The document provides an overview of catalysis. It defines a catalyst as a substance that speeds up a chemical reaction but is not consumed by the reaction. It discusses different types of catalysis including homogeneous catalysis where the catalyst is in the same phase as the reactants, and heterogeneous catalysis where the catalyst is in a different phase. The document also covers catalyst characterization techniques, factors that can lead to catalyst deactivation, and methods for catalyst regeneration. Examples are provided throughout to illustrate catalysis concepts and applications.

1. catalysis
Presented By
Anwar Ahmed
M. Pharm (2nd Sem.)
P’ceutical Chemistry
SPER, Jamia Hamdard
New Delhi.

2. 1) Introduction & Properties
2) Heterogeneous Catalysis
3) Homogenous Catalysis
4) Transition-metal & Organo catalysis
5) Bio-catalysis
6) Phase Transfer Catalysis
Contents:

3. CATALYST: The substances that alter the rate of a reaction but itself remains chemically unchanged at the end of the reaction is
called a Catalyst.
The process is called catalysis.
Promoter: Substance that increase the catalytic activity.
Catalytic poison: Decrease or stop catalytic activity.
Types of catalysis: It is of 2 types
(A) Homogenous catalysis (b) Heterogeneous catalysis
(a) Homogenous catalysis: reaction where the catalysts are in the same phase as the reactants.
E.g. Hydrolysis of ester into alcohol and acid catalyzed by H+ ions.
(B) Heterogeneous catalysis: reaction where the catalyst and reactant are in different phases.
E.g. Contact process for H2SO4 production catalyzed by Pt gauze or V2O5.
Introduction:

4.  A small quantity of the catalyst is enough to catalyze a large quantity of reactants into products.
 Though reactants are same, the type of catalyst used may decide the products formed.
 If 2 catalysts can catalyze the same reaction, the better catalyst is the one which produces a greater reduction in activation
energy.
 e.g. activation energy for the decomposition of H2O2 for different catalysts.
Properties:
CH CH
+ H2 CH3 CH3
Ethyne
Ethane
Pt
CH CH + H2
CH2 CH2
EtheneEthyne
Lindlar's
Catalyst
Catalyst Ea, kj/mol
None 75
MnO2 58
I 56
Colloidal Pt 49

5.  A catalyst lower the activation barrier for a transformation by introducing a new reaction pathway.
 Catalysts provide an alternate pathway for reaction.
 This alternate pathway requires lower activation energy and is easier to achieve and a larger number of molecules can react and
yield products.
Without
catalyst
With
catalyst

6. Advantage and Disadvantage
Advantage Disadvantage
Catalyst speed up the ROR, which saves
money.
They are very expensive to buy.
Catalyst allow the reaction to work at a
much lower temperature. This reduces the
energy used up in a reaction.
They often need to be removed from a
product and cleaned.
They save industries money. Different reactions use different catalysts,
so if you make more than one product you
need more than one catalyst.
Reusability. Catalyst can be ruined by impurities, so
they stop working.

7.  Heterogeneous catalysis refers to the form of catalysis where the phase of the catalyst differs from that of that
reactants.
 Heterogeneous catalysis has at least four steps:
1) Adsorption of the reactant onto the surface of the catalyst.
2) Activation of the adsorbed reactant.
3) Reaction of the adsorbed reactant.
4) Diffusion (desorption) of the product from the surface of catalyst.
Heterogeneous catalysis

8. Colloidal metal are
prepared by
reduction of salt by
P, Acetone, Tannin
or CO.
Metallic sponges
are formed from
the reduction of a
salt in alkaline
solution with
formaldehyde.
Skeletal metals are formed
by leaching out one metal
from alloy.
e.g. Raney nickel prepared
from alloy of Ni and Al in
presence of NaOH.
Preparation of heterogeneous catalyst
Metallic glasses are
alloy that cool
down so rapidly so
that any crystal
structure had no
enough time to
develop.
Metallic powders can
be prepared by
reducing salts in a
stream of a reducing
gas like H2, chlorides
and oxide of metals.
Evaporated
metal films are
prepared by
sputtering metal
wires in
vacuum.

9.  Catalyst characterization and analysis plays a key role in catalyst development, ongoing quality control during manufacturing and
also during fouling or performance related investigations, laboratory testing expertise and services. Understanding the composition,
the physical micro/nanostructure, porosity and surface properties can all assist in achieving a better performance or resolve a failure
issue.
 Following techniques are used to characterize the catalyst: BET surface area, TPO, SEM, TEM, EDX, XRD and TGA etc.
 TPO (Temperature programmed oxidation): Gas mixture (Oxygen diluted in Helium) is used to perform analysis. Dynamic TPO
with on-line mass spectrometry is used to monitor oxygen consumption and which confirms percent coking occurred in a catalyst.
Characterization
SEM (Scanning Electron Microscopy): Give information
of external morphology, surface topography.
Image of de-NOx catalyst V2O5-WO3/TiO2 before and after
Deactivation.
TEM (Transmission Electron Microscopy): Provide information
on the structure, texture, shape and size of the sample.
TEM images of fresh and deactivated Co-alumina catalyst in
Fischer-Tropsch synthesis.

