Selective synthesis of propofol (2,6-diisopropylphenol), an intravenous anesthetic drug, by isopropylation of phenol over H-beta and H-mordenite

Article abstract of DOI:10.1039/c4ra03004d

Propofol (2,6-diisopropylphenol/DIPP) is the world's most widely used intravenous general anesthetic and is typically synthesized by isopropylation of phenol over an acid catalyst. It is highly difficult to stabilize bio-oil containing phenolic compounds. The isopropylation of this phenol (a model compound representing species in bio-oils) is one of the options to stabilize the bio-oil and convert it into valuable products. Probably for the first time, H-beta- and H-mordenite-catalysed vapour phase isopropylation of phenol with isopropyl alcohol (IPA) was studied to selectively synthesize DIPP. The optimization of various operating parameters such as molar ratio (phenol:IPA), weight hourly space velocity (WHSV), reaction temperature and time on stream were performed. H-beta (94% phenol conv. and 56% DIPP sel.) was found to be a potential and more active catalyst than H-mordenite (68% phenol conv. and 43% DIPP sel.) at optimized process parameters. A kinetic model is proposed to probe the intricate reaction kinetics and validated (R² > 0.98) by the experimental results. H-beta catalyst was observed to be stable for more than 25 h with 94% phenol conversion and 56% selectivity towards DIPP at optimized process parameters. The phenol conversion and DIPP selectivity obtained in the present study are higher than those reported so far. The activation energy obtained for isopropylation of phenol with IPA over H-beta is calculated to be 25.39 kJ mol^-1. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra03004d

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Selective synthesis of propofol
(2,6-diisopropylphenol), an intravenous anesthetic
drug, by isopropylation of phenol over H-beta
and H-mordenite
Cite this: RSC Adv., 2014, 4, 32467
*
Kakasaheb Y. Nandiwale and Vijay V. Bokade
Propofol (2,6-diisopropylphenol/DIPP) is the world's most widely used intravenous general anesthetic and is
typically synthesized by isopropylation of phenol over an acid catalyst. It is highly difficult to stabilize bio-oil
containing phenolic compounds. The isopropylation of this phenol (a model compound representing
species in bio-oils) is one of the options to stabilize the bio-oil and convert it into valuable products.
Probably for the first time, H-beta- and H-mordenite-catalysed vapour phase isopropylation of phenol
with isopropyl alcohol (IPA) was studied to selectively synthesize DIPP. The optimization of various
operating parameters such as molar ratio (phenol : IPA), weight hourly space velocity (WHSV), reaction
temperature and time on stream were performed. H-beta (94% phenol conv. and 56% DIPP sel.) was
found to be a potential and more active catalyst than H-mordenite (68% phenol conv. and 43% DIPP sel.)
at optimized process parameters. A kinetic model is proposed to probe the intricate reaction kinetics and
validated (R2 > 0.98) by the experimental results. H-beta catalyst was observed to be stable for more
than 25 h with 94% phenol conversion and 56% selectivity towards DIPP at optimized process
parameters. The phenol conversion and DIPP selectivity obtained in the present study are higher than
those reported so far. The activation energy obtained for isopropylation of phenol with IPA over H-beta
Received 4th April 2014
Accepted 27th June 2014
DOI: 10.1039/c4ra03004d
www.rsc.org/advances
is calculated to be 25.39 kJ molꢀ1
.
adhesives, agricultural chemicals and pharmaceuticals.3,7–15 In
particular, isopropylation of phenol with isopropyl alcohol (IPA)
also produces 2,6-diisopropylphenol (DIPP/propofol), a very
important drug.9–12 Propofol (DIPP) is the world's most widely
used intravenous general anaesthetic;16 moreover, it is the
active ingredient in Diprivan. Furthermore, the isopropyl group
on the ring can be reacted to make phenol carboxylic acids and
esters, opening up new avenues for many synthetic routes. In
this work, we have evaluated the isopropylation of phenol, a
model compound representing species in bio-oils with IPA
catalysed by H-beta and H-mordenite zeolites, aiming to selec-
tive synthesize propofol.
