METHODS BASED ON ACTIVATING THE REACTING SUBSTANCE:Experimental method

<< SYNTHETIC METHODS BASED ON ACTIVATING THE REACTANT:HALOGENATION OF BENZENE

SYNTHESIS OF MATERIALS BASED ON SOLUBILITY PRINCIPLE >>

Chapter - 3

METHODS BASED ON ACTIVATING THE REACTING SUBSTANCE

R. Mahalakshmy

1. INTRODUCTION

The art of carrying out efficient chemical transformations is a major concern in modern

organic synthesis. Two aspects are of utmost importance when considering the outcome of a

reaction, viz., selectivity and efficiency (optimization of yields).

The new procedures

developed should also be compatible with our environment and thus facilitate preserving our

resources. The right activation mode is, therefore, development of methods that promote an

efficient chemical transformation. In this article, activation should be understood in a rather

wide sense. In one-way it is described as a sort of catalysis facilitating the course of the

reaction by lowering the activation energy. Another way it is explained in relation to non-

catalytic path.

Activation mode

Physical

Chemical

(i) Microwave

(ii) Ultrasound

Catalytic

Non-catalytic

Aqueous

(iii) High Pressure

Ionic liquid

(i) Solvophobic

(i) Homogeneous

(ii) Heterogeneous

Supercritical

(ii) Solvent free

(iii) Biocatalysis

Micelles

(iii) Physicochemical

(iv) Photocatalysis

Micro emulsion

Electrochemical

Scheme 3.1. Types of activation mode

Activation is achieved in different ways, which may be classified into physical, chemical or

biochemical, physicochemical modes. Although exhaustivity is not the aim, this article tries

to give a survey on the most recent advances in either traditional modes (pressure, light,

3.2

Methods Based on Activating the Reacting Substance

chemical catalysis) or in novel techniques (microwaves, sonication, biocatalysis).

The

various activation modes discussed in this article are shown in scheme 3.1.

2. PHYSICAL METHODS FOR THE ACTIVATION OF REACTING

SUBSTANCE

2.1. Activation by Microwave

Microwaves are a form of electromagnetic waves (wavelength between 1cm and 1m). When

molecules with a permanent dipole are placed in an electric field, they become aligned with

that field. If the electric field oscillates, then the orientations of the molecules will also

change in response to each oscillation.

Most microwave ovens operate at 2.45 GHz,

wavelength at which oscillations occur 4.9 x109 times per second. Molecules subjected to

this microwave radiation are extremely agitated as they align and realign themselves with the

oscillating field, creating an intense internal heat that can escalate as quickly as 10° C per

second. This technique proves to be excellent in cases where traditional heating has a low

efficiency because of poor heat transmission and, hence, local overheating is a major

inconvenience.

Microwave energy is fast becoming the method of choice for both industrial and

academic chemists for driving reactions to completion, as it offers the safest, most effective

way to increase reaction rates and improve product yields, while promoting green chemistry.

Reactions that previously took hours, or even days, to complete can now be performed in

minutes. Decreasing reaction times offers teaching opportunities: students have more time

for design, optimization, characterization and analysis of reaction processes and products.

Additionally, microwave-assisted reactions are often performed in aqueous solutions or neat,

minimizing the need for organic solvents, simplifying the work-up process, and providing

"green" reaction conditions.

Is microwave assisted organic synthesis green and safe?

It's time to think of the environment and our impact on it. Microwave energy is an inherently

efficient way to transfer energy to a reaction, as it transfers kinetically rather than thermally.

Because of this quality, it is the ideal energy source for driving reactions and it also has the

following advantages.

Use water, ethanol or other environmentally benign solvents

Neat reactions/high conversions help eliminate waste

Non-hazardous reagents help students design safer syntheses

Use catalysts, not stoichiometric reagents

Synthetic Strategies in Chemistry

3.3

Not only is microwave-assisted chemistry is good for the environment, it is also safer for

chemists. Microwave synthesis systems designed for the laboratory offer an

Unmatched level of safety.

Eliminate hot plate burns

Reactions return to room temperature before removing from microwave

A few representative examples of microwave assisted chemical conversions are considered.

(i) Oxidation of Primary and Secondary Alcohol

A fast and facile microwave accelerated oxidation of primary alcohols to carboxylic acids

and secondary alcohols to ketones were carried out under organic/aqueous biphasic

conditions using 30% aqueous H2O2 in the presence of sodium tungstate and

tetrabutylammonium hydrogen sulfate (TBAHS) as a phase-transfer catalyst[1]. The

experimental procedure involves a simple mixing of an alcohol, Na2WO4, 2H2O and TBAHS

followed by the addition of 30% aqueous H2O2 in 25:1:1:125 molar ratios for primary and

25:1:1:40 molar ratio for secondary alcohols in an open vessel. Then the reaction mixtures

were placed inside a monomode microwave reactor and irradiated under a reflux condenser

for specific time. The best results were obtained when the temperatures of reaction mixtures

were set to 90° C and 100° C for primary and secondary alcohols, respectively.

H2O2, MW, 20 min

Na2WO4, TBAHS

(Yield= 84%)

H2O2, MW, 10 min

Na2WO4, TBAHS

(Yield= 92%)

(ii) Nucleaphilic Substitution Reaction

The synthesis of arylamines through direct nucleophilic substitution of aryl halides typically

requires highly polar solvents such as DMF and DMSO at high temperatures even with

highly activated aryl halides. A novel and efficient synthesis of N-arylamines by the reaction

of activated p-bromonitrobenzene with secondary amines (morpholine and N-phenylpi-

3.4

Methods Based on Activating the Reacting Substance

perazine) in the presence of basic Al2O3 under microwave irradiation was carried out under

solvent-free conditions in a simple domestic oven [2].

O2N

Al2O3, 3 min

Br + HN

O2N

MW (350W)

Yield= 80%)

Both alumina and amines are polar so they absorb microwaves effectively and consequently

the reaction is completed in a short time.

