Solvent-free synthesis of sulfonephthaleins, sulfonefluoresceins and fluoresceins under microwave irradiation

Article abstract of DOI:10.1135/cccc20021779

An efficient solvent-free synthesis of sulfonephthaleins, sulfonefluoresceins and fluoresceins under microwave irradiation is reported.

Full text of DOI:10.1135/cccc20021779

Synthesis of Sulfonephthaleins and Sulfonefluoresceins
1779
SOLVENT-FREE SYNTHESIS OF SULFONEPHTHALEINS,
SULFONEFLUORESCEINS AND FLUORESCEINS
UNDER MICROWAVE IRRADIATION
1
2,
3
Simon CIHELNÍK , Ivan STIBOR * and Pavel LHOTÁK
Department of Organic Chemistry, Institute of Chemical Technology, Prague, Technická 5,
1
2
3
166 28 Prague, Czech Republic; e-mail: si.ci@seznam.cz, stibori@vscht.cz, lhotakp@vscht.cz
Received April 8, 2002
Accepted October 29, 2002
An efficien t solven t-free syn th esis of sulfon eph th alein s, sulfon efluorescein s an d fluorescein s
un der m icrowave irradiation is reported.
Keyw ord s: Microwave assisted reaction s; Triph en ylm eth an e dyes; Acidobasic in dicators;
Ph th alein s; Green ch em istry.
Durin g th e last ten years a n um ber of publication s h ave described applica-
tion of th e m icrowave tech n ique in organ ic an d organ om etallic syn th esis1.
Sh ort reaction tim es (usually m in utes), superb purity of products an d en -
h an cem en t of ch em ical yields are usually quoted as m ajor advan tages of
th is m eth od. Un fortun ately, m ost experim en ts h ave been perform ed in do-
m estic oven s usin g classical organ ic ch em istry m eth odology in solven ts.
Safety problem s were described m ain ly in con n ection with low boilin g
poin ts an d h igh vapour pressures of solven ts2,3. Th is is likely th e drivin g
force for application of dry reaction tech n iques an d th eir couplin g with m i-
crowaves4–6
.
Th ere is an in creasin g in terest in th e use of en viron m en tally ben ign re-
agen ts an d con dition s an d particularly in solven t-free procedures7.
Avoidin g organ ic solven ts in organ ic syn th esis leads to a clean , efficien t
an d econ om ical tech n ology. Safety is largely in creased, work-up is con sider-
ably sim plified, cost is reduced, in creased am oun ts of reactan ts can be used
in th e sam e equipm en t, reactivities an d som etim es selectivities are en h an -
ced wh en workin g with out dilution .
Here we describe th e application of solven t-free m icrowave m eth odology
to th e syn th esis of sulfon eph th alein s an d sulfon efluorescein s – well-kn own
represen tatives of triph en ylm eth an e dyes. Th e com poun ds can be con sid-
ered as com plem en tary, especially with respect to th eir solubility, ch em ical
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi: 10.1135/cccc20021779

1780
Cihelník, Stibor, Lhoták:
reactivity, an d acid-base beh aviour. Con trary to sulfon eph th alein s, wh ich
exist in ion ic form , ph th alein s th em selves are believed to prefer th e lacton e
form . Man y m eth ods are described in literature for th e syn th esis of th ese
com poun ds, such as sim ple fusion of both com pon en ts8–11, som etim es
com bin ed with azeotropic rem oval of water12, or fusion in th e presen ce of
15,16
catalysts, such as POCl3 13, polyph osph oric acid14 an d POCl3–HClO4
.
Th e in h eren t drawbacks of all described syn th etic m eth ods are lon g h eatin g
(up to ten s of h ours) at precisely defin ed (program m ed) tem perature(s) an d
th e presen ce of acidic catalyst(s) n ecessary for h igh -yield reaction .
RESULTS AND DISCUSSION
We h ave foun d th at com m ercially available m on om ode MW reactor
(MWR) an d som etim es even dom estic oven (MWO), wh ich is a m ultim ode
applian ce, can brin g about profoun d en h an cem en t of th e efficien cy of pre-
paration of th ese com poun ds. Th e reaction tim es are sh orten ed to ten th s of
secon d, wh ich m ean s th e en h an cem en t of m ore th an th ree orders of m ag-
n itude. Moreover, th e reaction is extrem ely easy to perform . We h ave ap-
plied th is m eth od to th e syn th esis of com poun ds 1–17 (Sch em es 1–3).
