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INTRODUCTION
The concept of “catalysis” is acclaimed as a method of controlling the rate
and direction of a chemical reaction since it is introduced by Berzelius1 in 1835. It
coordinated a number of disparate observations on chemical transformations by
attributing them to a “catalytic force” and coined the term catalysis to refer to the
‘decomposition of bodies3 by this force. Now-a-days, “catalysts” are considered to
be indispensable components for the majority of chemical reactions. As enzymes,
they regulate an array of transformations within natural organisms from single
cells to man. Researchers employed catalysts as supports for our daily lives
starting with manufacture of fuels2, clothing3, plastic goods4, fertilizers5 and
medicines6. Hence, “catalysis” is well described as the cornerstone of all chemical
processes. Around 80% of all chemicals rely on catalysts of one kind or other
during their synthesis.
In general, catalysts are conveniently divided into two groups,
homogeneous and heterogeneous, according to whether or not the reactant and
products share the same phase as the catalyst. Homogeneous catalysis provides
mild and selective routes for the synthesis of valuable chemicals from simple
organic precursors. But the catalysts are more sensitive to air and moisture. In
addition, the catalysts are difficult to separate from the products. These problems
are avoided by employing heterogeneous catalysts, and hence these catalysts have
acquired more fascination among catalyst researchers. Although, numerous
catalysts are available to accelerate various reactions, chemists find inconvenience
to carry out immiscible substrate reaction. For example, the reaction between
1-chlorooctane with sodium cyanide7 could not proceed even after a long reaction
time owing to the existence of two different immiscible aqueous/organic phases.
Normally for any type of organic reaction, it is a necessary condition to
cause the perfect collision between the two reactants to get the desired product.
The immiscible substrate reaction8 are normally very slow (due to some practical
difficulties). This is particularly due to the sparingly soluble substrate in the
biphase media. There are variety of techniques available to circumvent this
problem via., increasing the agitation rate,9'11 using cosolvents12, such as alcohol
or methanol etc. Increasing the agitation rates in any chemical reaction involves
loss of mechanicl/electrical energies. Similarly using cosolvents also decrease the
rate of the reaction due to the hydrogen bonded with the substrates or catalyst. As
a remedial measure, researchers have used aprotic solvents, such as
dimethylsulfoxide, dimethyl formamide, hexamethylphosphoramide and
acetonitrile, to carry those immiscible substrate reactions. It is observed that the
use of cosolvents13 proceed the reaction without forming hydrogen bond and
ultimately increased the rate of the reaction. Unfortunately, this polar aprotic
solvent technique also has some disadvantages partially in industrial process; the
solvents are expensive and difficult to remove by-products, are often accompanied
by the generation of a desired product, requirement of high temperature,
anhydrous solvent and are definitely an environmental hazard in large scale
operations. In view of all these demerits, researchers/industrialist are not
interested to use aprotic solvents also.14"16
LI. PHASE TRANSFER CATALYSIS
Phase transfer catalysis came in to limelight in the mid-1960s17 and caught
attention of many researchers for carrying out a wide class of otherwise slow
heterogeneous reactions. Reactions of two substances located in different phases
are often inhibited because of the inability of the reactants to come together. For
example, the reaction between 1-chlorooctane with sodium cyanide could not
proceed even after allowing quite long time, hence for the first time Jerrouse used
phase transfer technique;18 these immiscible reactions are brought about by the
use of an agent which transfers one reactant across the interface into the other
phase so that the reaction can proceed. The phase transfer agent is, however, not
consumed during the course of the reaction but performs the transport duty
repeatedly. The component that is responsible for transfer of reactant from
aqueous to organic is called “Phase-transfer catalyst” and the whole process is
said to be “Phase-transfer catalysis” (PTC).
In performing a phase-transfer reaction; the choice of a suitable catalyst
plays a pivotal role. For any phase transfer catalyzed technique, the three factors
are paramount importance; the ability of the catalyst to transfer one reagent from
its phase into the phase of the second reagent; the reagent once transferred must be
available in a highly reactive form and the recycling ability of the catalyst.
1.1.1. EXAMPLES OF PHASE TRANSFER CATALYSTS
Based on the structure of the molecule, the phase transfer catalysts are
broadly classified as follows
1. Quaternary ammonium, phosphonium and arsonium ions.19'34
3
Where R is usually alkyl or benzyl and X refers to the different anions
in the catalyst.
35 36” * 372. Macrocyclic (Crown) ’ ’ and macrobicyclic ( Cryptate) ethers.
3. Open chain polyether38 and single chain poly ethers.3 9
4. N-alkylphosphoramides.40
5. Methylene bridged phosphorous and sulfur oxides.41
Phase transfer catalysts are generally active depending upon the central
onium atoms. Quaternary onium salts are stable up to 150 C in the absence of
alkali and less stable around 70-80°C in the presence of alkali. Now variety of
quaternary onium salts can be synthesized and are available commercially for
various immiscible substrate reactions. Lower quaternary onium salts are easily
recovered than with some higher salts due to its tendency to form stable emulsion.
