Solvent-free one-pot synthesis of sulfonephthaleins from saccharin and phenols

Article abstract of DOI:10.1080/00397911.2010.535946

Sulfonephthaleins can be synthesized in a single pot from saccharin and phenol via the in situ formation of 2-sulfobenzoic anhydride, followed by its reaction with phenol using H₂SO₄ as the condensing agent, in the absence of any solvent. This solvent-free synthesis is more economical and environmentally benign. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.535946

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Solvent-Free One-Pot Synthesis of
Sulfonephthaleins from Saccharin and
Phenols
V. H. Tillu a , D. K. Dumbre b , H. B. Borate a , R. D. Wakharkar a & V.
R. Choudhary b
a Organic Chemistry Division, National Chemical Laboratory, Pune,
India
b Chemical Engineering and Process Development Division, National
Chemical Laboratory, Pune, India
Available online: 07 Oct 2011
To cite this article: V. H. Tillu, D. K. Dumbre, H. B. Borate, R. D. Wakharkar & V. R. Choudhary
(2012): Solvent-Free One-Pot Synthesis of Sulfonephthaleins from Saccharin and Phenols, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:8, 1101-1107
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Synthetic Communications1, 42: 1101–1107, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.535946
SOLVENT-FREE ONE-POT SYNTHESIS OF
SULFONEPHTHALEINS FROM SACCHARIN
AND PHENOLS
V. H. Tillu,1 D. K. Dumbre,2 H. B. Borate,1 R. D. Wakharkar,1
and V. R. Choudhary2
1Organic Chemistry Division, National Chemical Laboratory, Pune, India
2Chemical Engineering and Process Development Division, National
Chemical Laboratory, Pune, India
GRAPHICAL ABSTRACT
Abstract Sulfonephthaleins can be synthesized in a single pot from saccharin and phenol via
the in situ formation of 2-sulfobenzoic anhydride, followed by its reaction with phenol using
H2SO4 as the condensing agent, in the absence of any solvent. This solvent-free synthesis is
more economical and environmentally benign.
Keywords H2SO4; phenols; saccharin; sulfonephthalein
INTRODUCTION
The sulfonepthaleins constitute an interesting group of compounds. Since the
discovery of sulfonefluorescein and the first synthesis of these compounds by
Remsen and his coworkers in 1884,[1] they have been used extensively both as
indicators and as diagnostic aids in clinical and experimental medicine. The sulfo-
nephthaleins in general and phenolsulfonephthaleins in particular have been exten-
sively used as a means of testing the renal function, because they are eliminated
Received June 24, 2010.
Address correspondence to V. R. Choudhary, Chemical Engineering and Process Development
Division, National Chemical Laboratory, Pune, India. E-mail: vr.choudhary@ncl.res.in or vrc0001@
yahoo.co.in
1101

1102
V. H. TILLU ET AL.
from the blood stream after intravenous injection almost quantitatively through the
kidneys.[2] Sulfonephthaleins such as bromophenol blue and bromocresol purple are
used for the extractive-spectrophotometric determination of antibiotics such as
ofloxacin, cinnarazine, enoxacin, and cisapride in bulk and dosage forms. These
methods are based on the formation of yellow ion-pair complexes between the
basic nitrogen of the drug and sulfonephthalein dyes, which were extracted in
chloroform. The absorbance was measured spectrophotometrically in the range of
408–412 nm.[3–5]
Though sulfonephthaleins are used widely, there are only a few reports about
their synthesis. Harden and Drake[6] synthesized a number of sulfonephthaleins
having four halogens in the o-sulfobenzoic acid part of the molecules. The sulfo-
nephthaleins were prepared by the addition of halogenated o-sulfobenzoic anhydride
to phenols heated at 110 ꢀC followed by addition of fuming stannic chloride and
heating at 120–140 ꢀC for a period of 4–12 h; the sulfonephthaleins were obtained
in poor yields, however.
Ondarff and Vose[7] reported that sulfonefluorescein can be prepared by heat-
ing dihydroxylbenzoyl-benzene-o-sulfonic acid at 160–170 ꢀC for 2 h by eliminating
o-sulfobenzoic anhydride and water. Hydroxyhydroquinolsulfonephthalein was
synthesized by heating o-sulfobenzoic acid chloride with hydroxylhydroquinol.[8]
In the detailed study for preparation of m-cresol sulfonephthalein, Orndarff and
Purdy[9] found that the products of the condensation of m-cresol with o-sulfobenzoic
acid anhydride depend on the temperature of the reaction.
Considering the importance of the phenolsulfonephthalein group of com-
pounds as indicators and diagnostic aids in clinical fields, development of a better
synthetic method for these compounds is very important. The main purpose of this
study was to use readily available saccharin as the starting material instead of
o-sulfobenzoic acid or anhydride in the synthesis of sulfonephthaleins. In this com-
munication, we report a two-step synthesis of phenolsulfonephthalein from sac-
charin and phenol in a single pot, using H2SO4 as the condensing agent, as
described in Scheme 1. In the first step, saccharin (1) is converted to o-sulfobenzoic
anhydride (3) which on reaction with phenol is converted to a corresponding
Scheme 1. Synthesis of phenolsulfonephthalein from saccharin and phenol: (a) conc. H2SO4=oleum,
140 ꢀC, 3 h; (b) phenol, conc. H2SO4, 140 ꢀC, 3 h.