To the best of our knowledge, open literature on the iso-
propylation of phenol to propofol is very limited.3,7–15 Wei et al.13
reported 61% phenol conversion and 70% IPP selectivity over
MCM-49 at optimized reaction conditions. Wang et al.14 repor-
ted the use of a hierarchically structured ZSM-5 zeolite of c-axis-
oriented nano-rods in a continuous alkylation of phenol with
isopropanol. They obtained a maximum phenol conversion of
58% and a maximum yield of 40% IPP over NZ160-08 catalyst.13
Recently, Wang et al.15 used modied SAPO-11 zeolites as
catalysts for the alkylation of phenol with IPA and reported 55%
phenol conversion and 77% selectivity towards IPP. All these
reports led to the formation of IPP not DIPP.13–15 There are very
1 Introduction
Recently, processing of renewable raw materials from ligno-
cellulosic biomass into value added chemicals and fuels has
gained much attention from researchers.1–3 The bio-oils
obtained by fast pyrolysis of lignin are highly viscous, very
corrosive and have low heating value; hence, they require
upgrading (further processing) to be applicable as fuel.4 In order
to improve these qualities, hydro-deoxygenation processes,
which increase the H/C molar ratio and decrease the O/C molar
ratio, have been utilized.5 However, due to difficulties in
complete removal of oxygen, the phenolic compounds oen
exist in the nal bio-oil composition. An alkylation has been
used to further improve bio-oils by enhancing their H/C
ratios.3,6 Alkylated phenols obtained from bio-oil could serve as
useful chemicals for industrial applications.
In addition, isopropylation of this phenol (a model
compound representing species in bio-oils) would be a green
process to produce industrially important isopropylphenol
(IPP). IPP nds extensive applications in avouring agents,
Catalysis and Inorganic Chemistry Division, CSIR - National Chemical Laboratory,
Pune- 411008, India. E-mail: vv.bokade@ncl.res.in; Fax: +91-20-25902634; Tel: +91-
20-25902458
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Table 1 Comparison of isopropylation of phenol achieved with various alkylating agents over different catalysts
Phenol
Propofol/
Substrate
Phenol
Alkylating agent
Propylene
Process
Catalyst
conversion
DIPPselectivity
Reference
Continuous
Zeolites (Y, BEA, MOR, ZSM-5,
TNU-9 and ZSM-11)
H-b
2–10%
<5%
Xu et al.3
Phenol
Phenol
Phenol
Phenol
Phenol
Phenol
Phenol
Propylene
Propylene
Isopropyl acetate
IPA
IPA
IPA
IPA
Continuous
Continuous
Continuous
Batch
Continuous
Continuous
Continuous
80%
71%
76.8%
50%
100%
68%
94%
30%
31%
13%
16%
52%
43%
56%
Wang et al.7
H-USY
Wang et al.7
Fe–Al-MCM-41 (50)
Cs2.5H0.5PW12O40/K-10
Al2O3
H-mordenite
H-beta
Savidha et al.9
Yadav & Salgaonkar11
Klemm & Taylor12
Present study
Present study
few reports on the synthesis of DIPP.3,7–12 Xu et al.3 have used 9.42ꢁ–9.85ꢁ, 13.5ꢁ–14.01ꢁ, 15.21ꢁ–15.74ꢁ, 19.14ꢁ–20.13ꢁ, 21.83ꢁ–
various types of zeolites such as Y, BEA, MOR, ZSM-5, TNU-9 22.32ꢁ, 25.28ꢁ–26.75ꢁ, 27.01ꢁ–28.71ꢁ, 30.42ꢁ–31.41ꢁ, 35.11ꢁ–
and ZSM-11 for gas phase alkylation of phenol with propylene. 36.07ꢁ, 43.92ꢁ–44.93ꢁ and 47.61ꢁ–49.59ꢁ, which conrmed
Alkylation of phenol with propylene has been reported over H-b, phase purity and crystallinity.18 The obtained XRD patterns
USY and Cs+ exchanged HZSM.7,8 Vapour phase alkylation of agreed well with those reported in the literature.17,18 Initially,
phenol with isopropyl acetate has been performed over Zn–Al- isopropylation of phenol without catalyst (thermal), over H-beta
MCM-41, Al-MCM-41 and Fe–Al-MCM-41 catalysts.9,10 Iso- and H-mordenite was carried out at the following reaction
propylation of phenol with IPA has been reported over 20% conditions: molar ratio (phenol : IPA) of 1 : 2, WHSV of 4 hꢀ1
(w/w) Cs2.5H0.5PW12O40/K-10 (ref. 11) and Al3O3 catalyst.12 All and reaction temperature of 473 K. All the experiments were
these studies reported less phenol conversion and DIPP selec- performed in triplicate and had 3% error as depicted by the
tivity, more catalyst deactivation, and less catalyst stability.