Phosphonium salts are thermally more stable than ammonium salts up to 150-
170°C; where as ammonium salts loose their activity rather rapidly at temperature
greater than about 110 -120°C.
1.2. GENERAL MECHANISM FOR THE PHASE TRANSFER
CATALYZED REACTION
Liquid-Liquid PTC corresponds to a system made of two phases: an
organic phase containing a liquid reagent with (or without) an organic solvent
non-miscible in water and an aqueous phase containing in most cases a
nucleophilic reagent M+Y‘. Moreover a quaternary ammonium or phosphonium
catalyst is partitioned between the two phases.
4
5
1.2.1. CLASSIFICATION OF PHASE TRASFER CATALYSIS
Phase transfer catalysis can be classified into three different categories
based on the physical states of the two phases. They are liquid/liquid, liquid/solid,
and gas/solid PTC techniques.
1.2.1.1. Liquid-Liquid Phase transfer catalysis
Liquid-Liquid PTC (LL-PTC) composed of two phases; an organic phase
containing a liquid reagent (RX) immiscible with water and an aqueous phase
containing a nucleophilic reagent(Nu’) and the quaternary onium catalyst (Q+X").
Starks8,16 and Malcosaza42'44 reported two different mechanism with best
illustration viz., extraction and interfacial mechanism. When sodium cyanide was
mixed with octylchloride, no product was observed even after prolonged time,
eventhough the former one is soluble in water. But on the introduction of catalytic
amount of quaternary ammonium chloride, an exchange occurs in the aqueous
phase between Na+CN’ and B114N+C1-. The ion pair, BimN'CI", due to presence of
16 carbons of the quaternary ammonium ion, phase transfers into organic where
the reaction take place. According to the interfacial mechanism, a molecule of an
organic substrate say phenylacetonitrile(RH) in the organic phase located near the
interface is deprotonated by the hydroxide ion which is also available near the
interface but within the aqueous phase (step 1). An ion pair [Na+R‘] is thus formed
at the boundary and as such is insoluble in both the phases. The anchored [Na+R-]
remains at the interface until the catalyst cation draws the organic anion deep into
the bulk organic phase in the form of new ion pair [QR~|. The quaternary counter
ion X- is simultaneously liberated into the aqueous phase (step 2). Finally, [Q+R-]
reacts with alkyl halide substrate R Y to produce the product R-R (step 3) and the
[Q+Y-] thus formed may reenter a next catalytic cycle. The interfacial mechanism
is shown below;
6
If a complexant is added, the solid M+Y- is solubilized in the solvent and
reacts under mild conditions. In a specific example, potassium permanganate is
added to a solution of benzene containing an olefin. Under these conditions the
crystals of KMn04 stand at the bottom of the flask, the solvent is colourless and
no reaction occurs. If a small amount of 18 crown 6 is added, the solvent
immediately turns purple (the permanganate dissolves) and the olefin is smoothly
oxidized. The complexants first used were the crown ethers, prepared by
Pedersen35, which showed high complexing abilities of alkali and alkaline earth
cations with the following properties.
7
a. extraction of cations owing to the selective complexation, which
b. activation of the anion paired to the complexed cation; the anion is said
results in the separation of enantiomers and open new promises in asymmetric
induction.
Presently the majority of current syntheses are more likely to be carried
out with liquid-liquid transfer conditions, with quaternary ammonium and
phosphonium catalysts. Solid-liquid catalysis using complexants is still hampered
by the high price of catalysts like crown-ethers or cryptants. In some cases, when
water needs to be strictly avoided, reactions are conducted under solid-liquid
conditions, with a quaternary ammonium or phosphonium catalyst (not a
complexant). Moreover, in order to solve the problem of catalyst recovery a new
technique has been proposed.
1.2.1.3.Gas-liquid phase transfer catalysis
Another interesting variant of the two phase catalytic method with great
potential was reported and developed by Tund48'50 and co-workers. GL-PTC
provide a continuous-flow through the molten thermally stable PTCs such as
depends upon the size and the substitution of the macrocyclic ethers45.
to be “naked”46
The chiral host molecules designed by Cram et al47 have achieved splendid
phosphonium salt crown ether and polyethylene glycol supported on a solid
nucleophile without solvent. The GL-PTC technique is the analogy of gas-liquid
chromatography. This can be chemically linked with inorganic support. Number
of reactions had been carried out following GL-PTC technique, for instance, the
synthesis of ethers and thioethers51’52, interconversion of alkyl halides53’54,
esterification 55 and trans-esterification56 are very important reactions.
