One step liquid phase heterogeneous synthesis of phenytoin over MgAl calcined hydrotalcites

Article abstract of DOI:10.1016/j.catcom.2010.05.004

Heterogeneous liquid phase synthesis of phenytoin (5,5-diphenylhydantoin) was carried out over MgAl calcined hydrotalcites for the first time under environmental friendly conditions. The catalytic activity results showed very high conversion (80-95%) and selectivity (90-95%) of the desired product phenytoin over MgAl calcined hydrotalcites. The calcined hydrotalcites can be recycled without further loss in the activity and the possible mechanism of the reaction is also proposed.

Full text of DOI:10.1016/j.catcom.2010.05.004

Catalysis Communications 11 (2010) 1063–1067
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
One step liquid phase heterogeneous synthesis of phenytoin over MgAl
calcined hydrotalcites
⁎
Divya Sachdev, Amit Dubey
Chemistry Group, Birla Institute of Technology and Science, Pilani, Rajasthan-333031, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Heterogeneous liquid phase synthesis of phenytoin (5,5-diphenylhydantoin) was carried out over MgAl
calcined hydrotalcites for the first time under environmental friendly conditions. The catalytic activity results
showed very high conversion (80–95%) and selectivity (90–95%) of the desired product phenytoin over MgAl
calcined hydrotalcites. The calcined hydrotalcites can be recycled without further loss in the activity and the
possible mechanism of the reaction is also proposed.
Received 23 February 2010
Received in revised form 5 May 2010
Accepted 6 May 2010
Available online 16 May 2010
© 2010 Elsevier B.V. All rights reserved.
Keywords:
Phenytoin
Heterogeneous catalysis
Mixed oxides
1. Introduction
geneous catalysts, hydrotalcites (HTs) otherwise referred as Layered
Double Hydroxides have received a tremendous attentions due to
Phenytoin (5,5-diphenylhydantoin) is a useful pharmacological
compound and widely prescribed as an anticonvulsant agent,
treatment of grand mal, psychomotor epilepsy ulcers, epidermolysis
bullosa, inflammatory conditions [1–4] and for the treatment of many
more diseases including HIV [1,2]. Conventionally, phenytoin and its
derivatives are synthesized by well known Bucherer–Bergs reac-
tion [3]. In the past, many homogeneous methods were developed to
synthesize hydantoin and their derivatives [4] such as α-amino
amides with triphosgene [5], amino acids with acetic anhydride and
ammonium thiocyanate (thiophenytoin), carbodiimides with α, β-
unsaturated carboxylic acids, nitriles with organometallic reagents,
[6–8] α-amination of esters by Cu(I) [9] and reaction of aldehydes and
ketones with gallium (III) triflate salts [10]. In addition, microwave
synthesis, solid phase technologies [11,12] and the esoteric syntheses
of hydantoins involving complex rearrangements [13,14] have also
been reported for the synthesis of phenytoins. Very recently, the
synthesis of 5,5-diphenyl-2,4-imidazolidinedione (phenytoin) deri-
vatives were reported using Almonds [15]. However, the use of
homogeneous reagents for the synthesis of phenytoins limits their
practical utilization because of the difficulties associated with the
product purification, to overcome the effluent treatment problems
and for environmental concerns. But no heterogeneous system has
been reported so far for the synthesis of phenytoins. Therefore, the
development of heterogeneous catalytic system for this one step
selective conversion is strongly encouraged. Among various hetero-
their potential use as catalysts, ion exchange, adsorption and
petrochemical applications [16] . Structurally, these materials can be
perceived with the structure of brucite Mg (OH)2 lattice wherein an
isomorphous substitution of Mg2+ by Al3+ occurs and the resulting
excess positive charge is compensated by anions occupying the
interlayer space along with water molecules. The basic properties of
Mg/Al hydrotalcites and their calcined forms have been effectively
utilized for many base catalyzed transformations [17,18]. In our
earlier work, we have also exploited copper containing ternary
hydrotalcites for selective oxidation/hydroxylation of aromatics [19].
In order to explore the basic properties of the hydrotalcites, we report
for the first time the potential use of M (II)/Al (where M (II)=Mg, Ni,
Co, Zn) calcined hydrotalcites for the liquid phase synthesis of
phenytoins under environmental friendly conditions.
2. Experimental
All chemicals were used from Sigma Aldrich without further
purification. The hydrotalcites were prepared by the low supersatura-
tion technique. Two solutions; solution (I) containing the desired
amount of metal nitrates and solution (II) having precipitating agents
(i.e., NaOH and Na2CO3), were added simultaneously, while maintaining
the pH around 9–10 under stirring at room temperature. The addition
took around 100 min and the final pH of the solution was adjusted to 10.
The samples were aged at 338 K for 18 h, filtered, washed with hot
water (until total absence of nitrates and sodium in the washing
liquids), dried in an air oven at 353 K for 12 h and the solids synthesized
were hand ground. In all cases, the atomic ratio between the divalent
and trivalent cations was varied between 5:1 and 1:5. The samples were
⁎
Corresponding author.
E-mail addresses: amitdubey@bits-pilani.ac.in, amitdubey75@yahoo.com
(A. Dubey).
1566-7367/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2010.05.004