error bars in the relevant gures. The time courses of the phenol
In view of the studies mentioned above,3,7–15 there has been conversion and selectivity towards DIPP are shown as Fig. 2. The
no report on use of H-beta and H-mordenite catalysts for vapour phenol conversion obtained at 240 min followed the trend of
phase isopropylation of phenol using IPA as an alkylating agent
for the selective synthesis of DIPP (Table 1). The use of
heterogeneous solid acid catalysts may be a very promising
method for the synthesis of propofol based on their activity,
selectivity, and re-usability and the increasing demand for
ecologically and environmentally harmonized routes in the
chemical industry.
Thus, we are presenting maybe for the rst time the use of
H-beta and H-mordenite for vapour phase isopropylation of
phenol (a model compound representing species in bio-oils)
with IPA as an alkylating agent. The present study involves
optimization of process parameters such as molar ratio (phe-
nol : IPA), weight hourly space velocity (WHSV), reaction
temperature and time on stream in order to achieve higher
phenol conversion and selectivity towards propofol (DIPP). A
kinetic model is also proposed and validated with experimental
data.
2 Results and discussion
2.1 Catalyst performance
X-ray diffraction patterns of synthesized catalysts H-beta and H-
mordenite have shown the characteristic peaks of the zeolites
with no contribution due to other crystalline or amorphous
phases (Fig. 1).17,18 The characteristic peaks of H-beta that
appeared in the 2q ranges of 6.44ꢁ–9.44ꢁ, 19.32ꢁ–24.42ꢁ, 26.30ꢁ–
27.52ꢁ, 32.72ꢁ–34.16ꢁ and 42.84ꢁ–44.82ꢁ conrmed the fully
crystalline pure H-beta zeolitic phase (Fig. 1).17 Characteristic
ngerprints of H-mordenite were observed in the 2q ranges of Fig. 1 X-ray diffraction patterns of H-beta and H-mordenite.
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Fig. 2 Isopropylation of phenol with IPA over thermal, H-beta and H-
mordenite at the following reaction conditions: weight of catalyst of
1 g; molar ratio (phenol : IPA) of 1 : 2; WHSV of 4 hꢀ1 and reaction
temperature of 473 K.
Fig. 3 Effect of molar ratio on the isopropylation of phenol with IPA
over H-beta at the following reaction conditions: weight of catalyst of
1 g; WHSV of 4 hꢀ1 and reaction temperature of 473 K.
(phenol : IPA) of 1 : 4 and reaction time of 240 min. This may be
because at the lower concentration of phenol, more active sites
of catalyst would be available for the surface adsorption of IPA,
which in turn, results in quantitatively large formation of
propylene and diisopropyl ether (DIPE) to react with phenol and
also favours formation of DIPP.9–12 However, at ratios above 1 : 4
(phenol : IPP), the phenol conversion (73%) and selectivity
towards DIPP (51%) were marginally increased. Hence, the
optimal phenol to IPA molar ratio of 1 : 4 was used in further
experiments.
2.2.2 Effect of weight hourly space velocity (WHSV). The
inuence of WHSV (2–6 hꢀ1) on phenol conversion and selec-
tivity towards DIPP over H-beta was investigated (Fig. 4). The
phenol conversion was observed to be decreased from 72% to
62% with an increase in WHSV from 4 to 6 hꢀ1. This decrease in
phenol conversion with increasing WHSV may be due to less
contact time. With the increase in WHSV (4–6 hꢀ1), the DIPP
selectivity was also observed to be decreased from 50% to 46%
(Fig. 4). This decrease in DIPP selectivity with increasing WHSV
may be due to the less external surface reaction and a decrease
in the formation of propylene and DIPE due to less contact time.