R1
R1
R1
O
HO
R2
OH
R2
HO
R2
MW
+
O
2
S
O
S
R3
R3
O
O
O
R3
O
1, R1 = R2 = R3 = H
2, R1 = CH3, R2 = R3 = H
3, R1 = R2 = H, R3 = CH3
4, R1 = R3 = CH3, R2 = H
5, R1 = CH3, R2 = H, R3 = (CH3)2CH
6, R1 = OH, R2 = R3 = H
7, R1 = R2 = CH3, R3 = H
8, R1 = Ph, R2 = R3 = H
SCHEME 1
Several of th em are kn own com poun ds, prepared by tradition al m eth ods.
We h ave repeated th eir preparation un der MW irradiation . Th e results ob-
tain ed are sum m arised in Table I.
Several n ew com poun ds, ph th alein s, sulfon eph th alein s, an d sulfon e-
fluorescein s, h ave been prepared usin g th is m eth odology; th e results are
sum m arised in Table II.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of Sulfonephthaleins and Sulfonefluoresceins
1781
O
O
R3
S
R3
R3
O
R1
O
R1
R
R1
MW
+
O
O
2
S
R
OH
R
O
O
R2
R2
R2
9, R1 = R2 = R3 = H, R = OH
10, R = R2 = OH, R1 = R3 = H
11, R2 = CH3, R = OH, R2 = R3 = H
12, R2 = H, R = OH, R1,R3 =
13, R = R2 = R3 = H, R1 = OH
SCHEME 2
O
R1
O
R1
O
MW
+
2
O
R
OH
R
R
O
R2
R2
R2
O
14, R = OH, R1 = R2= H
15, R = OH, R1 = H, R2 = CH3
16, R = OH, R1 = 4(5)-NO2, R2 = H
17, R = R2 = OH, R1 = H
SCHEME 3
It is im m ediately clear th at th e reaction s perform ed un der MW irradia-
tion are alm ost in stan tan eous. We h ave used both MWO an d MWR appli-
an ces. Th e reaction perform ed in MWO (th e sim plest procedure) can be
easily perform ed on th e 10 g scale. Care h as to be taken to th e ch oice of th e
reaction vessel – as th e very im portan t factor is th e flat bottom large
en ough to preven t local overh eatin g in th e reaction m elt. Usually a stan -
dard 750-m l Erlen m ayer flask is large en ough to perform reaction s in
50–100 g batch es. Both solid com pon en ts h ave to be powdered an d m ixed,
th en placed in th e reaction vessel an d at least partly m elted by application
of extern al h eat (also addition of a sm all am oun t of an in ert solven t (cata-
lyst) can be used to dissolve at least partly th e solid m ixture). Th en MW ir-
radiation (typically 525 W) is applied for a given period. Th e crude reaction
product is boiled with water an d isolated, e.g., by precipitation usin g eith er
kn own procedures or th ose described in Experim en tal.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1782
Cihelník, Stibor, Lhoták:
TABLE I
Microwave syn th esis (525 W, 2–5 g batch ) of sulfon eph th alein s, sulfon efluorescein s an d
fluorescein s
Solven t or
catalyst
b
Meth oda
Tim e, s
Yield, %
RF
Com poun d
1
2
A
A
A
A
A
A
A
B
B
15
12
10
15
15
12
15
25
30
–
–
0.23
0.29
0.34
0.51
0.59
0.14
0.11
0.11
0.28
82
91c
3
–
15
4
xylen e
ch loroben zen e
H3PO4
xylen e
xylen e
H3PO4
55
5
69
6
29c
77c
74
10
10
14
97
a
b
See th e text.
Stan dard TLC (Silufol, pyridin e, 4-m eth ylpen tan -2-ol, 40% aqueous di-
c
m eth ylam in e 1:1:1). Optim ised.