Thus, the microwave irradiation has been successfully applied in organic chemistry.

Spectacular accelerations, higher yield under milder reaction conditions and higher product

purities have all been achieved so far. More over, by using this technique, a number of

reactions has been carried out successfully that do not occur by conventional heating and

even modifications of selectivity (chemo, regio and stereoselectivity) are obtained.

2.2. Activation by Ultrasound

Ultrasounds are acoustic waves with frequencies ranging from 20 to 100 MHz. They are

mechanical waves that are not absorbed by solid and, therefore, they do not induce heating.

They are transmitted through any substances solid, liquid or gas, which possesses elastic

properties.

How does ultrasound accelerate a chemical reaction?

The energy of ultrasound is insufficient to cause chemical reactions, but when it travels

through media a series of compressions and rarefactions are created, the rarefaction of liquids

leading to cavities. During rarefaction, the negative pressure developed by the power of

ultrasound is enough to overcome the intermolecular forces binding the fluid and tear it,

producing cavitation bubbles. The succeeding compression cycle can cause the micro bubbles

to collapse almost instantaneously with the release of large amounts of energy.

The

enormous rise in local temperatures and pressures produces a dramatic beneficial effect of

reaction acceleration, with relatively short times being required for completing the reaction

such that the decomposition of thermally labile products is minimised.

A schematic

representation of cavitaional erosion of solid is given in Fig. 3.1.

Synthetic Strategies in Chemistry

3.5

Fig. 3.1. Cavitational erosion of solid

How to carry out a chemical reaction in an ultrasonic bath?

A number of common reactions used in synthetic organic chemistry can be carried out more

efficiently using ultrasound. These reactions can be performed by immersing a reaction

vessel into an ultrasonic bath (Fig. 3.2) or by immersing an ultrasonic probe (horn) into a

reaction medium.

Fig. 3.2. Apparatus for carrying out a reaction in an ultrasonic cleaning bath

(Reproduced from a general article entitled, "Ultrasound: A Boon in the Synthesis of Organic

Compounds" published in Resonance, 1998, 3, 56)

There are several advantages of this method and they are:

(i)

It increases the yield and the percentage of by-products decreases.

(ii)

Reactions occur faster, so that lower temperatures can be used.

(iii)

Reaction times decrease by a factor five to fifty for identical isolated yields.

3.6

Methods Based on Activating the Reacting Substance

(iv)

It provides alternative pathways for reactions, due to the formation of high-energy

intermediates.

In the following text several specific applications of Sonochemistry are given [3].

(i) Preparation of organometallic reagents

Sonochemistry enables reactions involving organometallic reagents to be carried out safely.

The reaction of magnesium with ethyl, butyl and phenyl bromides in aqueous diethyl ether or

in n-dibuty1 ether containing 50% benzene or light petroleum is accelerated by utilising

ultrasound.

R-Mg-X

R-X + Mg

R = C2H5 , nC4H9 , C6H5

X = Cl, Br

(ii) Oxidation of alcohol

The oxidation of alcohols by solid potassium permanganate in hexane and benzene is

significantly enhanced by sonication in an ultrasonic bath.

KMnO4

(iii) Reformatsky reaction

The Reformatsky reaction can be carried out in high yield (98 %) in just 30 minutes at 2530o

C as compared to conventional method, which gives only 50% yield after 12 hours at 80o C.

NaX

C4H8C=O + BrCH2COOEt + Zn

C4H8C(OH)CH2COOEt

(iv) Breakdown of polymeric organometallic compound

The breakdown of polymeric organotin fluoxides is carried out by sonication method. For

this reaction, there is 900-fold increase in rate as compared to conventional reflux.

[R3SnF]n

nR3SnX

R=Me, nBu or Ph

X=Cl, Br, NCO

Synthetic Strategies in Chemistry

3.7

(*Note: In the above examples the symbol

represents the sonication method)

In addition to the types of reactions mentioned, ultrasound has also been used in the case of

enzyme catalysed reactions, polmer chemistry and coal liquification.

Extension of

combination of sonochemistry with other specific methods, such as photochemistry and

electrochemistry appear to be promising. Since it is an upcoming and a recent field of

interest, there is a great deal more to explore in ultrasonics as an important tool in order to tap

its full potential for the discovery of new reactions utilising highly energetic sound waves.

The sonochemical boom is turning out to be a real boon for synthetic chemistry.

2.3. Activation by high pressure

Pressure represents a mild non-destructive activation mode, generally respecting the

molecular structure by limiting decomposition or further evolution of the products. The

specific effects of high pressure can be of important value for organic synthesis. The kinetic

pressure effect is primarily determined by the variation of volume due to changes in the

nuclear positions of the reactants during the formation of the transition state. Related to

volume requirements are steric effects since the bulkiness of the molecules involved in the

transition state conditions the magnitude of the steric interactions.

As a consequence,

pressure affects volume changes and should have an effect on steric congestion.

As a mild activation mode, pressure may be considered of value in the synthesis of

thermally fragile molecules, permitting a lowering of the temperature.

In addition, the

selectivity is generally preserved or even improved under such conditions. High-pressure

chemistry is now recognized as a powerful method to achieve synthetic organic reactions,

which are not readily accessible by usual means. The applications of this technique to

organic reactions like Diels-Alder [4] and Cyclo addition [5] are discussed.

(i) Diels-Alder reaction

The high pressure (0.8 GPa) Diels-Alder reaction of N-methyl-2(1H)-pyridones with

cyclooctyne at 90° C affords 1:1 cycloadducts in 60 - 80% Yield. No adduct is recovered at

normal pressure due to the extrusion of methyl isocyanate.

H3C

CH3

3.8

Methods Based on Activating the Reacting Substance

(ii) Cycloaddition reaction

Cycloaddition of mesityl oxide to isoprene is also carried out at high pressure in

LiClO4/Diethy ether medium.