1.2.1.4. Gas-Solid Phase Transfer catalysis (GS-PTC)
Yet another classification of PTC technique is a report of Gas-Solid phase
transfer catalysis.57 It is indicated that by passing a gaseous alkyl halide over a
catalytic column composed of a salt, a solid support and a phase transfer catalyst,
a substitution product was obtained. The phase transfer catalyst was either free or
immobilised on a silica matrix and thus the synthesis of alkyl iodides and esters
were possible. 58
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1.3. ADVANTAGES OF PHASE TRANSFER CATALYSTS59
(i) Increase productivity
(a) Higher the chemical yield
(b) Reduced the cycle time
(c) Reduce or consolidate unit operations
(d) Increase reactor volume efficiency
(ii) Improve environmental performance
(a) Eliminate, reduce or replace solvent
(b) Reduce non-product output
(iii) Increase quality •
(a) Improve selectivity
(b) Reduce variability
(iv) Enhance safety
(a) Control exotherms
(b) Use less hazardous raw materials
(v) Reduce other manufacturing cost
(a) Eliminate workup unit operation
(b) Use alternate less expensive or easier to handle raw materials
1.4. TRIPHASE CATALYSIS
Although, the soluble phase-transfer catalysts are so efficient and much
familiar to carry out two-phase reactions particularly for synthesis of speciality
chemicals with higher quantum yield, their usage is limited due to various reasons.
The main challenge in designing liquid/liquid industrial PTC process has
been the separation of the catalyst from the product. The chemical equilibrium
separation of the process which are used in the purification of the product usually
consume energy to get a product of a highly purity. In order to overcome this
difficulty, Regen and his coworkers60'64 proposed a so called "triphase catalysis",
in which the catalyst is immobilized on a solid support (organic and inorganic
10
substances). From the industrial application point of view, this solid supported-
catalyst can be easily separated from the final products simply by mechanical
separation, such as centrifugation or filtration. In addition, either the plug flow
reactor (PFR) or the continuous stirred tank reactor (CSTR) can be used to carry
out the triphase catalytic reaction. Several reactions for hydrolysis and
displacement were investigated with success. In genera!, both the organic solid
polymer and inorganic solid silica65,66 and aluminium oxide67 can be used as the
support of the triphase catalyst. Plowever, the inorganic solid silica and aluminium
oxide fracture easily during the agitation. Solid polymers are commonly used as
the support of the triphase catalyst.
1.4.1. REACTION MECHANISM
As developed by Regen, the reaction of triphase catalysis is carried out in a
three-phase liquid (organic)-solid (catalyst)-liquid (aqueous) system. The reaction
process between two immiscible reactants by triphase catalysis in a porous solid
pellet may involve as follows (a) mass transfer of reactants from bulk solution to
the surface of the catalyst pellet; (b) diffusion of reactants to the interior of the
catalyst pellet through pores; (c) surface or intrinsic reaction, of reactants with the
active sites of the catalyst pellet; (d) diffusion of products outward to the exterior
of the catalyst pellet through pores, and; (e) mass transfer of product to the bulk
solution from the surface of the catalytic pellet.
Probably the first pre-mediated and successful use of a polymer-supported
phase transfer catalyst was that reported by Regen60'64 using polymer-bound
11
benzyltrialkyl ammonium salts, although the results of investigations by Brown,68
using similar species and Montanari, ' using supported phosphonium salts,
crown ethers and cryptands70 in addition, followed quickly afterwards. Regen has
suggested the term “Triphase catalysis,73’82 the cross linked polymer being
regarded as a distinct third phase. Although this description may not be
particularly accurate in the-light of emerging experimental results, it does provide
a useful qualitative picture and the expression is gaining continued popularly.
If a similar mechanism to the one proposed for unbound catalysts operates
in supported system, then it is necessary to imagine the phase boundary existing at
the catalytic sites as depicted below,
Organic phase
The process of transporting anions back and forth across the boundary can
then occur via local backbone and side chain motion of the catalyst support. This
model would predict the efficiency of the catalysis to be improved by increasing
the length and hence the flexibility of the linkage between the catalyst and the
polymeric backbone by introducing a ‘spacer arm’ and this seems to be so in
practice. Number of applications of polymer-supported PTC’s in organic reactions
have been reported.80'101 This technique has the advantage of homogeneous
catalysis owing to the selection of a catalyst having an appropriate molecular
structure and heterogeneous catalysis since the catalyst is easily filtered off and
recovered after the reaction. However, the rates were often less than most of
• S7 88analogous soluble phase transfer catalysis because of diffusional limitations.1 ’
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1.5. DIFFERENT TYPES OF MECHANISMS IN PHASE TRANSFER
CATALYSIS
Two major mechanisms have been proposed so far to explain the behavior
of most phase transfer catalyzed reactions initiated by the hydroxide ion,
(PTC/OH- systems) the Stark’s Extraction mechanism8 and the Makosza’s
interfacial mechanism.102
1.5.1. STARK’S EXTRACTION MECHANISM
This mechanism describes liquid-liquid PTC in which an ion-pair, formed
by extraction of anion Y' into the organic phase by the onium salt cation Q1,
undergoes a rapid displacement with RX. The new salt [Q+X‘] then returns to the
aqueous phase, where Q+ picks up a new Y‘ ion for the next cycle (Scheme 1).