TABLE II
Microwave syn th esis of sulfon eph th alein s an d sulfon efluorescein s
b
Com poun d
Meth oda
Tim e, s
Catalyst
RF
Yield, %
7
7
A
A
A
A
B
B
B
B
B
B
B
15
16
15
25
35
30
25
30
30
30
25
xylen e
–
0.63
0.63
0.69
0.6
19
34c
75
66
70
79
23
56
68
82
47
8
H3PO4
H3PO4
H3PO4
H3PO4
H3PO4
H3PO4
H3PO4
H3PO4
H3PO4
9
9
0.6
11
12
13
15
16
17
0.63
0.69
0.60
0.60
0.68
0.53
a
b
See th e text.
Stan dard TLC (Silufol, m eth an ol, butan ol, water, aqueous am m on ia
c
30:18:4:3). 21% after purification to ch rom atografically pure substan ce.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of Sulfonephthaleins and Sulfonefluoresceins
1783
Th e reaction tim e is h igh ly depen den t on th e reactivity of th e ph en ol
used. With MWR, all im portan t reaction variables can be con trolled an d a
h igh level of reproducibility attain ed. Th e syn th esis of 2,6-xylen olsulfon e-
ph th alein (7) h as been optim ised. Th is n ew dye was prepared in a MWO in
a low yield (Table II). It follows from Fig. 1 th at th e con sum ption of en ergy
is h igh in th e first 10–20 s, th en th e exoth erm ic reaction h eats th e reaction
m ixture to tem perature above 70 °C in th e sam e period of tim e an d th e
tem perature does n ot ch an ge afterwards (th e reaction vessel is placed in th e
Dewar flask of MWR).
Th e above data are in agreem en t with observation s an d fin din gs obtain ed
wh en th e reaction is perform ed in MWO. Usually th e reaction is fin ish ed
just before th e un reacted ph en ol an d volatile side products start to evapo-
rate. Th e syn th esis of 7 was perform ed in an optim ised way, wh ere th e reac-
tion m ixture was set aside just before all th e in ert (xylen e) was evaporated
an d th e reaction wen t to com pletion with out en ergy uptake. Th e optim ised
isolated yield of th e pure dye in a MWR 34% was ach ieved.
In reality, th e reaction tim e is an em pirical con stan t stron gly depen den t
on th e MW output an d th e size of th e reaction batch . For ph th alein s an d
sulfon eph th alein s, prolon ged MW h eatin g is accom pan ied by electroph ilic
rearran gem en t an d cyclisation to th erm odyn am ically stable xan th en e de-
rivatives. Th at is wh y it is n ot advisable to perform th e reaction at h igh
250
T, °C
200
150
100
50
20
40
Time, s
FIG. 1
A typical course of con den sation of 2,6-dim eth ylph en ol with 2-sulfoben zoic an h ydride in
MWR. Critical tem perature 250 °C. Irradiation power 40% of th e m axim um (- - - -); tem pera-
ture gradien t: 0–20, 20–40, 40–60 s (– · – · –); m easured tem perature (❑); irradiation period
(
)
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1784
Cihelník, Stibor, Lhoták:
MW outputs. Em pirically, 40–50% of th e m axim um output of MWR an d
400–550 W of MWO are close to optim um . For fluorescein s an d sulfon e-
fluorescein s, h owever, th e reaction can be carried out at a m axim um out-
put. Neverth eless, even in th ese cases, th e reaction is com plete usually
with in 15 m in at th e m axim um output (750 W) of MWO.
Th e tem perature of th e reaction m ixture in MWR m easured with IR sen -
sors was foun d to ran ge between 170 an d 180 °C for 7. Th e tem perature
m easured with a th erm oelectric sen sor in dom estic MWO was aroun d
170 °C, wh ich is in excellen t agreem en t. We h ave used both 2-sulfoben zoic
an h ydride an d th e correspon din g free acid in th e reaction s. Con trary to
usual procedures, we h ave typically used th e ph en ol:an h ydride ratio 1:1,
wh ich is less econ om ical as th e latter is by far th e m ost expen sive com -
poun d. On th e oth er h an d, purification of th e reaction m ixture is sim pler
as th e separation of ph en ol excess by tim e-con sum in g steam distillation
can be avoided. Th e free acid in th e form of th eir n on -stoich iom etric h y-
drates, wh ich is m uch ch eaper an d m ore accessible th an th e an h ydride
gives lower yields, probably due to water con ten t in th e reaction m ixture.