20 MPa, 100 C, 24 h

Dimers of

isoprene

LiClO4/Diethyether

Yield:52%

Yield:19%

When traditional synthetic strategies appear forbiddingly difficult or fail utterly, the pressure

parameter, possibly associated with other activation methods may be considered. Other

salient features of this method include:

(i)

Extreme simplicity of the method

(ii)

Capacity to induce ionogenesis

(iii)

Capacity to remove steric inhibition

Thus the notable advantages of this method materialize in new or improved synthetic routes,

and it adds another important dimension to the existing synthetic activation modes.

3. CHEMICAL METHODS FOR THE ACTIVATION OF REACTING

SUBSTANCE

3.1. Non-catalytic activation

3.1.1. Solvophobic activation

3.1.1a. Reaction in water

In the most recent decades, the use of water as a reaction solvent or co-solvent has received

much attention in synthetic organic chemistry, with sometimes surprising and unforeseen

results. It plays an essential role in life processes; however its use as a solvent has been

limited in organic synthesis. Despite the fact that it is the cheapest, safest and most non-toxic

solvent in the world, its presence is generally avoided through the dehydrative drying of

substrates and solvents. But still it can be considered as a unique solvent. Moreover, water is

the `solvent of Nature' and therefore the use of water as a medium for organic reactions is

one of the latest challenges for modern organic chemists.

Synthetic Strategies in Chemistry

3.9

There are many potential reasons to replace the classical organic solvents by water. They are

(i)

Cost, safety and environmental concern.

(ii)

Aqueous procedures are often referred to as green, environmentally friendly, or

benign.

(iii)

The unique solvation properties of water have been shown to have beneficial

effects on many types of organic reactions in terms of both the rate and selectivity.

(iv)

Experimental procedures may be simplified, since isolation of organic products

and recycling of water-soluble catalysts and other reagents can be achieved by

simple phase separation.

Selected few organic reactions run in an aqueous medium are considered.

(i) Wittig Reaction

Bergdahl and co-workers published the first report in the literature describing that Wittig

reactions of stabilised (and poorly water-soluble) ylides with aldehydes are unexpectedly

accelerated in an aqueous medium [6].

COR2

CHO

COR2

Ph3P

66-99%

R1= H, 2-NO2, 4-NO2, 2-CN, 4-OH, 4-OMe, 4-NH2, 2-OBn, 3-OBn

R2= Me, OMe, O-Bu, O-Troc, Ph

COR2

Ph3P

COR2

CHO

84-97%

X = S, NH

R1 = H, Br, Me, NO2

R2 = OMe, O-Bu

a) aldehyde (1 mmol), ylide (1.2-1.5 mmol), H2O (5 mL), 20-90ºC, 5 min - 4 h. Troc= 2,2,2-

trichloroethoxycarbonyl.

(ii) Mannich-type Reactions

Kobayashi and co-workers published an efficient (up to 94% yield) enantio- and

diastereoselective protocol for Mannich-type reactions of a hydrazono ester with silicon

3.10

Methods Based on Activating the Reacting Substance

enolates in aqueous medium. One example of a syn adduct from an (E)-silicon enolate and

two examples of anti adducts from (Z)-silicon enolates are reported [7].

NHBz R1

OSiMe3

BzHN

EtO

R1 = H, Me, Et, R2=H, Me, R3= Et, S-tBu, 4-Me-C6H4, 4-OMe-C6H4, 4-Cl-C6H4

MeO

NH HN

OMe

Where a = acyl hydrazono ester (0.4 mmol), silyl enol ether (1.2 mmol), ZnF2 (100 mol%), b

(10

mol%),

CTAB

(0.02

mmol),

H2O

(1.95

mL),

ºC,

CTAB=

cetyltrimethylammonium bromide.

(iii) Deprotection of Functional Groups

Methods for selective deprotection of functional groups are key tools for organic chemists.

The following examples, performed in water, open new possibilities for the use of this

challenging medium. Konwar and co-workers [8] reported a simple protocol for the

deprotections of oximes and imines under neutral conditions (yields up to 90%) using a

I2/surfactant/water system

X= OH, Ph

R1, R2 = alkyl

R1,R2= aryl

R1= H, alkyl, R2=aryl

Synthetic Strategies in Chemistry

3.11

where a= oxime or imine (1 mmol), I2 (20 mmol%), H2O (15 mL), SDS (0.2 mmol), 25-

40°C, 3.5-8 h.

The main obstacle to the use of water as reaction solvent is the negligible solubility of the

majority of organic compounds in water. This problem can be addressed by using aqueous

organic solvents or phase-transfer agents.

3.1.1b. Reaction in ionic liquid

Ionic liquids are low-melting-point salts that have attracted considerable attention recently as

greener alternatives to classical environmentally damaging solvents. "The interest is mainly

due to their peculiar properties such as absence of flammability, lack of measurable vapor

pressure, and good ability to dissolve organic, organometallic, and even some inorganic

compounds. These unique chemical and physical characteristics of ionic liquids are

increasingly enticing chemists to explore their use as media for organic synthesis.

Ionic liquids offer numerous advantages over conventional organic solvents for carrying out

organic reactions. They are,

(i)

Easy product recovery

(ii)

Catalysts can be recycled

(iii)

Ionic liquids can be reused

(iv)

Their thermodynamic and kinetic behavior is different

(v)

Rates of reaction are often enhanced and

(vi)

Selectivity is frequently better

Examples for Ionic Liquids

The most common classes of ionic liquids are alkylammonium salts, alkylphosphonium salts

alkylpyridinium salts, and N, N´-dialkylimidazolium salts. Few examples of cationic and

anionic ionic liquids are given in Fig. 3.3.

