SOME CONCEPTUAL DEVELOPMENTS IN SYNTHESIS IN CHEMISTRY

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Chapter - 16

SOME CONCEPTUAL DEVELOPMENTS IN SYNTHESIS IN

CHEMISTRY

Joyce DSouza

INTRODUCTION

Synthesis of materials play a crucial role in designing and discovering new materials and

also in providing better and less cumbersome methods for preparing known chemicals.

Most of the ten million or so chemical compounds that are known today, can be classified

into a relatively small number of subgroups or families.

More than 90 percent of the compounds are organic compounds. In turn, organic

compounds can be further subdivided into a few dozen major families such as the

alkanes, alkenes, alkynes, alcohols, aldehydes, ketones, carboxylic acids, and amines. An

important subset of organic compounds include biochemical compounds with four major

families: carbohydrates, proteins, nucleic acids, and lipids.

Because of their unique properties, multi-carbon compounds exhibit extremely large

variety and the range of application of organic compounds is enormous. They form the

basis of important constituents of many products and apart from a very few exceptions,

they form the basis of all earthly life processes. The different shapes and chemical

reactivities of organic molecules provide an astonishing variety of functions, like those of

enzyme catalysts in biochemical reactions of live systems. The autopropagating nature of

these organic chemicals is what life is all about. Products such as plastics, synthetic

fibres,food, explosives, paints and pigments, pharmaceuticals and pesticides and many

others have become readily available through the dynamic development of organic

synthesis.

Inorganic compounds are typically classified into one of five major groups: acids,

bases, salts, oxides, and others. A large class of compounds discussed in inorganic

chemistry textbooks are coordination compounds. Examples range from species that are

strictly inorganic, such as [Co(NH3)6]Cl3, to organometallic compounds such as

Fe(C5H5)2 (ferrocene)and extending to bioinorganic compounds, such as the hydrogenase

enzymes. Major classes of inorganic compounds that are studied under materials science

tend to be polymeric (non-molecular) and refractory, and often are of commercial interest

16.2

Some Conceptual Developments in Synthesis in Chemistry

such as a)alloys: brass, bronze, stainless steel; b)semiconductors : silicon , gallium

arsenide; c)superconductors : yttrium barium copper oxide .

SYNTHETIC ORGANIC CHEMISTRY

Synthetic organic chemistry is an applied science as it borders engineering involving

design, analysis, and/or construction of work for practical purposes. Organic synthesis of

a novel compound is a problem solving task, where a synthesis is designed for a target

molecule by selecting optimal reactions from optimal starting materials. Complex

compounds can have several reaction steps that sequentially build the desired molecule.

The synthesis proceeds by utilizing the reactivity of the functional groups in the

molecule. For example, a carbonyl compound can be used as a nucleophile by converting

it into an enolate, or as an electrophile, and the combination of the two is called the aldol

reaction. Designing practically useful syntheses always requires conducting the actual

synthesis in the laboratory. The scientific practice of creating novel synthetic routes for

complex molecules is called total synthesis.

There are several strategies to design a synthesis. The modern method of

retrosynthesis, developed by E.J. Corey, starts with the target molecule and splices it to

pieces according to known reactions. The pieces, or the proposed precursors, are further

spliced until ideally inexpensive and available starting materials are reached. Then, the

retrosynthesis is written in the opposite direction to give the synthesis. A "synthetic tree"

can be constructed, because each compound and also each precursor have multiple

syntheses.

Retrosynthetic Analysis

Disconnection: A retrosynthetic step involving the breaking of a bond to form two (or

more) synthons.

Synthon

Synthetic equivalent

Synthetic Strategies in Chemistry

16.3

Retron: A minimal molecular substructure that enables certain transformations.

Retrosynthetic tree: A directed acyclic graph of several (or all) possible retrosyntheses of

a single target.

Synthon: An idealized molecular fragment. A synthon and the corresponding

commercially available synthetic equivalent are shown below:

Target: The desired final compound.

Transform: The exact reverse of a synthetic reaction; the formation of starting materials

from a single product.

An example will allow the concept of retrosynthetic analysis to be easily understood.

In planning the synthesis of phenylacetic acid, two synthons are identified. A

nucleophilic "-COOH" group, and an electrophilic "PhCH2+" group. Of course, both

synthons do not exist per se; synthetic equivalents corresponding to the synthons are

reacted to produce the desired product. In this case, the cyanide anion is the synthetic

equivalent for the -COOH synthon, while benzyl bromide is the synthetic equivalent for

the benzyl synthon.

The synthesis of phenylacetylene determined by retrosynthetic analysis is thus:

1. PhCH2Br + NaCN → PhCH2CN + NaBr

2. PhCH2CN + 2 H2O → PhCH2COOH + NH3

16.4

Some Conceptual Developments in Synthesis in Chemistry

STRATEGIES

Functional Group Strategies: Manipulation of functional groups can lead to significant

reductions in molecular complexity.

Stereochemical Strategies: Numerous chemical targets have distinct stereochemical

demands. Stereochemical transformations (such as the Claisen rearrangement and

Mitsunobu reaction) can remove or transfer the desired chirality thus simplifying the

target.

Structure-Goal Strategies: Directing a synthesis towards a desirable intermediate can

greatly narrow the focus of an analysis. This allows bidirectional search techniques.

Transform-based Strategies: The application of transformations to retrosynthetic

analysis can lead to powerful reductions in molecular complexity. Unfortunately,

powerful transform-based retrons are rarely present in complex molecules, and additional

synthetic steps are often needed to establish their presence.

Topological Strategies: The identification of one or more key bond disconnections may

lead to the identification of key substructures : Disconnections that preserve ring

structures are encouraged; Disconnections that create rings larger than 7 members are

discouraged.

SYNTHETIC INORGANIC CHEMISTRY

Advances in inorganic chemistry have made significant contributions to modern living.

For instance, synthetic fertilizers manufactured from inorganic chemicals have increased

worldwide crop production. Inorganic substances used to fabricate silicon chips help

power the global information age. Metal alloys are used in automobiles and aircraft to

make them lighter and stronger. Companies use inorganic compounds to fabricate

concrete, steel, and glass--materials used to construct buildings, infrastructure, and other

public works around the world. In the United States, 10 of the 11 most commonly

produced chemicals are derived from inorganic elements. These 10 inorganic chemicals

(presented below in descending order of production) are used in a wide variety of

applications. Sulfuric acid is used to make fertilizers, synthetic fibers, and metals.

Synthetic Strategies in Chemistry

16.5

Nitrogen is used in recovering underground petroleum deposits, in the production of

ammonia, and as a blanketing material for shipping perishables such as fruits and

vegetables. Oxygen is used in the production of steel and plastics, in medical

applications, and in rocketry. Lime is used in the manufacture of steel and cement.

Ammonia is combined with sulfuric acid to make ammonium sulfate the most important

of the synthetic fertilizers. Sodium hydroxide is used in the manufacture of paper, soap,

detergents, and synthetic fibers, and is also a caustic material used as a drain cleaner.

Chlorine is used to manufacture vinyl chloride plastic, to disinfect drinking water, and to

bleach paper during manufacturing. Phosphoric acid is used to give soft drinks a tart

flavor and to make fertilizers. Sodium carbonate is used in the production of glass, paper,

and textiles. Nitric acid is used to make synthetic fibers, such as nylon; explosives, such

as nitroglycerin and TNT (trinitrotoluene); and is also combined with ammonia to make

fertilizer.

Because of its direct relevance to products of commerce, solid state inorganic

chemistry has been strongly driven by technology. Applications discovered in the 20th

century include zeolite and platinum-based catalysts for petroleum processing in the

1950's, high-purity silicon as a core component of microelectronic devices in the 1960's,

and "high temperature" superconductivity in the 1980's. The invention of X-ray

crystallography in the early 1900s by William Lawrence Bragg enabled further

innovation. Although some inorganic species can be obtained in pure form from nature,

most are synthesized in chemical plants and in the laboratory.

There is much chemical ingenuity in the synthesis of solid materials. While tailor-

making of materials of the desired structure and properties remains the main goal of solid

state chemistry and material science, it is not always possible. However, a rational

approach to the synthesis of solids may be evolved which requires an understanding of

the principles of crystal chemistry, and of thermodynamics, phase equilibria and reaction

kinetics.

Synthetic Strategies

Various types of chemical reactions have been used for the synthesis of solid materials.

Some of common reactions employed for the synthesis inorganic solids are listed below:

16.6

Some Conceptual Developments in Synthesis in Chemistry

(1) decomposition

B(s) + C(g)

A(s)

(2) combination

C(s)

A(s) + B(g)

(3) metathetic [combining (1) and (2) above]

C(s)

D(g)

A(s) + B(g)

(4) addition

C(s)

A(s) + B(s)

C(s)

A(s) + B(l)

C(s)

A(g) + B(g)

(5) exchange

AY(s)

BX(s)

AX(s) + BY(s)

AY(s)

BX(g)

AX(s) + BY(g)

More complex reactions involving more than one type of reaction are also commonly

employed in solid state synthesis. For example, in the preparation of complex oxides, it is

common to carry out thermal decomposition of a compound followed by oxidation (in air

or O2 ) essentially in one step:

CaMnO3(s) + 2CO2(g)

2Ca0.5Mn0.5CO(s) + 1/2 O2(g)

MgO(s) + Cr2O3(s)

MgCr2O4(s)

Specific reagents and reaction conditions are employed to carry out various processes

such as reduction, oxidation and halogenation in the synthesis of solids.

Synthetic Strategies in Chemistry

16.7

Reduction of oxides, for instance, may be carried out

in an atmosphere of (flowing) pure or dilute hydrogen or CO.

by heating oxides in argon or nitrogen for the purpose of lowering the oxygen

content

by application of vacuum at an appropriate temperature (vacuum annealing or

decomposition at low pressures)

The obvious means of reducing solid compounds by hydrogen is employed not only for

reducing oxides, but also halides and other compounds. Thermal decomposition of metal

halides also yields lower halides:

2MO(s) + H2O(g)

M2O3(s) + H2(g)

(eg. M = Fe)

ABO2.5(s) + 1/2H2O(g)

ABO3(s) + H2(g)

(e.g. LaCoO3)

MCl2(s) + HCl(g)

MCl3(s) + H2(g)

(eg. M = Fe)

heat

(eg. M = Fe)

MX2 + 1/2X2

MX3

Reduction of oxides and halides can also be accomplished by reacting with elemental

carbon or with a metal.