Water evaporated durin g th e reaction is assum ed to strip off substan tial
am oun ts of ph en ol th us m akin g th e reaction con dition s difficult to repro-
duce. Th is assum ption is supported by th e fact th at with n on -volatile resor-
cin ol th e reaction proceeds with th e sam e yield regardless of wh ich startin g
com poun d is used. As far as th e ratio of th e startin g m aterials is con cern ed,
we h ave used two altern atives. Meth od A: 2-sulfoben zoic an h ydride:ph en ol
= 1:1. In th is m eth od, h alf of th e expen sive an h ydride is used an d lost in
bin din g th e reaction water. Th e equilibrium of th e reaction is sh ifted to th e
righ t, to th e con sum ption of ph en ol. Meth od B: 2-sulfoben zoic an h ydride:
ph en ol = 1:2, wh ere th e ratio of th e reactan ts is stoich iom etric. Accord-
in gly, th e h igh con version is attain able on ly if th e free acid form ed durin g
th e reaction is im m ediately tran sform ed to th e startin g 2-sulfoben zoic an -
h ydride an d water. Th is reaction takes place on ly at tem peratures above
120 °C, wh ich is too h igh for less stable dyes. Th at is wh y th e latter proce-
dure can be used on ly for very stable fluorescein s an d sulfon efluorescein s.
An in ert solven t is added usually in th ose cases wh en th e startin g m ixture
of com pon en ts is solid. Several drops of a solven t (e.g. toluen e, xylen e or
ch loroben zen e) were used for a 10-g batch to en sure sm ooth m eltin g of th e
reaction m ixture.
It can be con cluded th at MW syn th esis of th e title com poun ds is th e
m eth od of ch oice, especially for th erm ostabile com poun ds.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of Sulfonephthaleins and Sulfonefluoresceins
1785
EXPERIMENTAL
Startin g com poun ds were purch ased from Fluka (resorcin ol, 2-m eth ylresorcin ol, n aph th a-
len e-1,3-diol), Lach em a Brn o (sulfon eph th alein s an d fluorescein , 2-sulfoben zoic an h ydride,
2,5-dim eth ylph en ol, th ym ol, m-cresol, h ydroquin on e, pyrocatech ol, pyrogallol, 5-m eth yl-
resorcin ol, guaiacol) an d ICI (2-ph en ylph en ol).
Experim en ts in MWO were typically perform ed in open 50-m l (<5 g batch es), 250-m l
(5–15 g batch es) an d 750-m l (25–100 g batch es) Erlen m eyer flasks placed on th e rotatin g
support of MW oven (Calex CMM17 with output con trol in th e ran ge 112–750 W). Th e
MWR experim en ts were perform ed in a m on om odal MW reactor Prolabo (Fran ce) equipped
with software Syn soft in an origin al glass vessel. Ch em ical sh ifts are given in ppm (δ-scale),
couplin g con stan ts (J) in Hz.
Gen eral Procedure
Method A. 2-Sulfoben zoic an h ydride (10 m m ol) an d th e correspon din g ph en ol (10 m m ol)
were powdered, m ixed with an in ert solven t or H3PO4 (85%), placed in a 50-m l Erlen m ayer
flask an d irradiated in MWO usin g an appropriate output an d reaction tim e. Th e reaction
m ixture was diluted with water (20 m l) an d boiled by sh ort irradiation at 375 W. Sulfon e-
ph th alein s are typically isolated by precipitation from th eir solution in 5% aqueous NaOH
with 15% HCl.
Method B. 2-Sulfoben zoic an h ydride or ph th alic an h ydride (5 m m ol) was m ixed with a
ph en ol (10 m m ol), powdered an d irradiated. Th e isolation of fluorescein s was followed by
th orough wash in g with h ot water givin g th e product of outstan din g quality. Th e given
yields are based on 2-sulfoben zoic an h ydride.
3,3-Bis(4-h ydroxyph en yl)-3H-2,1λ6-ben zoxath iole 1,1-Dioxide (Ph en ol Red, 1).
