3.6 Ultrasound assisted regioselective sulfonation of aromatic compounds with sulfuric

acid:

This method is one of a kind of sulfonation of aromatic compounds using sulfuric acid as

sulfonating agent under solvent free conditions by sonication. This simple and convenient

methodology shows a considerable enhancement in the reaction rate along with improved

selectivity compared with the reactions performed under silent conditions.

Figure 3.2: Sulfonation of aromatic compounds under sonication


25 By Anuja Sawant

Figure 3.3: Experimental setup for sulfonation of aromatic compounds under sonication

Table 3.7: Sulfonation of aromatic compounds with concentrated H2SO4 with and

without ultrasound

Entry Substrate Condition Time Conversion

(%)

Selectivity

(%)

Product Mp

(˚C)

1 Toluene Silent 24 h 70 90 Toluene-

4-

sulfonic

acid

99-

102

2 Toluene ))))) 45

min

76 100 99-

102

3 Benzene Silent 5 h 13 80 Benzene

sulfonic

acid

45-

47

4 Benzene ))))) 45

min

28 100 Benzene

sulfonic

acid

45-

47

5 Naphthale

ne

Silent 5 h 11 87 Naphthal

ene-1-

sulfonic

79-

81


26 By Anuja Sawant

acid

6 Naphthale

ne

))))) 45

min

66 100 Naphthal

ene-1-

sulfonic

acid

79-

81

7 o-Xylene Silent 5 h 37 90 3,4-

Dimethyl

-

benzenes

ulfonic

acid

81-

83

8 o-Xylene ))))) 45

min

70 100 3,4-

Dimethyl

-

benzenes

ulfonic

acid

81-

83

9 m-Xylene Silent 5 h 10 90 2,4-

Dimethyl

-

benzenes

ulfonic

acid

61-

63

10 m-Xylene ))))) 45

min

82 100 2,4-

Dimethyl

-

benzenes

ulfonic

acid

61-

63

11 p-Xylene Silent 5 h 70 90 2,5-

Dimethyl

-

benzenes

89-

91


27 By Anuja Sawant

ulfonic

acid

12 p-Xylene ))))) 45

min

76 100 2,5-

Dimethyl

-

benzenes

ulfonic

acid

89-

91

13 Anisole Silent 5 h 60 84 4-

Methoxy

-

benzenes

ulfonic

acid

88-

90

14 Anisole ))))) 45

min

80 100 4-

Methoxy

-

benzenes

ulfonic

acid

88-

90

15 Chloro

benzene

Silent 5 h 2 70 4-

Chloro-

benzenes

ulfonic

acid

85-

87

16 Chloro

benzene

))))) 45

min

10 100 4-

Chloro-

benzenes

ulfonic

acid

85-

87

Reaction condition: substrate (0.1 mol); concentrated H2SO4 (98 wt%) (0.12 mol);

agitation speed 200 rpm; temperature 25–30C; conversion is based on HPLC analysis.


28 By Anuja Sawant

3.6.1 Advantages:

Solvent free conditions

Ultrasound is the promoter

Enhancement in reaction rate

Improved selectivity

Improved conversion

3.6.2 Procedure:

1. In a typical reaction, a 100 ml round bottom flask equipped with mechanical stirrer was

placed at the centre of ultrasonic bath having maximum cavitations.

2. To it toluene (0.1 mol) was added and afterwards concentrated sulfuric acid (98 wt%,

0.12 mol) was added drop wise.

3. The reaction mixture was then sonicated at room temperature (25˚C) up to desired time.

4. The ultrasonic bath used had a frequency of 33 kHz and electric power rating of 100 W.

5. After completion the reaction mixture was subjected to HPLC analysis and the

experimental error is of ±5%. (Qureshi Z. S. et al., 2008)

3.7 Sulfonation of Polyhydroxyaromatics:

This method provides improved process for the sulfonation of hydroxyaromatics amenable to

direct isolation of the sulfonylated hydroxyaromatics in their free-acid forms. The process

allows for the recyclization of sulfuric acid and minimizes waste. The starting materials are

from a renewable resource, e.g., biomass. The products made include sulfonated catechol,

disulfonated pyrogallol and sulfonated protocatechuic acid.

Figure 3.4: General sulfonation reaction of polyhydroxyaromatics


29 By Anuja Sawant

Formula I:

R’ = SO3H or CO2H, R2 = H or OH

When R’ = SO3H or CO2H, R2 = H, product is Tiron TM

When R’ = SO3H or CO2H, R2 = OH, product is 4,5,6-trihydroxy-1,3-benzenesulfonic acid

When R’ = CO2H, R2 = H, product is 3,4-dihydroxy-5-sulfobenzoic acid

Formula II:

R’ = H OR CO2H

R2 = H OR OH

When R’ & R2 = H, compound is catechol.

