This document provides an overview of homogeneous catalysis and biocatalysis. It discusses various homogeneous catalysts including Wilkinson's catalyst, Ziegler-Natta catalysts, and catalysts used in hydrogenation and hydroformylation reactions. It also discusses the use of enzymes in organic synthesis, including hydrolysis reactions and the synthesis of tartaric acids. Finally, it covers immobilized enzymes and various methods for enzyme immobilization.

1. HOMOGENEOUS CATALYSIS &
BIOCATALYSIS
Under The Guidance Of :
Dr.K.MADHAVI,.
M.Pharm., Ph.D...
Presented By :
KAVYA.KAPARTHI,
2018MPH40B33,
1st year, M . pharm,
Pharmaceutical chemistry.

2. CONTENTS:-
 INTRODUCTION
 HYDROGENATION
 HYDROFORMYLATION
 ZIEGLER-NATTA CATALYST
 WILKINSON’S CATALYST
 EXAMPLES OF HOMOGENEOUS CATALYSIS USED IN
SYNTHESIS OF DRUGS
 BIOCATALYSIS
 USE OF ENZYMES IN ORGANIC SYNTHESIS
 IMMOBILIZED ENZYMES
 CONCLUSION
 REFERENCE

3. HOMOGENEOUS CATALYSIS
INTRODUCTION:
 When the reactants and the catalyst are in the same phase (i.e. liquid or gas), the
process is said to be Homogeneous catalysis.
 E.g: Hydrolysis of sugar is catalyzed by H+ ions furnished by sulphuric acid
 It mostly soluble organometallic complexes are used as catalysts.
C12H22O11(aq) + OH2 C6H12O6(aq) + C6H12O6(aq)
Glucose FructoseSolution
H2SO4
Sucrose

4. Advantages :
 Good contact with reactants.
Disadvantages :
 Catalysis needs to be separated after reaction.
 Catalyst recovery may be difficult because the temperature for the
distillation can destroy the catalyst.

5. HYDROGENATION
Definition:
 The addition of hydrogen to unsaturated compound in the presence of catalyst.
 Hydrogenation reaction is basically a reduction reaction.
 In homogeneous hydrogenation commonly used catalyst are rhodium and
ruthenium complexes viz., chloro tris (tri phenyl phosphine) rhodium (I),
[(C6H5)3P]3RhCl and Hydrido chloro tris(tri phenyl phosphine) ruthenium,
[(C6H5)3P]3RuClH .
 The rhodium complex is obtained by the reaction of rhodium chloride with
excess of triphenylphospine in boiling ethanol .
 This rhodium compound catalyses the hydrogenation of the terminal double
bond leaving the internal double bond .
RhCl 33H2O + (C6H5)3P
C2H5OH
Reflux
[(C6H5)3P]3RhCl
Rhodium chloride
Tri phenyl
phosphine

6.  It follows four steps they are
 Hydrogen addition
 Alkene addition
 Migratory insertion
 Reductive elimination of
the alkane, regeneration
of the catalyst.
Mechanism :-

7. Applications:
 Homogeneous catalysts are useful for selective hydrogenation of the
carbon- carbon double bond without hydrogenolysis of other
susceptible groups.
 E.g: Benzyl cinnamate is converted into the dihydro compound
without hydrogenolysis of the benzyl group .
 Allyl phenyl sulfide on reaction gives 93% phenyl propyl sulfide.
C6H5CH=CHCOOC6H5
C6H5CH2CH2COOC6H5
H2 ,[(C6H5)P]3RhCl
C6H6
Benzyl cinnamate
CH2=CHCH2SC6H5
CH3CH2CH2SC6H5
H2 ,[(C6H5)P]3RhCl
C6H6
Allyl phenyl sulfide

8. HYDROFORMYLATION
Introduction:
 The reaction of an alkene with carbon monoxide & hydrogen catalyzed by cobalt
or rhodium salts to form an aldehyde is called hydroformylation.
 Hydroformylation was discovered by Otto Rolene in 1938.
 Hydroformylation is also used for the manufacture of long chain fatty alcohols.
 The linear alcohols are used in detergents & are more biodegradable than the
branched ones.
CH2
R
+ CO + H2 H
R
O
+
H
CH3
R
O
Rh or Co
CH3
R
CH3
R
Alkene isomerization Alkene hydrogenation
Linear (normal)
Branched (iso)
Side reactions