1.5.2. INTERFACIAL MECHANISM
In the case of interfacial mechanism, the ‘quat’ frequently employed in
PTC/OH- reactions are tetrabutylammonium hydroxide and it does not exhibit a
measurable ability to extract the hydroxide ion. This would suggest that the
classical triethyl benzyl ammonium ion (TEBA) that is more hydrophilic would
extract the OH- to an even lesser extent. TEBA induces enhanced reactivity in
hundreds of PTC/OH- reactions, whereas nucleophilic substitutions proceed very
13
slowly. Since these nucleophilic substitutions have been characterized under
extraction mechanism, it was assumed that another mechanism must be involved
in PTC/OH" reactions. Maicosza102 thus proposed an alternative mechanism called
the “interfacial mechanism”.
Organic Phase
1.6. APPLICATIONS OF PHASE TRANSFER CATALYSIS
The applications of single-site phase transfer catalysts (SPTC) have been
well documented because of its high reaction rate, high selectivity, lower energy
requirements and moderate operating temperature. Owing to these positive
advantages, the soluble SPTC have been applied in several areas of chemistry viz.,
heterocyclic chemistry,103 macromolecular chemistry,104 industrial chemistry,105
dye chemistry105, and medicinal chemistry.106,107 The SPTC’s have been used
more specifically to the synthesis of various life saving dings or pharmaceutical
intermediates. It has also been used for general purpose reactions of varied
categories depending upon the strong base reactions such as alkylation (C-, N-,
0-, S-alkylation),108 chiral alkylations,109 oxidation,110 (permanganate,
hypochlorite/hypobromite, hydrogen peroxide, oxygen/air, persulfate, transition
metal co-catalysis (carbonylation, reduction and hydrogenation, coupling
reaction),110 condensation (Aldol,110 Michael,111 Witting,112,113 Darzens114),
elimination,108 addition,105 polymerization,105 dehydrohalogenation,105
nucleophilic aromatic substitution,108 nucleophilic aliphatic substitution108
reactions viz., esterification,108 various displacement reactions such as (cyanide,
halide, azide, sulfide, thiocyanate, sulfite, nitrite, hydroxide, carbonate, cyanate)108
and also for the preparation of organometalic compounds. The following
discussion describes some of the important/selective application of different
SPTC’s in various reactions exclusively in organic chemistry.
1.6.1. C-ALKYL ATIONS
C-alkylation is one of the most fundamental organic reactions for building
the carbon skeleton of organic compounds. The Carbon-hydrogen bond of typical
hydrocarbons does not easily lend itself to dissociation into a proton and a
carbanion. Either an extremely strong base is needed to deprotonate the C-H bond
of an inactivated hydrocarbon or the C-H bond must be activated by strong
electron withdrawing groups to stabilize the carbanion to be formed. It is known
that PTC technique is a simple and less expensive method for performing
alkylation reactions. Most of the alkylation studies reported in literature are
involved an organic phase in contact with 50% aq. NaOH solution and a
quaternary ammonium salt or a stoichiometric amount of a quaternary ammonium
ion-pair.115 Phenyl acetonitrile116 was the first compound reported to undergo
phase transfer C-alkylations in the presence of ethyl bromide, concentrated
aqueous sodium hydroxide/lmol-% TEBA, the reaction is mildly exothermic and
requires 3-5 hour at 28-35°C. Another interesting prospect arises when dihalides
are used to alkylate ketones. Apparently 4-membered ring formation is disfavored
to such an extent in the acenapthone case that 1,3-dibromopropane C-alkylates
and then O-alkylates after a second enolization.117 The product is the
tetracyclicenol ether as shown in the following scheme.
14
15
In general, alkyl bromides are better C-alkylating agents than chlorides
provided concentrated sodium hydroxide is used in considerable excess. Iodides
and to some extent bromides (with a lower excess of NaOH) have an adverse effect
on alkylation, because iodide is extracted into the organic phase is preference to the
phenyl acetonitrile anion. Recently, alkylations were carried out in the presence of
solid K2C03/dibenzo-18-crown-6 in benzene solution.123 The C-alkylation of P-
lceto esters is effected with 1-halopropane in the presence of N-Bu4Br and
NaOH.113
A convenient synthesis of a-mercapto alkanoic acids involves PTC
alkylation8 of dithiocarbamates and subsequent hydrolysis. Similarly, a-Substituted
phenyl acetaldehydes are C-alkylated in the presence of aqueous NaOH/NBu4I. It
has also been reported that free arylacetic acids can be a-alkyalted in a one-pot
solid/liquid (powdered KOH/CTI2CI2/TEBA)119 procedure as mentioned in the
following scheme.