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D. Sachdev, A. Dubey / Catalysis Communications 11 (2010) 1063–1067
named as M (II) M (III)-HT. Similarly ternary hydrotalcites M(II)M´(II)
Al-HT, M(II)/M´(II)=3 and (M(II)+M´(II))/Al=3) with different
combinations of co-bivalent metal ions were also synthesized to
compare the activity and selectivity. The fresh (as synthesized) samples
were calcined at different temperatures to obtain the mixed oxides with
varying acid–base properties.
2.1. Catalytic activity studies and product extraction
Typically, 2 mmol of benzil, 4 mmol of urea and 15 ml of solvent
(methanol) were mixed at desired temperature (298–373 K) and
different amount of catalyst (10–500 mg) was added at once to the
previously stirred reaction mixture in the glass reactor. The course of
the reaction was monitored by TLC by taking samples periodically for
24 h. The product confirmation was also done by gas chromatography
after considering the response factors of the authentic samples. After
the completion of the reaction, the catalyst was vacuumed filtered and
solvent was removed under reduced pressure to isolate the product A
(Scheme 1) and unreacted benzil by solvent extraction method
(discussed in detail in supplementary information 1.2) to account for
the mass balance. Finally, the product (A) was recrystallized with
ethanol, dried and weighed to calculate the isolated yield. The product
extraction was little difficult due to the solubility constraints of the
product with the reactants and therefore comparatively low yield of
product (A) was obtained. Similarly benzil was also isolated from the
reaction mixture and the total conversion is estimated on the basis of
benzil reacted. The melting point of the recrystallized product was
found to be 293–294 °C (literature m.p. — 294–295 °C). The IR (υ KBr)
and 1H-NMR spectra of the sample are in agreement with the
authentic (Supplementary information (SI)).
3. Results and discussions
Fig. 1A showed the powder X-ray diffraction (PXRD) pattern of the
MgAl-3 calcined at different temperatures (150, 400, 600 and 800 °C)
according to the thermal decomposition pattern of hydrotalcites [16].
The MgAl-3 is chosen based on the catalytic activity results (discussed
in catalytic activity studies). The peak at 2θ=42° and 65° can be
indexed to the formation of MgO and γ-Al2O3 phases and the peak at
2θ=36° indicates the formation of spinel MgAl2O4 [20]. Fig. 1B
showed the PXRD pattern of different atomic composition of Mg and
Al calcined at 600 °C. The spectrum also indicates the formation of
spinel MgAl2O4, MgO and γ-Al2O3 phases irrespective of Mg/Al
composition. The formation of spinel phase is facilitated more with
the samples having higher concentration of Mg contents.
Fig. 1. PXRD patterns of Mg/Al-3 calcined at different temperatures (A) and with
different Mg/Al ratio calcined at 873 K (B).
solution of benzoic acid. The calcined hydrotalcite (Mg/Al-3) was stirred
vigorously in 50 ml distilled water for 1 h and the solution was filtered.
The filtrate was then titrated with benzoic acid. The soluble basicity was
found to be 0.64 mmol/g whichis in agreementwiththe values reported
earlier [21,22]. The details of the basicity measurement are given in
(SI, 1.1). By knowing the universal basic properties of the calcined
Basic strength of the calcined MgAl hydrotalcite was qualitatively
determined by using Hammett indicators. 1 ml of Hammett indicator
was added to 25 mg of the samples and diluted with 10 ml of methanol.
The reactionmixturewas equilibrated for 4 h and after the equilibration,
color of the catalyst was noted (Table 1). The soluble basicity was also
determined by titration method using 0.02 mol/l anhydrous methanol
Scheme 1. Synthesis strategy for the production of phenytoin.