9.  Three commercial homogeneous catalytic processes for the
hydroformylation reaction deserve a comparative study.
 In the old process a cobalt salt was used.
 In the modified current version , a cobalt salt plus a tertiary phosphine are
used as the catalyst precursors.
 The third process uses a rhodium salt with a tertiary phosphine as the
catalyst precursor
process parameters cobalt cobalt+phossphine rhodium + phosphine
Temperature(0C) 140-180 160-200 90-110
pressure(atm) 200-300 50-100 20-10
Alkane formation low considerable low
main product aldehyde alcohol aldehyde
selectivity (%) to n-
butyraldehyde 75-80 85-90 92-95
isolation of catalyst
difficult; HCo(CO)4 is
volatile less difficult
less difficult ; water -soluble phosphine
a major advancement

10. Rhodium catalyzed hydroformylation:
 The high selectivity & mild conditions make the rhodium process
more attractive than the cobalt one for the manufacture of n-
butyraldehyde.
 In the process rhodium was recovered.
 It developing an elegant separation method based on water soluble
phosphines.

11. Mechanism:-

12.  It is important to note that hydroformylation with rhodium can also be effected in
the absence of phosphine.
 In such situation Co acts as the main ligand.
 Some complexes have the 18 electrons & while the rest are 16 electron ones.
 Second conversion of (5.3) to (5.4) &(5.5) to (5.6) are the insertion steps.
 The selectivity towards n-butyraldehyde is determined in the conversion of (5.3)
to (5.4).
 It is possible that a rhodium-isopropyl rather than rhodium-propyl complex is
formed.
 In such a situation on completion of the catalytic cycle isobutraldehyde will be the
product.
 The n-propyl & the i-propyl complexes of rhodium are formed and a mixture of n-
butyraldehyde & i-butyraldehyde is obtained.
 Third, the catalyst precursor (5.1) undergoes ligand dissociation to generate (5.2),
a coordinately unsaturated species.
 Finally, conversion of (5.6) to (5.7) is an oxidative addition reaction, while the
conversion of (5.7) to (5.2) occurs by reductive elimination.

13. Cobalt catalyzed hydroformylation:
 Cobalt catalysts operate at 1500C & 250 atm where as rhodium
catalysts operate at moderate temperature & 1 atm.
 Propylene coordination followed by olefin insertion into the metal
hydrogen bond in a markovnikov or anti markovnikov fashion gives
the branched or the linear metal alkyl complex.

14. Mechanism:-

15. ZIEGLER-NATTA CATALYSTS
Introduction :
 The German chemist “Karl Ziegler” (1898-1973) discovered in 1953 that
when TiCl4 & Al(C2H5)3 are combined together they produced an
extremely active heterogeneous catalyst for the polymerization of ethylene
at atmospheric pressure.
 “Giulio Natta”(1903-1979), an Italian chemist, extended the method to
other olefins like propylene & developed variations of the Ziegler catalyst
based on his findings on the mechanism of the polymerization reaction.
 The Ziegler- Natta catalyst family includes halides of titanium chromium,
vanadium & zirconium, typically activated by alkyl aluminium compounds.
 Ziegler-Natta received the Nobel prize in chemistry for their work in 1963.

16. Ziegler-Natta catalysis for the polymerization of olefins:
 Polymers are large molecules with molecular weights in the range of 104 to
106.
 These consist of small building units known as monomers.
 E.g.: polyethylene is made up of ethylene monomers.
 In all of these cases a single monomer is repeated several times in the polymer
chain. The number of repeating units determines the molecular weight of the
polymer.

17. There are typically three parts to most polymerizations:
Initiation
Propagation
Termination

18. Initiation:
 Generating the active catalyst from a less active catalyst precursor.
Propagation:
 The polymer chain growth portion of the reaction that occurs over &
over again.
LnM-Cl + AlR3
+MAO
+ZnR2
LnM-R + AlR2Cl
LnM-Cl + H- LnM-H + Cl

19. Termination:
 A reaction step that stops the polymer chain growth .
M
CH3
M-H + CH2 CH3
CH3 CH3M-H +
H2

20. Advantages:
 Relatively high specificity.
 Relative low reaction temperature.
 Generally far more selective for a single product.
 Far more easily studied from chemical & mechanistic aspects.
 Far more active.
Disadvantages:
 Far more difficult for achieving product / catalyst separations.