However, marginal variations in phenol conversion (74–72%)
and DIPP selectivity (52–50%) were observed with an increase in
WHSV from 2 hꢀ1 to 4 hꢀ1. This indicates that above a WHSV
of 2 hꢀ1 the phenol conversion and DIPP selectivity were not
inuenced by interphase limitations (external diffusion).19
Hence, a WHSV of 2 hꢀ1 with the maximum phenol conversion
(74%) and selectivity towards DIPP (52%) was used in further
experiments.
H-beta (62%) > H-mordenite (54%) > thermal (without catalyst)
(22%). Higher surface area and higher micropore volume (Vmi-
cro) along with much smaller crystal size may be the decisive
reasons for the higher activity of H-beta compared to H-mor-
denite (Table 2). In addition, selectivity towards DIPP over
H-beta (46%) was higher than over H-mordenite (30%), which is
˚
attributed to the greater pore size of H-beta (7.5 A) compared
˚
to H-mordenite (6.5 A). Hence, the detailed optimization of
process parameters was carried out for the isopropylation of
phenol with IPA over H-beta to maximize the phenol conversion
and DIPP selectivity. The comparative performance of H-mor-
denite at optimized process parameters is also discussed later.
2.2 Optimization of process parameters
2.2.1 Effect of molar ratio. Isopropylation of phenol with
IPA was carried out by varying the molar ratio of phenol to IPA
from 1 : 2 to 1 : 6 over H-beta to assess its effect on the catalytic
activity and selectivity. All the experiments were conducted in a
kinetically controlled regime. The following hypotheses were
used for the reaction: the rate of an alkylation is not controlled
by the dehydration rate and the reaction follows adsorption of
phenol and IPA on two different sites, which is discussed later.
The time courses of the phenol conversion and selectivity
towards DIPP over H-beta catalyst at different molar ratios are
shown as Fig. 3. The phenol conversion and selectivity towards
DIPP increased with an increase in the molar ratio from 1 : 2 to
1 : 4. The maximum values of phenol conversion (72%) and
selectivity towards DIPP (50%) were obtained at a molar ratio
Table 2 Physicochemical properties of catalysts
Catalyst
Si/Al (bulk)
BET surface area (m2 gꢀ1
)
Crystal size (mm)
Vmicro (cc N2 gꢀ1
)
Total acidity (mmol gꢀ1
)
H-beta
H-mordenite
10
10
535
426
0.2–0.3
1–2
0.221
0.188
0.51
1.28
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Fig. 4 Effect of WHSV on the isopropylation of phenol with IPA over
H-beta at the following reaction conditions: weight of catalyst of 1 g;
molar ratio (phenol : IPA) of 1 : 4; and reaction temperature of 473 K.
Fig. 5 Effect of reaction temperature and time on the isopropylation
of phenol with IPA over H-beta at the following reaction conditions:
weight of catalyst of 1 g; molar ratio (phenol : IPA) of 1 : 4; and WHSV
of 2 hꢀ1
.
The effect of particle size on the rate of reaction was studied
by varying catalyst particle size from 35 mm to 355 mm. It has
been revealed that the phenol conversion and DIPP selectivity
remain constant below an average catalyst particle size of 82.5
mm. This proved there were no external diffusional and internal
diffusional resistances below an average catalyst particle size of
82.5 mm.20 Hence, this particle size (82.5 mm) of catalyst was
used in all experiments. This ensured that all the experiments
were performed under chemical reaction kinetic control.
WHSV of 2 hꢀ1 and a temperature of 533 K. The comparative
performance of H-mordenite was also evaluated at the optimized
process parameters. The maximum phenol conversion of 68%
and DIPP selectivity of 43% were obtained over H-mordenite.