Methyl 2-phenyl sulfmyl acetates can be converted into cinnamic esters by
a one-pot alkylation. The C-alkylation of chloromethane sulfonamides gives 55-
88% yield when a small amount of TIMPT is present in addition to
NBu4Br/50%NaOH.120 Aryl acetylenes was also synthesized from alkyl iodides in
16
the presence of powdered KOH/18-crown-6 in fair yields without catalyst
(NaOH/PTC) gave unpleasant mixtures of products on reaction with ethyl iodide or
benzyl and allyl halides respectively.m’123
The cyclopentadiene was alkylated with tert-butyl bromide, 5(3%NaOH and
Aliquat-336 as a PTC which gives 44% of yield.124’125
greatly improved by complexation of aiyl group with chromium tricarbonyl.
1.6.2. CARBENE REACTIONS
Phase transfer catalyst was little more than a curiosity in the late 1960's
when Makosza first published his two-phase method for the generation of
dichlorocarbene. Using a reservoir of 50% aqueous sodium hydroxide, a
cosolvent of chloroform with olefin, and a catalytic amount ol benzyltriethyl
ammonium chloride, Makosza was able to achieve high yields of
cyclopropanation products. Dichlorocyclopropanation had previously been a
difficult reaction to conduct and the ease and economy of the new method
attracted broad interest in the organic chemical community. Dichloiocarbene
could be generated in a two phase aqueous-organic system in which NaOH was
used as base and that first captured the attention of the organic chemical
121poisoning. In contrast, 1,3,3-triphenyl propane and phenyl acetylene
Des Abbayes et al. 131 reported the alkylation of aryl acetic esters and was
17
community. Apart from several methods reported in literature for generation of
dihalocarbenes,132-136 the phase transfer catalytic method in aqueous conditions
seemed more facile in view of its easy handling, cost effectiveness, high yields
and purity of products etc., Makosza133 reported the following
dichlorocycloproponation of cyclohexene.
They have also formulated the mechanism for the reaction leads to
formation of dichlorocyclopropanation product under phase transfer conditions.
Initially, reaction of CHCI3 with OH' gave the CCI3 ’ anion intermediate at the
aqueous-organic phase boundary, where it was transferred into the organic phase
by the quaternary cation and from where the dichlorcarbene is generated.
Dihalocarbenes are very useful compounds that can be reduced to
cyclopropane derivatives treated with sodium to give allenes and can be converted
to a number of other products. Literature reports of the generation and reaction of
dichlorocarbene [.CCI2] stress the importance of operating under strictly
anhydrous conditions because of the ready and rapid hydrolysis of
dichlorocarbene. Cinquini and Coworkers137 reported the reaction of styrene with
18
dichlorocarbene produced from the reaction of aqueous CHCI3 with NaOH in the
presence of phase transfer catalyst to yield l,l-dichloro-2-phenyl cyclopropane.
It should be noted that this reaction, sometimes called the Makosza
reaction was simultaneously discovered by Starks, and examples are reported in a
patent, which is contemporaneous with Makosza's paper.
In some cases, the dichlorocyclopropanation product is not isolated but
undergoes secondary reactions and rearrangement. For example, the
dichlorocarbene adducts of norbornene138 and 3-methylindole139 are examples. In
both cases, the intermediate adduct loses chloride by ionization and simultaneous
opening of the cyclopropane ring to an allylic carbonium ion leads to ring
expanded products as illustrated in eqns. (1) and (2).
In addition to dichlorocarbene, dibromo-,140-142 chlorofluoro-,143
bromofluoro-,144fluoroiodo-,145 chloroiodo-146 and diiodocarbenes146 have all been
generated under phase transfer catalytic conditions. Attempts to generate
difluorocarbene have been unsuccessful. Of these dihalocarbenes, only
dibromocarbene has been extensively studied. It has been found that good yields
of dibromocarbene from the relatively expensive bromoform can be obtained
when a small amount of alcohol (preferably n-butanol) is added to the reaction
mixture141 and the best catalyst for the reaction is not a quaternary salt, but
tributylamine.142
1.6.3. OTHER ORGANIC REACTIONS
There are several organic reactions reported in literature such as N-
allcylation,147 0-alkylation,14s S-alkylation,149 Aldol condensation,150 Witting
reactions,151 dehydrohalogenation,152 oxidation,153 reduction,154 etc., under PTC
conditions. All these products are more useful in pharmaceuticals, agricultural
chemicals and other purposes than the other products.
1.6.4. CONDENSATION REACTIONS
1.6.4.1. MICHAEL ADDITION
Michael reaction is important particularly for C-C bond formations, and
sterioselective variants have been extensively investigated in recent years.