BF4-, PF6-, SbF6-, NO3-,

CF3SO3-, (CF3SO3)2N-, ArSO3-,

CF3CO2-, CH3CO2-, Al2Cl7-

R1 NH

Fig. 3.3. Cationic and anionic ionic liquids

3.12

Methods Based on Activating the Reacting Substance

Synthesis and applications of halide based ionic liquid

Halide-based ionic liquids ILX (IL represents cations such as 1, 3-dialkylimidazolium, 1-

alkylpyridinium and tetraalkylammonium; X represents halide anions) can be used as

reagents in nucleophilic substitution for the conversion of alcohols to alkyl halides. This

reaction provides an alternative way of preparing other types of ionic liquids (ILA) based on

the conjugate bases of acids (HA) [9].

-H2O

ILA + RX

ILX + HA + ROH

Where,

ILX: halide-based ionic liquids; X=Cl, Br, I; HA: acids; ROH: alcohols

ILA: new ionic liquids with conjugate bases of HA

These halide-based ionic liquids (ILX) can also be used as reaction media for copper-

catalyzed nucleophilic aromatic substitution reaction for formation of aryl nitriles (ArCN).

Cu catalyst

ArCN

ArY + NaCN

ILX, -NaY

ArY: Aryl halides, Y= I or Br, ILX: halide-based ionic liquid

X= Cl, Br, I; Cu catalysts: CuX, X= Cl, Br, I, CN

Trihalide-based ionic liquids (ILX3) that can be used as reagents as well as reaction media in

halogenation reactions

-2H2O

ILX + 2HX + H2O2

ILX3

ILX: halide-based ionic liquids, X= Cl, Br, I

HX: hydrogen halides

"The rapid growth of interest in ionic liquids is mainly limited to people in academia and

national laboratories," "There is a lot of skepticism among industrial chemists, probably

because our understanding of these materials is limited. Before we see industrial chemists

enthusiastically involved in exploring the field, a lot of work has to be done. We need

information on the toxicity and safety of these materials and their effect on the environment,

as well as an assessment of their life cycles. Also, we need cost analyses compared with

existing technologies. In addition, it is important to develop a good database of all the

information available on ionic liquids. Unless we have all this information, the growth will be

limited to a few sectors only."

Synthetic Strategies in Chemistry

3.13

3.1.1c. Reaction in supercritical media

What is a supercritical fluid?

Supercritical fluids may be defined as the state of a compound, mixture or element above its

critical pressure (Pc) and critical temperature (Tc), but below the pressure required to

condense it into a solid. It possesses the characteristics of both fluid and gaseous substances:

the fluid behavior of dissolving soluble materials, and the gaseous behavior of excellent

diffusibility. They occupy a point where pure and applied science meets head on. This is a

feature that has attracted many workers to the field. A general phase diagram for critical

fluid is given in Fig. 3.4.

Fig. 3.4. General phase diagram for super critical fluid

(Reproduced from the web page: http://www.ed406.upmc.fr/cours/shaldon.pdf)

Reactions under supercritical conditions have been used for large-scale industrial production

for most of the twentieth century, but the application of supercritical fluids (SCFs) in the

synthesis of complex organic molecules is only just emerging. Research in this field has been

particularly active in the last decade of this century, because the following special properties

of SCFs make them attractive solvents for modern synthetic chemistry.

3.14

Methods Based on Activating the Reacting Substance

Increased reaction rates and selectivities resulting from the high solubility of the

reactant gases

Rapid diffusion of solvents

Weakening of the solvation around the reacting species and the local clustering of

reactants or solvents.

These fluids are easily recycled and allow the separation of dissolved compounds by a

gradual release of pressure

Sequential and selective precipitations of the catalyst and product would be possible.

Example for Carboncarbon bond formation reactions in supercritical fluids

(i)

Diels-Alder reaction

The DielsAlder reaction is the most widely-used synthetic method for the synthesis of

polycyclic ring compounds. Kolis et al [10] have reported the possibility of performing

DielsAlder reactions in superheated and scH2O due to the unique properties of scH2O [11].

The reactions tested were the cycloadditions of cyclopentadiene (1) with diethyl furmarate (2)

and diethyl maleate (4) using scH2O as the solvent. They obtained yields of 10 and 86% for 3

and 5, respectively, after 1 h. Although the yield of the endo/exo-2, 3-diethyl ester of 5-

norbornene 3 was low, equal amounts of both isomers of 5 were formed in good yield from

the cis diene.

CO2Et

scH2O

CO2Et

375 oC, 1h

EtO2C

CO2Et

scH2O

CO2Et

375 oC, 1h

CO2Et

3.1.2. Solvent Free or Solid State Reaction

Synthetic Strategies in Chemistry

3.15

A solvent-free or solid-state reaction may be carried out using the reactants alone or

incorporating them in clays, zeolites, silica, alumina or other matrices. Thermal process or

irradiation with UV, microwave or ultrasound can be employed to bring about the reaction.

Solvent-free reactions obviously reduce pollution, and bring down handling costs due to

simplification of experimental procedure, work up technique and saving in labour. These

would be especially important during industrial production.

Often, the products of solid state reactions turn out to be different from those obtained in

solution phase reactions. This is because of specific spatial orientation or packing of the

reacting molecules in the crystalline state. This is true not only of the crystals of single

compounds, but also of co-crystallized solids of two or even more reactant molecules. The

host-guest interaction complexes obtained by simply mixing the components intimately also

adopt ordered structure. The orientational requirements of the substrate molecules in the

crystalline state have provided excellent opportunities to achieve high degree of

stereoselectivity in the products. This has made it possible to synthesize chiral molecules

from prochiral ones either by complexation with chiral hosts or formation of intermediates

with chiral partners.

Experimental method

If two or more substrates are involved in the reaction, they are thoroughly ground together in

a glass mortar or cocrystallized, and allowed to stay at room temperature or transferred to a

suitable apparatus and heated carefully in an oil bath or exposed to appropriate radiation until

the reaction is complete.

More sophisticated reaction procedures are also adopted, if

necessary. TLC can monitor the progress of the reaction. In some cases, a small quantity of

water or a catalyst may be added. If it is a single-compound reaction, it is subjected to heat or

radiation directly. Care is to be taken to collect the volatile products, if they are produced. In

this article illustrative examples representing a number of organic syntheses performed under

both thermal and photochemical conditions are described [12].