21. WILKINSON’S CATALYST
 Wilkinson’s catalyst is the common name for chloro tris (tri phenyl phosphine)
rhodium (I) [(C6H5)3P]3RhCl.
 It is a red brown colored solid that is soluble in hydrocarbon solvents such as
benzene, & more so in tetra hydro furan (or) chlorinated solvents such as
dichloromethane.
 The compound is widely used as a catalyst for hydrogenation of alkenes.
 Rhodium is able to form 6 coordinate complexes.
Rh
–
PPh3
Ph3P
Cl PPh3

22. Preparation:
 It is used in the selective hydrogenation of alkenes & alkynes
without affecting the functional groups like : C=O, CN, NO2 , aryl,
CO2R etc.,.
RhCl33H2O + 4PPh3 Rh
–
PPh3
Ph3P
Cl PPh3
+ OPPh3 2HCl 2H2O+ +
C2H5OH
Reflux
R
3
R
1
R
R
2
RhCl(PPh3)3
H2(atm)
Benzene -ethanol
RT
R
3
R
1
R
R
2

23. Mechanism:

24. Selective hydrogenation by Wilkinson’s catalyst:
 Wilkinson’s catalyst can be used to achieve selective hydrogenation.
 Less substituted & sterically less hindered double bonds are
selectively hydrogenated.
 Exocyclic double bonds are selectively hydrogenated over
endocyclic double bond.
Desulfonation :
ArSO2Br ArBr
RhCl(PPh 3)
aromatic sulfonyl bromide Aryl bromide
CH2 CH3RhCl(PPh 3)
H2,benzene
CH3
CH2
CH3
CH3
CH3
CH3
RhCl(PPh 3)
H2,benzene

25. Examples of homogeneous catalysis used in
synthesis of drugs:
Synthesis of poly ( hydroxyl alkanoate)s:
 Synthesis of poly (alpha-methyl-beta-pentyl-beta-propiolactone)
(pmpp) from the corresponding lactone using a zinc complex.
O
OCH3
H3C(CH 2)4
CH3
CH3 O
CH3
O (H2C)4CH3
(ArON 2)ZnOEt
n

26. Synthesis of dihydro derivatives:
 Benzyl cinnamate gives the dihydro derivative in the presence of
rhodium complex.
Synthesis of poly(lactic acid):
 Poly (lactic acid) is a biodegradable aliphatic polyster synthesized
from lactide.
O
O
O
O
H
H
O
O
O
O
H
H CH3
CH3
O
O
O
CH3
O CH3
n
+
poly (lactic acid)
+
O
O
O
O
CH3
CH3
(s,s)-lactide
(R,R)-lactide (s,s)-lactide
(R,R)-(salbin)AlOMe
O
O
O
O
H2
,
RhCl(Pph3)

27. BIOCATALYSIS
 A catalyst is a substance which alters to promote the reaction & a substance especially an
enzyme, that initiates or modifies the rate of chemical reaction in a living body is termed
as biocatalyst.
 They are enzymes or microbes that initiate or accelerate chemical reactions.
Types of biocatalyst:
 Biocatalyst are different types they are:
Oxidoreductases
Transferases
Hydrolases
Lyases
Isomerases
Ligases
Kinase

28. Use of enzymes in organic synthesis
 Enzymes have great potential as catalyst for use in synthetic organic
chemistry.
 The applications of enzymes in synthesis have been limited to relatively
small number of large number of large scale hydrolytic processes used in
industry & to a large number of small scale synthesis of products used in
research.
Hydrolysis of N-acyl amino acids:
 The hydrolytic enzymes “amidases” are useful for the hydrolysis of N-
acyl amino acids for the synthesis of aminoacids & in the formation of
amide bonds in polypeptides & proteins.
 This method is the resolution of aminoacids.
NHCH3 COO
-
O R
NHCH3 CO2
O R
+ CO2NH2
R

29.  D-,L- & mesotartaric acids have been synthesized by using
epoxidehydrolases .
COO
COO
O
COO
-
COO
-
COO
-
OH
O
-
OC
OH
COO
-
OH
O
-
OC
OH
H2O2
Na2WO4
E1
E2
D-Tartarate
L-Tartarate
COO
COO
O
COO
-
COO
-
COO
-
OH
O
-
OC
OH
H2O2
Na2WO4
E3
Meso Tartarate
E1=D-Tartarate epoxidase
E2=L-Tartarate epoxidase
E3=Epoxide hydrolysate
from rabbit liver
microsomes.