2.2.4 Effect of time on stream (TOS) and stability of cata-
lyst. The stability of H-beta catalyst in the isopropylation of
phenol with IPA as an alkylating agent was evaluated at the
optimized process parameters: a molar ratio (phenol : IPA) of
1 : 4, a WHSV of 2 hꢀ1 and a temperature of 533 K. The catalyst
was observed to stable for more than 25 h with stable phenol
conversion of 93% and selectivity towards DIPP of 56% (Fig. 6).
This may be due to the vapour phase isopropylation reaction
delay the coke formation on the catalyst surface. Aer 25 h, the
2.2.3 Effect of reaction temperature. The inuence of
reaction temperature is very essential, as kinetic parameters,
such as rate of reaction and activation energy, are directly
dependent on variation in temperature. Fig. 5 depicts the effect
of temperature on the conversion and selectivity of the iso-
propylation reaction of phenol with IPA as an alkylating agent
over H-beta. The steady rise in the phenol conversion prole
with a rise in temperature from 453 to 533 K was observed. The
H-beta catalyst was observed to be stable in this temperature
range. The phenol conversion was found to be increased from
66% to 93% with a rise in temperature from 453 to 533 K. This
may be due to rise in temperature accelerating the rate of reac-
tion. The selectivity towards DIPP was also observed to be
increased from 52% to 56% with an increase in temperature
from 473 to 533 K. The increase in DIPP selectivity suggests that
its own rate of alkylation was much higher than the rate of
formation of isopropylphenol from direct alkylation of phenol
and from the rearrangement of isopropyl phenyl ether. With a
further increase in temperature from 553 to 573 K, the phenol
conversion was found to be decreased from 93% to 66%. The
obtained decline in phenol conversion at higher temperature
may be attributed to deisopropylation of isopropyl phenol (the
product) into lower hydrocarbons and phenol.11 The selectivity
of DIPP was observed to be decreased with an increase in
temperature above 533 K. Hence, the temperature of 533 K
was chosen as an optimum temperature and was used in further
experiments. The optimum process parameters for the iso-
Fig. 6 Time on stream study of the isopropylation of phenol with IPA
over H-beta at the following reaction conditions: weight of catalyst of
1 g; molar ratio (phenol : IPA) of 1 : 4; WHSV of 2 hꢀ1; and reaction
propylation of phenol were a molar ratio (phenol : IPA) of 1 : 4, a temperature of 533 K.
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conversion of phenol was observed to be decreased to 87%. The where M is the molar ratio (phenol : IPA), Xp is the fractional
catalyst was regenerated in situ by calcination at 823 K for 5 h in conversion of phenol, kp is the rate constant of the iso-
presence of air to remove the organic coke deposited on active propylation of phenol, w is the weight of catalyst, Cp0 is the
sites. The regenerated catalyst was observed to regain its cata- initial concentration of phenol and t is the reaction time.
lytic activity at 93% phenol conversion and 56% DIPP selectivity.
Eqn (11) is an expression of a second-order reaction. The
reaction rate constants at different temperatures can be obtained
from a linear plot of ln((M ꢀ XP)/M(1 ꢀ XP)) versus (M ꢀ 1)CP0t.
Fig. 7 shows a linear relationship between ln((M ꢀ XP)/M(1 ꢀ XP))
and (M ꢀ 1)CP0t at different reaction temperatures (453–533 K).
Both reaction rate constants and R2 values of trend lines at
different reaction temperature were obtained by linear
regression (R2 > 0.98) using the soware OriginPro70 (Table 3).
The rate constant was found to be increased with an increase in
reaction temperature. Moreover, the straight lines of the
plots tted the experimental data well (Fig. 7). This is a clear
indication that the developed kinetic model is valid for this
reaction.