Examples

(i) Solid-state reactions are not really a new concept. They have been reported even in

undergraduate text books. In fact, the historically significant first organic synthesis of

urea by Wöhler achieved in 1828 belongs to this class

Solid

NH4NCO

NH2-CO-NH2

3.16

Methods Based on Activating the Reacting Substance

(ii) Pyrolytic distillation of barium or calcium salts of carboxylic acids to prepare ketones is

even now a commonly used procedure.

(Ph-CH2-COO)2Ba

Ph-CH2-CO-CH2-Ph + BaCO3

(iii) Michael Addition

The addition of a nucleophile to a carbon-carbon double bond with a strong electron-

withdrawing group at the vinylic position is known as Michael addition.

NO2

Al2O3

CH3NO2

(iv) Aldol Reaction

Aldol condensation is an important reaction of aldehydes and ketones in forming carbon-

carbon bonds. The addition of an enol or enolate ion of an aldehyde or a ketone to the

carbonyl group of an aldehyde or a ketone is aldol addition, or aldol condensation, if water is

eliminated in a subsequent step to produce a, b-unsaturated aldehyde or ketone. Many

variations of this reaction are known and are called by different names.

NaOH

Solid r.t

Ar-CHOH-CH2-CO-Ar' + Ar-CH=CH-CO-Ar'

ArCHO + Ar'-CO-CH3

5 min; 97%

( In solution only 11% yield was realized in 5 min)

(v) Oxidations of alcohol to ketone/aldehyde

Cr-Oxides

t-Bu

Solid

Cr-Oxides

CHO

CH2OH

Solid

Synthetic Strategies in Chemistry

3.17

3.1.3. Activation by Physicochemical Methods

3.1.3a. Reaction in Micellar media

Micelles are dynamic colloidal aggregates formed by amphiphilic surfactant molecules.

These molecules can be ionic, zwitterionic, or non-ionic, depending on the nature of their

head groups, their micelles being classified in the same way. In dilute solutions, amphiphile

molecules exist as individual species in the media and these solutions have completely ideal

physical and chemical properties. As the amphiphile concentration increases, aggregation of

monomers into micelles occurs and, as a consequence, these properties deviate gradually

from ideality. This concentration is called the critical micellisation concentration. During

the formation of micelles, head group repulsions are balanced by hydrophobic attractions and

for ionic micelles, also by attractions between head groups and counterions. Hydrogen bonds

can be also formed between adjacent head groups.

It is well known that performing the reactions in micellar media instead of pure bulk

solvents can alter the rates and pathways of all kinds of chemical reactions.

Micelles are

able to

(a) Concentrate the reactants within their small volumes,

(b) Stabilise substrates, intermediates or products and

dissociation constants, physical properties, quantum efficiencies and reactivities are

changed.

Thus, they can alter the reaction rate, mechanism and the regio- and stereochemistry. For

many reactions, rate increments of 5100-fold over the reactions in homogeneous solutions

have been reported. In some cases, rate increments may be higher and increments in the order

of 106-fold have been observed.

Example

(i) Ring opening reaction of epoxide

The ring opening reaction of styrene oxide with NaCN was studied in the micellar solution of

sodium dodecyl sulfate (SDS) as an anionic micelle at different concentrations in the

presence of catalytic amounts of Ce(OTf )[13].

Micelle(SDS)

PhCH(OH)CH2CN + PhCH(CN)CH2OH

Ce(OTf)4, Cat, rt, NaCN

92%

3.18

Methods Based on Activating the Reacting Substance

The CMC of SDS= 8.1x10-3 M

Thus, it is established that, in many cases, performing the reactions in micellar media instead

of organic solvents can alter rates and the pathways of the reactions.

3.1.3b. Reaction in Microemulsion Media

When water is mixed with an organic liquid immiscible with water and an amphiphile,

generally a turbid milky emulsion is obtained which, after some time, separates again into an

aqueous and an organic phase. On the water-rich side, the mixtures consist of stable

dispersions of oil droplets in water, which coagulate with rising temperature. A sponge like

structure is obtained if the mixtures contain approximately equal amounts of water and oil.

On the oil-rich side, dispersed water droplets are found, which coagulate with decreasing

temperature. The size of the domains is a function of the amphiphile concentration and the

volume fractions of water and oil. Since microemulsions contain both a polar component

(water) and a non-polar component (oil), they are capable of solubilising a wide spectrum of

substrates. The mechanism of solubilisation is similar to that in micellar solutions. The

micelles are replaced by the oil domains, which are capable of solubilising all kinds of

hydrophobic substances. The solubilisation of polar substances takes place analogously

through the aqueous domains of the microemulsion.

The solubilisation capacity of

microemulsions is generally superior to that of the micellar solutions and can therefore, affect

the rate and course of a certain reaction.

The use of microemulsions as media for organic reactions is a way to overcome the

reagent incompatibility problems that are frequently encountered in organic synthesis. In this

sense, microemulsions can be regarded as an alternative to phase transfer catalysis. The

microemulsion approach and the phase transfer approaches can also be combined, i.e. the

reaction can be carried out in a microemulsion in the presence of a small amount of phase

transfer agent. A very high reaction rate may then be obtained. The reaction rate in a

microemulsion is often influenced by the charge at the interface and this charge depends on

the type of surfactant used. For instance, reactions involving anionic reactants may be

accelerated by cationic surfactants. The surfactant counterion also plays a major role for the

reaction rate. The highest reactivity is obtained with small counterions, such as acetate, that

are only weakly polarizable. Large polarizable anions, such as iodide, bind strongly to the

interface and may prevent other anionic species to reach the reaction zone.