D. Sachdev, A. Dubey / Catalysis Communications 11 (2010) 1063–1067
1065
Table 1
Table 3
Basic strength of MgAl hydrotalcites calcined at 873 K.
Variation of the yield of phenytoin over different Mg/Al compositions calcined at 873 K
(conditions as in Table 2).
Catalyst
Base strength
Mg/Al
ratio
Conversiona
(%)
Product selectivity
(%)
Isolated yieldb
(%)
Surface area
(m2/g)
Mg/Al 5
Mg/Al 3
Mg/ Al 2
Mg/Al 1
Mg/Al 0.2
12bpKBH+ b18.5
18.4bpKBH+ b26.5
11bpKBH+ b18.4
11bpKBH+ b18.4
11bpKBH+ b15
A
B
0.2
1
2
3
5
20
28
40
94
70
94
93
95
95
92
6
7
5
5
17
19
26
73
53
304
171
117
152
41
hydrotalcites, in the present report, emphases are mainly devoted to the
catalytic studies.
a
Based on the benzil reacted.
Based on isolated phenytoin (A).
b
3.1. Catalytic studies
3.1.1. Effect of different bivalent metals in binary M (II)/Al hydrotalcites
The catalytic activity on the fresh (as synthesized) binary
hydrotalcites with M (II)/Al-3 (where M (II)=Ni, Zn, Co, Cu) (SI,
Table S1) showed very low conversion, yield and the selectivity of the
desired product A. It is generally known that the thermal decompo-
sition of hydrotalcites at 873 K results in the formation of mixed
oxides with enhanced basic properties (M(II)–O–Al) and hence the
catalytic activity was tested on all the binary calcined M(II)Al-HTs.
Table 2 showed very high conversion, yield and selectivity of the
product (A) in all the calcined hydrotalcites indicating the influence
of enhanced acidic–basic properties (Bronsted or Lewis) [23–25]
compared to the fresh hydrotalcites. In order to see the influence
of different atomic compositions of different bivalent metal ions in
M(II)/Al on the catalytic activity and selectivity (Table S2, SI), the
results concluded that highest conversion (94%), yield (73%)
and the selectivity (95%) of the product (A) was obtained on the
Mg/Al-3 mixed oxides (Table 3). A careful analysis of the catalytic
results on the calcined Mg/Al series revealed that the catalytic
activity increased with increase in the Mg contents up to Mg/Al-3
and then decreased with further increase in the Mg concentration
at Mg/Al-5. The high activity of Mg/Al-3 can be attributed to the
more basicity and high surface area compared to Mg/Al-5 calcined
hydrotalcites (Tables 1 and 3). It is to be mentioned here that no
conversion was obtained in the blank reaction (without catalyst)
and very low conversion and selectivity of the desired product (A)
was obtained on commercial MgO, Al2O3 (basic) and KOH further
indicate the necessity of the mixed oxides (both acid–base pro-
perties) in controlling the selectivity of the product (Scheme 2,
proposed mechanism). In order to see the effect of calcined ternary
hydrotalcites, the catalytic activity was studied on calcined ternary
hydrotalcites but very low conversion of phenytoins was observed
(SI, Table S3) compared to binary calcined hydrotalcites. These
results are similar to the earlier reports and may be due to the
formation of different mixed oxide phases (not shown) responsible
for activity and selectivity [26]. Hence calcined Mg/Al-3 catalyst was
selected for further detailed catalytic studies. Screening of different
solvents (SI, Fig. S1) indicates that the maximum conversion is
achieved using methanol as a solvent. It seems that the conversion of
the desired product phenytoin depends directly on the polarity and
the nature (protic or aprotic) of the solvent because the hydride
transfer is considered to be easier in protic solvent. Similarly the
reaction temperature (Fig. 2) and the catalyst weight (SI, Fig. S2)
were optimized for better activity and selectivity.
3.1.2. Effect of calcinations temperature
The calcinations temperature plays an important role in altering
the acid–base properties of the mixed oxides (Mg–O–Al). Therefore
the catalyst (Mg/Al-3) was calcined at different temperature (423 K,
723 K, 873 K, and 1073 K) in order to seek for better activity and
selectivity (Table 4). It was observed that the catalytic conversion and
the yield of the desired product increased with increase in the
calcinations temperature up to 873 K and slightly decreased at 1073 K
under our experimental conditions. These results clearly demonstrate
the generation of different acidic–basic properties of the mixed oxides
generated at different calcinations temperatures responsible for this
reaction. Hence the catalyst calcined at 873 K was chosen for further
studies.
3.1.3. Time-on-stream studies (TOS)
The time-on-stream studies (Fig. 3) were carried out using calcined
Mg/Al-3 and KOH to compare the activity and selectivity of the desired
product. The catalytic results on Mg/Al-3 catalyst indicated that the
product conversion as well as yield of the product increased with
increasing time and the reaction was completed within 10 h with 95%
selectivity of the product (A). However, the reaction was allowed to
proceed further for 24 h to check the formation of secondary products or
the inter conversion of the product(s). But, no difference in the activity
and selectivity was noted indicating that the product formed is quite
stable under our experimental conditions. On the other hand the initial
kinetics of the reaction was observed slightly faster with KOH but the
conversion and the selectivity of the product (A) decreased significantly
after 6 h of the reaction time (Fig. 4), with the formation of other side
products (Scheme 1, product B) clearly indicating the necessity of both
the acid–base properties (solid support) to control the product
selectivity (Scheme 2).
Table 2
Variation of total conversion, product selectivity and product yield over different
catalysts (hydrotalcites, M(II)Al used are calcined at 873 K).
Catalyst
Conversiona
(%)
Product selectivity
(%)
Isolated yieldb
(%)
A
B
Blank
MgO
Al2O3 (basic)
KOH
Mg/Al-3
Ni/Al-3
Zn/Al-3
Cu/Al-3
Co/Al-3
0
60
15
80
94
44
40
18
5
–
–
–
71
80
73
95
92
90
89
90
29
20
22
5
44
9
61
73
31
27
12
–
8
3.1.4. Effect of substrate: urea molar ratio
10
11
10
Table 5 showed that the conversion as well as yield increased with
increase in the molar concentration of urea up to 1:2 with 95% selectivity
of the desired product (A). However, the conversion decreased with
further increase in the ratio (1:3) without significantly affecting the
selectivity. These results are opposite to the results observed under
homogeneous conditions and therefore the present catalyst MgAl-HTlc
Reaction conditions: benzil — 420 mg, urea — 240 mg, solvent — methanol, catalyst
weight — 50 mg, temp. — 338 K, reaction time — 24 h.
a
Based on the benzil reacted.
Based on isolated phenytoin (A).
b