When R’ is H, R2 is OH, compound is pyrogallol.

When R’ is CO2H, R2 is H, compound is protocatechuic acid.

Biomass refers to the carbon atoms in the form of cellulose, lignocellulose, and hemicellulose

and starch contained in nonfood and food plants such corn, sweet sorghum and sugar cane

and their waste which cannot be used as a food source which can be broken down to simple

sugars which can be converted into compounds of Formula II.

Figure 3.5: Sulfonation of Catechol in Concentrated H2SO4


30 By Anuja Sawant

Figure 3.6: Sulfonation of Protocatechuic acid (PCA) with H2SO4 at 120C

Figure 3.7: Sulfonation of Pyrogallol (PG) with concentrated H2SO4 at RT


31 By Anuja Sawant

Figure 3.8: Sulfonation of pyrogallol (PG) with H2SO4 at 90C for 5h

Table 3.8: Comparison of conventional methods for sulfonation of hydroxyaromatics


Conventional methods Newer greener method

Process with

catechol

Expensive as the source

varies with the supply:

either short supply and/or

high priced

Uses oleum or fuming

sulfuric acid

Avoids the use of oleum or

fuming sulfuric acid

Neutralization of the

sulfonylated reaction mixture is

required in order to separate

sulfonylated hydroxyaromatic as

its sodium salt

Process with

pyrogallol

Low yield

Lead to product mixtures,

or make an alkali metal salt

product which can lead to

undesirable salt waste

streams

Complicates recycling of

the sulfonylation agent

Often requires high

temperature for a significant

High yield

Lower waste stream issues this

process is more environmentally

acceptable

Runs at RT or elevated

temperature


32 By Anuja Sawant

time, which adds to the cost

of the final product

Process with

Protocatechuic

acid (PCA)

No process for commercial

production of PCA has been

available previously in

sufficient scale.

PCA is obtained from microbial

synthesis from glucose as the

starting material derived from

renewable starch or cellulose

feestocks

The product obtained is SPCA,

which precipitates from the

reaction solution as the free acid.

No neutralization is required and

the product is free of alkali metal

salts.

3.7.1 Advantages:

Biomass is a starting source for the reactants.

The sulfonation reaction uses concentrated H2SO4 can be recycled.

3.7.2 Disadvantages:

Neutralization of the sulfonylated reaction mixture is required in the process with

catechol and pyrogallol.

3.7.3 Procedure:

1. Into a 1L RBF containing 682g of concentrated (98%) sulfuric acid, was added 150g of

catechol at RT.

2. The mixture was heated at 95˚C for 5h.

3. When the reaction mixture was cooled to 50˚C, 232g of 47% (by weight) NaOH solution

in water was added drop wise via an addition funnel to the reaction mixture to precipitate

1,2-dihydroxy-3,5-benzenedisulfonate sodium salt.

4. Upon complete addition of NaOH solution, the reaction mixture was cooled to 15-25˚C

and the precipitate was filtered through a Buichner funnel.


33 By Anuja Sawant

5. The solid was washed with isopropanol (600 mL) and dried under vacuum at 60˚C to

yield 312g (73% yield) of 1,2-dihydroxy-3,5-benzenedisulfonate sodium salt as an off-

white solid. (Frost et al. 2011)

3.8 Method for the sulfonation of compounds comprising free hydroxyl (OH) groups or

primary or secondary amines:

The methods for preparing sulfated compounds reported in the prior art generally induce

cleavage of the chains of the polymers during the O or N sulfonation and, thus, cause the

formation of potentially toxic reactional residues. It would therefore be advantageous to

avoid this drawback by enabling the controlled addition of sulfonate groups under controlled

conditions such that the structural integrity of the initial polymer is not altered. The synthesis

methods described do not make it possible to obtain products in accordance with the criteria

of sufficient reproducibility assuring the maintenance of molecular integrity and the absence

of contaminants. The sulfonation methods are performed at a very acid pH value which does

not enable preservation of the integrity of the polymer chain especially if this chain is

constituted of natural sugars. Moreover, these sulfonation conditions lead to decarboxylations

that are very difficult to control. One of the improved methods is based on the sulfonation of

polysaccharides using an SO3-amine (DMF, pyridine or triethylamine) and the examples

presented are exclusively obtained with SO3-pyridine. This methods moreover leads to

formation of residual traces of pyridine, the human toxicity of which is well known, and does

not appear to enable the absence of formation of fragments of the polysaccharide chain.