10.  It is a material, usually a solid with a high surface area, to which a catalyst is affixed. The activity of heterogeneous
catalysts & nano material-based catalysts occur at the surface atoms. Great efforts is made to maximize the surface area
of a catalyst by distributing it over the support.
 E.g. of support- Carbon, alumina and silica.
 Preparation method: 2 type of method are employed (a) Impregnation (b) Co-precipitation
Supported Catalysis

11. Loss in catalytic activity due to chemical, mechanical or thermal processes. Heterogeneous catalysts are more prone to deactivation.
Time scales for catalyst deactivation vary considerably; for example, in the case of cracking catalysts, catalyst mortality may be on
the of seconds, while in ammonia synthesis the iron catalyst may last for 5-10 years.
(1). POISONING: Not only blocks the active sites, but also induce changes in the electronic or geometric structure of the surface.
E.g. N, P As, Sb, O, S, Se, Te (grp. VA and VIA), F, Cl, Br, I (grp. VIIA), Pb, Hg, Bi, Sn, Zn, Cd, Cu, Fe (Toxic heavy metals &
ions)
E.g. In Ammonia synthesis the O2, H2O, CO, S, C2H2 act as a poison for Fe and Rh catalyst.
Advantage of Poisoning: V2O5 is added to Pt to suppress SO2 oxidation to SO3 in diesel emissions control catalysts.
(2). FOULING: Physical deposition of species onto surface of catalytic surface and catalytic pores.
Fouling of catalyst due to carbon deposition is coking.
(3). THERMAL DEGRADATION: Thermally induced loss of catalytic surface area, support area.
(4). ATTRITION/CRUSHING: Loss of catalytic material due to abrasion, loss of internal surface area due to mechanical induced
crushing of catalyst.
Catalytic Deactivation

12.  The loss of catalytic activity in most processes is inevitable. When the activity has declined to a critical level, a
choice must be made among four alternatives: (1) restore the activity of the catalyst, (2) use it for another
application, (3) reclaim and recycle the important and/or expensive catalytic components, or (4) discard the
catalyst.
 The ability to reactivate a catalyst depends upon the reversibility of the deactivation process. For example, carbon
and coke formation is relatively easily reversed through gasification with hydrogen, water, or oxygen.
 Some poisons or foulants can be selectively removed by chemical washing, mechanical treatments, heat
treatments, or oxidation, others cannot be removed without further deactivating or destroying the catalyst.
 E.g. of Regeneration of poisoned catalyst: Some frequently used regeneration techniques include (regeneration
of sulfur poisoned Ni, Cu, Pt and Mo) treatment with O2 at low oxygen partial pressure and steam at 700-800OC
 Regeneration of coked catalysts: Gasification with O2, H2O, CO2 and H2
 C + O2 → CO2 ; C + H2O → CO + H2 ; C + CO2 → 2CO ; C + 2H2 → CH4
 Promoters can be added to increase rate of gasification (e.g. K or Mg in Ni for steam reforming)
Catalytic regeneration

13.  Continuous flow system have advantage over batch system in terms of productivity, heat and mixing efficiency,
safety & reproducibility.
 Commercially available starting material successively passed through four column containing achiral and chiral
heterogeneous catalyst to produce (R)-Rolipram, an anti-inflammatory drug & one of the family of GABA
derivatives.
 Simply by replacing a column packed with a chiral heterogeneous catalyst with another column packed with
opposing enantiomer, we obtained (S)-Rolipram.
 Rolipram is selective PDE4 inhibitor & particularly effective for subtype PDE4B.
 Rolipram is known to be a possible antidepressant & has been reported to have anti-inflammatory,
immunosuppressive, anti-tumor effects and has also been proposed as a treatment for multiple sclerosis and has
been suggested to have antipsychotic effects.
 It has been reported that (R)-Rolipram has anti-inflammatory activity but (S)-Rolipram does not.
Heterogeneous Catalysis in drug synthesis
continuous flow synthesis of (R) & (S)-Rolipram

14. .
Reaction assembly

15.  First of all the Aldehyde and Nitroalkane catalyzed by Si-NH2/CaCl2 and toluene to obtained Nitroalkene. (Flow 1)
 Nitroalkene react to methyl malonate catalyzed by PS-(S)-pybox-CaCl2 in presence of triethylamine and toluene to obtained g-nitroester
(Flow 2) which further reduced by catalyst Pd/(DMPSi-C) into g-lactum. (Flow 3)
 In final stage of rolipram synthesis the hydrolysis and decarboxylation of the ester part of g-lactum is occur in the presence of Silica
supported carboxylic acid (Si-COOH). (Flow 4)
Multistep continuous flow synthesis of (S)-rolipram