30. IMMOBILIZED ENZYMES
 Enzyme immobilization may be defined as a process of confining the enzyme molecules to a solid
support over which a substrate is passed & converted to products.
 An immobilized enzyme is one whose movement in space has been restricted either completely or
to a small limited region.
 An immobilized enzyme is an enzyme that is attached to an inert, insoluble material such as
calcium alginate ( produced by reacting a mixture of sodium alginate solution & enzyme solution
with calcium chloride).
 This can provide increased resistance to changes in conditions such as PH , temperature & several
environmental factors.
 It also allows enzymes to be held in place throughout the reaction, following which they are easily
separated from the products & may be used again a far more efficient process & so is widely used
in industry for enzyme catalyzed reactions.
 An alternative to enzyme immobilization is whole cell immobilization

31. Salient features of enzyme immobilization:-
 Enzymes are more or less physically confined in the course of a definite
continuous catalytic process. They may be suitably recovered from the reaction
mixture & used over & over again there by gainfully improving the economic
viability of the entire process.
 It may be accomplished by fixing the enzyme molecules to or with in certain
appropriate substance.
 It should be absolutely critical that both the substrate & the products migrate
quite freely in & out of the phase to which the specific molecules are actually
confined.
 Certain enzymes which are thermolabile in nature could be made heat stable by
attachment into inert polymeric supports.
 Immobilized enzymes may be recycled, rapidally controlled, operated
continuously, products easily separable, above all the enzyme (i.e., stability PH)
are altered favourably.

32. Methods of immobilization:-
 Carrier binding
physical adsorption
Covalent bonding
Ionic bonding
Cross linking
Entrapment
Occlusion within a cross linked gel
microencapsulation

33. 1.Carrier binding:-
Physical adsorption :
 This method is based on the physical adsorption of enzyme on the surface
of water-insoluble carriers.
 E.g.: suitable adsorbents are ion-exchange matrices, porous carbon, clay,
hydrous metal oxides, glasses & polymeric aromatic resins.
 The bond between the enzyme & carrier molecule may be ionic, covalent,
hydrogen, coordinated covalent or even combination of any of these
immobilization can be brought about by coupling an enzyme either to
external or internal surface of the carrier.

34. Advantages of adsorption:-
 Little or no confirmation change of the enzyme.
 Simple & cheap
 No reagents are required
 Wide applicability & capable of high enzyme loading.
Disadvantages of adsorption:
 Desorption resulting from changes in temperature, PH, & ionic
strength.
 Slow method.

35. Covalent bonding:-
 Covalent bonding is the most widely used method for immobilizing enzymes. The
covalent bond between enzyme & a support matrix forms a stable complex.
 The functional group present on enzyme, through which a covalent bond with
support could be established, should be non essential for enzymatic activity.
 The most common technique is to activate a cellulose based support with cyanogen
bromide, which is then mixed with the enzyme.
Advantages:-
 Strength of binding is very strong, little or no leakage from the support.
 This is a simple, mild & often successful method of wide applicability.
Disadvantages;-
 Enzymes are chemically modified & can denaturated during immobilization.
 Small amounts of enzymes may be immobilized.

36. Cross linking:-
 This method is based on the formation of covalent bonds between the
enzyme molecules, by means of multifunctional reagents, leading to 3
dimensional cross linked aggregates.
 The most common reagent used for cross linking is glutaraldehyde.
Advantages of cross linking :-
 Very little desorption (enzyme strongly bound).
 Best used in conjugation with other methods.
Disadvantages of cross linking:-
 May cause significant changes in the active site.