3MCl2 (e.g. M = Nd, Fe)

2MCl3 + M

3MCl3(s) + M'Cl3(g)

3MCl4 + M'(s)

(e.g. M = Hf, M' = Al)

M2O3 + 3M

5MO

(e.g. M = Nb)

Inorganic Synthetic Methods

Some Conceptual Developments in Synthesis in Chemistry

16.8

Inorganic synthetic methods can be classified roughly according to the volatility or

solubility of the component reactants. Soluble inorganic compounds are prepared using

the methods of organic synthesis.

Techniques employed in Inorganic synthesis

Oven techniques: For thermally robust materials, high temperature methods are often

employed. For example, bulk solids are prepared using tubular furnaces, which allow

reactions to be conducted up to ca. 1100 °C. Special equipment e.g. ovens consisting of a

tantalum tube through which an electric current is passed, can be used for even higher

temperatures up to 2000 °C.

Melt methods: If volatile reactants are involved, the reactants are often put in an

ampoule that is evacuated and then sealed. The sealed ampoule is then put in an oven and

given a certain heat treatment to melt the reactants together and then later anneal the

solidified melt.

Solution methods: Solvents are used to prepare solids by precipitation or by evaporation.

At times the solvent is used hydrothermally, i.e. under pressure at temperatures higher

than the normal boiling point. A variation on this theme is the use of flux methods, where

a salt of relatively low melting point is added to the mixture to act as a high temperature

solvent in which the desired reaction can take place.

Gas reactions: Many solids react readily with reactive gases like chlorine, iodine,

oxygen etc. Others form adducts with gases like CO or ethylene. Such reactions are often

carried out in a tube that is open ended on both sides and through which the gas is passed

A special case of a gas reaction is a chemical transport reaction which entails the

reversible conversion of nonvolatile chemical compounds into volatile derivatives. This

method may also be used as a process for purification and crystallization of non-volatile

solids. These are often carried out in a sealed ampoule to which a small amount of a

transport agent, e.g. iodine is added. The ampoule is then placed in a zone oven. This is

essentially two tube ovens attached to each other which allows a temperature gradient to

be imposed. The volatile derivative migrates through a sealed, evacuated glass tube

heated in a tubular furnace. Elsewhere in the tube where the temperature is held at a

different value, the volatile derivative reverts to the parent solid and the transport agent is

released. The transport agent is thus catalytic. The technique requires that the two ends of

Synthetic Strategies in Chemistry

16.9

tube be maintained at different temperatures. Such a method can be used to obtain the

product in the form of single crystals suitable for structure determination by X-ray

diffraction.

Air and moisture sensitive materials: Many solids are hygroscopic and/or oxygen

sensitive. Many halides e.g. are very 'thirsty' and can only be studied in their anhydrous

form if they are handled in a glove box filled with dry (and/or oxygen-free) gas, usually

nitrogen.

Synthetic Methods

A large variety of inorganic solid materials has been prepared in recent years by

traditional ceramic method, which involves mixing and grinding powders of the

constituent oxides, carbonates and such compounds and heating them at high

temperatures with intermediate grinding when necessary. The low-temperature chemical

routes, however, are of greater interest so as to have better control of the structure,

stoichiometry and phase purity. Noteworthy chemical methods of synthesis include the

precursor method, coprecipitation, combustion method, the gel method, topochemical

methods and high-pressure methods. Some of the methods are outlined below.

1. Ceramic Method

The most common method of preparing solid materials is by reaction of the component

materials in the solid state at elevated temperatures. Several oxides, sulphides,

phosphides, have been prepared by this method. Knowledge of the phase diagram is

generally helpful in fixing the desired composition and conditions for synthesis.

Platinum, silica and alumina containers are generally used for the synthesis of metal

oxides, while graphite containers are employed for sulphides and other chalcogenides as

well as pnictides. If one of the constituents is volatile or sensitive to the atmosphere, the

reaction is carried out in sealed evacuated capsules. Most ceramic preparations require

relatively high temperatures which are generally attained by resistance heating. Electric

arc and skull techniques give temperatures up to 3300 K while high- power CO2 lasers

give temperatures up to 4300 K.

The ceramic method suffers from several disadvantages. They are:

1. When no melt is formed during the reaction, the entire reaction has to occur in

the solid state, initially by a phase boundary reaction at the points of contact between the

Some Conceptual Developments in Synthesis in Chemistry

16.10

components and later by diffusion of the constituents through the product phase. As the

reaction progresses, diffusion paths become increasingly longer and the reaction rate

slower. The product interface between the reacting particles acts as a barrier. The reaction

can be speeded up to some extent by intermittent grinding between heating cycles.

2. There is no simple way of monitoring the progress of the reaction in the

ceramic method. It is only by trial and error (by carrying out X-ray diffraction and other

measurements periodically) that one decides on appropriate conditions that lead to

completion of the reaction. Because of this difficulty, one frequently ends up with

mixtures of reactants and products.

3. Separation of the desired product from these mixtures is generally difficult, if

not impossible.

4. It is sometimes difficult to obtain a compositionally homogeneous product by

the ceramic technique, even when the reaction proceeds almost to completion.

In spite of such limitations, ceramic techniques have been widely used for the

synthesis of solid materials. Mention must be made, among others, of the use of this

technique for the synthesis of rare earth mono-chalcogenides such as SmS and SmSe. The

method involves heating the elements, first at lower temperatures (870-1170 K) in

evacuated silica tubes; the contents are then homogenized, sealed in tantalum tubes and

heated to around 2300 K.

Various modifications of the ceramic technique have been employed to overcome

some of the limitations. One of these relates to decreasing the diffusion path lengths. In a

polycrystalline mixture of reactants, the individual particles are approximately 10 m in

size, representing diffusion distances of roughly 10,000 unit cells. By using freeze-

drying, spray-drying, coprecipitation, and sol-gel and other techniques, it is possible to

reduce the particle size to a few hundred ångströms and thus effect a more intimate

mixing of the reactants.

In spray-drying, suitable constituents dissolved in a solvent are sprayed in the form of

fine droplets into a hot chamber. The solvent evaporates instantaneously, leaving behind

an intimate mixture of reactants, which on heating at elevated temperatures gives the

product.

Synthetic Strategies in Chemistry

16.11

In freeze-drying, reactants in a common solvent are frozen by immersing in liquid

nitrogen and the solvent is removed at low pressures.

In coprecipitation, the required metal cations taken as soluble salts (e.g. nitrates) are

coprecipitated from a common medium, usually as hydroxides, carbonates, oxalates,

formats or citrates. In actual practice, one takes oxides or carbonates of the relevant

metals, digests them with an acid (usually HNO3) and then the precipitating reagent is

added. After filtering the precipitate and drying, it is heated to the required temperature in

a desired atmosphere to produce the final product. For example, tetraethylammonium

oxalate has been used to prepare superconducting YBa2Cu408. The decomposition

temperatures of the precipitates are generally lower than the temperatures employed in

the ceramic method.

2. Combustion Method

Combustion synthesis or self-propagating high-temperature synthesis makes use of a

highly exothermic reaction between the reactants to produce a flame due to spontaneous

combustion which then yields the desired product or its precursor in finely divided form.

Borides, carbides, oxides, chalcogenides and other metal derivatives have been prepared

by this method. In order for combustion to occur, one has to ensure that the initial

mixture of reactants is highly dispersed and has high chemical energy. For example, one

may add a fuel and an oxidizer when preparing oxides by the combustion method, both

these additives being removed during combustion to yield only the product or its

precursor. Thus, one can take a mixture of nitrates (oxidizer) of the desired metals along

with a fuel (e.g. hydrazine, glycine or urea) in solution, evaporate the solution to dryness

and heat the resulting solid to around 423 K to obtain spontaneous combustion, yielding

an oxidic product in fine particulate form. Even if the desired product is not formed

immediately after combustion, the fine particulate nature of the product facilitates its

formation on further heating. In order to carry out combustion synthesis, the powdered

mixture of reactants (0.1-100 m particle size) is generally placed in an appropriate gas

medium which favours an exothermic reaction on ignition. The combustion temperature

is anywhere between 1500 and 3500 K, depending on the reaction. The advantages of this

method are that

Some Conceptual Developments in Synthesis in Chemistry

16.12

reaction times are very short since the desired product results soon after the

combustion.

a gas medium is not always necessary.

This is so in the synthesis of borides, silicides and carbides where the elements are quite

stable at high temperatures. Combustion in a nitrogen atmosphere yields nitrides. Nitrides

of various metals have been prepared in this manner. Azides have been used as sources of

nitrogen. The following are some typical combustion reactions:

MoSi2 + 7MgO

MoO3 + 2SiO2 + 7Mg

WC + Al2O3

WO3 + C + 2Al

TiB2 + 5MgO

TiO2 + B2O3 + 5Mg

TaN

Ta2N

after burning

Most of the ternary or quaternary oxides can also be prepared by this method. All the

superconducting cuprates have been prepared by this method, although the resulting

products in fine particulate form have to be heated to an appropriate high temperature in a

desired atmosphere to obtain the final cuprate. Table 16.1 lists typical materials prepared

by the combustion method.

Synthetic Strategies in Chemistry

16.13

Table 1. Typical materials prepared by the Combustion method

Oxides

BaTiO3, LiNbO3, PbMoO4

Carbides

TiC, Mo2C, NbC

Borides

TiB2, CrB2, MoB2, FeB

MoSi2, TiSi2, ZrSi2

Silicides

Phosphides

NbP, MnP, TiP

WS2, MoS2, MoSe2, TaS2

Chalcogenides

Hydrides

TiH2, NdH2

3. Precursor Method

Synthesis of complex oxides by the decomposition of compound precursors has been

known for some time. For example, thermal decomposition of LaCo(CN)6.5H20 and

LaFe(CN)6.6H20 in air readily yields LaCoO3 and LaFeO3 respectively. BaTiO3 can be

prepared by the thermal decomposition of Ba[TiO(C204)2], while LiCrO2 can be prepared

from Li[Cr(C2O4)2(H20)2]. Ferrite spinels of the general formula MFe204 (M-Mg, Mn, Ni,

Co) are prepared by the thermal decomposition of acetate precursors of the type

M3Fe6(CH3COO)1703OH.12C5H5N. Chromites of type MCr204 are obtained by the

decomposition of (NH4)2M(CrO4)2.6H20. Carbonates of metals such as calcium,

magnesium, manganese, iron, cobalt, zinc and cadmium are all iso-structural, possessing

the calcite structure. We can therefore prepare a large number of carbonate solid solutions

containing two or more cations in different proportions.