16.  Imidazopyridine is an important pharmacophore and is widely found in many biologically active compounds.
 In particular, imidazo[1,2-a]pyridine is an essential fragment present in several anxiolytic drugs such as Alpidem, Necopidem,
Saripidem and the drug treat insomnia Zolpidem.
One pot synthesis of Alpidem and Zolpidem by Cu-
catalyzed TCC
N
NH2
Rn
O
R1
R2
N
N
R1
R2
Rn
CuCl (5 mol%)
Cu(OTf)2 (5 mol%)
Toluene, 120o
C
12-16 h
(Yield 93%)
Imidazopyridines Nucleus
Aminopyridine Aldehyde Alkyne
+ +
Pr
N Pr
O
N
Cl
N
Cl
Alpidem
N
O
N
N
Zolpidem
O
N
N
N
Necopidem
O
N
N
N
Cl
Saripidem

17.  In homogeneous catalysis the catalysts are present in the same phase as the substances which are going into the reaction phase.
 The homogeneous forms of catalysts are nothing but chemical compound which remains in same phase as the reactants and help in
accelerating the process of chemical change.
 Hydrogenation: is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence
of a catalyst such as Ni, Pd or Pt. The process is commonly employed to reduce or saturate organic compounds.
 Application: In food industry for large scale production of vegetable oils. Hydrogenation converts liquid vegetable oils into solid or
semi-solid fats.
 In petrochemical processes, hydrogenation is used to convert alkenes and aromatics into saturated alkanes (paraffins) and cycloalkanes
(naphthenes), which are less toxic and less reactive.
Homogenous catalysis
R
+ H2
R CH3
Catalyst
Alkene AlkaneHydrogen

18. Hydroformylation: Hydroformylation, popularly known as the "oxo" process, is a Co or Rh catalyzed reaction of olefins with CO and
H2 to produce the value-added aldehydes. The metal hydride complexes namely, the Rhodium based HRh(CO)(PPh3)3 and the cobalt based
HCo(CO)4 complexes, catalyzed the hydroformylation reaction.
R3
R2
R4
R1
R2
C
H
H
OH
R2
H
C
R1 R3
R3
H
R1
O
H
CO/H2
Catalyst +
Hydrocyanation: It is most fundamentally, the process whereby H+
and –CN ions are added to a molecular substrate. Usually the substrate is
an alkene and the product is a nitrile.
 A key step in Hydrocyanation is the oxidative addition of hydrogen
cyanide to low–valent metal complexes.
 In Hydrocyanation of unsaturated carbonyls addition over the
alkene competes with addition over the carbonyl group.
 It is basically used in steroids synthesis.
CN
H
H
CN
+
CN
H
CN
CN
H
H
a
b
c
3PN
2M3BN
3PN
Adiponitrile
1,3 butadiene

19.  Wilkinson's catalyst, is the common name for chlorido-tris(triphenylphosphane)rhodium(I), a coordination complex of rhodium with the
formula RhCl(PPh3)3 (Ph = phenyl). It is a red-brown colored solid that is soluble in hydrocarbon solvents such as benzene, and more so
in tetrahydrofuran or chlorinated solvents such as dichloromethane. The compound is widely used as a catalyst for hydrogenation of
alkenes. It is named after chemist and Nobel Laureate, Sir Geoffrey Wilkinson, who first popularized its use.
 Wilkinson's catalyst is usually obtained by treating rhodium(III) chloride hydrate with an excess of triphenylphosphine in refluxing
ethanol.
RhCl3(H2O)3 + 4 PPh3 → RhCl(PPh3)3 + OPPh3 + 2 HCl + 2 H2O
Uses: It is used in the selective hydrogenation of alkenes and alkynes without affecting the functional groups like: C=O, CN, NO2, Aryl,
CO2R etc.
Wilkinson catalysts
Rh+
PH
PH PH
Cl-

20.  Most chiral ligands combine with metals to form chiral catalyst engages in a chemical reaction in which chirality is transfer to the
reaction product. Chiral induction are also known as asymmetric induction.
 If we want to create a new chiral center in a molecule, our starting material must have prochirality (the ability to become chiral in one
simple transformation). The most common prochiral units that give rise to new chiral centers are the trigonal carbon atoms of alkenes
and carbonyl groups, which become tetrahedral by addition reactions.
 One of the simplest transformations you could imagine of a prochiral unit into a chiral one is the reduction of a ketone.
 The left hand structure has a C2-rotational axis whereas the right hand structure is asymmetric. Arrows indicate the proposed trajectories
for attack by substrates, identical colors lead to identical transition states (and hence products) with red arrows being disfavored due to
steric repulsion.
Chiral Ligands & Chiral Induction