2.3 Kinetic modeling and estimation of kinetic parameters
A model built on the hypothesis of two catalytic sites, S1 and S2,
is proposed.11 In the studied temperature range (453–533 K), the
alkylation rate was not monitored by the rate of dehydration,
but the reaction mechanism involved a dual site mechanism
including adsorption of reactants on two different sites, and
then surface reaction of adsorbed reactant species to give the
desired product. In the present case, the isopropylation of
phenol (P) adsorbed on site S2 with IPA (I) adsorbed on the
adjacent site S1 to give the 2,6-diisopropylphenol (propofol - D)
as desired product and water (W) as byproduct, which is formed
due to the following surface reaction as shown below:
To consider the effect of reaction temperature on the kinetic
model, the Arrhenius equation can be written as follows:
K1
-
I
ꢀ
ꢁ
I þ S1
P þ S2
IS1
(1)
(2)
(3)
ƒƒƒƒƒƒƒƒƒƒ!ƒƒ
Ea
kP ¼ A exp ꢀ
(12)
RT
K2
-P
PS2
ƒƒƒƒƒƒƒƒƒƒ!ƒƒ
where R is the gas constant (8.314 J molꢀ1 Kꢀ1).
The plots of ln kp can be used as a function of the reciprocal
KSR
ƒƒƒƒƒƒƒƒƒƒ!ƒƒ
PS2 þ IS1
DS2 þ WS1
temperature,
ꢀ
ꢁ
Ea
ln kP ¼ ꢀ
þ ln A
(13)
The site balance is given as follows,
RT
CT ꢀ S1 ¼ CV ꢀ S1 + CI ꢀ S1 + CW ꢀ S1
CT ꢀ S2 ¼ CV ꢀ S2 + CP ꢀ S2 + CD ꢀ S2
(4)
(5)
The following adsorption equilibriums for different species
are observed:
K1
W
ƒƒƒƒƒƒƒƒƒƒ!ƒƒ
-
W þ S1
E þ S1
WS1
ES1
(6)
(7)
K1
-
E
ƒƒƒƒƒƒƒƒƒƒ!ƒƒ
Thus, the rate of reaction of phenol is as follows:
kSRCT ꢀ S1CT ꢀ S2K1 ꢀ ICIK2 ꢀ PCP
ꢀ rP ¼
ð1 þ K1ꢀICI þ K1ꢀWCW þ K1ꢀECEÞð1 þ KPCP þ KDꢀSCDÞ
(8)
With weak adsorption of all species, it gives the following:
Fig. 7 Kinetic model plot of the isopropylation of phenol with IPA over
H-beta to obtain the reaction rate constants at different temperatures.
ꢀrP ¼ kPwCICP
(9)
where
Table 3 Reaction rate constants (kp) and R2 values of trend lines for
the isopropylation of phenol with IPA over H-beta at different
temperatures
kP ¼ kSRCT ꢀ S1CT ꢀ S2K1ꢀIK2 ꢀ P
(10)
Writing in terms of conversion and further integration
results in,
Temperature (K)
453
473
493
513
533
kp ꢂ 10ꢀ3(L gꢀ1 minꢀ1
)
1.74
2.19
2.91
3.69
4.76
ðM ꢀ XPÞ
R2
0.9939 0.9932 0.9875 0.9964 0.9899
ln
¼ ðM ꢀ 1ÞkPwCP0t
(11)
Mð1 ꢀ XPÞ
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The plot of ln kp versus 1/T for the isopropylation of phenol continuous vapour phase over H-mordenite and H-beta, which
with IPA over H-beta is represented by a straight line (Fig. 8). has not been reported to date. In this context, the present
Both the pre-exponential factor (A) and activation energy (Ea) method of using H-mordenite and H-beta for the synthesis of
were obtained by linear regression (R2 > 0.99) using the soware propofol (2,6-isopropyl phenol/DIPP) by isopropylation of
OriginPro70. The activation energy (Ea) and pre-exponential phenol (a model compound representing species in bio-oils)
factor (A) for isopropylation of phenol with IPA over H-beta were with IPA offers a greener methodology with potential advan-
25.39 kJ molꢀ1 and 1.4375 L minꢀ1 molꢀ1, respectively. This tages with respect to a higher phenol conversion of 94% and a
indicates that the isopropylation reaction was in the kinetic selectivity towards propofol of 56% over H-beta, which is much
regime owing to the high activation energy.