37. Entrapment
 In entrapment, the enzymes or cells are not directly attached to the support surface, but
simply trapped inside the polymer matrix.
 Entrapment is carried out by mixing the biocatalyst into a monomer solution, followed by
polymerization initiated by a change in temperature or by a chemical reaction.
 Polymers like polyacrylamide, collagen, cellulose acetate, calcium alginate or carrageenan
etc., are used as the matrices.
Advantages:-
 Loss of enzyme activity upon immobilization is minimized.
Disadvantage :-
 The enzyme can leak into the surrounding medium.
 Another problem is the mass transfer resistance to substrates & products.
 Substrate cannot diffuse deep into the gel matrix.

38. Comparision between Enzyme Immobilization
method:-
Characteristic Adsorption
Covalent
binding
Entrapme
nt
Membrane
confinement
Preparation Simple Difficult Difficult Simple
Cost Low High Moderate High
Binding force Variable Strong Weak Strong
Enzyme leakage Yes No Yes No
Applicability Wide Selective Wide Very wide
Running problems High Low High High
Matrix effects Yes Yes Yes No
Large diffusional
barriers No No Yes Yes
microbial protection No No Yes Yes

39. Advantages of immobilization:-
 Multiple or repetitive use of a single batch of enzymes.
 Immobilized enzymes are usually more stable.
 Ability to stop the reaction rapidly by removing the enzyme from the reaction
solution.
 Product is not contaminated with the enzyme.
 Easy separation of the enzyme from the product.
 Allows development of a multienzyme reaction system.
 Reduces effluent disposal problems.
 Increased functional efficiency of the enzyme.
 Minimum reaction time & cost effective.
 Less labour input in the process.

40. Disadvantages:-
 It gives rise to an additional bearing on cost for isolation, purification and
recovery of active enzyme.
 It invariably affects the stability & catalytic activity of enzymes.
 The technique may not prove to be of any advantage one of the substrate is
found to be insoluble.
 Certain immobilization protocols offer serious problems with respect to the
diffusion of the substrate to have an access to the enzyme.
 Industrial applications are limited as very few companies are using
immobilized enzymes or whole cells.
 Enzymes are inactivated by the heat generated in the system.
 Some enzymes became unstable after immobilization.

41. Applications of immobilization:
 Industrial production:- Industrial production of antibiotics, beverages,
aminoacids etc., uses immobilized enzymes.
 Food industry:- Enzymes like pectinases & celluloses immobilized on suitable
carriers are successfully used in the production of jams, jelly's & syrups from fruits
& vegetables.
 Research :- The use of immobilized enzyme allow researcher to increase the
efficiency of different enzymes such as different proteases for cell & organelle
lysis.
 Biodiesel production from vegetable oils.
 Textile industry :- Scouring, biopolishing & desizing of fabrics.
 Waste water management

42. Uses of immobilized enzymes:-
Biotransformation
Secondary metabolite production
Biosensors
ELISA
Food industry, etc.,.

43. CONCLUSION

44. Reference:-
 Organic reaction mechanisms, fourth edition, by V.K.Ahluwalia, Rakesh kumar
parashar.
 Tkatchenko, in Comprehensive Organometallic Chemistry, ed. by G. Wilkinson,
F. G. A. Stone, and E. W. Abel, Pergamon Press, Vol. 8, 1982, pp. 101–223.
 HOMOGENEOUS CATALYSIS Mechanisms and Industrial Applications , ed. By
Sumit Bhaduri, Double Mukesh, page:85-99.
 Homogeneous Catalysis with Metal Complexes Fundamentals and Applications, ed.
By Gheorghe Duca, Series Editors .
 Homogeneous Catalysts Activity – Stability – Deactivation ,ed,by Prof. Dr. Piet W.N.M.
van Leeuwen, Dr. John C. Chadwick .
 Principles of organic synthesis, Third edition, by Sir Richard Norman, James M.Coxon.
 BIBLIOGRAPHY:Outlines of Biochemistry- Eric Conn.
 Immobilization of Enzymes: A Literature Survey: Beatriz Brena , Paula González-
Pombo , and Francisco Batista-Viera.


45.  http://www.easybiologyclass.com/enzyme-cell-immobilizationtechniques/
 http://www.scribd.com/doc/31429014/Immobilized-Enzymes