21.  Chiral ligands work asymmetric induction somewhere along
the reaction coordinate. The image depicted on the right side
gives a general idea how a chiral ligand may induce an
enantioselective reaction.
 The ligand (in green) has C2 symmetry with its nitrogen,
oxygen or phosphorus atoms hugging a central metal atom (in
red). In this particular ligand the right side is sticking out and
its left side points away. The substrate in this reduction is
acetophenone and the reagent a hydride ion.
 In absence of the metal and the ligand the re face approach of
the hydride ion gives the (S)-enantiomer and the si face
approach the (R)-enantiomer in equal amounts (a racemic
mixture like expected).
 The ligand/metal presence changes all that. The carbonyl
group will coordinate with the metal and due to the steric bulk
of the phenyl group it will only be able to do so with its si face
exposed to the hydride ion with in the ideal situation exclusive
formation of the (R) enantiomer.
Chiral fence

22.  A Ziegler–Natta catalyst, named after Karl Ziegler and Giulio Natta, is a catalyst used in the synthesis of polymers of 1-alkenes
(alpha-olefins). 2 broad classes of Ziegler-Natta catalysts are employed:
 Heterogeneous supported catalysts based on titanium compounds are used in polymerization reactions in combination with co-
catalysts, organoaluminum compounds such as triethylaluminium, Al(C2H5)3. This class of catalyst dominates the industry.
 Homogeneous catalysts usually based on complexes of Ti, Zr or Hf. They are usually used in combination with a different
organoaluminum co-catalyst, methylaluminoxane (or methylalumoxane, MAO). These catalysts traditionally contains
metallocenes but also feature multidentate oxygen- and nitrogen-based ligands.
Commercial Application: In synthesis of variety of polymers like: Polyethylene, Polypropylene, Polymethylpentene,
Polybutadiene, Polyisoprene, Polyacetylene etc.
Ziegler-Natta catalyst

23.  Contribution of homogeneous catalytic process in chemical industry is significantly smaller compared to heterogeneous catalytic
process, it is only about 17-20 %. But importance of homogeneous catalysis is increasing significantly. The significance of
homogeneous catalysis is growing rapidly particularly in the area of pharmaceutical and polymer industry. Some of the important
industrial processes include:
1. Oxidations of alkenes such as production of acetaldehyde, propylene oxide etc.
2. Polymerization such as production of polyethylene, polypropylene or polyesters.
Examples: Acid catalyzed condensation of phenol and acetone to bisphenol which is an important intermediate in the manufacture of
epoxy resin and polycarbonates.
 Synthesis of L-dopa: The asymmetric hydrogenation of cinnamic acid derivatives involves synthesis of L-Dopa. L-Dopa is a drug
for treating Parkinson’s disease. It is one of the recently developed industrial processe. The C atom bonded to the NH2 group is the
chiral center. The enantiomer D-Dopa is ineffective form.
 The reaction is carried out in the presence of rhodium complex having asymmetric diphosphine ligand which induces enantio-
selectivity. The hydrogenation reaction is carried out with a substituted cinnamic acid. The main step in L-Dopa synthesis, the
hydrogenation of prochiral alkene to a specific optical isomer.
Homogenous catalysis in drug synthesis

24. Catalyst is prepared by reacting Rh salt with an alkene chloride, such as hexadiene chloride or cyclooctadiene chloride,
producing a cationic Rh species.
OAc
OCH3
COOH
NHAc OAc
OCH3
COOH
NHAc
HO
OH
COOH
NH2
Catalytic
Asymmetric
Hydrogenation
Hydrolysis
L-DOPA
3-(3',4'-dihydroxy phenyl) L-Alanine

25. Transition-metal: The transition metals are the group of metals in the middle section of the periodic table.
- Many of the transition metals behave as catalysts, either as the metal itself or as a compound.
- The d-orbitals are what give transition metals their distinguished properties. The transition metal ions the outermost d-orbitals are
incompletely filled with electrons so they can easily give and take electrons. This makes transition metals prime candidates for catalysis.
The outermost s and p-orbitals are usually empty and therefore less useful for electron transfer.
Transition-metal & organo-catalysis in organic
synthesis: metal-catalyzed reactions

26. Transition metal catalysts are either homogeneous catalysts or heterogeneous catalysts.
Examples of catalysis
(1). The Haber Process: This is one of the best-known reactions involving a transition metal catalyst. It is the formation of
ammonia from nitrogen and hydrogen using iron as the catalyst. This is a heterogeneous system.
(2) Desulfurization: Raney nickel is used in organic synthesis for desulfurization. For example, thioacetals will be reduced to
hydrocarbons in the last step of the Mozingo reduction.
Transition metal catalysts
S
SR
R
R
CH2
R
H3C CH3 ++
H2, Raney Ni
Thioacetal
Ethane Nickel sulfide
2 NiS