The current method provides a method for sulfonating compounds having one or more free

hydroxyl functional groups and/or one or more optionally substituted primary or secondary

functional groups, including treating then compounds with a complex of SO3-DMF in the

presence of an acid capture agent. It makes it possible to control with a high level of rigor

and precision the conditions for substitutions of the sulfonate groups on compounds

containing hydroxyl functional group or primary or secondary amine functional groups. The

term “acid capture agent” means a substance or mixture of substances capable of reacting

selectively with free protons in solution. After addition of the acid capture agent to a reaction

medium, the protons are trapped by the acid capture agent and no longer participate in

reduction of the pH value because they are no longer active. The method is remarkable in that

it makes possible to avoid the use of excessively acidic pH values and thus substantially

eliminate the risk of cleavage of the treated compounds. The method moreover has the


34 By Anuja Sawant

advantage of not introducing toxic substances that are difficult or impossible to eliminate

completely. The method is applicable to monomers, oligomers and polymers.

Table 3.9: Comparison of conventional methods for sulfonating compounds having one

or more free hydroxyl functional groups and/or one or more optionally substituted

primary or secondary functional groups versus newer greener method

Conventional Methods for sulfonating

compounds having one or more free

hydroxyl functional groups and/or one or

more optionally substituted primary or

secondary functional groups


Generally induce cleavage of the chains

of the polymers during the O or N

sulfonation and, thus, cause the

formation of potentially toxic reactional

residues

Avoids introduction of toxic substances

that are difficult or impossible to eliminate

completely.

Performed at a very acid pH value which

does not enable preservation of the

integrity of the polymer chain.

Avoids the use of excessively acidic pH

values by using an acid capture agent and

thus substantially eliminate the risk of

cleavage of the treated compounds.

Structural integrity of the initial polymer

is not altered.

3.8.1 Advantages:

Avoids introduction of toxic substances that are difficult or impossible to eliminate

completely.

It makes it possible to control with a high level of rigor and precision the conditions for

substitutions of the sulfonate groups.

Structural integrity of the initial polymer is not altered.


35 By Anuja Sawant

3.8.2 Procedure:

1. Solubilization or preparation of a homogeneous solution of the compound to be

sulfonated in an anhydrous solvent or cosolvent such as dimethylformamide (DMF) or a

cosolvent composed of formamide and dimethylformamide.

2. Addition at ambient temperature (about 20-22˚C) of a molar excess of an acid capture

agent such as 2-methyl-2-butene, miscible in the cosolvent.

3. Rapid addition of the SO3-DMF complex under agitation.

4. Agitation of the mixture obtained in the preceding step for one to two hours at a

controlled temperature below about 30˚C.

5. Stopping the reaction by progressive addition of the mixture to an alkaline solution, e.g.,

a 2% solution of sodium bicarbonate (NaHCO3) or another alkali, with monitoring of the

pH value such that it is not lower than about 4 to obtain the salts of the compound to be

sulfonated.

6. Purification of the sulfonated compound obtained by tangential ultrafiltration against

water (the water being of the quality of water for human injection) via an ultrafiltration

membrane. (Petit et al., 2008)

3.9 Sulfonation method for zonisamide intermediate in zonisamide synthesis and their

novel crystal forms:

The invention provides a method for sulfonation of a zonisamide intermediate and crystalline

forms of the zonisamide intermediate in the form of acid and metallic salts. It is a novel

sulfonation process for preparing zonisamide intermediate of benzisoxazole acetic acid and

the crystalline forms thereof. The sulfonation processes in this method use chlorosulfonic

acid as well as acetic anhydride and sulfuric acid in an inorganic solvent. Crystalline forms of

benzisoxazole methane sulfonic acid (BOS-H) and its salts (BOS-Na, NOS-Ca, and BOS-Ba)

and their novel preparation processes are included in this method. Zonisamide is known as

1,2-benzisoxazole-3-methane sulfonamide or 3-(sulfamoylmethyl)-1,2-benzisoxazole. It has

the following chemical formula:


36 By Anuja Sawant

Figure 3.9: Chemical Formula of Zonisamide

Zonisamide is currently available as an anti-epileptic agent which possesses anti-convulsant

and anti-neurotoxic effects. Several routes for zonisamide synthesis have been described in

literature. The synthesis route from 4-hydroxy-coumarin via benzisoxazole methane sulfonic

acid (BOS-Na) uses chlorosulfonic acid (in this case the reagent is the reaction solvent, gives

disulfonatedbenzisoxazole-derivative (S-BOS) as the main reaction by-product. It is a

difficult method due to the great sensitivity of the reaction product. The second method

includes the preparation of BOA starting from 4-hydroxy-coumarin, followed by the

sulfonation reaction of BOA to BOS. The reagent chlorosulfonic acid is used in large excess