Carbonate solid solutions are ideal precursors for the synthesis of monoxide solid

solutions of rock-salt structure. The facile formation of rock-salt oxides by the

decomposition of carbonates of calcite structure is due to the close (possible topotactic)

relationship between the structures of calcite and rock-salt. The monoxide solid solutions

can be used as precursors for preparing spinels and other complex oxides. Besides

monoxide solid solutions, a number of ternary and quaternary oxides of novel structures

16.14

Some Conceptual Developments in Synthesis in Chemistry

can be prepared by decomposing carbonate precursors containing the different cations in

the required proportions. A number of ternary and quaternary metal oxides of perovskite

and related structures can be prepared by employing hydroxide, nitrate and cyanide solid

solution precursors as well.

4. Topochemical Reactions

A solid state reaction is said to be topochemically controlled when the reactivity is

controlled by the crystal structure rather than by the chemical nature of the constituents.

The products obtained in many solid state decompositions are determined by

topochemical factors, especially when the reaction occurs within the solid without the

separation of a new phase. In topotactic solid state reactions, the atomic arrangement in

the reactant crystal remains largely unaffected during the course of the reaction, except

for changes in dimension in one or more directions. Dehydration of WO3.H20 or

MoO3.H20 to give WO3 or MoO3 is one such reaction. Dehydration of many other

hydrates such as VOPO4.2H20 and HMoO2PO4.H20 is also found to be topotactic.

Intercalation reactions are generally topotactic in nature. Decomposition of V2O5 to form

V6O13 is a similar reaction. The reduction of NiO to nickel metal proceeds

topochemically.

a)Dehydration of Mo1_xWxO3.H2O

Mo1_xWxO3 solid solutions can be prepared by the ceramic method (by heating MoO3 and

WO3 in sealed tubes at around 870 K) or by the thermal decomposition of mixed

ammonium metallates. These methods, however, do not always yield monophasic

products owing to the difference in volatilities of MoO3 and WO3. Therefore, it was

sought to prepare Mo1_xWxO3 by topochemical dehydration of the hydrates, the process

being very gentle. MoO3.H2O and WO3.H2O are isostructural and the solid solutions

between the two hydrates are prepared readily by adding a solution of MoO3 and WO3 in

ammonia to hot 6M HNO3. The hydrates Mo1_xWxO3.H2O crystallize in the same

structure as MoO3.H2O and WO3.H2O with a monoclinic unit cell. The hydrate solid

solutions undergo dehydration under mild conditions (around 500 K) yielding

Mo1_xWxO3 which crystallizes in the ReO3-related structure of WO3. The ReO3 structure

of MoO3 is metastable and is produced only by topotactic dehydration under mild

conditions. This preparation of ReO3-1ike MoO3 by mild chemical processing is

Synthetic Strategies in Chemistry

16.15

significant. Bulk quantities of MoO3 in the ReO3 structure have been prepared by mild

dehydration of the hydrate.

b)Reduction of perovskite oxides

Reduction of the high temperature superconductor YBa2Cu307 to YBa2CuO6 (Fig. 16.7) is

a topochemical process.

5. Intercalation Compounds

Intercalation reactions of solids involve the insertion of a guest species (ion or molecule)

into a solid host lattice without any major rearrangement of the solid structure:

x[host]

(guest)x[host]

x(guest) +

stands for a vacant lattice site.

where

Tungsten and molybdenum bronzes, AxWO3 and AxMoO3 (A=K, Rb, Cs) are generally

prepared by reaction of the alkali metals with the host oxide. Electrochemical methods

are also employed for these preparations. A novel reaction that has been employed to

prepare bronzes which are otherwise difficult to obtain involves the reaction of oxide host

with anhydrous alkali iodides:

16.16

Some Conceptual Developments in Synthesis in Chemistry

Mo1-xWxO3

y(AI)

→

Ay.Mo1-xWxO3

y/2 I2

Atomic hydrogen has been inserted into many binary and ternary oxides. Recently, iodine

has been intercalated into the superconducting cuprate, Bi2CaSr2Cu2O8, causing an

expansion of the c-parameter of the unit cell, without destroying the superconductivity.

6. Sol-gel Method

The sol-gel method is a wet chemical method and a multi-step process involving both

chemical and physical processes such as hydrolysis, polymerization, drying and

densification. The name "sol-gel" is given to the process because of the distinctive

increase in viscosity which occurs at a particular point in the sequence of steps. A sudden

increase in viscosity is the common feature in sol-gel processing, indicating the onset of

gel formation. In the sol-gel process, synthesis of inorganic oxides is achieved from

inorganic or organometallic precursors (generally metal alkoxides). The important

features of the sol-gel techniques are better homogeneity compared with the traditional

ceramic method, high purity, lower processing temperature, more uniform phase

distribution in multicomponent systems, better size and morphological control, the

possibility of preparing new crystalline and non-crystalline materials, and lastly easy

preparation of thin films and coatings. The sol-gel method is widely used in ceramic

technology. The important steps in sol-gel synthesis are:

Hydrolysis. The process of hydrolysis may start with a mixture of a metal alkoxide and

water in a solvent (usually alcohol) at the ambient or a slightly elevated temperature.

Acid or base catalysts are added to speed up the reaction.

Polymerization. This step involves condensation of adjacent molecules wherein H2O and

ROH are eliminated and metal oxide linkages are formed. Polymeric networks grow to

colloidal dimensions in the liquid (sol) state.

Gelation. In this step, the polymeric networks link up to form a three-dimensional

network throughout the liquid. The system becomes somewhat rigid, characteristic of a

gel. The solvent as well as water and alcohol remain inside the pores of the gel.

Aggregation of smaller polymeric units to the main network continues progressively on

aging the gel.

Synthetic Strategies in Chemistry

16.17

Drying. Here, water and alcohol are removed at a moderate temperature (less than 470

K), leaving a hydroxylated metal oxide with residual organic content. If the objective is

to prepare a high surface area of aerogel powder with low bulk density, the solvent is

removed supercritically.

Dehydration. This step is carried out between 670 and 1070 K to drive off the organic

residues and chemically bound water, yielding a metal oxide with up to 20%-30%

microporosity.

Densification. Temperatures in excess of 1270 K are used to form the dense oxide

product.

Many complex metal oxides are prepared by a modified sol-gel route without actually

preparing metal alkoxides. For example, a transition metal salt solution is converted into

a gel by the addition of an appropriate organic reagent. In the case of cuprate

superconductors, an equimolar proportion of citric acid is added to the solution of metal

nitrates, followed by ethylene diamine until the solution attains a pH of 6-6.5. The blue

sol is concentrated to obtain the gel. The xerogel is obtained by heating at approximately

420 K. The xerogel is decomposed at an appropriate temperature to obtain the cuprate.

The sol-gel technique has been used to prepare sub-micrometre metal oxide powders

with a narrow particle size distribution and unique particle shapes (e.g. A12O3, TiO2,

ZrO2, Fe2O3). Uniform SiO2 spheres have been grown from aqueous solutions of

colloidal SiO2. Small metal clusters (e.g. nickel, copper, gold) have been prepared by in

situ chemical reduction of metal salts. Metal-ceramic composites (e.g.Ni-AI2O3, Pt-ZrO2)

can also be prepared in this manner. By employing several variants of the basic sol-gel

technique, a number of multicomponent oxide systems have been prepared. Typical of

these are: SiO2-B2O3, SiO2-TiO2, SiO2-ZrO2, SiO2-A12O3, ThO2-UO2 . A variety of

ternary and still more complex oxides have been prepared by this technique. Different

types of cuprate superconductors have also been prepared by this method. These include

YBa2Cu307, YBa2Cu408, Bi2CaSr2Cu208 and Pb2Sr2Ca 1 -xYxCu3O8.

6. Alkali Flux Method

The use of strong alkaline media, either in the form of solid fluxes or molten (or aqueous)

solutions, has enabled the synthesis of novel oxides. The alkali flux method stabilizes

higher oxidation states of the metal by providing an oxidizing atmosphere. Alkali

16.18

Some Conceptual Developments in Synthesis in Chemistry

carbonate fluxes have traditionally been used to prepare transition metal oxides such as

LaNiO3. A good example of an oxide synthesized in a strongly alkaline medium is the

pyrochlore, Pb2(Ru2-xPbx)O7-y where Pb is in the 4 + state; this oxide is a bifunctional

electrocatalyst. The procedure for preparation involves bubbling oxygen through a

solution of lead and rubidium salts in strong KOH at 320 K. The so-called alkaline

hypochlorite method is used in many instances. For example, La4NiOl0 was prepared by

bubbling Cl2 gas through a NaOH solution of lanthanum and nickel nitrates.

YBa2Cu408 has been prepared by using a Na2CO3-K2CO3 flux in a flowing oxygen

atmosphere. KOH melt has been used to prepare superconducting Ba1-xKxBiO3.

7. Electrochemical Method

Electrochemical methods have been employed to advantage for the synthesis of many

solid materials. Typical of the materials prepared in this manner are metal borides,

carbides, silicides, oxides and sulphides. Vanadate spinels of formula MV2O4 as well as

tungsten bronzes have been prepared by the electrochemical route. Tungsten bronzes are

obtained at the cathode when current is passed through two inert electrodes immersed in a

molten solution of the alkali metal tungstate, A2WO4 and WO3; oxygen is liberated at the

anode. Blue molybdenum bronzes have been prepared by fused salt electrolysis. Mono-

sulphides of uranium, gadolinium, thorium and other metals are obtained from a solution

of the normal valent metal sulphide and chloride in an NaC1-KCI eutectic. LaB6, is

prepared by taking La2O3 and B2O3 in an LiBO2-LiF melt and using gold electrodes.