27.  Organo-catalysis uses small organic molecules predominantly composed of C, H, O, N, S and P to accelerate chemical reactions.
 The advantages of organo-catalysts include their lack of sensitivity to moisture and oxygen, their ready availability, low cost, and low
toxicity, which confers a huge direct benefit in the production of pharmaceutical intermediates when compared with (transition) metal
catalysts.
 Organo-catalysts for asymmetric synthesis can be grouped in several classes:
 Biomolecules: Proline, phenylalanine. Secondary amines in general. The cinchona alkaloids, certain oligopeptides.
 Synthetic catalysts derived from biomolecules.
 Hydrogen bonding catalysts, including TADDOLS, derivatives of BINOL such as NOBIN, and organo-catalysts based on thioureas
 Triazolium salts as next-generation Stetter reaction catalysts
Organo-catalysis
OH
OH
BINOL
OH
H2N
NOBIN
TADDOL

28. Examples of asymmetric reactions involving organo-catalysts are:
(1). Asymmetric Diels-Alder reactions ; (2). Asymmetric Michael reactions ; (3). Asymmetric Mannich reactions ;
(4). Shi epoxidation ; (5). Organo-catalytic transfer hydrogenation.
Asymmetric Michael Reaction: The reaction between cyclohexanone and β-nitrostyrene sketched below, the base proline is
derivatized and works in conjunction with a protic acid such as p-toluenesulfonic acid.
The synthesis of warfarin from 4-hydroxycoumarin and benzylideneacetone .
EXAMPLES OF ASYMMETRIC REACTIONS

29. Asymmetric Mannich Reaction:
The asymmetric Mannich reaction with an unmodified aldehyde was carried with (S)-proline as a naturally occurring
chiral catalyst.

30. Catalytic nucleophilic substitution reactions comprise some of the most commonly used catalytic processes in synthetic organic chemistry.
The original cross-coupling reactions formed C-C bonds, however catalytic carbon heteroatom C-X formation has now been developed
where X = N, O, S, P, Si, B.
Suzuki Coupling: The coupling of organoboron reagents has become the most commonly used cross-coupling process. Organoboron
reagents are less toxic than organotin reagents and tend to undergo coupling reactions in the presence of a variety of functional groups.
Suzuki showed that addition of a hard base, e.g. OH− or F− , causes the organoboron reagent to undergo cross-coupling by generating a
four-coordinate anionic organoboron reagent that transfers the organic group from boron to the metal catalyst.
Metal-catalyzed reactions
X R+RM
Catalyst
B(OH)2 Br
R R
2 eq K2CO3 aq.
3 mol% Pd(PPh3)4
Benzene,
+

31. Kumada Coupling: Kumada coupling involves coupling of a Grignard reagent with alkyl, vinyl or aryl halides in the presence of a
Ni transition metal catalyst providing an economic transformation.
Stille Coupling: The Stille Coupling is a versatile C-C bond forming reaction between stannanes and halides or pseudohalides, with
very few limitations on the R-groups.
The main drawback is the toxicity of the tin compounds used, and their low polarity, which makes them poorly soluble in water.

32.  Bio-catalysis can be defined as the use of natural substances to speed up the chemical reaction. The natural substance can be one or
more enzymes or cells.
 It is broadly defined as the use of enzymes or whole cells as biocatalyst for industrial or academic synthetic chemistry.
 Enzymes properties such as stability, activity, selectivity and substrate specificity can now be engineered in the labs.
Enzymes In Organic Synthesis
 Single steps in organic synthesis can be accomplished using enzymes .
 Preserves stereo-chemical centers, which can be important for drug.
 Eliminates need for protection/deprotection.
 Can be done in an aqueous environment thus, favors green chemistry.
Bio-catalysis

33. .
Types Of Enzymes

34.  The synthesis of carbon–carbon bonds in nature is performed by a vast variety of enzymes, however the bulk of
the reactions are performed by a rather limited number of them. Indeed, for the synthesis of fatty acids just one
carbon–carbon bond forming enzyme is necessary.
 Contrary to expectation, virtually none of the enzymes that nature designed for building up molecules are used
in organic synthesis. This is because they tend to be very specific for their substrate and can therefore not be
broadly applied.
 Fortunately an ever increasing number of enzymes for the formation of carbon–carbon bonds are available.
Many of them are lyases and, in an indirect approach, hydrolases. These classes of enzymes were designed by
nature not for making but for breaking down molecules.
 As reagents that were designed by nature for degrading certain functional groups, they are robust but not very
substrate specific. However, they are specific for the functional group they destroy in nature and generate in the
laboratory or factory. Equally important, they are very stereo-selective. Hence these enzymes are ideal for the
application in organic synthesis.
Enzyme in Organic synthesis