ONE-POT SYNTHESIS OF SULFONEPHTHALEINS
1103
o-sulfonephthalein at 140–170 ꢀC. Synthesis using microwave heating has also been
attempted. This one-pot synthesis of sulfonephthaleins via the in situ prepared
o-sulfobenzoic anhydride has several advantages, such as enhancement in yield, sim-
plification, reduced reaction and processing time, and solvent-free condition.
RESULTS AND DISCUSSION
The synthesis of phenolsulfonephthalein from saccharin and phenol was car-
ried out using different homogeneous and heterogeneous catalysts. The results are
presented in Table 1.
As can be seen from the results, the greatest yield of phenol sulfonephthalein
was obtained when 1 mmol of saccharin and 3 equivalents of concentrated H2SO4
(98%) were heated with 2.2 mmol of phenol at 140 ꢀC for 3.5 h. The product was
identified as phenol red by direct comparison with the commercial sample. All the
spectral and analytical data measured by high-performance liquid chromatography
(HPLC) of our product were in full agreement with the commercial sample of phenol
red. Elemental analysis showed absence of nitrogen, thus ruling out the formation of
phenolsulfonephthalein 2 (Scheme 1). These results reveal that saccharin is most
probably hydrolyzed to form 2-sulfobenzoic anhydride (3, Scheme 1) with the
elimination of ammonia in the form of ammonium sulfate, and the resulting
2-sulfobenzoic anhydride is reacted with phenol to form phenol red. To confirm
this assumption, saccharin was heated with concentrated H2SO4 at 140 ꢀC for 3 h.
After cooling the reaction mixture and the usual workup, a colorless crystalline
product was obtained. It was characterized with the help of NMR and mass spec-
troscopy as 2-sulfobenzoic anhydride 3 (mp 121 ꢀC, lit. mp[3] 120 ꢀC). 2-Sulfobenzoic
1
anhydride: H NMR (DMSO d6 þ CDCl3): d 8.10–8.33 (m, 4H, ArH), LCMS: 184
(Mþ), 120, 104, 92, 76 (100), 64. The elemental analysis of 3 showed the absence
of nitrogen. Also, when saccharin was heated with 20% oleum at 140 ꢀC for 3 h,
2-sulfobenzoic anhydride 3 was obtained after the usual workup. No phenolsulfo-
nephthalein was formed in the reaction when H2SO4 was replaced by HCl or solid
acid, such as ZnCl2, EPZ, Hb zeolite, or Dowex-50 (Table 1).
Table 1. Synthesis of phenlosulfonephthalein from saccharin and phenol under different reaction
conditions
Saccharin
(mmol)
Phenol
(mmol)
Temp.
(ꢀC)
Time
(h)
Yielda
(%)
Expt.
Reagent=catalyst
H2SO4 (3 eq.)
Oleum (3 eq.)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
3
140
140
140
100
140
140
160
140
3.5
3.5
3.5
5
26
4
3
2
H2SO4 (2 eq.)
H2SO4 (3 eq.)
18
5
3
2.2
3
H2SO4 (3 eq.)
HCl (3 eq.)
3.5
3.5
10
27
0.0
0.0
0.0
3
ZnCl2 (10%)=EPZ-10 (20%)
Hb=Dowex-50 (20%)
3
5
aYields indicated here are isolated yields. Phenol red is water soluble and could not be fully recovered
after workup.