Crystalline transition metal phosphides are prepared from solutions of oxides with alkali

metal phosphates and halides. Superconducting Bal-xKxBiO3 has been prepared

electrochemically.

Although the electrochemical method is old, the processes involved in the synthesis

of various solids are not entirely understood. Generally one uses solvents whose

decomposition potentials are high (e.g. alkali metal phosphates, borates, fluorides, etc.).

Changes in melt composition could cause limitations in certain instances.

8. High Pressure Methods

The use of high pressures for solid state synthesis has become increasingly common in

recent years. With the development of high-pressure technology, commercial equipment

permitting simultaneous use of both high-pressure and high-temperature conditions has

Synthetic Strategies in Chemistry

16.19

become available. For the 1-10 kbar pressure range, the hydrothermal method is often

employed. In this method, the reaction is carried out either in an open or a closed system.

In the open system, the solid is in direct contact with the reacting gas (F2, O2 or N2)

which also serves as a pressure intensifier. A gold container is generally used in this type

of synthesis. This method has been used for the synthesis of transition metal compounds

such as RhO2, PtO2 and Na2NiF6 where the transition metal is in a higher oxidation state.

Hydrothermal high pressure synthesis under closed system conditions has been employed

for the preparation of higher-valence metal oxides. An internal oxidant such as KClO3 is

added to the reactants, which on decomposition under reaction conditions provides the

necessary oxygen pressure. For example, pyrochlores of palladium(IV) and platinum(IV),

Ln2M207, (Ln = rare earth) have been prepared by this method (970 K, 3 kbar).

(H30)Zr2(PO4)3 and a family of zero thermal expansion ceramics (e.g. Ca0.5Ti2P3O12)

have also been prepared hydrothermally. Another good example is the synthesis of

borates of aluminium, yttrium and such metals wherein the sesquioxides are reacted with

boric acid. Oxyfluorides have been prepared in HF medium [75]. Zeolites are generally

prepared under hydrothermal conditions in the presence of alkali. The alkali, the silica

component and the source of aluminium are mixed in appropriate proportions and heated.

The reactant mixture forms a hydrous gel which is then allowed to crystallize under

pressure for several hours to several weeks between 330 and 470 K. In a typical

synthesis, AI2O3.3H20 dissolved in concentrated NaOH solution (20 N) is mixed with a

solution

Na2SiO3.9H20

obtain

gel

(of

composition

2.1Na2O.Al2O3.2.1SiO2.60H2O ) which is then crystallized to give zeolite A. The Na2O-

SiO2-Al2O3-H2O system yields a large number of materials with the zeolitic framework.

Under alkaline conditions, aluminium is present as Al(OH)4 anions. The OH- ions act as

a mineralizing catalyst while the cations present in the reactant mixture determine the

kinds of zeolite formed.

Besides water, some inorganic salts are also encapsulated in some zeolites. Several

zeolite structures are found in the K2O-SiO2-Al2O3-H2O system as well. Li2O, however,

does not give rise to many microporous materials. Group IIA cations yield several

zeolitic products.

16.20

Some Conceptual Developments in Synthesis in Chemistry

Zeolitization in the presence of organic bases is useful for synthesizing silica-rich

zeolites. Silicalite with a tetrahedral framework enclosing a three-dimensional system of

channels (defined by 10 rings wide enough to absorb molecules up to 0.6 nm in diameter)

has been synthesized by the reaction of tetrapropylammonium (TPA) hydroxide and a

reactive form of silica between 370 and 470 K. The precursor crystals have the

composition (TPA)20.48SiO2.H20 and the organic cation is removed by chemical reaction

or thermal decomposition to yield microporous silicalite which may be considered to be a

new polymorph of SiO2. The clathrasil (silica analogue of a gas hydrate), dodecasil-1H, is

prepared from an aqueous solution of tetramethoxysilane and N(CH3)4OH; after the

addition of aminoadamantane, the solution is treated hydrothermally under nitrogen for

four days at 470 K. The use of template cations has enabled the synthesis of a variety of

zeolite materials. Cations such as (NMe4)+ fit snugly into the cages (e.g. sodalite cages of

sodalite and SAPO or gmelinite cages of zeolites omega). Neutral organic amines have

also been used (e.g. in the synthesis of ZSM-5). Many new microporous materials,

including those based on AlPO4 (analogue of SiO2), gallosilicates and aluminogerminates

(analogues of aluminosilicates), have been prepared. AlPO4-based materials are prepared

by the crystallization of gels formed by adding an organic template to a mixture of active

alumina, H3PO4 and water at a pH of 5-8 around 470 K. Pressures in the range 10-150

kbar are commonly used for solid-state synthesis. In the piston-cylinder apparatus

consisting of a tungsten carbide chamber and a piston assembly, the sample is contained

in a suitable metal capsule surrounded by a pressure-transducer (pyrophyllite). Pressure is

generated by moving the piston through the blind hole in the cylinder. A microfurnace

made of graphite or molybdenum is incorporated in the design. Pressures up to 50 kbar

and temperatures up to 1800 K are readily reached in a volume of 0.1 cm3 using this

design. In the anvil apparatus, first designed by Bridgman, the sample is subjected to

pressure by simply squeezing it between two opposed anvils. Although pressures of

around 200 kbar and temperatures up to 1300 K are reached in this technique, it is not

popular for solid-state synthesis since only milligram quantities can be handled. An

extension of the opposed anvil principle is the tetrahedral anvil design, where four

massively supported anvils disposed tetrahedrally ram towards the centre where the

sample is located in a pyrophyllite medium together with a heating arrangement. The

Synthetic Strategies in Chemistry

16.21

multi-anvil design has been extended to cubic geometry, where six anvils act on the faces

of a pyrophyllite cube located at the centre. The belt apparatus provides the best high-

pressure-high-temperature combination for solid-state synthesis. This apparatus, which

was used for the synthesis of diamonds some years ago is a combination of the piston-

cylinder and the opposed anvil designs. The apparatus consists of two conical pistons

made of tungsten carbide, which ram through a specially shaped chamber from opposite

directions. The chamber and pistons are laterally supported by several steel rings making

it possible routinely to reach fairly high pressures (around 150 kbar) and high

temperatures (approximately 2300 K). In the belt apparatus, the sample is contained in a

noble metal capsule (a BN or MgO container is used for chalcogenides) and surrounded

by pyrophyllite and a graphite sleeve, the latter serving as an internal heater. In a typical

high-pressure run, the sample is loaded, the pressure raised to the desired value and then

the temperature increased. After holding the pressure for about 30 min, the sample is

quenched (400 Ks-1) while still under pressure. The pressure is released after the sample

has cooled at room temperature.

High-pressure methods have been used for the synthesis of several materials that

cannot possibly be made otherwise. In general, the formation of a new compound from its

components requires that the new composition have a lower free energy than the sum of

the free energies of the components. Pressure can aid in the lowering of free energy in

different ways.

(a)Pressure delocalizes outer d electrons in transition-metal compounds by increasing the

magnitude of coupling between the d electrons on neighbouring cations, thereby lowering

the free energy. A typical example is the synthesis of ACrO3 (A = Ca, Sr, Pb) perovskites

and CrO2.

(b) Pressure stabilizes higher-valence states of transition metals, thus promoting the

formation of a new phase. For example, in the Ca-Fe-O system only CaFeO2.5 (brown-

millerite) is stable under ambient pressures. Under high oxygen pressures, iron is

oxidized to the 4+ state and hence CaFeO3 with the perovskite structure is formed.

synthesis of new phases. The synthesis of A~MoO3 bronzes, for example, requires

16.22

Some Conceptual Developments in Synthesis in Chemistry

populating the empty d orbitals centred on molybdenum; at ambient pressures, MoO3 is

stabilized by a ferroelectric distortion of MoO6 octahedra up to the melting point.

(d) Pressure alters site-preference energies of cations, and facilitates the formation of new

phases. For example, it is not possible to synthesize A2+Mn4+O3 (A = Mg, Co, Zn)

ilmenites because of the strong tetrahedral site preference of the divalent cations. One

therefore obtains a mixture of A[AMn]O4(spinel) + MnO2(rutile) under atmospheric

pressure instead of monophasic AMnO3. However, the latter is formed at high pressures

with a corundum-type structure in which both the A and Mn ions are in octahedral

coordination.

(e) Pressure can suppress the 6s2 core polarization in oxides containing isoelectronic

Tl+, Pb2+, Bi3+ cations. For example, perovskite-type PbSnO3 cannot be made at

atmospheric pressure because the mixture of PbO + SnO2 is more stable than the

perovskite.

Thus, solid-state reactions are generally slow under ordinary pressures even when the

product is thermodynamically stable. Pressure has a marked effect on the kinetics of the

reaction, reducing the reaction times considerably, and at the same time giving more

homogeneous and crystalline products. For instance, LnFeO3, LnRhO3 and LnNiO3 (Ln =

rare earth) are prepared in a matter of hours under high-pressure-high-temperatue

conditions, whereas at ambient pressure the reactions require several days (LnFeO3 and

LnRhO3) or they do not occur at all (LnNiO3 ). Thus LnFeO3 is formed in 30 min at 50

kbar.

In several (AX)(ABX3)n series of compounds, the end members ABX3 and A2BX4,

having the perovskite and K2NiF4 structures respectively, are formed at atmospheric

pressures, but not the intermediate phases such as A3B2X7 and A4B3X10. Pressure

facilitates the synthesis of such solids. Sr3Ru2O7 and Sr4Ru3O10 are formed in 15 min at

20 kbar and 1300 K.

High-pressure methods

have been

employed

the synthesis

of novel

superconducting cuprates. A rudimentary example is the preparation of oxygen-excess

La2CuO4 under high oxygen pressure. A more interesting example is the synthesis of the

next homologue with two CuO2 layers. La2Cal- xSrxCu2O6 which had earlier been found

to be an insulator was rendered superconducting by heating it under oxygen pressure.

Synthetic Strategies in Chemistry

16.23

YBa2Cu408 was first prepared under high oxygen pressure, but this was soon found

unnecessary. However, superconducting cuprates with infinite CuO2 layers of the type

Ca1-xSrxCuO2 or Sr1-xNdxCuO2 can only be prepared under high hydrostatic pressures

which help to give materials with shorter Cu-O bonds. It should be noted that Ca1-

xSrxCuO2

prepared at ambient pressure is insulating.