and it is also the reaction solvent. The reaction is not selective and S-BOS is a main product

of the reaction. The synthetic parthway via the sulfonation reaction of BOA comprises of two

steps lesser as compared to the synthetic pathway via the bromination reaction. In addition,

the sulfonation reactions require a large amount of chlorosulfonic acid which poses

undesirable environmental problems. Another method describes using the sulfonating agent

chlorosulfonic acid:dioxane complex. Although the sulfonation method using this complex is

selective, this method is not safe because of the serious environmental problem of the

dioxane present in the reaction waste. There is a continuous need to improve the sulfonation

method that is both convenient and environmentally safe. This invention provides an

unexpected novel sulfonation process to prepare the intermediate of zonisamide. Neither

patents have characterized the existence of any crystalline forms of this product. This method

relates to more convenient methods for sulfonation of benzisoxazole acetic acid (BOA). The

sulfonation process involves a reaction that does not use dioxane and eliminates the problem

of the waste.


37 By Anuja Sawant

Table 3.10: Comparison of conventional methods for sulfonation of a zonisamide

intermediate versus newer greener method

Conventional methods for sulfonation of a

zonisamide intermediate


Formation of by-product

Reagent chlorosulfonic acid is used in large

excess

Chlorosulfonic acid:dioxane complex is used

which is not safe

Does not use dioxane and eliminates

the problem of the waste.

3.9.1 Advantages:

Involves a reaction that does not use dioxane and eliminates the problem of the waste.

3.9.2 Procedure:

Preparation of BOS-Na: Ac2O/H2SO4 in Ethyl-Acetate

1. In a 250 mL reactor, equipped with thermometer, mechanical stirrer and condenser was

charged ethyl acetate (80 mL), H2SO4, 98% (22 grams, 1.3 eq.) and acetic anhydride (23

grams, 1.3 eq.) and the mixture was cooled to -5˚C.

2. To the above mixture, BOA was added (20 grams, 1eq.).

3. The reaction mixture was then heated to reflux and the reflux was continued for 4 hours.

4. After the completion the reaction mixture was cooled to the room temperature and

aqueous NaOH (10%) was added (120 mL).

5. Upon stirrin, the product precipitates as sodium salt.

6. After 2 hours the product was filtrated, washed with ethyl acetate (2 X 25 mL) and dried

in vacuum-oven at 80˚C.

7. The yield was 20.33 grams BOA-Na having 100% purity by HPLC. (Mendelovici et al.,

2005)


38 By Anuja Sawant

4. REFERENCES

Karki A., Paatero E., Heikkila H., Mononen H., Paananen H., Tiihonen H. “Sulphonated

polymer resin and preparation thereof.” US 6,664,340 B1. (16 Dec., 2003)

Hajipour A. R., Mirjalili Bi. Bi. F., Zarei A.,Khazdooz L. and Ruoho A. E. "A novel method

for sulfonation of aromatic rings with silica sulfuric acid",Tetrahedron Letters, 45, 6607–

6609, (2004)

Sułkowski W. W., Nowak K., Sułkowska A., Wolińska A., Bajdur W. M., Pentak D. and

Mikuła B. “Chemical recycling of Polystyrene. Sulfonation with different sulfonation

agents”, Mol. Cryst. Liq. Cryst., 523, 218=[790]–227=[799], (2010)

Dubac J., Le Roux C., Repichet S. “Process for the sulfonation of an aromatic compound.”

US 6,455,738. (24 Sep., 2002)

Umrigar V. M., Chakraborty M. and Parikh P. A. “Microwave Assisted Sulfonation of 2-

Naphthol by Sulfuric Acid: Cleaner Production of Schaeffer’s Acid”, Ind. Eng. Chem. Res.,

46, 6217-6220,(2007)

Qureshi Z. S., Deshmukh K. M., Jagtap S. R., Nandurkar N. S., Bhanage B. M. “Ultrasound

assisted regioselective sulfonation of aromatic compounds with sulfuric acid”, Ultrasonics

Sonochemistry,16,308–311,(2009)

U.S. Patent Application No. 12/859,922, Publication No. 2011/0046412 A1 (published Feb.

24, 2011) (Frost J., Bui V., applicant)

Petit E., Garcia-Papy D., Barbier-Chassefiere V. “Method for the sulfonation of compounds

comprising free hydroxyl (OH) groups or primary or secondary amines.” US 7,396,923 B2.

(8 Jul., 2008)

Mendelovici M., Nidam T., Schwartz E., Wizel S. “Sulfonation method for zonisamide

intermediate in zonisamide synthesis and their novel crystal forms.” US 6,841,683 B2. (11

Jan., 2005)

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