Method A (MW O). Ph en ol (47 g, 0.5 m ol) was fused with a h eat-gun in a 750-m l
Erlen m eyer flask (92 g, 0.5 m ol) of fin ely groun d o-sulfoben zoic an h ydride was added an d
th e resultin g m ixture was m ixed. Th e flask was th en placed in MWO, th e output was set at
450 W an d irradiation was started. Com plete h om ogen isation took place with in several sec-
on ds, followed by th e colour ch an gin g quickly from red to dark red (12–15 s) accom pan ied
by evolution of large am oun ts of water an d ph en ol. Th e reaction m ixture started to vigor-
ously boil an d becam e m ore viscous. At th is m om en t, th e irradiation was switch ed off an d
th e reaction m ixture was set aside for 2–3 m in . Th en water (120 m l) was added an d th e m ix-
ture was boiled at th e 325 W irradiation output for 3–4 m in . Excess ph en ol was usually
stripped off by th is procedure. Th e reaction m ixture was cooled, filtered an d precipitated.
Th e isolated yield was 72.2 g (81.6%).
3,3-Bis(4-h ydroxy-3-m eth ylph en yl)-3H-2,1λ6-ben zoxath iole 1,1-Dioxide (o-Cresol Red, 2)
Method A (MWO). A m ixture of o-cresol (1.08 g, 10 m m ol) an d 2-sulfoben zoic an h ydride
(1.84 g, 10 m m ol) was placed in a 50-m l Erlen m eyer flask an d xylen e (0.5 m l) was added.
After irradiation in MWO at 525 W for 10–12 s, water (10 m l) was added an d th e m ixture
was boiled for several m in utes un til all cresol reacted. Th e work-up was sim ilar to th at in
th e precedin g procedure. Yield 1.73 g (90.6%).
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1786
Cihelník, Stibor, Lhoták:
3,3-Bis(4-h ydroxy-2-m eth ylph en yl)-3H-2,1λ6-ben zoxath iole 1,1-Dioxide (m-Cresol Purple, 3)
Method A (MWO). Th e dye was syn th esised from m-cresol (3-m eth ylph en ol) un der th e
sam e con dition s as Ph en ol Red (1) usin g m eth od A in a yield of 15%. Th e product was iden -
tical with com m ercial sam ple (Lach em a Brn o, Czech Republic).
3,3-Bis(4-h ydroxy-2,5-dim eth ylph en yl)-3H-2,1λ6-ben zoxath iole 1,1-Dioxide
(p-Xylen ol Blue, 4)
Method A (MW O). Th e dye was prepared in 55% yield from p-xylen ol (2,5-dim eth yl-
ph en ol) usin g th e m eth od described for Ph en ol Red (1). Th e on ly differen ce was th e addi-
tion of a few drops of xylen e for a better h om ogen isation of th e reaction m ixture. Th e
product was iden tical with com m ercial sam ple (Lach em a Brn o, Czech Republic).
3,3-Bis(4-h ydroxy-5-isopropyl-2-m eth ylph en yl)-3H-2,1λ6-ben zoxath iole 1,1-Dioxide
(Th ym ol Blue, 5)
Method A (MWO). Th e dye was prepared in 69% yield from th ym ol usin g th e procedure
described for Ph en ol Red (1) with addition of a few drops of ch loroben zen e for a better h o-
m ogen isation of th e reaction m ixture. Th e product was iden tical with com m ercial sam ple
(Lach em a Brn o, Czech Republic).
3,3-Bis(3,4-dih ydroxyph en yl)-3H-2,1λ6-ben zoxath iole 1,1-Dioxide (Pyrocatech ol Violet, 6)
Method A (MWO). Th e dye was prepared in 29% yield from pyrocatech ol usin g th e sam e
con dition s as th ose used for Ph en ol Red (1) with addition of few drops of 85% H3PO4 for a
better h om ogen isation of th e reaction m ixture an d also as a catalyst. Th e product was ch ar-
acterised by com parison with a com m ercially available laboratory stan dard (Lach em a Brn o,
Czech Republic).