9. The pyrosol Process: a novel chemical method for depositing films

Pyrolysis of sprays is a well known method for depositing films. Thus, one can obtain

films of oxidic materials such as CoO, ZnO and YBa2Cu307 by the spray pyrolysis of

solutions containing salts (e.g. nitrates) of the cations. A novel improvement in this

technique is the pyrosol process involving the transport and subsequent pyrolysis of a

spray generated by an ultrasonic atomizer. When a high frequency (100 kHz-10 MHz

range) ultrasonic beam is directed at a gas-liquid interface, a geyser is formed and the

height of the geyser is proportional to the acoustic intensity. Its formation is accompanied

by the generation of a spray, resulting from the vibrations at the liquid surface and

cavitation at the liquid-gas interface. The quantity of spray is a function of the intensity.

Ultrasonic atomization is accomplished using an appropriate transducer made of PZT

located at the bottom of the liquid container. A 500-1000 kHz transducer is generally

adequate. The atomized spray which goes up in a column fixed to the liquid container is

deposited onto a suitable solid substrate and then heat treated to obtain the film of the

material concerned. The flow rate of the spray is controlled by the flow rate of air or any

other gas. The liquid is heated to some extent, but its vaporization should be avoided. The

source liquid contains the relevant cations in the form of salts dissolved in an organic

solvent. Organometallic compounds are often used (e.g. acetates, alkoxides,

acetylacetonates, etc.). Proper gas flow is crucial to obtain satisfactory conditions for a

good liquid spray.

The pyrosol process is in some way between chemical vapour deposition and spray

pyrolysis, but the choice of source compounds for the pyrosol process is larger than that

available for chemical vapour deposition. Films of a variety of materials have been

obtained by the pyrosol method. The thickness of the films can be anywhere between a

few hundred angstroms to a few micrometres. Films of superconducting cuprates such as

16.24

Some Conceptual Developments in Synthesis in Chemistry

YBa2Cu3O7 have also been prepared by the pyrosol process. Epitaxy has been observed

in films deposited onto single-crystal substrates.

10. Czochralski Process for Semiconductor Materials

Semiconductors with predictable, reliable electronic properties are necessary for mass

production. The level of chemical purity needed is extremely high because the presence

of impurities even in very small proportions can have large effects on the properties of

the material. A high degree of crystalline perfection is also required, since faults in

crystal structure (such as dislocations, twins, and stacking faults) interfere with the

semiconducting properties of the material. Crystalline faults are a major cause of

defective semiconductor devices. The larger the crystal, the more difficult it is to achieve

the necessary perfection. Current mass production processes use crystal ingots between

four and twelve inches (300 mm) in diameter which are grown as cylinders and sliced

into wafers.

Because of the required level of chemical purity and the perfection of the crystal

structure which are needed to make semiconductor devices, special methods have been

developed to produce the initial semiconductor material. A technique for achieving high

purity includes growing the crystal using the Czochralski process. An additional step that

can be used to further increase purity is known as zone refining. In zone refining, part of

a solid crystal is melted. The impurities tend to concentrate in the melted region, while

the desired material recrystalizes leaving the solid material more pure and with fewer

crystalline faults. In manufacturing semiconductor devices involving heterojunctions

between different semiconductor materials, the lattice constant, which is the length of the

repeating element of the crystal structure, is important for determining the compatibility

of materials.

The Czochralski process is a method of crystal growth used to obtain single crystals

of semiconductors (e.g. silicon, germanium and gallium arsenide), metals (e.g. palladium,

platinum, silver, gold), salts and some man-made (or lab) gemstones. The most important

application may be the growth of large cylindrical ingots, or boules, of single crystal

silicon. Other semiconductors, such as gallium arsenide, can also be grown by this

method, although lower defect densities in this case can be obtained using variants of the

Bridgeman technique.

Synthetic Strategies in Chemistry

16.25

High-purity, semiconductor-grade silicon (only a few parts per million of impurities) is

melted down in a crucible , which is usually made of quartz. Dopant impurity atoms such

as boron or phosphorus can be added to the molten intrinsic silicon in precise amounts in

order to dope the silicon, thus changing it into n-type or p-type extrinsic silicon. This

influences the electrical conductivity of the silicon. A seed crystal, mounted on a rod, is

dipped into the molten silicon. The seed crystal's rod is pulled upwards and rotated at the

same time. By precisely controlling the temperature gradients, rate of pulling and speed

of rotation, it is possible to extract a large, single-crystal, cylindrical ingot from the melt.

Occurrence of unwanted instabilities in the melt can be avoided by investigating and

visualizing the temperature and velocity fields during the crystal growth process [1].

This process is normally performed in an inert atmosphere, such as argon, and in an inert

chamber, such as quartz.

Size of Crystals: While the largest silicon ingots produced today are 400 mm in diameter

and 1 to 2 metres in length, 200 mm and 300 mm diameter crystals are standard industrial

processes. Thin silicon wafers are cut from these ingots (typically about 0.2 - 0.75 mm

thick) and can be polished to a very high flatness for making integrated circuits, or

textured for making solar cells.

Impurity Incorporation: When silicon is grown by the Czochralski method the melt is

contained in a silica (quartz) crucible. During growth the walls of the crucible dissolve

into the melt and Czochralski silicon therefore contains oxygen impurities with a typical

concentration of 1018 cm

-3

. Perhaps surprisingly, oxygen impurities can have beneficial

effects. Carefully chosen annealing conditions can allow the formation of oxygen

precipitates. These have the effect of trapping unwanted transition metal impurities in a

process known as gettering. Additionally, oxygen impurities can improve the mechanical

strength of silicon wafers by immobilising any dislocations which may be introduced

during device processing. It has experimentally been proved in the 1990s that the high

oxygen concentration is also beneficial for radiation hardness of silicon particle detectors

used in harsh radiation environment ( eg. CERN's LHC/S-LHC projects) [2, 3, 4].

Therefore, radiation detectors made of Czochralski- and Magnetic Czochralski-silicon are

considered to be promising candidates for many future high-energy physics

experiments.[5][6] However, oxygen impurities can react with boron in an illuminated

16.26

Some Conceptual Developments in Synthesis in Chemistry

environment, such as experienced by solar cells. This results in the formation of an

electrically active boronoxygen complex that detracts from cell performance. Module

output drops by approximately 3% during the first few hours of light exposure [7].

The Bridgman technique is a method of growing single crystal ingots or boules. The

method involves heating polycrystalline material in a container above its melting point

and slowly cooling it from one end where a seed crystal is located. Single crystal material

is progressively formed along the length of the container. The process can be carried out

in a horizontal or vertical geometry. It is a popular method of producing certain

semiconductor crystals, such as gallium arsenide where the Czochralski process is more

difficult.

Purification process: Zone melting is a method of separation by melting in which a

molten zone traverses a long ingot of impure metal or chemical.

Zone refining: In zone refining, solutes are segregated at one end of the ingot in order to

purify the remainder. The molten region melts impure solid at its forward edge and leaves

a wake of purer material solidified behind it as it moves through the ingot. The impurities

concentrate in the melt, and are moved to one end of the ingot. Zone refining was

developed in Bell Telephone Laboratories as a method to prepare high purity materials

for manufacturing transistors. Its early use was on germanium for this purpose, but it can

be extended to virtually any solute-solvent system having an appreciable concentration

difference between solid and liquid phases at equilibrium. This process is also known as

the Float zone process, particularly in semiconductor materials processing.

Zone leveling : Zone melting is also used to concentrate the impurities for analytical or

other purposes. In zone leveling, the objective is to distribute solute evenly throughout

the purified material, which may be sought in the form of a single crystal. For example,

in the preparation of a transistor or diode semiconductor, an ingot of germanium is first

purified by zone refining. Then a small amount of antimony is placed in the molten zone,

which is passed through the pure germanium. With the proper choice of rate of heating

and other variables, the antimony can be spread evenly through the germanium. This

technique is also used for the preparation of silicon for use in computer chips.

Heaters: A variety of heaters can be used for zone melting, with their most important

characteristic being the ability to form short molten zones that move slowly and

Synthetic Strategies in Chemistry

16.27

uniformly through the ingot. Induction coils, ring-wound resistance heaters, or gas flames

are common methods. Another method is to pass an electric current directly through the

ingot while it is in a magnetic field, with the resulting magnetomotive force carefully set

to be just equal to the weight in order to hold the liquid suspended. Zone melting can be

done as a batch process, or it can be done continuously, with fresh impure material being

continually added at one end and purer material being removed from the other, with

impure zone melt being removed at whatever rate is dictated by the impurity of the feed

stock.

Zone Remelting: Another related process is zone remelting, in which two solutes are

distributed through a pure metal. This is important in the manufacture of semiconductors,

where two solutes of opposite conductivity type are used. For example, in germanium,

pentavalent elements of group V such as antimony and arsenic produce negative (n-type)

conduction and the trivalent elements of group III such as aluminium and boron produce

positive (p-type) conduction. By melting a portion of such an ingot and slowly refreezing

it, solutes in the molten region become distributed to form the desired n-p and p-n

junctions.

Biocatalysis

Pharmaceutical industry has been a rapidly growing field. About 54% of drug molecules

are chiral, and resolution remains an important and cost-effective approach to chiral

molecules. In order to achieve a typical enantiomeric purity of 99.5%, resolution is often

accomplished at the price of restricting the overall maximum yield of a process to 50% at

most. While metal catalyzed reactions have become prevalent in recent years, their use in

manufacturing requires great effort to identify appropriate catalysts, solvents and reaction

conditions. Reproducibility and robustness can remain a problem, especially with regard

to sensitivity to substrate quality and small variation in reaction parameters. There is a

clear need for new methodologies to produce chiral molecules. Enzymes are highly

efficient with excellent regioselectivity and stereoselectivity. By conducting reactions in

water under ambient reaction conditions, both the use of organic solvents and energy

input are minimized. Furthermore, one can design processes with high energy efficiency

and safe chemistry by conducting reactions at ambient temperature under ambient

16.28

Some Conceptual Developments in Synthesis in Chemistry

atmosphere, and atom economy can be increased by avoiding extensive protection and

deprotection sequences.