higher than that the reported at milder operating parame-
ters.3,7–15 A maximum phenol conversion of 68% and DIPP
selectivity of 43% was obtained over H-mordenite at optimized
process parameters. H-beta catalyst was also observed to be
highly active and stable for 25 h. This study demonstrates the
principles of green chemistry such as a safe synthetic method,
reusable heterogeneous catalyst, ambient operating parameters
and minimized material diversity (high selectivity of desired
product).20 This study provides an efficient catalytic process
to stabilize bio-oils containing phenolic compounds and to
synthesize more valuable products such as propofol. The scale-
up work is an on-going activity and will be considered in future
publications. This study opens an avenue for the development
of an eco-friendly catalytic process for the selective synthesis of
propofol (DIPP), a widely used intravenous general anaesthetic.
2.4 Merits of the present method
Xu et al.3 reported gas phase alkylation of phenol with propylene
over various zeolites such as Y, BEA, MOR, ZSM-5, TNU-9 and
ZSM-11 and obtained phenol conversions of 2–10% and selec-
tivity towards DIPP of <5%. Wang et al.7 studied C alkylation of
phenol with propylene over H-b and USY and obtained phenol
conversions of 80% and 71% and selectivities towards DIPP of
30% and 31%, respectively. They have also reported the vapour
phase alkylation of phenol with propylene using HZSM5 by
varying the Si/Al ratio and introducing Cs+ sites via ion
exchange Cs+ and reported a 50% decrease in the original
selectivity.8 Savidha et al.9,10 reported the vapour phase alkyl-
ation of phenol with isopropyl acetate catalysed by Zn–Al-MCM-
41, Fe–Al-MCM-41 and Al-MCM-41. They obtained a maximum
phenol conversion of 76.8% and 13% selectivity towards DIPP
over Fe–Al-MCM-41 (50) catalyst.9,10 Yadav and Salgaonkar
reported isopropylation of phenol with IPA over 20% (w/w)
Cs2.5H0.5PW12O40/K-10 in a batch process and obtained the
maximum phenol conversion of 50% with a selectivity towards
DIPP of 16%.11 Klemm and Taylor reported 100% phenol
conversion with 52% DIPP selectivity over Al3O3 catalyst.12
Table 1 describes the merits of the present method. All of the
reported studies referenced in Table 1 have some limitations in
terms of lower activity value, less catalyst stability and the use of
an alkylating agent such as propylene or isopropyl acetate,
which leads to fast deactivation by coking. In order to eliminate
these limitations, the use of IPA as an alkylating agent and an
improved version of the catalyst will be advantageous. The
present study was carried out using IPA as an alkylating agent in
3 Conclusions
Selective synthesis of propofol (2,6-isopropyl phenol/DIPP) by
isopropylation of phenol using isopropyl alcohol (IPA) as an
alkylating agent over the zeolites H-beta and H-mordenite was
carried out, probably for the rst time. H-beta was observed to
be the optimum catalyst over H-mordenite. A maximum phenol
conversion of 94% with 56% selectivity towards propofol was
achieved over H-beta, which is far better than reported values.
H-beta catalyst was also observed to be highly active and stable
for 25 h. A second order kinetic model is proposed and validated
with experimental data with an R2 > 0.98. The activation energy
is calculated to be 25.39 kJ molꢀ1. This indicates that the iso-
propylation reaction is kinetically controlled owing to the high
activation energy. Thus, isopropylation of phenol (a model
compound representing species in bio-oils) over H-beta can be
considered an environmental benign catalytic process to
stabilize bio-oils and make products that are more valuable.
This study opens an avenue for the development of an eco-
friendly catalytic process for the selective synthesis of propofol.
4 Experimental section
4.1 Materials
Phenol and isopropyl alcohol (IPA) were obtained from E. Merck
Ltd., Mumbai, India. All reagents used were of analytical quality
and used as received.
4.2 Catalyst synthesis and characterization
The protonic forms of zeolite catalysts H-beta and H-mordenite
with Si/Al ratio of 10 were synthesized according to the reported
procedures.17,18 The crystallinity and phase purity of the
Fig. 8 Arrhenius plot of the isopropylation of phenol with IPA over
H-beta to obtain the activation energy and pre-exponential factor.