3,3-Bis(4-h ydroxy-3,5-dim eth ylph en yl)-3H-2,1λ6-ben zoxath iole 1,1-Dioxide
(2,6-Xylen olsulfon eph th alein , 7)
Method A (MWO). Th e dye was prepared in 19% yield from 2,6-dim eth ylph en ol usin g th e
procedure described for Ph en ol Red (1). A few m illilitres (2–5 m l) of xylen e as a h om ogen i-
sation an d th erm ostatic agen t was added an d th e reaction m ixture was irradiated for 15 s,
followed by an oth er 15 s with out irradiation to com plete th e reaction . Th e h ot reaction
m ixture was quen ch ed with water, th e solid was dissolved in 20% NaOH an d precipitated by
addition of 15% HCl. Th is procedure was repeated twice. For C23H20O5S (408.5) calculated:
67.30% C, 5.40% H, 7.81% S; foun d: 67.28% C, 5.53% H, 7.67% S. 1H NMR (D2O–K2CO3):
1.92–1.96 s, 12 H (-CH3); 6.78–6.82 d, 1 H (arom . H); 6.98–7.00 s, 4H (arom . H); 7.50–7.56 t,
1 H (arom . H); 7.56–7.62 t, 1 H (arom . H); 7.92–7.96 d, 1 H (arom . H).
Method A (MWR). An appropriate tem perature gradien t was set (cf. Fig. 1, reaction tim e
60 s, 40% reactor output, critical tem perature 180–250 °C). A m ixture of 2-sulfoben zoic an -
h ydride (1.84 g, 0.01 m ol) an d 2,6-dim eth ylph en ol (1.32 g, 0.01 m ol) was partly fused with
a h eat-gun in 20-m l reaction vessel, placed in MWR, rotation was switch ed on an d irradia-
tion started. Th e h ot reaction m ixture was th en diluted with water (5 m l) followed by 20%
aqueous NaOH (5 m l). Precipitation of th e dye was perform ed by addition of 15% HCl an d
th is procedure was repeated twice. Th e ch rom atograph ically pure com poun d 0.86 g (21%)
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of Sulfonephthaleins and Sulfonefluoresceins
1787
was collected. For C23H20O5S (408.5) calculated: 67.30% C, 5.40% H, 7.81% S; foun d:
67.28% C, 5.53% H, 7.67% S. 1H NMR (D2O–K2CO3): 1.92–1.96 s, 12 H (-CH3); 6.78–6.82 d,
1 H (arom . H); 6.98–7.00 s, 4 H (arom . H); 7.50–7.56 t, 1 H (arom . H); 7.56–7.62 t, 1 H
(arom . H); 7.92–7.96 d, 1 H (arom . H).
3,3-Bis(4-h ydroxy-3-ph en ylph en yl)-3H-2,1λ6-ben zoxath iole 1,1-Dioxide
(2-Ph en ylph en olsulfon eph th alein , 8)
Method A (MWO). Th e product was prepared in 75% yield an alogously to Ph en ol Red (1)
from 2-ph en ylph en ol usin g a few drops of con cen trated H3PO4. For C31H20O5S (504.6)
calculated: 73.50% C, 4.38% H, 6.33% S; foun d: 73.09% C, 4.53% H, 6.08% S. 1H NMR
(D2O–K2CO3): 6.46–6.54 d, 1 H (arom . H); 7.02–7.40 m , 14 H (arom . H); 7.42–7.50 t, 1 H
(arom . H); 7.52–7.60 t, 1 H (arom . H); 7.82–7.92 d, 1 H (arom . H).
2-(6-Hydroxy-3-oxo-3H-xan th en -9-yl)ben zen e-1-sulfon ic Acid (Sulfon efluorescein , 9)
Method A (MWO). Th e dye was prepared in 66% yield from resorcin ol an d 2-sulfoben zoic
an h ydride usin g gen eral m eth od A with th e addition of few drops of 85% H3PO4. Th e
sulfon efluorescein could n ot be an alysed by com bustion due to sublim ation at h igh tem per-
atures. 1H NMR (D2O–K2CO3): 6.44–6.46 s, 2 H (arom . H); 6.48–6.52 d, 2 H (arom . H);
6.84–6.88 d, 2 H (arom . H); 6.90–6.94 d, 1 H (arom . H); 7.52–7.56 t, 1 H (arom . H);
7.62–7.68 t, 1 H (arom . H); 7.98–8.02 d, 1 H (arom . H).