Michael addition157 of diethylmalonate to esters of 2-(l-hydroxyalkyl) propionate
was studied and reported with a high stereoselectivity towards the syn-
diastereomer (4:1 to 20:1) using 18-Crown-6 as a catalyst and catalytic amount of
KF was used as the base in dimethyl sulfoxide or acetonitrile as solvent. Similarly,
multiple Michael addition was achieved155 to form mostly tetra-, penta- and hexa
ester’s and they were focused as potential lubricants. Two types of C-H bonds
were deprotonated. Methylene (pKa~9) was first deprotonated and added to the
double bond of methyl acrylate. The resulting methylene groups, alpha to the ester
(pKa~19-20) were then deprotonated and added to other methylacrylate
19
20
molecules. Michael addition of a deactivated methylene (sulfonic acid alpha to
ester) to acrylate esters was performed and selectively yielded mono-addition
products in 56-95% yield.157
methyl acrylate under PTC/high concentration of aqueous base (50%) condition.
1.6.4.2. Barzen’s condenzation
Makosza et al.116 first reported Darzens reactions in presence of PTC.
Chloroacetonitrile was allowed to react with the cyclohexanone in the presence of
NaOH (50%) and triethylbenzyl ammonium, chloride for about 30 min. at
15-20 °C and the product viz., glycidic nitrile was obtained «79%.
Reierson et al.158 reported the Michael addition of cyclopentadiene with
Toke et al.159 also reported chiral phase transfer catalysts in the Michael
addition of 2-nitropropane to chalcone reaction using asymmetric PTC.
Similarly, a-Chlorophenylacetonitrile was also condensed with
benzaldehyde in the presence of 50% NaOH, TEBAC 160 as a PTC using benzene.
21
Recently Balakrishnan et al.161 also reported the Darzen’s condensation
between the cyclohexanone with n-bromobutane under di-site phase transfer
catalyst.
1.7. CHIRAL PHASE TRANSFER CATALYSIS
It is well known that the application of achiral phase transfer catalyst has
been frequently applied in various fields of chemistry, particularly in the organic
synthesis.162,163 However, asymmetric synthesis reactions using chiral phase
transfer catalyst have not been extensively studied as compared to general
asymmetric synthesis reactions.163,164 The field of catalytic asymmetric synthesis
is providing synthetic chemists with a new and powerful tool for the potential
asymmetric synthesis of complex organic molecules. The most notable catalysts
165are transition metals to promote the reactions in the presence of a chiral ligands.
It is true that most of the popular catalytic synthesis are inorganic in nature; one
must not forgot the use of purely organic catalysts like (S)-proline166 simple
peptide and particularly the best popular choice of viz., “ cinchona alkaloids”.
Normally, the asymmetric organic chemists used to select their asymmetric
catalysts based on the factors like (i) the variety of reactions that the catalyst can
promote (ii) the availability of both enantiomeric catalyst at a reasonable cost (iii)
the foremost factor is the stability of that catalyst. The updated literature survey
reveals that the “cinchona alkaloids” are popular chiral source, since it meets all
these criteria and making them one of the most adoring asymmetric catalysts to
date. The constituents of cinchona alkaloids consist of two pseudo enantiomeric
pairs such as cinchonine and cinchonidine, quinine and quinidine. These
constituents are extracted from the Bark of the cinchona tree; at a native of
tropical region. Due to the presence of various functional groups and hence its
structure cinchona alkaloids, emerged as versatile chiral basic catalysts.167 The
earliest uses of cinchona alkaloids in asymmetric catalysts were demonstrated by
Pracejus in 1960’s to catalyze the symmetric alkaholysis of ketenesir’8 and
subsequently Morrison and Mosher169 and Wynberg167 have employed the same
for different prochiral synthesis. The asymmetric version of chiral phase transfer
catalyst (CPTC) derived from the cinchona alkaloids have been developed and
successfully employed to different types of useful organic reactions. 170a,b‘ 171'173
The first pioneering work for the development of cinchona alkaloids-type phase
transfer catalysts was introduced by O’Donnell et al.17/1-176 and showed that
benzylammonium salts derived from one of the versatile cinchona alkaloids viz.,
“Cinchonidine” and were used for the asymmetric alkylation of the glycinate
imines. The synthetic methodology has been developed for carbon-carbon bond
constructions by either anionic or cationic amino acid equivalents as well as the
process, which establish carbon-nitrogen176 and carbon oxygen bonds.
22
acids was introduced by O’ Donnell in 1989;177 used the liquid/liquid phase
transfer catalyzed asymmetric alkylation of N,N-diphenylmethylene glycine tert-
butyl ester (scheme 1) with the aid of N-benzyl cinchona alkaloid salts as phase
transfer catalysts and it is considered as a first generation catalyst (Fig la).