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D. Sachdev, A. Dubey / Catalysis Communications 11 (2010) 1063–1067
Scheme 2. Plausible mechanism.
[27] and hence offers a significant advantages over homogeneous
systems in controlling the selectivity of the product [28].
forms an intermediate (X) followed by ring closure via proton
abstraction in presence of Mg–O–Al mixed oxide. We believe that the
selectivity of the desired product (A) is controlled by the relative
3.1.5. Reusability of the catalysts
In order to see the reusability of the catalysts, the catalyst after the
reaction was filtered, washed thoroughly first with methanol, acetone
and finally with water. The catalyst was dried, calcined at 873 K and
finally subjected to fresh reaction. No difference in the activity and
selectivity was noted. Subsequently the catalyst was repeated for three
cycles without significant loss in the activity indicating the non-leaching
behavior of metal oxides from the catalyst during the course of reaction.
Table 4
Variation of calcination temperature on the yield of the phenytoin over Mg/Al-3 catalyst
(conditions as in Table 2).
Calcination temp.
(K)
Conversiona
(%)
Isolated yieldb
(%)
Product selectivity (%)
(A)
423
723
873
1073
24
86
94
83
15
61
73
63
95
95
95
90
3.1.6. Plausible mechanism of the reaction
The probable reaction mechanism is proposed in Scheme 2.
Initially the nucleophilic substitution on carbonyl carbon by urea
a
Based on the benzil reacted.
Based on product phenytoin (A).
b
Fig. 2. Variation of total conversion with the reaction temperature over MgAl-3 catalyst
Fig. 3. Variation of total conversion with reaction time over KOH and MgAl calcined
(Conditions as in Table 2).
hydrotalcites (conditions as in Table 2).

D. Sachdev, A. Dubey / Catalysis Communications 11 (2010) 1063–1067
1067
activity results based on the yield and selectivity of the desired
product are beneficial over homogeneous catalysts generally
employed for this interesting synthesis. Moreover, the use of calcined
hydrotalcites may pave the new pathways for the synthesis of
hydantoin derivatives with multifunctional substitutions for which
the efforts are currently underway.
Acknowledgement
AD thanks the Institute and DST (Department of Science and
Technology, New Delhi, Govt. of India) for financial support. D.
Sachdev thanks CSIR (Council of Scientific and Industrial Research) for
senior research fellowship and Punjab University (SAIF) for carrying
out PXRD spectrum.
Appendix A. Supplementary data
Fig. 4. Variation of product selectivity of phenytoin with the reaction time over KOH
and MgAl-3 calcined hydrotalcites (conditions as in Table 2).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.catcom.2010.05.004.
Table. 5
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4. Conclusions
In conclusion, MgAl calcined hydrotalcites were reported for the
first time as heterogeneous catalyst for the synthesis of 5,5-
diphenylhydantoin under milder reaction conditions. The catalytic