Biocatalysis is emerging as one of the greenest technologies as a result of recent advances

in genomics, proteomics and pathway engineering (large scale DNA sequencing,

structural biology, protein expression, high throughput screening, directed enzyme

evolution and metabolic engineering). Application of the twelve principles of green

chemistry can deliver higher efficiency and reduce the environmental burden during

chemical synthesis.

As the green chemistry movement gains momentum, fresh opportunities of research

and development have been opened up to improve the efficiency of chemical processes

while simultaneously reducing production costs. The attention is focused on reducing the

use and generation of large quantities of hazardous substances which frequently

accompanies the synthesis of a pharmaceutical agent, at each of the numerous steps, each

of which involve feedstocks, reagents, solvents, and separation. The following case

studies depict the developments and improvements in the synthetic strategies of various

chemicals.

CASE STUDY 1: Production of LY300164 (Talampanol) : An example of the

reduction of hazardous materials is the use of a chemoenzymatic synthesis for the

production of LY300164 (Talampanol) for treating epilepsy and neurodegenerative

diseases. The first generation synthesis, which starts from 5-allyl-1,3-benzodioxole 1,

suffers from a low yield of 16%, and requires the use of a large amount of organic

solvents and chromium oxide, a cancer-suspect agent, to oxidize racemic alcohol 2 to

ketone 3 (Scheme 16.1).

Synthetic Strategies in Chemistry

16.29

Scheme 16.1.

In order to improve its synthesis, a second generation route was developed involving a

biocatalytic ketone reduction of 3 by Zygosaccharomyces rouxii to give (S)-2 with a

yield of 96% and >99.9% ee (enantiomeric excess) (Scheme 16.2). Acid-catalyzed

reaction with 4-nitrobenzaldehyde led to 1-arylisochroman 4, which was subsequently

oxidized to ketal 5 in the presence of oxygen. The final product LY300164 was obtained

after formation of hydrazone 6, and cyclization via mesylate 7 to give 8 followed by Pd-

catalyzed nitro group reduction.

16.30

Some Conceptual Developments in Synthesis in Chemistry

Scheme 16.2.

By using a chemoenzymatic approach, not only was the overall yield improved to 51%

from 16% in the old route, the new synthetic pathway eliminated the use of transition

metal oxidants and a large volume of organic solvents by judicious adjustment of

oxidation states and integration of a biotransformation. For example, using the

biocatalytic process, approximately 340000 L of solvents and 3000 kg of chromium

waste were eliminated for the production of every 1000 kg of LY300164.

CASE STUDY 2: Production of Pregabalin

Synthetic Strategies in Chemistry

16.31

Most enzymatic catalysis achieves high regio- and stereoselectivity under mild

conditions, allowing new and more efficient processes to be designed with significant

advantages over chemical approaches. For example, in the first generation route for the

production of pregabalin, chemical resolution of the racemic γ-amino acid 11, which was

prepared from the racemic cyanodiester 9 (CNDE) after hydrolysis and decarboxylation,

took place at the end of the process (Scheme 3). To obtain a high optical purity (99.5%)

of the final API, (S)-mandelic acid resolution was followed by another step of

recrystallization in THF/H2O with a combined two-step yield of 2529%. As a result, the

overall yield for the route is only 1821% and over 70% of all process materials before

the resolution step including nickel were ultimately turned into wastes. Since the

undesired enantiomer could not be recycled, this modest efficiency leads to a large

amount of wastes and excessive reactor capacity requirements.

To overcome these issues, a second generation process using a fungal lipase was

developed, where enzymatic resolution occurred at the first step and the undesired

enantiomer 13 could be easily recycled (Scheme 4). Regio- and stereospecific hydrolysis

of 9 led to the mono acid 12 with 45% conversion and >98% ee. After decarboxylation of

12 and phase splitting, mono ester 14 was telescopically subjected to basic hydrolysis and

hydrogenation to give the final product. Simple operation as a result of using water as the

solvent significantly improved process efficiency. Comparing with the first generation

synthesis, not only are a large amount of (S)-mandelic acid completely eliminated, the

biocatalytic process also rendered it unnecessary to use most organic solvents. This

stands in contrast to a typical process for the production of an API, where 80% of all

wastes are solvents. If spent solvents are incinerated instead of being recovered, the life-

cycle profile and impacts are considerably increased. Moreover, recycling of the

undesired enantiomer 13 doubled both the yield (40% vs. <21%) and throughput. Overall,

it was projected that at the peak of manufacturing, the biocatalytic aqueous process would

annually eliminate the usage of over thousands of metric tons of rawmaterials including

mandelic acid, CNDE and nickel, and tens millions of gallons of alcoholic solvents and

THF associated with the classic resolution route.

16.32

Some Conceptual Developments in Synthesis in Chemistry

Scheme 16.3.

Scheme 16.4.

CASE STUDY 3: Atorvastatin Calcium

Atorvastatin calcium is the active ingredient of Lipitor R, the first drug with annual sales

exceeding $10B. In the current process, the key chiral building block in the synthesis of

atorvastatin is ethyl (R)-4-cyano-3-hydroxybutyrate (15) with an annual demand

estimated to be about £440 000, which was then converted to atorvastatin side chain 18

upon Claisen condensation, borane-chelation controlled reduction, both under cryogenic

Synthetic Strategies in Chemistry

16.33

conditions, followed by protection of the two hydroxy groups and Ni-catalyzed nitrile

group hydrogenation. The final API atorvastatin was produced after PaalKnorr

condensation of 18 with a diketone (Scheme 5). A number of biocatalytic approaches

have been reported for the synthesis of (R)-4-cyano-3-hydroxybutyrate 15. For example,

a green process has recently been reported using a two-enzyme system under neutral

conditions in water (eq. 1, Scheme 16.6). In this process, the first step involves

enantioselective enzymatic reduction of ethyl 4-chloroacetoacetate to give 19 followed by

a biocatalytic cyanation of the chlorohydrin to produce 15.

Alternatively, 15 was synthesized from inexpensive racemic epichlorohydrin via

nitrilase-catalyzed desymmetrization of meso-3-hydroxyglutaronitrile 20 (eq. 2, Scheme

6). By applying gene site saturation mutagenesis to improve the stereoselectivity of the

biocatalyst, the ee of the desired product reached 99% under a 3M loading of the

substrate. The synthesis is short and utilizes an inexpensive starting material. Both the

ketoreductase (eq. 1, Scheme 6) and nitrilase processes (eq. 2, Scheme 6) led to

significant reduction of byproducts, wastes and organic solvents associated with existing

chemical routes. Recently, a more concise approach to install the atorvastatin side chain

was reported by using a microbial deoxyribose-5-phosphate aldolase (DERA). This

enzyme catalyzes the sequential aldol condensation between one equivalent of amino

aldehye 21 and two equivalents of acetaldehyde to form lactol 22 with excellent ee (98%)

and de (97%), which was then converted to the statin side chain 18 upon oxidation,

protection and esterification. Using this method, the overall process to atorvastatin was

shortened significantly and two cryogenic steps in the existing process were eliminated

(Scheme 7). It is estimated that hundreds of metric tons of raw materials and solvents will

be reduced each year by using the chemoenzymatic route in concomitant with significant

reduction in energy consumption.

16.34

Some Conceptual Developments in Synthesis in Chemistry

Scheme 16.6.

Synthetic Strategies in Chemistry

16.35

Scheme 16.7.

Rosuvastatin :

Similar approaches have been applied to the synthesis of the side chain of rosuvastatin,

the API of Crestor(R) (Scheme 8). By a combination of activity- and sequence-based

screening, a Novel DERA was discovered from environmental DNA libraries leading to

an enzymatic process to obtain lactol 23 with volumetric productivity of 720 g L-1 day-1

under an enzyme loading of 2% wt/wt.

Scheme 16.8.

16.36

Some Conceptual Developments in Synthesis in Chemistry

CASE STUDY 4: Industrial Production of b-lactam Antibiotics :

Biocatalysis is uniquely suited to the development of green chemistry routes for complex

molecules, which are often labile and densely functionalized. As a result of high

selectivity and mild conditions, enzymatic catalysis has been applied to the industrial

production of b-lactam antibiotics, which are mostly derived from 6-aminopenicillanic

acid (6-APA) or 7-aminodesacetoxycephalosporanic acid (7-ADCA). The annual world

production of 6-APA and 7-ADCA were estimated to be over 8000 and 600 t,

respectively. Until recently, they were prepared from penicillin G, a fermentation product

derived from non-ribosomal peptide synthase (NRPS), by chemical deacylation, where

the carboxy group of the penicillin G is first protected by silylation, followed by selective

deacylation via the imidoyl chloride (25), and removal of the protecting group (Scheme

9). The method uses stoichiometric amounts of the silylating agent, and a large amount of

hazardous

chemicals

and

solvents

such

phosphorus

pentachloride

and

dichloromethane.

Scheme 16.9

Synthetic Strategies in Chemistry

16.37

In contrast, enzymatic deacylation of penicillinGby penicillin G acylase was

accomplished in water at room temperature requiring no protection and deprotection of

other functional groups (Scheme 10). Moreover, under kinetic control, an immobilized

penicillin aclyase was also able to catalyze the acylation of 6-APA and 7-ADCA with

either D-phenylglycine methyl ester (PGA), D-phenylglycine amides (PGA) or their

parahydroxylated analogs to produce a wide range of semi-synthetic b-lactam antibiotics

such as ampicillin, amoxicillin, cefaclor, cephalexin and cefadroxil (Scheme 16.10). As a

result of the biotransformation, raw material efficiency and E-factor were significantly

improved from the first generation of chemical processes.

Scheme 16.10.

16.38

Some Conceptual Developments in Synthesis in Chemistry

CASE STUDY 5: Paclitaxel (Taxol R_)

Plant secondary metabolites have provided a rich and renewable resource of natural

products for drug development. However, establishing a stable supply of the active

compounds from plants is often difficult. A prominent example is Paclitaxel (Taxol R_),

a complex diterpenoid alkaloid originally isolated from the bark of the pacific yew tree

Taxus brevifolia with a yield of 0.014%. In addition, isolating Paclitaxel required

stripping the bark from the yew trees, thus killing a slow growing tree in the process,

which takes about 200 years to mature.