Method B (MWO). A m ixture of resorcin ol (1.1 g, 10 m m ol) an d 2-sulfoben zoic an h ydride
(0.92 g, 5 m m ol) with several drops of 85% H3PO4 in a 50-m l Erlen m eyer flask was irradi-
ated at 640 W for 15 s. Th e sem isolid m ixture was th en diluted with water (25 m l), NaOH
(0.8 g) was added an d th e m ixture was boiled un til everyth in g dissolved (several m in utes).
Th e product was precipitated by careful addition of 10% aqueous HCl (50 m l). Th e suspen -
sion was boiled for a wh ile, th en h ot-filtered, wash ed with h ot water, collected an d dried to
yield 1.3 g (70% ) of 9. Th e sulfon efluorescein could n ot be an alysed by com bustion due to
sublim ation at h igh tem peratures. 1H NMR (D2O–K2CO3): 6.44–6.46 s, 2 H (arom . H); 6.48–
6.52 d, 2 H (arom . H); 6.84–6.88 d, 2 H (arom . H); 6.90–6.94 d, 1 H (arom . H); 7.52–7.56 t,
1 H (arom . H); 7.62–7.68 t, 1 H (arom . H); 7.98–8.02 d, 1 H (arom . H).
2,4,5,6,7-Pen tah ydroxy-3-oxo-3H-xan th en -9-yl)ben zen e-1-sulfon ic Acid
(Pyrogallol Red, 10)
Method A (MWO). Th e dye was prepared in 77% yield from pyrogallol usin g th e sam e pro-
cedure as described for Ph en ol Red (1) with addition of a few drops of xylen e for a better
h om ogen isation of th e reaction m ixture. Th e product was iden tical with com m ercial labora-
tory stan dard (Lach em a Brn o, Czech Republic).
2-(6-Hydroxy-5,6-dim eth yl-3-oxo-3H-xan th en -9-yl)ben zen e-1-sulfon ic Acid
(Meth ylsulfon efluorescein , 11)
Method B (MW O). Th e dye was prepared in 79% yield from 2-m eth ylresorcin ol an d
2-sulfoben zoic an h ydride usin g th e procedure described for 9. Meth ylsulfon efluorescein
could n ot be an alysed by com bustion due to sublim ation at h igh tem peratures. 1H NMR
(D2O–K2CO3): 1.92–1.94 s, 6 H (-CH3); 6.48–6.52 d, 2 H (arom . H); 6.84–6.88 d, 2 H (arom . H);
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1788
Cihelník, Stibor, Lhoták:
6.90–6.94 d, 1 H (arom . H); 7.52–7.56 t, 1 H (arom . H); 7.64–7.68 t, 1 H (arom . H); 7.98– 8.02 d,
1 H (arom . H).
2-(9-Hydroxy-5-oxo-5H-diben zo[a,j]xan th en -14-yl)ben zen e-1-sulfon ic Acid
(Naph th osulfon efluorescein , 12)
Method B (MW O). Th e dye was prepared in 23% yield from n aph th oresorcin ol (n aph -
th alen e-1,3-diol) an d 2-sulfoben zoic an h ydride an alogously to sulfon efluorescein (9). Naph -
th osulfon efluorescein could n ot be an alysed by com bustion due to sublim ation at h igh
tem peratures. 1H NMR (D2O–K2CO3): 6.44–6.46 s, 2 H (arom . H); 6.48–6.52 d, 2 H (arom . H);
6.72–6.7 t, 2 H (arom . H); 6.84–6.88 d, 2 H (arom . H); 6.90–6.94 d, 1 H (arom . H); 6.98–7.02 d,
2 H (arom . H); 7.06–7.12 t, 2 H (arom . H); 7.20–7.24 d, 2 H (arom . H); 7.52–7.56 t, 1 H
(arom . H); 7.62–7.68 t, 1 H (arom . H); 7.98–8.02 d, 1 H (arom . H).