1104
V. H. TILLU ET AL.
Different sulfonephthaleins were synthesized from saccharin and different
substituted phenols, using concentrated H2SO4 (3 eq.); the results are presented in
Table 2. All the products were identified by spectral analysis. o-Cresol, m-cresol,
xylenol, and aminophenol had red, purple, blue, and purple colors respectively.
Table 2. Synthesis of different phenolsulfonephthaleins [reaction mixture ¼ saccharin (1 mmol) þ
substituted phenol (2.2 mmol) þ conc. H2SO4 (3 eq.)]
Expt. Substituted phenol Temp. (ꢀC) Time (h)
Product
Yield (%)
1
2
3
140
110
110
4
4
4
33
34
18
4
5
140
170
4
2
21
22
-do-
-do-

ONE-POT SYNTHESIS OF SULFONEPHTHALEINS
1105
Table 3. Microwave synthesis of phenolsulfonephthalein from saccharin and phenol
Expt.
Saccharin
Phenol
Catalyst
Time (s)
Yield (%)
1
2
3
4
5
1 (equiv.)
1 (equiv.)
1 (equiv.)
1 (equiv.)
1 (equiv.)
0.5 (equiv.)
2.2 (equiv.)
3 (equiv.)
2.2 (equiv.)
nil
H2SO4 (3eq)
H2SO4 (3eq)
H2SO4 (3eq)
Aa
36
36
10
21
22
36
120
120
No reaction
93 (2-sulfobenzoic anhydride)
H2SO4 drops
aBF3 etherate, Dowex-50, Amberlyst-15, HCl, Hb zeolite, HY zeolite, or ZnCl2.
Scheme 2. Plausible mechanism for formation of sulfonephthalein from sulfobenzoic anhydride and
phenol.
Microwave-mediated condensation of saccharin with phenol was also
attempted to improve the product yield (Table 3). Other acidic reagents such as
BF3-etherate, Dowex-50, Amberlyst-15, HCl, Hb zeolite, HY zeolite, and ZnCl2 were
tried instead of H2SO4. However, only the concentrated sulfuric acid or oleum was
found to give the desired result (Table 3). A good yield of phenolsulfonephthalein
was obtained by irradiating 1 equivalent of saccharin with 2.2 equivalents of phenol
and 3 equivalents of H2SO4 in a domestic microwave for 36 s. The microwave-
assisted synthesis of substituted phenolsulfonephthaleins was also attempted, but
the results obtained were not consistent, most probably because of the lack of tem-
perature control in the domestic microwave oven.
The formation of sulfonephthalein from substituted phenol and o-sulfobenzoic
anhydride has been extensively studied. The formation of the sulfonephthalein takes
place in two stages (Scheme 2). First, a molecule of anhydride combines with a mol-
ecule of substituted phenol to form addition compound, a tautomeric substance (an
intermediate acid). The intermediate acid then reacts with 1 mol of phenol to give the
corresponding sulfonephthalein.
EXPERIMENTAL
Synthesis of 3,3-Bis(4-hydroxybenzoxathiole-1,1-dioxide (Phenol
Red) (Table 1, Entry 5)
Saccharin (2 mmol) and H2SO4 (3 equivalent) were added to a three-necked,
round-bottomed flask provided with magnetic needle, water condenser, and CaCl2

1106
V. H. TILLU ET AL.
guard tube. The reaction mixture was heated to 140 ꢀC for 1 h, and 2.2 mmol phenol
was added to it. The reaction mixture was then heated under stirring at 140 ꢀC for
4 h. After completion of the reaction (TLC), the reaction mixture was poured into
ice water, and steam distillation was carried out to remove phenol. The crude pro-
duct was washed with benzene and diethyl ether to remove saccharin. The residue
was then dissolved in hot sodium carbonate solution and filtered, and filtrate acidi-
fied was with diluted HCl. The precipitated colored solid product was filtered, dried,
and purified by column chromatography on silica gel.
Synthesis of Sulfonephthaleins in Microwave
In a thick glass vial, saccharin and phenol in 1:2.2 ratio were added. This was
followed by an addition of concentrated H2SO4. The vial was kept in a beaker and
heated in the microwave oven (720 W) for 36 s to 5 min. The colored product was
cooled and subjected to purification as described earlier.
Preparation of 2-Sulfobenzoic Anhydride
(1) A mixture of saccharin (100 mg) and concentrated H2SO4 (3 drops) was heated
at 140 ꢀC for 3 h in an oil bath. On cooling, a colorless crystalline solid product
was obtained; it showed a sharp melting point at 121 ꢀC.
(2) In a thick glass vial, saccharin (100 mg) and concentrated H2SO4 (3 drops) were
added, and the mixture was heated in the microwave oven for 32 s. A clear color-
less solution was obtained, which on standing became a crystalline solid product
[yield 95 mg (95%), mp 121 ꢀC].
The same reaction, when carried out by using oleum (3 drops) for 47 s, yielded
93 mg (93%) of the product.
In conclusion, the synthesis of different phenolsulfonephthaleins was achieved
in one pot from saccharin and phenol or substituted phenol via the in situ formation
of 2-sulfobenzoic anhydride. The synthesis from saccharin instead of the expensive
sulfobenzoic anhydride, use of H2SO4 as condensing agent, and solvent-free reaction
make this method more economical and environmentally benign.
Spectroscopic Data
3,3-Bis(4-hydroxybenzoxathiole-1,1-dioxide (phenol red) (Table 1,
1
Entry 5). Mp: >300 ꢀC; IR (nujol): 1583.94, 1553.83, 1460.01, 1366.04 cmꢁ1; H
NMR: d 7.52 (d, J ¼ 8 Hz, 4H), 7.83 (dd, J ¼ 8 Hz, 8H), (DMSO-d6 þ CDCl3):
8.08–8.63 (m, 4H); 13C NMR (200 MHz): d 156.99, 139.84, 131.87, 130.20, 128.55,
127.57, 113.65, 9928, 93.88.
3,3-Bis(4-hydroxy-2-methylphenyl)-3H-2,1k6-benzoxathiole-1,1-dioxide
(o-cresol red) (Table 2, Entry 1). Mp: 295 ꢀC; IR (nujol): 2924.68, 2854.74,
1
1625.01, 1459.4 cmꢁ1; H NMR (200 MHz) (DMSO-d6 þ CDCl3: d 1.34 (s, 6H),
5.87 (d, J ¼ 6 Hz, 2H), 6.34–6.41 (m, 4H), 6.70–6.76 (m, 2H), 7.34 J ¼ 6 Hz, 2H);
13C NMR (200 MHz): d 168.48, 152.83, 141.63, 136.66, 134.10, 133.54, 128.10,
125.80, 117.74, 77.20, 14.88; LCMS: 405.0 (Mþ þ Na), 383.1 (Mþ þ 1).