Figure 1. The different generations of chiral phase transfer catalysts derived
from cinchona alkaloids in different periods.
The second generations of CPCT’s (Fig.lb) derived from cinchona
alkaloids were subsequently developed and reported by the same 0 Donnell and
co-workers on 1994178 i.e the N-alkyl O-alkyl cinchona alkaloid salts. Then the
third generation of CPCTC’s was described independently by Lygo17'J and
Corey180 in 1997 in which 9-anthracenylmethylcinchonidinium bromide (Fig. 1 c)
was introduced as an effective unit making the nitrogen face, leading to
substantially improved enantiomeric excess (figure 1). Recently, Maaioka et
al.181 developed very efficient non-cinchona alkaloid catalysts, C2-symmetric
chiral quaternary ammonium salts prepared from (S)-binaphthol.
In connection with the development of Sharpless asymmetric
dihydroxylation, the discovery of ligands with two independent Cinchona alkaloid
units attached to heterocyclic spacers led to considerable increases in both the
enantioselectivity and the scope of the substrate. Recently, dimeric182 (Figure 2)
2a, 2b and trimeric183 2c quaternary cinchona catalysts derived from o~, m- or p-
xylene dibromide (2a), 9,10-dibromo anthracenyl (2b) and mesitylene tribromide
respectively have been employed as chiral PTC’s achieving good
enantioselectivities.
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Figure 2. Various types of dimeric and trimeric CPTC’s
25
1.8. APPLICATIONS OF CMPTC’S FOR THE VARIOUS ASYMMETRIC
REACTIONS
1.8.1. Alkylation of Schiff bases : Synthesis of a-amino acids
Alkylation of glycine Schiff bases is a well known and straight forward
procedure for the synthesis of a-amino acids in the racemic or optically active
form. Depending on the reaction sequence used, either mono- or disubstituted-
amino acids are available.
Further studies on this process by O’Donnel and co-workers 176'177’184
showed that the active species involved in the reactions were not N-
benzylammonium salts of the alkaloid, but O-alkyl-N-benzylammonium salts such
as lb which are formed in situ from the alkaloid and alkylating agents. An O-ally 1
group was found to be preferred over an O-benzyl substituent. Enantioselectivities
of the alkylation reactions catalyzed by second generation catalysts were slightly
better compared to those of the first, generation catalysts.
Scheme 2. Mono alkylation of Schiff base under CPTC’s conditions
Mono alkylation of schiff base was a key step for seveial asymmetric
syntheses of unnatural amino acids; metal-binding 2-amino-o-(2,2 -
bipyridinyl)propanoic acid,185’186 pyridinoxoamino acid derivatives, ^ as well as
220 such as cyclopropane and epoxides. Aziridines are highly strained. Ring strain
renders aziridines susceptible to the ring-opening reactions that dominate their
chemistry as shown below, makes them useful synthetic intermediates that folly
deserve a prominent place in the arsenal of the organic chemist.
In view of the long history of aziridine chemistry, it is not surprising that
the literature on the subject is very extensive. For the interested reader requiring a
general introduction, several excellent discussions are available.221 The ability of
aziridines to undergo highly regio-and stereo selective ring-opening reactions
makes them very valuable in organic synthesis. This ability has not gone
unnoticed in nature, where a number of molecules possessing an aziridine ring
have been shown to exhibit potent biological activity, which is intimately
associated with the reactivity of the strained heterocycle.
Structure-activity relationships have identified the aziridine ring as being
essential for antitumour activity and a vast amount of work has been concentrated
on synthesizing derivatives of these natural products with increased potency.
There are several reports for the synthesis of Chiral aziridines (Figure 3) from
various substrates via, nitrenes, azirines, aminoalcohols, imines, etc.
27
Chiral aziridines are very important substances in asymmetric synthesis
since they have been shown to be useful chiral auxiliaries, chiral ligands for
transition metals and chiral substrates in the preparation of biologically active
species such as amino acids, beta-lactams and alkaloids.222 Although many
methodologies are available for chiral aziridines, only a very few are catalytic in
nature.221 An efficient catalytic synthesis of chiral N-tosylaziridines has been
developed by Jacobsen and Evans. Recently, Jacobsen"" has reported a
catalytic asymmetric method for N-arylaziridines with enantiomeric excesses up
to 67% but in poor yields.
Lobo et al.226 also reported a new catalytic enantioselective method for N-
arylaziridines based on the quaternary salts of Cinchona alkaloids as phase-
transfer catalysts. Further they also have previously reported that N-acyl-N-
arylhydroxylamines and O-acyl-N-arylhydroxylainines are efficient aziridinating
agents for electron deficient olefins. But they are obtaining aziridines in moderate
to good yields and enantiomeric excesses up to 62% (Scheme 4) under chiral
phase transfer catalyst conditions.