Scheme 16.11

On the other hand, the complexity of the Paclitaxel molecule makes commercial

production by chemical synthesis from simple compounds impractical. As a result, a

Synthetic Strategies in Chemistry

16.39

semisynthetic process was developed starting from 10-deacetylbaccatin III (Scheme

16.11),

Scheme 16.12.

a more abundant taxoid biosynthesized from isoprenyl diphosphate and farnesyl

diphosphate in the needles of the European yew tree Taxus baccata, which could be

isolated with a yield of 0.1% without harm to the trees. In this route, 10-deacetylbaccatin

16.40

Some Conceptual Developments in Synthesis in Chemistry

III was first acetylated and silylated. The resulting 7-triethylsilyl baccatin III (27) was

then coupled to an N-acyl-blactam (28) to install a phenylisoserine side chain at the C-

13 position followed by deprotection to afford Paclitaxel. Overall, however, the

semisynthetic process is still complex requiring eleven chemical transformations

including the preparation of 28 and seven isolations.

Consequently, an alternative

process to Paclitaxel was developed using Taxus cell fermentation and extraction from

culture medium, followed by recrystallization.

Starting from the two isoprenoid precursors, isoprenyl diphosphate and farnesyl

diphosphate (Scheme 12), geranylgeranyl pyrophosphate synthetase catalyzes the

coupling to give geranylgeranyl pyrophosphate, 29, which is then cyclized and then

converted to baccatin III 30 through a series of enzymatic transformationsincluding

hydroxylation, acylation, oxidation and generation of the oxetane ring. The side chain in

31 was installed by enzymatic transfer of phenylisoserine. To achieve a high titer of

Paclitaxel production, cell cultures from various species of Taxus and different elicitors

to induce Paclitaxel production have been examined. For example, methyl jasmonate was

able to enhance Paclitaxel production to 110 mg L-1 every 2 weeks in cell suspension

culture of T. media. The plant cell fermentation process led to an elimination of the

eleven chemical transformations and a large amount of hazardous solvents and wastes,

which came with the semi-synthesis route. Recent advances in metabolic engineering

have created another opportunity to develop green processes for relatively complex

molecules. An example is the production of shikimic acid for the synthesis of oseltamivir

phosphate (Tamiflu) for treatment and prevention of in.uenza virus infections. In the

current ten-step commercial synthesis (Scheme 16.13), the key intermediate is shikimic

acid 32, which was produced by a genetically engineered E. coli strain deficient in both

shikimate kinase isozymes or isolated from the star anise.

The metabolic engineering efforts have led to the development of an E. coli strain

capable of producing the molecule with a titer of 84 g L-1 and a yield of 33% from

glucose. This acid was subsequently converted into a diethyl ketal 33, which was then

transformed to the oseltamivir phosphate after side chain installation, reductive opening

of the ketal, base-catalyzed epoxide ring closure (34) followed by aziridination (35). One

drawback of the above process is the use of the hazardous azide reagent to prepare the

Synthetic Strategies in Chemistry

16.41

aziridine intermediate 35. To eliminate the use of azides, an azide-free chemoenzymatic

synthesis of oseltamivir phosphate was recently reported that comprised fewer synthetic

steps than the commercial process.

Scheme 16.13.

Scheme 16.14.

16.42

Some Conceptual Developments in Synthesis in Chemistry

In this method, the key intermediate is aminoshikimic acid (37) that was produced from

glucose by a two-step microbial process using Bacillus pumilus to generate kanosamine

36 followed by an engineered E. coli to give 37 (Scheme 16.14). The new route has an

overall yield of 22% from aminoshikimic acid and holds great potential if the

biosynthesis of aminoshikimic acid can be further improved.

CASE STUDY 6: Fine Chemicals

Due to the exquisite regioselectivity under mild conditions, biotransformations often

offer great advantages over chemical synthesis in large-scale production of fine

chemicals, which is usually energy intensive and generates a large amount of wastes and

gas emissions. The first example of enzymatic manufacture of a bulk chemical involves

the conversion of acrylonitrile to acrylamide, which is the monomer of widely used

polyacrylamide. The chemical manufacturing process involves hydration of acrylonitrile

at 70120oC by Raney copper resulting in a large volume of toxic wastes and HCN. In

addition, the acrylamide produced by this fashion requires considerable purification as it

tends to polymerize under the harsh reaction conditions. Acrylic acid is also a byproduct

of chemical hydration. Many nitrile hydratases catalyze the conversion of acrylonitrile

into acrylamide.For example, immobilized Rhodococcus rhodochrous J1 was able to

produce acrylamide at a concentration of 400 g L-1 in a fed batch process under 10 .C.

There is no need to recover residual acrylonitrile because the yield of the enzymatic

conversion is almost 100%. Currently the microbial process is operated at a scale of >40

000 t year-1. It is much greener and more economical than the chemical process. In

addition to acrylamide, Rhodococcus rhodochrous J1 was also used to prepare a variety

of amides in high concentration and throughput in water (Fig. 16.1). The drive toward

environmentally benign synthesis and sustainable development in the chemical industry

is contributing to a growing interest in the use of renewable feed stocks and reduction of

hazardous wastes in manufacturing. Consequently, carbohydrates such as glucose derived

from corn starch or cellulosic biomass provide an intriguing alternative to the current use

of nonrenewable petroleum as starting materials. The keys to the success of this transition

are the elaboration of new synthetic routes, as well as the design and engineering of

robust microbial biocatalysts. Two examples are the development of biocatalytic

syntheses of adipic acid and catechol from glucose. Adipic acid , one of the monomers

Synthetic Strategies in Chemistry

16.43

used in the manufacture of nylon 6,6, is currently produced at 2.2 million metric tons per

year. The existing route to adipic acid first entails oxidation of cyclohexane, mostly

derived from benzene, to a mixture of cyclohexanol and cyclohexanone by oxygen with a

cobalt catalyst at a temperature of 150160 ºC. This mixture was then converted to adipic

acid by oxidation in nitric acid (Scheme 16.15).

Scheme 16.15

Scheme 16.16

16.44

Some Conceptual Developments in Synthesis in Chemistry

Due to its massive scale, adipic acid manufacture has been estimated to account for some

10% of the annual increase in atmospheric nitrous oxide levels.

Benzene is a carcinogen and volatile chemical and is derived from nonrenewable

fossil fuels. Biocatalytic routes to adipic acid have been reported in which glucose was

converted to cic,cis-muconic acid followed by hydrogenation (Scheme 16.16). The

biosynthetic pathway leading to the production of cic,cis-muconic acid was assembled by

expressing Klebsiella pneumoniae aro Z-encoded 3-dehydroshikimate dehydratase, aroY-

encoded protocatechuate decarboxylase,44c and Acinetobacter calcoaceticus catA-

encoded catechol 1,2-dioxygenase in a 3-dehydroshikimate-syntheszing E. coli strain.

The resulting heterologous biocatalyst E. coli WN1/pWN2.248 was able to produce 37

gL-1 of cic,cis-muconic acid (42) in 22% yield from glucose in one-pot via intermediates

39, 40 and 41 (Scheme 16.16). Catalytic hydrogenation of cic,cis-muconic acid affords

adipic acid in 97% yield.

Scheme 16.17.

In the above metabolic pathway, catechol is an intermediate in the route to cic,cis-

muconic acid. As a result, this technology may also be applied to the production of

catechol, which is manufactured at an annual volume of 25000 metric tons as an

important chemical building block for flavors, pharmaceuticals, agrochemicals,

Synthetic Strategies in Chemistry

16.45

polymerization inhibitors and antioxidants. Although some catechol is distilled from coal

tar, phenol is the starting material for the production of the majority of catechol, and was

obtained by Hock-type air oxidation of benzene-derived cumene (pathway A, Scheme

17).47 Direct microbial synthesis of catechol from glucose resulted in only 5% yield due

to its high toxicity to the production host. The issue was circumvented by microbial

production of a less toxic intermediate protocatechuate using E. coli KL3/pWL2.46B

followed by chemical decarboxylation in water (pathway B, Scheme 16.17).

By this strategy, the overall yield of catechol from glucose was improved to 43%. As

illustrated in microbial syntheses of adipic acid and catechol, manufacture of chemicals

of major industrial importance from renewable feedstocks offer significant environmental

advantages and economic opportunities. A single genetically engineered microbe is able

to catalyze the conversion of glucose in water at near-ambient pressure and temperature.

The spectrum of chemicals that could be synthesized from glucose can be further

expanded by the construction of heterologous biocatalysts and integration of microbial

and chemical transformations.

Scheme 16.18.

16.46

Some Conceptual Developments in Synthesis in Chemistry

Research aimed at increasing synthetic efficiency and overcoming product toxicity and

isolation problems are critical to move biocatalytic syntheses from proof-of-concept into

practical routes to compete with existing chemical routes based on petroleum. Another

example using metabolic engineering is microbial production of 1,3-propanediol. The

emergence of a new 1,3-propanediol (PDO)-based polyester has dramatically increased

the demand for PDO in recent years. Once a fine chemical, PDO is now becoming a bulk

chemical as its production volume will increase to a level of one million tons annually.

Historically, PDO was produced from petroleum chemicals from two different chemical

processes. One uses propylene as the starting material, which was catalytically oxidized

to acrolein, followed by hydration to 3-hydroxypropionaldehyde (pathway A, Scheme

18). An alternative process starts from ethylene oxide obtained from oxidation of

ethylene (pathway B, Scheme 18). Ethylene oxide was then converted to 3-

hydroxypropionaldehyde by hydroformylation under high pressure. The conversion of 43

to PDO requires hydrogenation over a rubidium or nickel catalyst under high-pressure.

To lower the cost of PDO and reduce the negative environmental impact of its

production, a recombinant E. coli strain was developed to produce PDO from glucose.

The E. coli strain was modified to contain genes from Saccharomyces cerevisiae, which

is capable of producing glycerol from glucose, and Klebsiella pneumoniae, which

contains the metabolic pathway of glycerol to PDO (Scheme 19).

Scheme 16.19.

Synthetic Strategies in Chemistry

16.47

The engineered strain relies on a predominantly heterologous carbon pathway that diverts

carbon from dihydroxyactone phosphate (DHAP) to PDO. Two genes from yeast

encoding glycerol 3-phosphate dehydrogenase (dar1) and glycerol 3-phosphate

phosphatase (gpp2) directs glycolysis pathway to glycerol. Two genes from K.

pneumoniae

encoding

glycerol

dehydratase

(dhaB1-3)

and

1,3-propanediol

oxidoreductase (dhaT) then transform glycerol to PDO. Significant modifications were

then made to the base strain by extensive metabolic engineering to improve the

fermentation productivity. Additional genes from dha operon were incorporated into the

engineered strain to stabilize glycerol dehydratase via reactivation. Moreover, an E. coli

endogenous oxidoreductase (yqhD) was found to be superior to dhaT in providing high

PDO titer (¡«130 g L-1). As a result, the yield of PDO production in one-pot from

glucose was eventually improved to 51% (g g-1).

In contrast to the chemical processes to PDO, the biocatalytic process uses a

renewable resource and was run at close to room temperature without added pressure.

The bioprocess to PDO also reduces the energy consumption by 40% and green gas

emissions by 20%. As of December 2006, shipments of corn sugar-derived PDO have

been initiated from a 100 million-lb per- year plant. The successful development of a bio-

based PDO process showed that it is possible to produce bulk chemicals in a more cost-

effective way than the chemical processes while adhering to the principles of green

chemistry.

CASE STUDY 7: Polymers

Another recent application of biocatalysis for green chemistry development is the

production of polymeric materials. Enzymatic polymerization, i.e., in vitro synthesis of

polymers using isolated enzymes, offers a number of advantages over conventional

chemical methods that often require harsh conditions and the use of toxic reagents.

Benefiting from high regio and enantioselectivities under mild conditions, an enzymatic

approach provides a new synthetic strategy for the production of novel polymers, which

are otherwise dif.cult to get by chemical transformations. Enzymatic polymerization has

been applied to the synthesis of a number of polymers such as polyesters, polycarbonates,

polysaccharides, polyurethanes, polyaromatics and vinyl polymers using oxidoreductases,

transferases and hydrolases.

16.48

Some Conceptual Developments in Synthesis in Chemistry

For example, a simple, environmentally-friendly, and versatile method was recently

developed to produce polyol-containing polyesters through selective lipase-catalyzed

condensation polymerization between diacids and reduced sugar polyols such as sorbitol

(Scheme 20). Instead of using organic solvents, the monomers adipic acid, glycerol and

sorbitol were solubilized within binary or ternary mixtures, and no preactivation of adipic

acid was needed. The direct condensation of adipic acid and sorbitol was performed in

bulk at 90 oC for 48 h using immobilized lipase B from Candida Antartica (Scheme 20).

The product, poly(sorbityl adipate), had an average molecular weight of 10880 (Mn) and

17030 (Mw) respectively.

Scheme 16.20

By replacing a fraction of sorbitol with 1,8-octanediol, copolyesters of adipic acid, 1,8-

octanediol, and sorbitol were obtained in the molar ratio of 50 : 35 : 15 with an Mw of

>100 000. Similar results were also obtained with glycerol in place of sorbitol as the

natural polyol (not shown). The condensation reactions with gycerol and sorbitol building

blocks proceeded with high regioselectivity without protectiondeprotection of functional

groups. Although the polyol monomers contain three or more hydroxy groups, only two

are highly reactive in enzymatic polymerization. Therefore instead of obtaining highly

cross-linked products, the high regioselectivity leads to lightly branched polymers where

Synthetic Strategies in Chemistry

16.49

the degree of branching varies with the reaction time and monomer stoichiometry. The

mild reaction conditions also facilitate the polymerization of chemically and thermally

sensitive molecules. Alternative chemical polymerization would necessitate the use of

stoichiometric amount of coupling agents. The biocatalytic approach is also versatile for

simultaneous polymerization of lactones, hydroxyacids, cyclic carbonates, cyclic

anhydrides, amino alcohols, and hydroxythiols as a result of high regioselectivity.

Another example is enzyme-catalyzed ring-opening polymerizations of lactones and

cyclic carbonates, which offer number of advantages over chemical methods including

mild reaction conditions and improved propagation kinetics and/or molecular weights.

The ring-opening polymerization of pentadecalactone and trimethylene carbonate

catalyzed by the lipase PS-30 and Novozyme-435 in bulk at 70 oC afforded high average

molecular weight and moderate dispersity products (not shown). Enzymatic

polymerization also allows structural control by regioselective incorporation of

multifunctional initiators such as carbohydrates. In the ring-opening polymerization of e-

caprolactone or trimethylene carbonate with ethyl glucopyranoside as an initiator

catalyzed by porcine pancreatic lipase, the polymerization occurred selectively from the

6-hydroxyl position (Scheme 21). Since both ethyl glucopyranoside and the monomers

are liquids, the reaction could be carried out in the absence of solvents. The novel

amphiphilic product was prepared in one-pot without the need of protection and

deprotection chemistry. Hydrolases were also able to catalyze transesterification reactions

between a monomer and a polymer or between two homopolyesters that differ in main

chain structure. For example, Novozym-435 catalyzed transesterification between

polypentadecalactone (4300 g mol-1) and polycaprolactone (9200 g mol-1) resulted in

random

copolymers

within

one

hour.

addition

catalyzing

metal-free

transesterification under mild conditions, lipases endow transesterfication reactions with

remarkable selectivity, allowing the preparation of block copolymers that have selected

block lengths. Recent advances in biocatalysis have also made an in road in the

manufacture of biodegradable plastics such as polyhydroxyalkanoates (PHA) and

polylactides (PLA). Polyhydroxyalkanoates are a class of natural polyesters produced by

many bacteria in the form of intracellular granulates as a carbon and energy reserve.

Since the initial discovery of poly-3-hydroxybutyrate (PHB), more than 130 hydroxyacid

16.50

Some Conceptual Developments in Synthesis in Chemistry

monomer compositions have been identified that have been classified as short-chain and

medium-chain hydroxyalkanoates. Once extracted from bacterial cells, the biobased

polymers display diverse material properties that range from thermoplastics to elastomers

depending upon their monomer unit composition. The environmental benefit of using

biodegradable PHA and the utilization of abundant, renewable starch as a starting

material for its synthesis provide an appealing alternative to the commonly used

petroleum-derived plastics. Of all the PHAs, PHB copolymers are the most extensively

studied. The biosynthetic pathway of polyhydroxybutyrate consists of three enzymatic

reactions (Scheme 22).Thiolase catalyzes the condensation of two molecules of acetyl-

CoA to form one molecule of acetoacetyl-CoA, which is then reduced to (R)-3-

hydroxybutyryl-CoA

by aNADPH-dependent acetoacetyl-CoA dehydrogenase. The

crucial polymerization of 44 is catalyzed by a PHB synthase with concomitant

regeneration of coenzyme A (Scheme 16.22).

Scheme 16.22.

PHB homopolymer is a stiff and brittle material. The high melting temperature of PHB

limits the ability to process the biopolymer. Incorporation of 3-hydroxyvalerate into PHB

renders a poly(3-hydroxybutyrate-co-3-hydroxyvalerate) block copolymer 48, which can

be processed at a lower temperature while still retaining excellent mechanical properties.

The monomer (R)-3-hydroxyvaleryl-CoA 47 is produced from condensation of acetyl-

CoA and propionyl-CoA to 3-ketovaleryl-CoA (46) followed by reduction catalyzed by

acetoacetyl-CoAdehydrogenase (Scheme 23). With the advances in genome sequencing

projects, novel PHA synthases with different activities and substrate specificities have

Synthetic Strategies in Chemistry

16.51

been identified. Together with metabolic engineering of diverse, heterologous pathways

for efficient biosynthesis of the monomer substrates from renewable starting materials,

high yielding production of polyhydroxyalkanoates has been achieved via microbial

fermentation. Accumulation of PHA in genetically engineered Pseudomonas reached

90% of the cell weight. Typical molecular weight of the polymer ranges from 50 000 to 1

000 000 Da. Recent research efforts have been devoted to the production of PHA in

transgenic plants. Direct production of PHA in plants has the potential to dramatically

lower the manufacturing cost, and reduce the burden of plastic wastes as a result of

biodegradability to environmentally friendly products.

Scheme 16.23.

CONCLUSIONS

The new development in synthetic chemistry is green chemistry, and the principles

involved have created newer opportunities to develop new technologies to improve

chemical processes. A recent study shows that among the 1039 chemical transformations

16.52

Some Conceptual Developments in Synthesis in Chemistry

analyzed for the synthesis of 128 drug molecules, chemical acylations are one of the most

common transformations which, however, are generally inefficient. Development of

catalytic, low waste acylation methods would significantly improve the environmental

performance of many syntheses. The discovery of new regioselective and catalytic

oxidations would greatly increase flexibility in synthetic design, as illustrated in the green

and biocatalytic synthesis of pharmaceuticals and fine chemicals. Biotransformations are

uniquely suited to deliver high stereo- and regioselectivity in water at ambient

temperature and atmosphere, and are able to catalyze reactions that are challenging for

traditional chemistry. The key is to integrate synthetic chemistry, biological

transformations and process development and biocatalysis is positioned to be a

transformational technology for chemical production with improved synthetic efficiency.

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1. James A. Schwarz, Cristian Contescu & Adriana Contescu, Chem.Rev., (1995)

95477

2. Ningqing Ran, Lishan Zhao, Zhenming Chenb & Junhua Tao, Green Chem.,

10 (2008) 361.

3. C. N. R. Rao, Materials Science and Engineering, BI8 (1993) 1.

4. Abraham Szöke, William G. Scott & János Hajdu, FEBS Letters 553 (2003) 18.

5. The Way of Synthesis: Evolution of Design and Methods for Natural Products

Tomas Hudlicky, Josephine W. Reed, 2007, Wiley-VCH.

6. Synthesis of Inorganic Materials, Ulrich Schubert, Nicola Hüsing, 2005,Wiley-VCH.

7. Härkönen et al., Nucl. Instr. and Meth. A 541 (2005) 202.

8. leksic et al., Ann. of NY Academy of Sci. 972 (2002) 158.

9. Lindström et al., Nucl. Instr. and Meth. A 466 (2001) 308 and cited literature therein.

10. C. N. R. Rao Materials Science and Engineering B,Volume 18, Issue 1, 1993, 1.

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Wittcoff, 2003, Wiley-VCH.

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