ONE-POT SYNTHESIS OF SULFONEPHTHALEINS
1107
3,3-Bis(4-hydroxy-3-methylphenyl)-3H-2,1,k6-benzoxathiole-1,1-dioxide
(m-cresol purple) (Table 2, Entry 2). Mp: 296 ꢀC; IR (nujol): 2927.47, 2855.46,
1603, 1455.75, 1215.76, 757.18, 669.01 cmꢁ1
;
1H NMR (200 MHz, DMSO-d6 þ
CDCl3): d 1.05 (s, 6H), 6.10–6.13 (m, 2H), 6.75–6.81 (m, 4H), 6.93 (d, J ¼ 6 Hz,
1H), 7.00–7.10 (m, 2H), 7.35 (d, J ¼ 6 Hz, 1H); 13C NMR (300 MHz, DMSO-d6 þ
CDCl3): d 167.89, 154.79, 142.62, 138.68, 136.24, 133.83, 133.46, 127.82, 127.12,
119.85, 117.93, 77.43, 14.59; LCMS: 405.2 (Mþ þ Na), 383.3 (Mþ þ 1).
3,3-Bis(4-hydroxy-2,5-dimethylphenyl)-3H-2,1k6-benzoxathiole-1,1-
dioxide (p-xylenol blue) (Table 2, Entry 3). Mp: 215 ꢀC; IR (nujol): 3369.60,
2924.39, 2855.01, 1628.77, 1460.51, 1256.86, 761.76, 659.9 cmꢁ1
;
1H NMR
(200 MHz, DMSO-d6 þ CDCl3): d 1.45 (s, 12H), 5.91–6.03 (m, 2H), 6.45–6.68 (m,
3H), 6.76–6.88 (m, 2H), 7.50–7.61 (m, 1H); 13C NMR (200 MHz, DMSO-d6 þ
CDCl3): d 167.95, 154.37, 142.89, 138.37, 131.08, 128.03, 126.81, 126.35, 125.89,
77.46, 19.47, 13.70, LCMS (m=e): 411.2 (Mþ þ 1), 433.1 (Mþ þ Na).
3,3-Bis(2-amino-4-hydroxyphenyl)-3H-2,1k6-benzoxathiole-1,1-dioxide
(Table 2, Entry 4). IR (nujol): 3566.52, 3373.62, 3020.10, 1644.30, 1451.66, 1258.28,
753.14, 606.21 cmꢁ1; 1H NMR (200 MHz, DMSO-d6 þ CDCl3): d 6.85–6.92 (m, 6H),
6.99–7.02 (m, 2H), 7.03–7.05 (m, 2H); 13C NMR (200 MHz, DMSO-d6 þ CDCl3): d
167.72, 143.08, 137.56, 132.43, 130.56, 130.13, 126.91, 124.40, 121.75, 118.05, 77.0,
LCMS: 417.10 (Mþ þ 1). (Mp: not determined).
ACKNOWLEDGMENT
V. R. C. and D. K. D. are grateful to the National Academy of Sciences, India,
for the Senior Scientist Platinum Jubilee Fellowship and Project Assistantship,
respectively.
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