2-(2,7-Dih ydroxy-9H-xan th en -9-ylium -9-yl)ben zen e-1-sulfon ate
(Hydroquin on esulfon efluorescein , 13)
Method B (MWO). Th e dye was prepared in 56% yield from h ydroquin on e an d 2-sulfo-
ben zoic an h ydride usin g th e procedure described for sulfon efluorescein (9). Th e h ydro-
quin on esulfon efluorescein could n ot be an alysed by com bustion due to sublim ation at h igh
tem peratures. 1H NMR (D2O–K2CO3): 6.42–6.44 s, 2 H (arom . H); 6.48–6.52 d, 2 H (arom . H);
6.82–6.86 d, 2 H (arom . H); 6.90–6.94 d, 1 H (arom . H); 7.52–7.56 t, 1 H (arom . H); 7.62–
7.56 t, 1 H (arom . H); 7.98–8.02 d, 1 H (arom . H).
2-(6-Hydroxy-3-oxo-3H-xan th en -9-yl)ben zoic Acid (Fluorescein , 14)
Method B (MWO). Fluorescein was syn th esised from resorcin ol an d ph th alic an h ydride
usin g gen eral m eth od B, irradiation 30 s, with addition of few drops of 85% H3PO4. Th e
yield was 97% (optim ised, based on an h ydride). Th e product was iden tical with com m ercial
stan dard (Lach em a Brn o, Czech Republic).
2-(6-Hydroxy-4,5-dim eth yl-3-oxo-3H-xan th en -9-yl)ben zoic Acid
(4,5-Dim eth ylfluorescein , 15)
Method B (MWO). From 2-m eth ylresorcin ol (248 m g, 2 m m ol), ph th alic an h ydride (148 m g,
1 m m ol) an d on e drop of 85% H3PO4 (MWO, 350 W, 30 s), com poun d 15 (230 m g, 68%)
was isolated usin g repeated precipitation from aqueous am m on ia. For C22H16O5 (360.4)
calculated: 73.33% C, 4.48% H, 22.20% O; foun d: 72.98% C, 4.60% H, 22.52% O. 1H NMR
(D2O–K2CO3): 1.92–2.00 s, 6 H (-CH3); 6.56–6.62 d, 2 H (arom . H); 6.68–6.74 d, 2 H (arom . H);
7.22–7.28 d, 1 H (arom . H); 7.48–7.62 m , 2 H (arom . H); 7.70–7.76 d, 1 H (arom . H).
2-(6-Hydroxy-3-oxo-3H-xan th en -9-yl)-4(5)-n itroben zoic Acid; A Mixture of Isom ers
(4′(5′)-Nitrofluorescein , 16)
Method B (MWO). Th e dye was prepared in 82% yield from 4-n itroph th alic an h ydride an d
resorcin ol with a catalytic am oun t of H3PO4 an alogously to th e 4,5-dim eth ylfluorescein (15)
procedure. For C20H11NO7 (377.3) calculated: 63.67% C, 2.94% H, 3.71% N; foun d: 63.41% C,
2.98% H, 3.63% N. 1H NMR (D2O–K2CO3): 6.48–6.54 s, 2 H (arom . H); 6.56–6.62 d, 2 H
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of Sulfonephthaleins and Sulfonefluoresceins
1789
(arom . H); 6.68–6.74 d, 2 H (arom . H); 7.22–7.26 d, 1 H (arom . H); 7.52–7.58 d, 1 H (arom . H);
7.74–7.78 s, 1 H (arom . H).
(4,5,6-Trih ydroxy-3-oxo-3H-xan th en -9-yl)ben zoic Acid (Gallein , 17)
Method B (MW O). Th e dye was prepared in 47% yield from ph th alic an h ydride an d
pyrogallol with a catalytic am oun t of H3PO4 an alogously to th e 4,5-dim eth ylfluorescein
procedure (15). For C20H12O7 (364.3) calculated: 65.94% C, 3.32% H; foun d: 65.69% C,
3.42% H. 1H NMR (D2O–K2CO3): 6.56–6.62 d, 2 H (arom . H); 6.68–6.74 d, 2 H (arom . H);
7.22–7.28 d, 1 H (arom . H); 7.48–7.62 m , 2 H (arom . H); 7.70–7.76 d, 1 H (arom . H).
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