35.  Cyanohydrins are versatile building blocks that are used in both the pharmaceutical and agrochemical industries.
For the synthesis of cyanohydrins nature provides the chemist
with R- and S-selective enzymes, the hydroxynitrile lyases
(HNL). These HNLs are also known as oxynitrilases and
their natural function is to catalyze the release of HCN from
natural cyanohydrins like mandelonitrile and acetone
cyanohydrin. This is a defense reaction of many plants.
It occurs if a predator injures the plant cell. The reaction also
takes place when we eat almonds. Ironically the benzaldehyde
released together with the HCN from the almonds is actually
the flavor that attracts us to eat them.
Enzymatic synthesis of cyanohydrins

36.  Different plant families having different structure of HNLs (Hydroxynitrile lyases) some resembles Hydrolases or Carboxypeptidase
while other evolved from oxidoreductases.
 Although many of the HNLs are not structurally related they all utilize acid-base catalysis. No co-factors need to be added to the
reactions nor do any of the HNL metallo-enzymes require metal salts.
 Many stereo-selective HNLs are available like S & R.
 R-selective Prunus amygdalus HNL is available from almonds. This enzyme is successfully utilize to synthesize both aromatic and
aliphatic R-cyanohydrines.
Enzymatic synthesis of cyanohydrins using HNLs
Prunus amygdalus HNL can be employed
for the bulk production of
(R)-o-chlormandelonitrile, however with
a modest enantioselectivity. (ee 83%)

37.  When replacing Alanine 111 with Glycine the mutant HNL showed a remarkably high enantioselective towards o-
chlorobenzaldehyde and the corresponding cyanohydrin was obtained with an enantioselectivity of 96.5%.
 Hydrolysis with conc. HCl yields the enantiopure (S)-o-chloromandelic acid,an intermediate for the anti-thrombotic drug
Clopidogrel.
Synthesis of Clopidogrel from Mutant PaHNL

38.  Recently it was described that site directed mutagenesis has led to a Prunus amygdalus HNL that can be
employed for the preparation of (R)-2-hydroxyl-4-phenyl butyronitrile with excellent enantioselectivity (ee>96%).
 This is a chiral building block for the enantioselective synthesis of ACE inhibitors such as Enalpril.
Synthesis of Enalpril by mutant PaHNL

39.  The discovery of the S-selective HNLs is more recent. The application of the S-selective Hevea brasiliensis HNL
was first described in 1993.
 Indeed, this enzyme is not only a versatile catalyst in the laboratory, industrially it is used to prepare (S)-m-
phenoxymandelonitrile with high enantiopurity (ee>98%).
 This is building block for the pyrethroid insecticides Deltamethrin & Cypermethrin.
Synthesis of S-selective Insecticides

40.  Immobilization is the process of adhering biocatalysts (isolated enzymes or whole cells) to a solid
support. The solid support can be an organic or inorganic material, such as derivatized cellulose or
glass, ceramics, metallic oxides, and a membrane.
 Immobilization of an enzyme confines or localizes it.
 Multiple or repetitive use of a single batch of enzymes.
 The ability to stop the reaction rapidly by removing the enzyme from the reaction solution (or vice
versa).
 Enzymes are usually stabilized by immobilization.
 Product is not contaminated with the enzyme especially useful in the food and pharmaceutical
industries.
Immobilized enzymes/cells in organic reaction

41. Method of immobilization

42.  Most commonly used carriers for enzyme immobilization are polysaccharide derivatives such as
cellulose, dextran, agarose, and polyacrylamide gel.
 The carrier-binding method can be further sub-classified into: – Physical adsorption, Ionic binding,
Covalent binding.
 Carriers used for physical adsorption: Activated carbon, silica gel, alumina, starch, clay,
glass, modified cellulose etc.
 Carriers for ionic binding : CM-cellulose, aberlite, Dowex-50, polyaminopolystyrene.
 Carriers for covalent attachment :
1. Natural supports--- Agarose, dextran, cellulose.
2. Synthetic supports---Polyacrylamide derivatives.
Carrier Binding

43.  Immobilization of enzymes has been achieved by intermolecular cross-linking of the protein, either to
other protein molecules or to functional groups on an insoluble support matrix.
 Cross-linking an enzyme to itself is both expensive and insufficient, as some of the protein material
will inevitably be acting mainly as a support.
 Cross-linking is best used in conjunction with one of the other methods. The most common reagent
used for cross-linking is glutaraldehyde.
Cross-linking of enzymes

44.  The entrapment method of immobilization is based on the localization of an enzyme within the lattice of a
polymer matrix or membrane. It is done in order to retain protein while allowing penetration of substrate.
 It can be classified into lattice and micro capsule types.
 Lattice-Type entrapment: It involves entrapping enzymes within the interstitial spaces of a cross-linked
water-insoluble polymer. Some synthetic polymers such as polyarylamide, polyvinyl alcohol and natural polymer
(starch) have been used to immobilize enzymes using this technique.
 Microcapsule-Type entrapping: It involves enclosing the enzymes within semi permeable polymer
membranes. The preparation of enzyme micro capsules requires extremely well-controlled conditions.
entrapment

45.  Phase transfer catalysis (PTC) refers to reaction between two substances, located in different immiscible phases, in
the presence of catalyst.
 Phase transfer catalysis is mainly used for synthesis of organics such as pharmaceuticals, dyes, chemicals etc.
 In this process one phase acts as a reservoir of reacting anions. The second phase, which is the organic phase,
contains the organic reactants and catalysts generating lipophilic cations. The reacting anions enter the organic
phase in ion pairs with lipophilic cations of the catalyst. Since the phases are mutually immiscible the reaction
does not proceed unless the catalyst, usually a tetra alkyl ammonium salt, Q+X– is present.
 The catalyst transfers reacting anions into the organic phase in form of lipophilic ion-pairs produced according to
the ion-exchange equilibrium 1(a). In the organic phase the anions react such as in nucleophilic substitution as
shown in 1(b) where alkyl halides undergo nucleophilic substitution. A variety of other reactions with participation
of inorganic anions such as addition, reduction, oxidation, etc. can take place efficiently using this methodology.
Phase transfer catalysis

46. n
Classification of PTC

47.  In LLPTC, the nucleophile ( M + Y - ) is dissolved in an aqueous phase, whereas in SLPTC it is a solid suspended
in the organic phase.
 Traditionally, more applications of PTC have been reported in liquid-liquid systems, although there is a distinct
advantage in operating in the solid-liquid mode in some reactions since the elimination of the aqueous phase
lowers the degree of hydration of the ion pair, leading to an increase in its reactivity. Thus, higher selectivities and
yields are sometimes obtained by operating in the solid-liquid mode as compared to operation in the liquid-liquid
(aqueous-organic) mode.
 For example, reaction of phenyl acetylene with benzyl bromide in the presence of CO and NaOH with TDA-1
as PT catalyst and a cobalt carbonyl complex as co-catalyst gives phenyl acetic acid when operated as a liquid-
liquid system due to rapid hydrolysis of the acyl cobalt carbonyl intermediate, whereas using solid NaOH gives
the corresponding lactone.
Fundamental of ptc

48.  GLPTC involves the use of PTC in gas-liquid-solid systems, where the organic substrate is in a gaseous form and
is passed over a bed consisting of the inorganic reagent or some other solid reagent/co-catalyst (commonly, solid
K2CO3) in solid form or an inert inorganic support both of which are coated with a PT catalyst in its molten state.
Although, strictly, this is a gas-liquid-solid tri-phase system, it has traditionally been referred to as GLPTC.
 Advantages of GLPTC include ease of adaptation to continuous flow operation (with the gaseous reagents flowing
continuously over the solid bed), absence of organic solvent since the organic substrate is present in gaseous form,
ease of recovery of the PT catalyst as it is directly loaded onto the solid bed, and better selectivity than LLPTC in
some cases.
 A wide variety of reactions can be carried out under GLPTC conditions including a special class of reactions using
dialkyl carbonates, typically dimethyl carbonate (DMC). In methylene activated compounds, DMC acts first as a
carboxymethyl agent that allows protection of methylene active derivatives and permits nucleophilic displacement
to occur with another molecule of DMC. This method of synthesis has been piloted for the synthesis of anti-
inflammatory drugs like Ketoprofen in Belgium.
 GLPTC include halogen exchange, esterifications, etherifications, isomerizations, alkylations, transhalogenations,
Wittig and Horner reactions, and the synthesis of primary alkyl halides from primary alcohols.

49. Catalyst used in PTC

50. Ptc with other techniques
Techniques Example Reference
Ultrasound Michael addition of involving the addition of chalcone to
diethyl malonate in SLPTC mode.
Ratoarinoro et al. (1992)
Contamine et al. (1994)
Microwaves Ethoxylation of o, p-nitrochloro benzene. Yuan et al. (1992)
Microphases Synthesis of benzyl sulfide by reaction of solid sodium
sulfide with benzyl chloride.
Hagenson et al. (1994)
Electro-organic
synthesis
Anthracene oxidation to anthraquinone using Mn+3/Mn+2 as
the redox mediator.
Chou et al. (1992)
Photochemistry Reduction of nitrobenzenes to the corresponding oximes or
quinones using viologens.
Tomioka et al. (1986)
Metal co-catalyst Selective hydrogenation of a, b-unsaturated carbonyl
compounds using rhodium trichloride and Aliquat 336.
Azran et al. (1986)