Scheme 4. Enantioselective aziridination of hydroxamic acids
Recently Jacobsen et al.223 have studied the synthesis of N-arylaziridines
using bisoxazolines Copper (I) complex and reported an enantiomeric excess up to
reported a new catalytic enantio selective method for the preparation of N-aryl
aziridines in the presence of quaternary salts of cinchona alkaloids as a soluble
phase transfer catalysts. They have also studied that the N-arylhydroxylamines
and O-acyl-N-arylhydroxylamines as an efficient aziridinating agents for electron
deficient olefins and reported different chiral aziridines using cinchona alkaloid
derived chiral phase transfer catalyst, but here the chemical yield is 80% with
yield up to only 38%.
In this context, we envisaged that good results could be obtained with this
type of cinchona derived ammonium salts if a builder group containing starting
materials were employed as a bridge between the alkaloid moieties, in analogy to
Lygo’s,179 Park,183 Jew182 and Corey's180 improvements relative to the monomeric
catalysts. In order to improve the catalytic efficiencies and ee’s, the catalysts were
examined by newly synthesized single, dimeric, trimeric and tetrameric catalysts
derived from inexpensive starting materials with cinchona alkaloids as a chiral
moieties. The catalytic efficiencies were studied by the syntheses of a-amino
acids and N-aryl aziridines.
67% with a modest chemical yield (< 50%). Joao Aires-de-sousa et al226 have also
1.9. THE ORIGIN OF MULTI-SITE PHASE TRANSFER CATALYST
Phase transfer catalysis has become, in recent years, a widely used, well
established synthetic technique, applied with advantage to multitude of organic
transformations. In addition to steadily increasing number of reports in the
primary literature,6 20 there are several reviews,221’222 comprehensive monographs
and an ACS audio course which describes the phase transfer process and which
provide extensive compilation of phase transfer agents and reaction type. While
the lists of applications and in many cases the synthetic results are impressive,
phase transfer catalysts (PTCs) suffer some of the same disadvantages as more
conventional homo- and heterogeneous catalysts, i.e., separation and recovery. A
catalyst which contains only one reactive site is known as single site phase
transfer catalyst viz., tetraethyl ammonium chloride (TEAC), tetraethyl
phosphonium chloride (TEPC), tetrabutyl phosphonium bromide (TBPB) etc. If
the PTC has more than one active site, they are called as "Multi site phase transfer
catalyst” (MPTC). The soluble single site phase transfer catalyst such as TEAC,
TEPC, TBPB, viz are immensively popular due to their availability and easy
reaction work up. Even though, the vast number of the single site catalysts are
available for research, the selection of catalyst mainly depends on the scale of
economy. The efficacy of the catalytic activity of these multisite PTCs towards
simple Sn2 reactions was reported. In general multisite PTCs offer the potential ot
providing greater PTC activity and to effect a particular synthetic transformation
under mild conditions.
Systematic survey of the literature reveals that the studies of Idoux et al227 as
a first report dealing with multisite-phase transfer catalysts containing only three
active site (phosphonium ion) type of soluble and insoluble polymei-bound catalyst.
Balakrishnan et al34,115,161 had also reported the soluble MPTC containing two and
three active site (triethyl ammonium ion) type of catalysts which are used tor the
30
Balakrishnan et al.115 and Wang et al.161,230 have also reported soluble ammonium
quaternary onium ions having two active sites and the efficiency of the di-site
PTC were also examined through simple S>j2 reactions and some weak
* * ion 183 ">30nucleophihc SnAr reactions, Recently, dimeric and trimeric chiral
quaternary ammonium catalysts were synthesized from o-, m- or p-xylene
dibromide, bis(bromomethyl)naphthalenes and mesitylene tribromide
respectively. These CPTC’s have been employed for C-alkylation of
N-(diphenylmethylene)glycine tert-butyl ester and have been found to be good in
terms of chemical yield and ee’s. In the recent past our research group also
developed multi active centres of achiral and chiral catalysts. Recently we
condition containing six-site catalysts.
There is no other report on the MPTC containing more than four active site
either in soluble or insoluble form. No doubt that the number of catalytic site can
decide the efficiency of reaction which in turn control the economy of the reaction
process. Taking in to consideration the above mentioned aspects, we have decided to
synthesise novel soluble, as well as, insoluble achiral and chiral multisite PTC
containing maximum possible active sites (two to thirty two sites) catalysts from
pinene, dichlorocarbene addition to (R)-limonene, Darzen’s condensation to
4-nonanolide with l,6-dibromohexan-2-one, Michael addition to cyclopentadiene
with methylmethacrylate and enantio selective synthesis of a-amino acids & N-aryl
aziridines respectively.
various alkylation reactions. Maurizio et al228 reported poly(ethylene glycol)
supported tetrakis quaternary ammonium catalyst and it is recyclable in nature.
Jew et al.182 had also developed multi-active chiral centre which contained three
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