Example

Synthetic Strategies in Chemistry

3.19

(i)

Nucleophilic substitution reactions were performed in H2O/CO2 (w/c)

microemulsions

formed

with

anionic

perfluoropolyether

ammonium

carboxylate (PFPE COO-NH4+) surfactant. These reactions between hydrophilic

nucleophiles

and

hydrophobic

substrates

were

accomplished

environmentally benign microemulsion without requiring toxic organic solvents or

phase transfer catalysts.

(ii)

The reaction between benzyl chloride and potassium bromide to form benzyl

bromide is the first organic reaction performed in w/c microemulsion [14]. This

reaction between a nonaqueous compound soluble in CO2 and a CO2-insoluble

salt may be expected to take place at or near the surfactant interface.

+ K+Br-

K+Cl-

3.1.4c. Electrochemical Activation

Reactive intermediates such as carbocations, carbanions, radicals and radical ions can be

electrochemically generated from various electroactive species. Those intermediates may

react chemically (C) or electrochemically (E) according to EC, ECE mechanisms. Anodic

oxidations produce acidic or electrophilic species, which can react with nucleophiles or (and)

eliminate protons or electrophiles. Cathodic reductions afford basic or nucleophilic species,

which can react with protons or electrophiles or (and) eliminate nucleophiles. In this way,

using direct electrolytes can selectively perform functional group conversion, substitution

reactions, addition reactions, cleavage reactions and coupling reactions.

Activation by

transition metal catalysts is required when the organic substrate is not electroactive or leads to

non desired reactions. The metal-catalysed electrosynthesis proceeds by a double activation:

i) chemical activation of the organic substrate by the electrogenerated active form of a

transition metal catalyst that generates an organometallic species more easily reduced than

the organic substrate, ii) followed by activation by electron transfer of the organometallic

species formed in the previous chemical activation step. This double chemical and

electrochemical activation causes new reactions to proceed, which involve either, the

classical organic reactive species, produced in any electrochemical steps (carbanions) or

organometallic complexes (anionic or neutral) as the basis of new reactivity.

Example

3.20

Methods Based on Activating the Reacting Substance

Allylations of aldehyde

Using a recyclable electrochemical process (up to five cycles with excellent yield), a tin-

mediated protocol for the allylation of aldehydes (95-100% yield) is developed [15].

R= Alkyl, aryl

Where a = graphite electrode (2.0 V), aldehyde (5 mmol), allyl bromide (8 mmol), SnCl2 (10

mmol), H2O (10 mL), r.t., 6-10 h.

3.2. Catalytic Method of Activation

The word catalysis came from the two Greek words, the prefix, cata meaning down, and the

verb lysein meaning to split or break. A catalyst breaks down the normal forces that inhibit

the reactions of the molecules; a widely accepted definition of catalyst being, `a substance

that increases the rate of approach to equilibrium of a chemical reaction without itself being

substantially consumed in the reaction process'. Catalysis is the phenomenon of a catalyst in

action, wherein lowering of the activation energy is a fundamental principle that applies to all

forms of catalysis homogeneous, heterogeneous or enzymatic.

Broadly catalysis can be divided into five categories:

(i)

Homogeneous Catalysis: Both the reactant and catalysts are present in the same

phase

(ii)

Heterogeneous Catalysis: Reactant and catalysts are present in separate phase,

the catalyst is solid and the reactant either liquid or gas

(iii)

Bio Catalysis: Also known as enzyme-catalysis.

(iv)

Photo Catalysis: Energy for reactions is from light source (hν) (e.g. TiO2

photocatalytic purification and treatment of H2O)

3.2.1. Homogeneous catalysis

Homogeneous catalysis is a chemistry term which describes catalysis where the catalyst is in

the same phase (ie. solid, liquid and gas) as the reactants and products.

The hydrolysis of esters by acid catalysis is an example of this - all reactants and catalyst are

dissolved in water:

CH3CO2CH3(aq) + H2O(l) ↔ CH3CO2H(aq) + CH3OH(aq) - with H+ catalyst.

Synthetic Strategies in Chemistry

3.21

Example

Hydrogenation of maleic acid to succinic acid

H2, Pd/C

EtOH

Advantage and drawbacks

Highly efficient in terms of slectivity (i.e. regioselectivity. enantiomeric excesses) and

reaction rates, due to ther monomolecular nature.

Catalyst recovery can be very difficult (due to the homogeneous nature of the

solution).

Product contamination by residual catalyst or metal species is a problem.

3.2.2. Heterogeneous Catalysis

Heterogeneous catalysis is a chemistry term which describes catalysis where the catalyst is

in a different phase (ie. solid, liquid and gas, but also oil and water) to the reactants and

products. Heterogeneous catalysts provide a surface for the chemical reaction to take place

on.

Example

(i) Synthesis of Ammonia by Haber process

3H2(g) + N2(g) ↔ 2NH3(g) - catalysed by Fe(s).

In the Haber process to manufacture ammonia, finely divided iron acts as a heterogeneous

catalyst. Active sites on the metal allow partial weak bonding to the reactant gases, which are

adsorbed onto the metal surface. As a result, the bond within the molecule of a reactant is

weakened and the reactant molecules are held in close proximity to each other. In this way

the particularly strong triple bond in nitrogen is weakened and the hydrogen and nitrogen

molecules are brought closer together than would be the case in the gas phase, so the rate of

reaction increases

(ii) Hydrogenation of ethene on a solid support

In order for the reaction to occur one or more of the reactants must diffuse to the catalyst

surface and adsorb onto it. After reaction, the products must desorb from the surface and

diffuse away from the solid surface. Frequently, this transport of reactants and products from

one phase to another plays a dominant role in limiting the reaction rate. Understanding these

3.22

Methods Based on Activating the Reacting Substance

transport phenomena and surface chemistry such as dispersion is an important area of

heterogeneous catalyst research. Catalyst surface area may also be considered. A pictorial

representation of hydrogenation of ethane on solid support is shown in Fig. 3.5.