51. Application Reaction
Chiral synthesis using cinchinidium derived optically active PT catalyst
 Synthesis of INDACRINONE, a diuretic drug
candidate.
C-alkylation of indanone derivatives and oxindoles
using cinchona alkaloids.
 Synthesis of chiral a-amino acids. Alkylation of imines, glycine derivatives, and Schiff
base derivatives.
Polymerization reactions
 Condensation reactions Synthesis of polycarbonates, polyester, polysulfonates
and polyethers.
 Anionic polymerization Diene polymerization in the presence of crown ethers.
 Chemical modification of polymers Modification of chloromethyl substituted polystyrene
and poly vinyl halide
Application of PTC

52. Agrochemicals
 Synthesis of an antidote for herbicides N-alkylation of hexamethylenetetramine with
chloromethyl ketones.
 Synthesis of herbicides and insecticides Selective o-alkylation and o-phosphorylation of ambient
pyridinates.
 Synthesis of naturally occurring
PELLITORINE, possessing insecticidal activity.
PTC vinylation of (E)-1-iodo-1-heptane with vinyl
acetate.
 Synthesis of an intermediate for the preparation of
insecticidal pyrethroids
PTC Wittig reaction of trans-caronaldehyde ethyl ester
with 50% NaOH & an in-situ generated PT catalyst.
Perfumery and Fragrance Industry
 Enhancement and augmentation of aroma of
perfumes
Alkylation of acetophenone moiety with ally chloride.
 Synthesis of phenyl acetic acid, an intermediate in
the perfumery industry
Carbonylation of benzyl chloride in the presence of a
palladium based catalyst.

53. Compounds with Biological Activity
 One-pot synthesis of carboxamides and peptides Reaction of a free acid or a carboxylic ester with an
amine with KOH/K2CO3 and a phenyl phosphonate
coupling agent.
 Synthesis of intermediates in nucleic acid
chemistry
Regioselective synthesis of p-toluenesulfonyl
derivatives of carbohydrates and nucleosides.
 Synthesis of aminopyrroles, intermediates in
synthesis of biologically active compounds like
pyrrolyltriazines
N-alkylation of N-unsubstituted 3-aminopyrrole with
TDA-1 as PT catalyst.
Other specialty chemicals
 Synthesis of allytribromophenol, a flame retardant
polymer
Etherification of hindered tri-bromophenol with ally
bromide.
 Synthesis of spiro derivatives of
tetrahydrothiophene, a characteristic fragment of
many alkaloids
Spiro-linking of tetrahydrothiophene ring to a
substituted quinolizidine skeleton.
 Synthesis of b-lactums Reaction of amino acids and methane sulfonyl
chloride.

54. Pharmaceuticals
 Synthesis of various drugs like dicyclomine,
ohenoperidine, oxaladine, ritaline etc.
Alkylation of phenylacetonitrile using NaOH, instead of
expensive sodium ethoxide.
 Synthesis of (R)-fluorenyloxyacetic acid, useful
in the treatment of brain edema.
Use of nonionic surfactant, Triton X with a cinchinidium
based PT catalyst to accelerate the alkylation step.
 Synthesis of commercial antibiotic,
chloramphenicol
Aldol condensation in the presence of NaOH and a PT
catalyst
 Synthesis of clomipramine and imipramine, an
antidepressant
N-alkylation of carbazones, phenothiazines, acridanone
and indoles using alkyl halides and aq. NaOH/solid
K2CO3.
 Synthesis of lysergic acid based pharmaceuticals
and other molecules with the indole skeleton
Facile and selective monoalkylation of the indole
nitrogen using PTC, instead of using K-azide in liquid
ammonia at -40OC.
 Synthesis of calcitriol derivatives o-alkylation using t-butylbromoacetate.
 Synthesis of penicillin based compounds Selective esterification of benzylpenicillin using a-
chloroethyl carbonate.

55. 1) “Green Chemistry and Catalysis”, Roger A. Sheldon, Isabel Arends, Ulf Hanefold, WILEY-VCH Verlag GmbH &
Co. KGaA, Weinhein, Germany; Pg. no. 106, 223-244, 250, 304, 310, 314.
2) “Multistep Continuous-flow Synthesis of (R)- and (S)-Rolipram using Heterogeneous Catalyst”, Tetsu Tsubogo,
Hidekazu Oyamada & Shu Kobayashin. (DOI: 10.1038/nature14343)
3) https://nptel.ac.in/courses/103103026/44
4) “General and efficient Copper-Catalyzed Three-Component Coupling Reaction towards Imidazoheterocycles:
One-Pot synthesis of Alpidem & Zolpidem”, Natalia Chernyak and Vladimir Gevorgyan; Angewandte Chemie.
(DOI: 10.1002/anie.200907291)
5) “Phase Transfer Catalysis: Chemistry & Engineering”, Sanjeev D. Naik and L.K. Doraiswamy, AIChE Journal
March 1998 Vol. 44, No. 3; Page No. 612-639.
References

56. Thank you