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synthesized samples were conrmed by powder X-ray diffrac-
tion (XRD) patterns using an X-ray diffractometer (Rigaku
Miniex, Tokyo, Japan). The XRD patterns were recorded on an
X-ray diffractometer (P Analytical PXRD system, Model X-Pert
PRO-1712) using CuKf radiation at a scanning rate of 0.0671
sꢀ1 in the 2q ranging from 5ꢁ to 60ꢁ (Fig. 1). The specic surface
area and micropore volume (Vmicro) of catalysts were obtained
from nitrogen adsorption–desorption isotherms measured in
an SA 3100 analyser (Beckman Coulter, CA, USA). The adsorp-
tion was carried out at 77 K overnight under nitrogen with a
residual vapour pressure of 0.3 Pa. Temperature-programmed
ammonia desorption (TPAD) was used to determine the total
acidity of all synthesized samples (Table 2). TPAD was per-
formed using a Micromeritics AutoChem 2910 (Norcross, GA,
USA). Briey, 0.5 g of sample was loaded and activated at 873 K
in a quartz cell, in the presence of He ow (20 mL minꢀ1) for 2 h.
Pre-saturation was accomplished by passing 10% ammonia in
He for 1 h at ambient temperature (303 K). Then, the sample
was ushed with helium for 1 h at 323 K to remove excess
ammonia. The adsorbed ammonia was desorbed in helium ow
(30 mL minꢀ1) with a heating rate of 10 K minꢀ1 as a function of
temperature from 323 to 773 K. Thermal conductive detector
(TCD) detected the desorbed ammonia.
Nomenclature
A
Pre-exponential factor (L minꢀ1 molꢀ1
Concentration of species i (mol Lꢀ1
)
Ci
CT
CV
D
E
Ea
I
)
Concentration of total sites of catalyst (mol Lꢀ1
)
Concentration of vacant sites of catalyst (mol Lꢀ1
2,6-Diisopropylphenol/DIPP/propofol
Diisopropyl ether/DIPE
)
Activation energy (J molꢀ1
IPA/Isopropyl alcohol
)
i–j
IPP
K
Species ‘j’ adsorbed on site ‘i’
Isopropylphenol
Adsorption/reaction rate constant
Reaction rate constants of isopropylation
kp
of phenol (g molꢀ1 minꢀ1
Molar ratio (phenol:IPA)
Phenol
)
M
P
S
SR
t
Vacant catalyst sites
Surface reaction
Time (min)
T
Temperature (K)
Total sites S of type ‘i’
Vacant sites S of type ‘i’
Weight of catalyst (g)
Water
T-Si
V-Si
w
W
Xp
Fractional conversion of phenol
4.3 Catalyst evaluation and analysis
Isopropylation of phenol with IPA over protonic forms of H-
beta and H-mordenite zeolite samples were carried out in a
continuous, down–ow, xed bed reactor SS316 (40 cm
length ꢂ 2 cm internal diameter) at atmospheric pressure.
The amount of 1.0 g (2 cm height) of 10–20 mesh granules of
self-bonded catalyst was loaded in the reactor. Prior to reac-
tion, the activation of catalysts was carried out at 723 K for 8 h
in air to drive off adsorbed hydrocarbon and moisture, if any.
Reactants (phenol and IPA) were fed through a syringe pump
(ISCO, USA) into the reactor at the desired reaction temper-
ature. The analysis of products was performed using a Shi-
madzu gas chromatograph (Model GC 15A), coupled with an
Apiezome L (B.P. 1/1) column and a ame ionization
detector. The column used was of 0.0032 m i.d. ꢂ 50 m
length. The conversion of phenol and selectivity towards
propofol (DIPP) as a function of time on stream over H-beta
catalysts was investigated at temperatures of 453–573 K with
a weight hourly space velocity (WHSV) of 2–6 hꢀ1 and feed
(phenol:IPA) molar ratios of 1 : 2 to 1 : 6.
Acknowledgements
The authors thank Dr Prashant S. Niphadkar from CSIR-NCL,
Pune (India) for editing the manuscript.
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