Ni or Pd catalyst

CH2=CH2

CH3-CH3

Fig. 3.5. Pictorial representation of hydrogenation of ethene on solid surface

(Reproduced from the web page: http://en.wikipedia.org/wiki/Heterogeneous_catalysis)

Advantages and drawbacks

Heterogeneously catalyzed reactions allow easy and efficient separation of high value

products from the catalyst and metal derivatives.

However, selectivity and rates are often limited by the multiphasic nature of this

system and/or variations in active site distribution from the catalyst preparation.

3.2.3. Enzyme or biocatalysis

Biocatalysis can be defined as the utilization of natural catalysts, called enzymes, to perform

chemical transformations on organic compounds. Both enzymes that have been more or less

isolated or enzymes till residing inside living cells are employed for this task.

The most important conversion in the context of green chemistry is with the help of

enzymes. Enzymes are known as biocatalyst and the transformations are referred to as

biocatalytic conversions. Enzymes are now easily available and are an important tool in

organic synthesis. Biocatalytic conversions have many advantages in relevance to green

chemistry. Some of these are:

Most of the reactions are performed in aqueous medium at ambient temperature

and pressure.

Biocatalytic conversions normally involve only one step.

Protection and deprotection of functional groups is not necessary

Synthetic Strategies in Chemistry

3.23

Reactions are fast reactions.

Conversions are stereospecific.

Special advantage of biochemical reaction is that they are chemoselective,

regioselective and stereo selective.

A number of diverse reactions are possible by biocatalytic processes, which are catalysed by

enzymes.

The major six classes of enzymes and the type reactions they catalyse are

discussed.

(i) Oxidoreductases: These enzymes catalyst oxidation-reduction reactions. This class

includes oxidases (direct oxidation with molecular oxygen) and dehydrogenases

(which catalyse the direct removal of hydrogen from one substrate and pass it on to

a second substrate.

(ii) Transferases: These enzymes catalyse the transfer of various functional groups. Eg.

Transaminase

(iii) Hydrolases: This group of enzymes catalyses hydrolytic reactions. Eg. Esterase

(esters)

(iv) Lyases: These are of two types, one which catalyses addition to double bond and the

other which catalyses removal of double bond. Both addition and elimination of small

molecules are on sp3 hybridised carbon.

(v) Isomerases: These catalyse various types of isomerisation, e.g. racemases, epimerases

etc.

(vi) Ligases: These catalyse the formation or cleavage of sp3 hybridised carbon.

The enzymes are specific in their action. This specificity of enzymes may be manifested in

one of the three ways:

a. An enzyme may catalyze a particular type of reaction, e.g. esterases

hydrolyses only ester. Such enzymes are called reaction specific.

Alternatively, an enzyme may be specific for a particular class of compounds.

These enzymes are referred to as substrate specific, e.g., Urease hydrolyses

only urea and phosphatases hydrolyse only phosphate esters.

b. An enzyme may exhibit kinetic specificity. For example, esterase hydrolyse

all esters but at different rates.

c. An enzyme may be stereospecific. For example, maltase hydrolyses alpha-

glycosides but not beta-glycosides. On the other hand emulsin hydrolyses beta

glycosides but not the alpha gluycosides.

3.24

Methods Based on Activating the Reacting Substance

d. It should be noted that a given enzyme could exhibit more than one

specificities.

The oxidation accomplished by enzymes or microorganisms excel in regiospecificity,

stereospecificity and enantioselectivity.

An unbelievably large number of enzymatic

oxidations have been accomplished.

Examples:

(i) Conversion of alcohol into acetic acid by bacterium acetic in presence of air (the process is

now known as quick-vinegar process)

Bacterium acetic

CH3CH2OH + O2

CH3COOH + H2O

(ii) Conversion of sucrose into ethyl alcohol by yeast (this process is used for the

manufacture of ethyl alcohol.

Invertase

2C6H12O6

C12H22O11 + H2O

Yeast

Invertase

C6H12O6

2C2H5OH + 2CO2

Yeast

(iii) Oxidation of Galactose

Galactose oxidase (GO) is a fungal enzyme that catalyzes the two-electron oxidation of D.

galactose to the corresponding aldehyde with the concomitant reduction of molecular oxygen

to hydrogen peroxide.

CH2OH

CHO

GOase

H2O2

(iv) Hydroxylation of aromatic rings

Benzene undergoes oxidation with Pseudomonus putida in presence of oxygen and gives the

cis-diol.

Synthetic Strategies in Chemistry

3.25

Pseudomonus

Putida

Cis-3,5-cyclohexdiene-1,2-diol

The path to new chemical entities often shows the limitations of existing tools both in

biocatalysis and organic chemistry. Organic synthetic procedures to prepare a compound in a

target-oriented synthesis can damage other functional parts of the molecule. Protection-

deprotection schemes can lead to a dead end, when a certain protecting group cannot be

cleaved off.

In biocatalysis, on the other hand, the required biocatalytic toolbox and

methodology might not be readily available, therefore limiting a biocatalytic approach. New

toolboxes, ingredients, and methodologies at the interface of classical organic synthesis and

biocatalytic reactions bridge the gap between these two areas. Since product isolation and

purification involves a substantial amount of time in the preparation of chemicals,

methodologies to simplify these tasks are necessary to get the pure product into the bottle

with less work-up time.

Efficient and safe new pharmaceuticals, intermediates and analytical reagents need to be

prepared under certain safety, health, and environmental and economical boundary

conditions.

Biocatalytic reactions have been shown to overcome these limitations

successfully and are becoming increasingly important in industrial manufacturing. Building

bridges between biocatalysis and organic synthesis will therefore create roads to new

synthetic strategies and technological frontiers of both fundamental and practical interest.

3.2.4. Photocatalysis

Photocatalysis is the acceleration of a photoreaction in the presence of a catalyst.

catalysed photolysis, light is absorbed by an adsorbed substrate. In photogenerated catalysis

the photocatalytic activity (PCA) depends on the ability of the catalyst to create electronhole

pairs, which generate free radicals (hydroxyl ions; OH-) able to undergo secondary reactions.

Its comprehension has been made possible ever since the discovery of water electrolysis by

means of the titanium dioxide. Commercial application of the process is called Advanced

Oxidation Process(es) (AOP). There are several methods of achieving AOP's that can but do

not necessarily involve TiO2 or even the use of UV. Generally the defining factor is the

production and use of the hydroxyl ion.

Example

(i) Chlorophyll as photocatalyst

3.26

Methods Based on Activating the Reacting Substance

Chlorophyll of plants is a type of photocatalyst. Photocatalysis compared to photosynthesis,

(Figure 6) in which chlorophyll captures sunlight to turn water and carbon dioxide into

oxygen and glucose, photocatalysis creates strong oxidation agent to breakdown any organic

matter to carbon dioxide and water in the presence of photocatalyst, light and water.

Fig. 3.6. Comparison of photocatalysis with photosynthesis

(Reproduced from the website: http://www.mchnanosolutions.com/whatis.html)

(ii) Epoxidation of trans and cis-2-hexene by TiO2

The reaction was carried out on photoirradiated TiO2 powder using trans-2-hexene or cis -2-

hexene as the starting material. From trans-2-hexene, trans-2, 3-epoxyhexane was obtained

as the main product with the ratio between trans and cis-2, 3-epoxyhexane being 98.4 to 1.6.

In the case of cis-2-hexene, the ratio of trans to cis-2, 3-epoxyhexane was 12.0 to 88.0.

trans-2,3-epoxyhexene

trans-2-hexene

cis- 2,3-epoxyhexene

TiO2

98.4

1.6

cis- 2,3-epoxyhexene

trans-2,3-epoxyhexene

cis-2-hexene

TiO2

12.0

88.0

A large number of recent reports on the photo catalytic reaction of organic compounds have

satisfied the basic requirement of organic synthesis, e.g isolation and identification of

product. Hence photocatalystic reaction is novel synthetic tool as well as activation mode.

Synthetic Strategies in Chemistry

3.27

4. CONCLUSION

The diversity of activation methods in organic synthesis has grown noticeably in recent years.

These methods have many advantages compared to traditional techniques. They also have

some drawbacks. A summary of advantages and drawbacks of a few activation methods,

which are discussed in this article are summarized in Table 3.1.

Table 3.1. Summary of features of activation processes

Activation mode

Advantages

Drawbacks

Large volume reactions

Hazardous temperature control

Fast reactions (Elimination of volatile Safety problems (reactions in

solution)

Microwave

products)

No reproducibility

Simple non-destructive method

Low volume reaction

No or little work-up

Cost of equipments

Pressure

Excellent reproduciblity

Limited to homogeneous

reactions (difficult of mixing)

Simple method

No generality

Large volume reaction

Cost of equipments

Ultrasound

No or little work-up

Hazardous temperature control

Adaptable to heterogeneous reaction

Considerable acceleration of rate No generality

Solvophobic

constant,

Possibility of hydrolysis

interactions

Cheap environmentally safe method

Low temperature efficient method

No generality (limited to a few

Enzymatic

Highly selective method

specific reactions)

catalysis

Cost enzymes

Sensitive to temperature

This article shows that the methods described are fast and efficient. Relatively high yields

are achieved in a very short time.

The methods and the results when compared with

conventional processes are found to be inexpensive, more eco-friendly and high yielding.

Therefore choosing the correct mode of activation for a particular reaction depends entirely

on the knowledge of chemists in this area. In conclusion, this article reports important

examples of activation modes highlighting the implementation of new synthetic strategies. It

may be of great help to chemists of present and future generation.

3.28

Methods Based on Activating the Reacting Substance

5. REFERENCES

1. D. Bogda and M.Ukasiewicz, Synlett, 1 (2000) 143.

2. J. S. Yadav and B. V. Subba Reddy, Green Chemistry, 2 (2000) 115.

3. V. Singh, K. P. Kaur, A. Khurana and G. L. Kad, Resonance, 3 (1998) 56.

4. K. Matsumoto, M. Ciobanu, M. Yoshita and T. Uschida, Heterocycls, 45 (1997) 15.

5. G. Jenner and R. Ben Salem, Tetrahedron, 53 (1997) 4637.

6. J. Dambacher, W. Zhao, A. El-Batta, R. Anness, C. Jiang and M, Bergdahl,

Tetrahedron Lett., 46 (2005) 4473.

7. T. Hamada, K. Manabe and S. Kobayashi, J. Am. Chem. Soc., 126 (2004) 7768.

P. Gogoi, P. Hazarika, and D. Konwar, J. Org. Chem., 70 (2005) 1934.

R. X . Ren, J.X. Wu, Org. Lett., 3 (2001) 3727.

10. M. B . Korzanski, and J. W. Kolis, Tetrahedron Lett., 38 (1997) 5611.

11. J. Gao, J. Am. Chem. Soc., 115 (1993) 6893.

12. G. Nagendrappa, Resonance, 7 (2002) 59.

13. N. Iranpoor, H. Firouzabadi and M. Shekarize, Org. Biomol. Chem., 1 (2003) 724.

14. B. Gunilla, C. Jacobson, T. Lee and K. P. Johnston, J. Org. Chem., 64 (1999) 1201.

15. Zha, A. Hui, Y. Zhou, Q. Miao, Z. Wang and H. Zhang, Org. Lett., 7 (2005) 1903.

Books

1. A.S. Bommarius, B.R. Riebel, Biocatalysis: Fundamentals and Application, Wiley

VCH Publisher, 2007.

2. V.K. Ahluwalia, N. Kidwai, New Trends in Green Chemistry, Kluwer Academic

Publishers and Anamaya Publishers, 2004.

3. M. Kaneko and I. Okura, Photocatalysis: Science and Technology, Biological and

medical physics series, Springer Publishers, 2003.

Websites

1. http://www.bentham.org/aos/Samples/aos1-1.htm

2. http://books.google.co.in

Table of Contents: